ASCO Guidelines

Dr. Nabil Saba shares the first evidence-based guideline on thyroid cancer from ASCO. He highlights recommendations on first- and subsequent-line systemic treatment – including multikinase inhibitors (MKIs), genomically targeted therapies, immunotherapy, and cytotoxic chemotherapy across four subtypes of thyroid cancer: well-differentiated, differentiated high-grade or poorly differentiated, anaplastic, and medullary thyroid cancer. He dives into the evidence supporting each recommendation and explains the importance of shared decision-making on the risks and benefits of each treatment option. Dr. Saba also touches on outstanding questions including sequencing of agents, addressing resistance, emerging biomarker targets, and management of toxicities.
Read the full guideline, "Systemic Treatment of Thyroid Cancer: ASCO Guideline."
TRANSCRIPT
This guideline, clinical tools and resources are available at https://ascopubs.org/topics/asco-guidelines/head-neck-cancer. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology.
Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.
My name is Brittany Harvey, and today I'm interviewing Dr. Nabil Saba from Emory University, lead author on "Systemic Treatment of Thyroid Cancer: ASCO Guideline." Thank you for being here today, Dr. Saba.
Dr. Nabil Saba: Pleasure to be here.
Brittany Harvey: And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Saba, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.
So then to dive into what we're here today to talk about, Dr. Saba, could you start us off by providing a general overview of the scope and purpose of this first ASCO guideline for thyroid cancer?
Dr. Nabil Saba: So thyroid cancer is a complex disease, and the complexity has been added with the advent of multiple systemic therapeutic agents that have recently come on as part of the standard of care for treating this disease. The guidelines have lagged behind, I believe, in terms of being able to clearly delineate how to use these agents and what clinical settings to use them. And so this guideline, I think, is a much-needed and much-awaited guideline for clinicians to allow them to understand better the use of systemic agents in the treatment of thyroid cancer.
And when we talk about systemic agents, what we want to specify is this applies mostly for patients with recurrent metastatic disease, patients who have failed the standard initial treatment, which continues to be surgical resection for these patients if surgery is possible, in addition to radioiodine therapy for the right clinical setting.
Brittany Harvey: Absolutely. It's a good point that this patient population for this guideline focuses mainly on recurrent disease and patients who have already received surgery and radioactive iodine therapy.
So then this guideline covers four subtypes of thyroid cancer, including well-differentiated, differentiated high-grade or poorly differentiated, anaplastic, and medullary thyroid cancer. As you mentioned, you address clinical questions on systemic therapies, including multikinase inhibitors, genomically targeted therapies, immunotherapy, and cytotoxic chemotherapy in both the first-line and subsequent lines for each of these subtypes. So I'd like to review the key recommendations by subtype.
So first, what are the key points for systemic therapy for well-differentiated thyroid cancer?
Dr. Nabil Saba: It's important to also stress the point that we have these different subtypes of thyroid cancer. So when we talk about radioiodine refractory, those are for patients who are candidates for radioiodine therapy, of course. This usually encompasses the well-differentiated thyroid cancer. So for this group of patients, the guideline focuses on whether the use of multikinase inhibitors compared to placebo or observation impacts the survival in the first-line setting, whether the use of targeted therapies compared to placebo impacts also the survival in the first-line setting, all in the radioiodine refractory setting, of course.
And then we tackle the issue of immunotherapy because this also is a topic that has entered the realm, if you like, of thyroid cancer and is being used in some subtypes of thyroid cancer. So we thought it would be important to raise the question of the role of immunotherapy compared to targeted agents or multikinase inhibitors, in addition to the role of cytotoxic therapy or chemotherapy, as we say, in this patient population. So the guideline goes through all of these questions and then makes specific recommendations as to the use of some of the agents in the first-line setting and second-line setting in case these patients progress after first-line setting.
So, for example, it's clear that for patients who are radioiodine refractory and who have well-differentiated thyroid cancer, multikinase inhibitors are centerpiece of the first-line treatment option. And for this patient population, the recommendation essentially is to use lenvatinib or sorafenib, even though lenvatinib is considered to be the first choice in this patient population in the first-line setting. For the subsequent line settings, patients should be offered cabozantinib, which has been also proven in randomized trials.
As far as genomically targeted therapy, there is always the contention of whether these agents should be initiated first in case the patient has a genomically altered disease. And so, for example, if the patient has a RET alteration or NTRK alteration, the recommendation here is in favor of using RET-targeted therapies such as selpercatinib or NTRK-targeted therapies such as larotrectinib or entrectinib for these patients as a first-line setting. If they do have the BRAF alteration, which is a commonly seen alteration in these settings, the guideline essentially indicates that this may be offered initially prior to treatment with multikinase inhibitors as well, even though the quality of the evidence here is rather lower, and the strength of the recommendation is conditional. And so it's clear that multikinase inhibitors, in the absence of any of these genomic alterations, is really the first line, and then the question becomes when do we use these genomically targeted approaches in patients who have genomically altered disease?
Which basically introduces also the complexity of the question here because we have multiple agents depending on these genomic findings. And then it is sometimes confusing for practitioners which one to use or what do we use first? And so I think the guideline provides clarity in terms of what is acceptable, what is rather not acceptable, what is based on a strong recommendation, what is based on a rather weaker recommendation. I think that's part of the value of such a guideline.
And then finally we have the question of radioiodine well-differentiated and the question of immunotherapy as a first line. And here we do not recommend using immunotherapy for this patient population. For patients with subsequent line settings, potentially adding pembrolizumab to a multikinase inhibitor is mentioned, however the evidence is low, and the strength of the recommendation is also conditional here. As far as chemotherapy, this is not recommended in this day and age for this patient population, however it may be considered also in patients who fail or progress on genomically targeted therapy and/or multikinase inhibitors.
So this is the summary of the recommendations for well-differentiated thyroid cancer, but certainly, for details, I would refer you to the actual guideline since there are many nuances that cannot be covered during just this discussion.
Brittany Harvey: Certainly. The full guideline will be available for listeners in our show notes, and there are many recommendation tables and figures that can help folks as they think through these recommendations. A lot of those key points are really important as clinicians think through which systemic therapies to offer and sequencing of these agents, as you mentioned.
Following those recommendations for well-differentiated thyroid cancer, what are the recommendation highlights for systemic therapy for differentiated high-grade or poorly differentiated thyroid carcinoma?
Dr. Nabil Saba: This entity is rather a rare entity. It's important to stress the fact that this entity has not really been very well represented in clinical trials, and so when we talk about differentiated high-grade or poorly differentiated, the information here is limited. However, the guideline infers on the recommendations to this subtype of thyroid cancer based on what we know for other subtypes. And I think because of the strength of evidence we have in the well-differentiated and the anaplastic thyroid cancer, this guideline for this subgroup of patients draws from these two guidelines and sort of makes recommendations based on this.
So in the first-line setting, of course, if patients don't have a genomically altered disease, we certainly would recommend lenvatinib or sorafenib like we do in the well-differentiated disease. For patients with genomically altered diseases, we follow sort of the same guideline as we have followed for the well-differentiated setting, with the caveat that the quality is rather lower here and the strength of the recommendation is rather conditional for this subtype of patients. And so I think the take-home message is we do have these recommendations similar to the well-differentiated, but the strength of these recommendations for this particular subgroup of thyroid cancer patients is not as strong, given the under-representation in clinical trials. And that's basically the summary of this disease. Same applies to immunotherapy as well as chemotherapy here.
Brittany Harvey: Absolutely. I think it's important to recognize where the evidence is not as strong, it's really important that the guideline panel has still offered up some recommendations to help clinicians in their daily practice as well.
The next subtype the guideline panel addressed, what does the expert panel recommend regarding systemic therapy for anaplastic thyroid cancer?
Dr. Nabil Saba: So it's important to remind the audience that this is a disease with dismal outcome, and this is rather a very, very rare type of thyroid cancer. So the challenge with anaplastic is we've had very little traditionally in terms of options for patients. However, this guideline highlights the advances that have happened in this disease over a relatively short period of time and stresses the important role of systemic agents. And so, for example, for non-genomically mutant anaplastic thyroid cancer in the first-line setting, the guideline does recommend lenvatinib with or without pembrolizumab. Even though the evidence of the quality is low and the strength of the recommendation is conditional, there is enough data that this recommendation could be made. The added complexity for anaplastic thyroid cancer is that this is a disease where multimodal approaches initially are really encouraged as well, including surgical resection primarily, but also potentially thinking about other modalities such as radiation therapy, as these patients have usually very aggressive disease.
And so as far as genomically targeted approaches, the story of targeting BRAF I believe has been a successful story in this disease. And again, for patients with BRAF V600E mutated anaplastic thyroid cancer in the first-line setting, the guideline is clear in saying that we should offer BRAF/MEK inhibitor targeted therapy, namely dabrafenib and trametinib based on published data; the quality is moderate, though the strength of the recommendation is strong, essentially because of the compelling data in these rather small studies. In the first-line setting, again, we may offer also BRAF/MEK inhibition with or without pembrolizumab as well, and the strength here is low, with the recommendation being conditional as well. So you can see here that unlike the other types, immunotherapy may play a bigger role here in this type of cancer compared to the well-differentiated carcinoma because of the nature of the disease, and this has been also stressed in other guidelines.
For patients who progress on genomically targeted therapy, there are not too many options, even though people can revert back to lenvatinib or lenvatinib and pembro. We do recommend participation in clinical trials for these patients because we really don't have any clear-cut options since the strength of these recommendations is conditional for these patients.
As far as the question of immunotherapy per se, we talked about lenvatinib with pembrolizumab. There is also data on ipilimumab and nivolumab. So we include that also as an option for the first-line setting, and we also include, obviously, the dabrafenib and trametinib in combination with pembrolizumab. And even though all these recommendations are conditional, the size of these clinical trials are single-arm phase II studies. In terms of chemotherapy, again, no recommendation in the first-line setting. However, for patients who fail MKI or fail immunotherapy, clinicians may offer cytotoxic chemotherapy. So you can see that in this rare disease, the recommendations already in 2026 indicate a complex tree of decision-making for a number of these cases. And I think this is where these guidelines offer value to many of the practitioners out there.
Certainly, they don't claim to answer any or every possible clinical scenario for these patients because anaplastic thyroid cancer, like any thyroid cancer or any malignancy, usually has to rely on careful evaluation on a case-by-case basis, and for this disease in particular, on a multidisciplinary evaluation based on evaluation by surgical team, by medical oncology, by radiation oncology. But hopefully, these guidelines help at least put in the systemic therapy within that context.
Brittany Harvey: Absolutely. I think this is also where, in the guideline, the clinical interpretation can really be helpful for readers. And as you mentioned, that multidisciplinary collaboration along with shared decision-making with patients on the risks and benefits of each treatment option is really critical here.
So the final subtype that the guideline expert panel addressed, what systemic therapies are recommended for medullary thyroid cancer?
Dr. Nabil Saba: Yes, so medullary thyroid cancer is a separate disease in its own merit, and biologically it's different from the other diseases. And even though it's a relatively rare thyroid cancer, there has been quite substantial advances in systemic therapy, and I think the guideline importantly highlights these advances for this type of thyroid cancer, and this subtype adds to the value of the guideline as well.
For these cancers, targeted therapy for patients who have RET alteration is really recommended as a first line. So for patients who have RET mutant disease, selpercatinib certainly is the treatment of choice, and this is based on high evidence and the recommendation being very strong here because it's based on randomized phase III data. In the subsequent line settings, however, patients with RET-altered disease who have progressed on selpercatinib, unfortunately, we don't have clear-cut recommendations, however, participation in clinical trials is recommended. If a trial is not available, we recommend that patients be offered vandetanib or cabozantinib in this situation.
For patients without the RET alteration, in other words, for patient populations with wild-type disease, the first-line setting should include cabozantinib or vandetanib based also on improved progression-free survival in randomized clinical trial, and here the recommendation is quite strong.
In terms of the role of immunotherapy here, there is very, very little role, and so we don't recommend using immunotherapy in the first-line setting or subsequent line setting. Similarly, for chemotherapy or cytotoxic chemotherapy, it's not recommended that patients be exposed to cytotoxic chemotherapy outside of a clinical trial, whether this be in the first-line setting or second-line setting. We say that in the second-line setting, if patients have failed genomically targeted therapy, clinicians may offer cytotoxic therapy, however, here the evidence is low, and the strength of the recommendation is conditional. And so clearly that tells you that advances have been substantial in this disease, specifically in the realm of targeted therapies, which is importantly highlighted in this guideline as well.
Brittany Harvey: Yes, it's great to see the advances across these different subtypes. So thank you for reviewing all of these recommendations. It's clear you and the panel spent a lot of time reviewing the evidence to craft these recommendations.
So you've already touched on this throughout our conversation already, but I'd like to ask, in your view, Dr. Saba, what is the importance of this guideline, and how will it impact both clinicians and patients with thyroid cancer?
Dr. Nabil Saba: This is a guideline that's important because of the complexity of management of thyroid cancer, in addition to the fact that there has been quite a few systemic therapeutic agents that have come to the scene in the disease, and those are used in specific situations. We talked about medullary thyroid cancer and the story of RET inhibition, for example, the question of sequencing of these agents is important - what do you choose first in terms of your choice depending on the clinical scenario, I think, is highlighted in this guideline. I think this is going to be extremely helpful to practitioners inside and outside the United States because it is going to offer a guide for them to essentially decide on what would be the standard therapeutic option that should be offered to these patients.
I know that many of these agents are not perhaps available in other countries, and I hope this guideline will also raise awareness, since it is coming from ASCO, that these agents need to be explored and considered for a large group of the population that may not have access to them, especially outside the United States and in third-world countries. And so I think from that angle, I think also the guideline is important in that it sets what is the accepted standard in terms of systemic therapy for these patients with these different diseases.
Brittany Harvey: Yes, these evidence-based guidelines certainly set a standard and it will be really important to have these in the hands of many different people to inform best practices for care.
Additionally, you've also mentioned earlier that several of the recommendations referred patients to clinical trials where there wasn't evidence. So I'd like to ask, what are the outstanding questions and ongoing research you are watching in the thyroid cancer space?
Dr. Nabil Saba: This guideline I would like to look at it as a start. This is a much-needed start, however, it also exposes us to the fact that there are so many unanswered questions yet. We still don't know the exact way or best way to sequence these agents. The story of, for example, multikinase inhibitors in well-differentiated thyroid cancers that have BRAF alteration, what is to be started first? Do you start with a multikinase inhibitor, or do you start with a BRAF inhibition? This is a topic of a cooperative group trial currently answering these questions in terms of what is the best sequencing because, you know, you do have the approved cabozantinib in the second line, for example, but you also have the approved BRAF inhibition, which could be done in the first or second line. And so sometimes that is confusing to clinicians for a good reason because no studies have really examined the question of the appropriate sequencing of these agents. And so I think the more we get these agents as available options for treating patients, the more pressing the question would be of what would be the best sequencing. So I think that's a major question to tackle, and hopefully clinical trials will tackle that.
I think the question of resistance to some of these agents, we don't talk too much about that in the guideline, but certainly these agents have limitations. Not every patient who gets a genomically targeted approach is to benefit from that. We've seen many patients who progress on these, and so the question is, how to overcome resistance? Even for the strong data that we have, for example, on RET alteration or NTRK, resistance mechanisms do happen, and we've seen patients who fail larotrectinib and then they need to go on other therapeutic options. And so I think clinical trials are crucial in answering all these questions, in addition to targeting other subtypes of thyroid cancers that have not really been very common. We know that RAS is also seen in some thyroid cancers, HRAS. There have been some studies along that line. ROS is another potential target. And so the question of resistance, I think the question of sequencing, in addition to the question of toxicity. Because, you know, how best to dose these agents? We talked about this a little in the guideline, but again, the focus on this guideline was not too much the toxicity management. So I think management of toxicities should also be a topic of interest that needs to probably accompany any systemic therapy guideline since we're using agents that people may not be too familiar with when they use it for the first time.
Brittany Harvey: Definitely. We'll look forward to the results of these trials that you mentioned to inform sequencing, resistance, new targets, and addressing toxicity and potentially inform updates to this guideline.
So I want to thank you so much for your work to develop this first ASCO guideline for thyroid cancer and for your time today, Dr. Saba.
Dr. Nabil Saba: It's been my pleasure and it's been a pleasure to actually accomplish this and publish this guideline because I do believe it will be of great benefit to the oncologic community.
Brittany Harvey: Absolutely. And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.
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Dr. Timothy Gilligan and Dr. Calvin Chou discuss the updated guideline on patient-clinician communication in oncology. They highlight clinical recommendations and strategies on topics such as communication skills and practices that apply at every visit, principles for telehealth interactions, cross-disciplinary communication, facilitating involvement of the patient's support network, discussing prognosis, goals of care, treatment selection – including clinical trials, end-of-life discussions, overcoming barriers to communication, facilitating discussions of cost of care and financial toxicity, mitigating stigma, and setting boundaries with patients. Dr. Gilligan and Dr. Chou also share how clinicians can enhance their communication skills through skills practice opportunities and experiential learning. They discuss how fundamental communication is to optimal patient care and look to the future on how generative AI may impact healthcare communication.

Read the full guideline, "Patient-Clinician Communication: ASCO Guideline Update" 
TRANSCRIPT
This guideline, clinical tools and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-26-00118      
Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.
My name is Brittany Harvey, and today I am interviewing Dr. Timothy Gilligan from Taussig Cancer Institute and the Center for Excellence in Healthcare Communication at Cleveland Clinic, and Dr. Calvin Chou from the University of California and Veterans Affairs Health Care System in San Francisco, co-chairs on "Patient-Clinician Communication: ASCO Guideline Update."
Thank you for being here today, Dr. Gilligan and Dr. Chou.
Dr. Timothy Gilligan: Thank you for having us.
Dr. Calvin Chou: Delighted to be here.
Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Gilligan and Dr. Chou who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.
So then I would like to dive into what we are here really today to talk about. So Dr. Gilligan, this guideline updates the patient-clinician communication guideline that was first published in 2017. What prompted this update and what is the scope of this updated guideline?
Dr. Timothy Gilligan: So I think with the first guideline, that was the first draft of it that we published five or six, seven years ago, really we were focused on getting the content right, what was the state of the knowledge at that time, and I was very happy with what came out of that. But when I looked back on it, I thought there were ways we could make it more accessible and more practical. Because what we really would like would be for people to apply what we know and then communicate more effectively with patients and colleagues. And one of the reasons I was really excited on the membership of the panel we had this time was I thought they were very well selected to help us do that, is to really think about what are practical guidelines, practical steps we can tell people to take that will improve their own experience and the experience of patients and the quality of care.
Brittany Harvey: Absolutely, thinking about operationalizing that guideline really improves the dissemination and the uptake of these recommendations.
So then, Dr. Chou, I would like to review the key recommendations and strategies across the clinical questions that the guideline addressed. I realize today with our limited time we may not be able to go through every recommendation and strategy, so we will start with some of the highlights. First, let's address the highlights of the process of communication with patients and their support networks. This includes the questions that address what communication skills and practices apply at every visit across the continuum of care, principles for telehealth interactions, cross-disciplinary communication, and facilitating involvement of the patient's support network. In your view, what are the most important recommendations across these clinical questions?
Dr. Calvin Chou: I think the thing that all clinicians know in their bones that they want to be able to do effectively with patients is to communicate information clearly, as well as to communicate in a way that really deepens the relationship, demonstrates empathy, and also demonstrates understanding bilaterally between the various parties. So the communication guidelines that we established in this group, they are fundamental to communication in all conversations throughout healthcare. And the first guideline talks about how clinicians and their team can communicate effectively with the patient and the patient's support network. And those include things like preparing ahead of time; getting a list of the topics that are important to the patient support network so that we can consider them in the visit; making certain that we are hearing what the patients' and the patients' support networks are saying very, very closely; responding to those empathically; and being able to have conversations about care throughout the visit that demonstrate respect and deepen the trust; and then finally, to have some kind of bidirectional understanding, usually through teach-back, that allow both sides to know that communication has occurred as opposed to just been downloaded.
The guidelines also talk about applying these same communication skills throughout telehealth communication - that is both in terms of synchronous communication, audio or video, as well as asynchronous communication, i.e., through secure messaging. We also talk about how we can use these same communication skills to communicate effectively with members of our own team. Interprofessional communication is an important part of all the work that we do, and how we can use these very, very same skills in communication with colleagues, with nursing staff, with social workers, and other allied health professionals. These are all very, very important, crucial members of our healthcare team in the delivery of care to our patients. And that is something that we really need to emphasize throughout to try to bring the best of communication in every conversation that we have.
Dr. Timothy Gilligan: I totally agree with that. Those are really important points. When I was looking over it in preparation for this podcast, it struck me that we have a lot of recommendations and a lot of small things that we can do either well or not well. And it reminded me of a quotation from a famous chef, Marco Pierre White, who said that perfection is a lot of little things done well. This guideline has a lot of little things that if you do them well, you get better outcomes. And I think the chef's point was that if you want a really delicious dish, you have to pay attention to all those little details. And I think if people go through the guidelines carefully and apply the skills that are along the lines of what Dr. Chou was talking about, we get better results. And those results are really important results. It is not only patient satisfaction, which is really important, but it is also quality of care and outcomes for patients. It is better medical care. It is a better day for us, we have a better day if we have better conversations. Poor communication creates endless headaches for everybody.
What I see in the guidelines is it is a lot of little best practices and it requires discipline to learn those. The good news is none of them I don't think are all that hard. The bad news is doing it consistently well every day requires discipline and practice. And what I would hope for these guidelines is that people will read them carefully and think about what they can do to apply what we know more consistently.
And I think the interprofessional communication piece, that was something we added this year, is really critical. Medicine has a bad history of really disrespectful behavior. It was almost normalized that different specialties would make fun of each other, that different professions would talk disrespectfully of each other. And we know now that uncivil behavior results in more healthcare errors. And it is not only bad for our teams and our culture, but it is bad for our patients if we are not communicating well with each other. So I thought it was really critical that we added that piece to the update.
Brittany Harvey: Absolutely. Those fundamental principles that Dr. Chou outlined are really key across every healthcare interaction, including those interdisciplinary interactions. And as you alluded to, Dr. Gilligan, I think it will really serve clinicians well to review the details and go through every table to read the recommendations and each individual strategy to help them improve their communication in day-to-day interactions.
Moving to some of those day-to-day clinical communication scenarios, Dr. Gilligan, I'd like to think through some of those key points. So what is recommended for discussion of prognosis, goals of care, treatment selection, including discussion of clinical trials, and end-of-life discussions?
Dr. Timothy Gilligan: So my perspective is that there is a broad theme of flattening the hierarchy that runs through these recommendations and this part of the guideline - that the sections that Dr. Chou just talked about really have a lot to do with the details. What does good communication look like? What are best practices that we can adopt? And I think these other sections are a little bit more, they also have a lot of specific guidelines, but there is a philosophical point that we do better when we talk to the patient at their own level. And we sometimes fail to do that. I remember from about 10 years ago I was in a room with a patient and one of the other doctors said to the patient, "We're going to bronch you tomorrow." And I was trying to think, like, what do they think the patient hears when we use language like that? Like they don't understand what the word means. We are just expecting them to step up to our level. We are not accommodating them, and I think that really interferes with our ability to form effective relationships with patients and communicate clearly.
So if we are going to talk about prognosis, goals of care, treatment selection, clinical trials, end of life, the first step for me is that we have to get down to the patient's level, which means listening. We have to ask them what they know, we have to get their perspective. We have to understand what their health literacy level is so that we can have a conversation that takes into account the patient's perspective. And we need to be humble and remember that the patient often has information that we do not have yet unless we ask them and listen to what they say. That is going to change what we think is the best plan of care. And so shared decision-making is really a critical piece of that.
One of my favorite trainers who I follow online says, "I make suggestions, you make decisions." And I like to bring that attitude into the room when I talk to patients. It is their life, it is their body, it is their health, it is their decision. It is not my decision. I don't get to tell them what to do. I want to make sure that they make a decision that is based on the best available evidence, but also a decision that is based on who they are and what their values are. And we try to give pointers to how we can have these conversations in a way that is really fully respectful of the patient's autonomy and the importance of the patient's expertise in their own body, their own lived experience. Because there is a risk that we come in with our white coat and we overpower them with our authority, our medical authority, our medical knowledge, and no one likes to be overpowered. And I think we all have a better day if we go in and have a conversation as human beings with each other.
Dr. Calvin Chou: I want to underscore this point of having the patient and their support network make the ultimate decisions. Reviewing the evidence from more general literature, it is clear that across demographics that only 10% of patients want us to make decisions for them. 90% of patients want to have at least some say, if not full say, in the decisions that they make, and this is true across age, across gender, educational status, socioeconomic status, veteran status. This is a very, very important point. I think oftentimes we go in thinking we know what's going to happen and we need to make them do that. Thinking about this as a conversation as opposed to a download is an important point.
Dr. Timothy Gilligan: And one thing that I think that the guidelines are relevant for here, which is I think one way to achieve honoring the patient autonomy, is to really make a commitment to having a good process, to not be committed to an outcome. So that when we start the conversation, we're not going to say it's a good conversation based on whether it ends up where I wanted it to end up. It's a good conversation based on whether we have a good process, a fair process. And the steps of good communication that are outlined in this guideline help us to establish a good process. And I think if we have a good process, we can trust it will take us to the appropriate outcome, which may be different than the outcome we thought was going to be the appropriate outcome when we started the conversation.
Brittany Harvey: Definitely. I think, as you mentioned, tailoring discussions to each individual patient and situation is really critical. And I think in every other podcast episode across guidelines we've really emphasized the importance of shared decision-making. And so talking through the process of it in this guideline will really have impacts across all of ASCO's guidelines.
Moving on to the next section of the guideline, this guideline also addresses barriers in the communication process. So Dr. Gilligan, what highlights are there for overcoming barriers to communication, facilitating discussions of cost of care and financial toxicity, mitigating stigma, and setting boundaries with patients?
Dr. Timothy Gilligan: Yeah, it's interesting. I want to hear Dr. Chou's perspective on this too. I thought that the communication skills are really important for these conversations, but less powerful or less effective, potentially. For instance, barriers to communication, the big one that comes to mind is language differences. If the patient and the clinician do not share the same language, that results in less good care unfortunately. It results in less good communication. Having skilled translators or interpreters there is essential, and using them with skill is essential, but it does not get us to equality. I mean the best thing for a patient is to have a clinician who speaks their language. Unfortunately, that's not possible. So the second best thing we can do is to have good interpreters or translators to help us work. And then for us to use those people effectively, because oftentimes we cut corners when working with interpreters and shortchange the patient. So it is important to do the best we can. I think it is also important to acknowledge that it's a challenge and no matter how good your communication skills are, it's not going to be the same conversation if you're talking through another person versus directly to the patient.
Similarly, with financial toxicity, it is important to talk about it. We need to be open about it. We need to talk to patients about it, but financial stress from healthcare is a real problem, and however well you communicate it, it doesn't make that problem go away. You know, in oncology, our drugs are obscenely expensive, and I can't communicate my way to lower prices. So I can talk about it and legitimize it and empathize, but I feel like I have more power in the other sections to really change the outcome by communicating well than I do with these. But it is important to talk about it. Patients are hugely affected by the cost of care and we need to talk about it with them.
I do think for mitigating stigma and setting boundaries, then our communication skills become more powerful. We see everyone in the healthcare system, and when working with individuals who have been subject to stigma because of aspects of their identity, we can help lessen their vulnerability and fear by proactively letting them know that we will strive to avoid perpetuating that stigma, that we will treat them with respect and address them as they wish to be addressed, that we will care for them as dignified and valued human beings. That is not always their experience in the system, but we can choose to be different. We can choose to do better. And our communication skills are important because listening and curiosity are super important in that space. Because if we are talking to people who may be different from us, we need to learn about them by listening and being open and being curious, and replacing, if we have any tendency towards judgment, to replace judgment with curiosity.
With setting boundaries, I think it is also really important. I don't think you can show up and be fully present with patients the way I want to, the way we want other people to, if we don't know that there are boundaries. And we know this in other aspects of our care, right? I go into the room and I do intimate physical exams and I ask about intimate aspects of the patient's life. And I'm allowed to do that because there is a non-negotiable barrier to any kind of sexual or romantic contact between me and my patients. We know there's a hard wall there that we don't cross that line, so that when I am doing an intimate exam, we know where that stops and that we're not going to cross boundaries there. But the same thing applies verbally, and I think doctors sometimes and other healthcare professionals sometimes feel like they need to accommodate the patient no matter what. I was hoping the guidelines would send a strong message that, you know, we don't need to put up with disrespectful behavior. That when you go into the room, as a clinician or as a patient, you should be treated with respect. You should feel safe, you should feel like you belong, and if patients are behaving in a way that violates that, then clinicians have a right to speak up and to set limits and to set boundaries. And if we know those boundaries are there, then I think we can lean in closer. If we don't know those boundaries are there, then we kind of have to hold back to protect ourselves.
And just to give one of like a million examples you can give, I don't know a woman in healthcare who hasn't had a patient say something sexually inappropriate to them at some point. And that's not okay. I want my colleagues to know that's not okay, and it's okay to set boundaries and they don't have to put up with that. And my hope is that if we know where the boundaries are, then we can step in closer. That's my perspective on these, but Calvin, please, I'd love to hear your thoughts.
Dr. Calvin Chou: I want to double-click on everything that you said, Tim. It is so important that we recognize what we have control over and what we don't have control over. And what we don't have control over, for example, language discordance or financial woes of a patient, I have no possible way of controlling that. And so the best I can do in those situations is to sit with them, empathize, and do what I can, whatever power I might have in advocacy or I often refer folks to a social worker that I work very, very closely with, because I have no agency over any of that.
At the same time, when we talk about mitigating stigma in healthcare encounters, we have full control over the biases that we have. We may not be aware of them, but we do have control over them ultimately. And so it is up to us really to examine our practices, to see where we have maybe been steered in the wrong direction, where we double down on internal implicit biases that we have carried for our entire lives. And that requires that we approach all of our encounters with everybody in healthcare, with humility, and with an extra eye toward understanding how we are coming across to them, and whether or not at least some of those interactions are infused with bias that we can decrease.
And then finally, with the idea of boundaries, there are boundaries in two directions, as Tim was saying a moment ago, that there are boundaries that we must place in between ourselves and patients during examinations and also during interactions. And there's also boundaries that we have to set up that require that we uphold the standards ethically of clinical medicine. And that is, there are certain things- I would never ask a patient out, for example, on a date. And that's an important proscription; that's an important boundary that we must set up between ourselves and patients. Those are clear barriers that we must not breach. There are some barriers that are a little bit less clear. For example, there are some instances where physicians are asking patients who have means to perhaps contribute to a foundation or contribute to the university or to make a large donation to an institution. In some instances, that's a much less clear boundary. For myself, I feel uncomfortable making those kinds of requests, and there are other instances where those requests are actually not just okay to do, but the patient is willing to do those kinds of things. So I think we need to consider that these boundaries are not always set in stone. Sometimes the boundaries move, sometimes the boundaries are different.
Brittany Harvey: Absolutely. I think this latest question covered a lot of ground, and I think some key points here are that treating everyone with dignity is really paramount to this guideline. Recognizing the challenges even when they're not solvable is really important, such as thinking about financial issues or perhaps not speaking the same language as a patient. And then building trust and mutual respect between patients and clinicians to establish clear boundaries is really important as well.
So, I want to thank you both for reviewing at a high level the recommendations and the strategies from this guideline, and I encourage listeners to review the full guideline and tables for all of the recommendations and strategies to implement these clinical recommendations.
So, Dr. Chou, this guideline panel also addressed one education question. So, what are the recommendations for effective ways for clinicians to enhance their communication skills?
Dr. Calvin Chou: Thanks for asking, Brittany. When we talk about all of these communication skills, Dr. Gilligan and I have talked for a long time about all these individual communication skills. These are not skills that are necessarily naturally formed within us and that we just roll out without any practice. And that's why we both feel, if I can speak for you, Tim, that we both feel that communication skills training, and high-quality communication skills training, is deeply important. This is training that is less about I'm listening to this podcast and therefore I can communicate better, it's more about skills practice opportunities, experiential learning, oftentimes using that horrifying word 'roleplay' that people don't like to think about roleplay before they're in it, but then once they've done those skills exercises they realize how important it is to actually have practiced some of these skills so that when you get into the real situation, you have an approach to it as opposed to trying to just improvise or make it up on the fly.
The other aspect of communication skills training that is deeply important is not just forming the words and speaking to somebody else, it also needs to incorporate practitioner self-awareness and situational awareness that allows us to understand what's going on within us emotionally and attitudinally so that we are interacting moment by moment with patients and their support networks in a way that's authentic, that brings the appropriate amount of vulnerability and expertise to deepen trust between all of those relationships.
And finally, when we talk about communication skills training, there are ways to do this kind of training that, I've used ChatGPT, for example, when I'm having some difficulty wondering how to navigate a particular situation, sometimes you can use ChatGPT to give you some suggestions on how to approach that interaction. But at the same time, the most important thing is to be able to have really meaningful practice with other people, with other human beings. Because as much as I might interact with a computer, that computer is not a human being. And what we are talking about is interpersonal communication with emphasis on 'person'. And us as human beings, we understand, in a way that ChatGPT probably will never fully understand, the nuances of the emotional reactions and the importance of human connection between people when we talk to each other. And so therefore, if we can't depend on computers to do this communication skills training, we need institutions to emphasize and invest in all of our continuing ability to communicate effectively with everybody in healthcare. This is probably one of the most important outcomes of this guideline, is not just that communication skills are important, and not just that communication skills training is important, it's that we need everybody to invest in everybody's ability to communicate with each other on the highest possible level that we can bring.
Brittany Harvey: Yes, I think it's really important that the panel addressed this question, to emphasize that it's not just individual clinicians, but institutions that really need to value communication and this training to make sure that clinicians are being the most effective communicators that they can be.
So, I'd like to move on to the next question, and Dr. Gilligan, ask, in your view, what is the importance of this guideline and how will it impact both clinicians and people with cancer?
Dr. Timothy Gilligan: So I would build off of what Dr. Chou was just talking about, which is what we're hoping is that it will serve as a resource that will give people interested in communicating better guidance on where to go, what to do, what are the best practices, what do we know at this time. if you want to get better, what are the methods that are going to help you get better. And ideally I hope it will inspire people to want to get better. Communicating is such a fundamental part of our day-to-day work in healthcare that it needs to be something that we're very, very good at. And as professionals we should aspire to be as good as possible.
A lot of this stuff is pretty basic, but we forget to do it. When I had young kids and was teaching them to ski, one of the ski instructors said to me once that there were Olympic skiers who trained at the same mountain where my kids were learning. And he said they would go down easy slopes and just practice basic techniques still. They were good enough to ski in the Olympics going at crazy speeds, but they kept going back to their fundamentals. And my son is a serious soccer player and they do role plays in soccer. They practice drills. They have scenarios they know are going to come up and they artificially recreate that scenario and they practice it over and over again. There's a famous line from a college football coach that you don't practice it until you get it right, you practice it until you can't get it wrong. And I think if people would bring that sense of professionalism to communication, it's a lifelong journey. I'm still trying to get better. It requires practice, it requires discipline. There's a lot that we know, but it doesn't happen without practice.
And as Dr. Chou was saying, it's a motor skill. You don't learn it by reading about it. You don't learn it by listening to us talk about it. You learn it by practicing it. And I practice with patients. Not in the sense that I'm doing an experiment, but I work on my skills with patients. And I see how it goes. And when things don't go well, I think of what I could have done differently. And when things do go well, I think of what did I do that helped it go well that I need to make sure I do again next time. And I think I'd love to see people adopt an attitude that they want to be fantastic communicators and they want to get better. And I think the guidelines provide a lot of clues and steps to take for all of us to get better.
Dr. Calvin Chou: I heard Tim, you talk about communication being a procedure and that we would never think about going into a room and sticking a central line into a patient without having practiced that over and over and over again to get it right. Not to get it right, to never get it wrong, like you were just saying. And so if we think about communication as the most common procedure in healthcare, then it behooves us all to do the best we can with it. It is a frame shift because we are communicating with each other all the time, oftentimes without thinking. And what we're advocating right now is for everyone to really bring it in terms of communication skills in all settings, because the effect of ineffective communication is not necessarily just making people feel bad. As Tim said at the top of the program, it also impinges on quality of care. It's not just the right thing to do, it's the safe thing to do.
Brittany Harvey: Absolutely. And highlighting the fundamentals here and practicing them as clinicians will improve each healthcare interaction.
So then, finally, to wrap us up, Dr. Chou, earlier you mentioned ChatGPT and thinking about maybe some technological advances and how those will impact in the future. What are the outstanding questions and priorities for future research for optimal patient-clinician communication?
Dr. Calvin Chou: I think there's a lot we still need to learn about in this very, very nascent time of interacting with generative artificial intelligence. We won't know what things are going to be like probably even tomorrow given the vast advances that AI is allowing us to do. And also, as I was mentioning earlier, what AI can never do is to bring the human element into these interactions. And I think that's part of what, maybe that's a lot of what brings people to healthcare, is if they're in need and they have some physical issue that we need to help them solve, it's not just a physical issue, it also is a deep emotional experience.
And we have heard many times now cautionary tales of when AI has led people astray to then, for example, allow them to die by suicide. And that is the last thing that we can allow to happen in healthcare. That is the ultimate low-quality item. We need to make certain that everybody is cared for with high quality and high safety. And we're definitely not there yet with AI. We hope that at some point we'll be able to work with AI in order to bring even better healthcare than we have right now, and I think that has been demonstrated to be possible. That is one major outstanding question that we're all going to have to wrestle with.
Brittany Harvey: I think that's absolutely a key point. With generative AI quickly evolving, there need to be guardrails in place. And like any intervention, thinking about how to maximize the benefits of it and reduce the harms to make sure that you're preserving that human interaction and communicating effectively, and that patients can receive their health information in an appropriate way.
So I want to thank you both so much for your work to update this guideline, to draft all of these recommendations and the strategies, and work with the entire panel to create this excellent product. So thank you for all that work and thank you for your time today, Dr. Chou and Dr. Gilligan.
Dr. Timothy Gilligan: Thank you.
Dr. Calvin Chou: Thank you, Brittany, so much.
Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.
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Dr. Lakshmi Rajdev and Dr. Manish Shah join the podcast to discuss the updated guideline on immunotherapy and targeted therapy in unresectable locally advanced, advanced, or metastatic gastroesophageal cancer. They share first-line and subsequent-line recommendations for both gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma based on actionable biomarkers including PD-L1 expression, MMR and/or MSI, CLDN18.2 expression, and HER2 status. They note the importance of the algorithms and tables in the guidelines that provide visual illustrations and quick reference guides of the evidence-based recommendations. They also comment on ongoing and recently presented trials that may impact future guidelines in this space.

Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update" at www.asco.org/gastrointestinal-cancer-guidelines"
TRANSCRIPT
This guideline, clinical tools and resources are available at www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02958     
Timestamps
·       00:00 – 02:15 Introduction and Overview
·       02:16 - 08:20 First-line treatment for patients with pMMR/MSS, HER2-negative gastroesophageal adenocarcinoma
·       08:21 –10:29 First-line treatment for patients with pMMR/MSS, HER2-positive gastroesophageal adenocarcinoma
·       10:30 – 14:39 First-line treatment for patients with dMMR/MSI-H, gastroesophageal adenocarcinoma
·       14:40 – 18:03 First-line treatment for ESCC
·       18:04 – 22:04 Second- and third-line therapy for gastroesophageal adenocarcinoma and ESCC
·       22:05 – 24:38 Importance of guideline
·       24:39 – 27:45 Outstanding questions and future research
 
Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  
My name is Brittany Harvey, and today I am interviewing Dr. Lakshmi Rajdev from the Icahn School of Medicine at Mount Sinai and Dr. Manish Shah from Weill Cornell Medicine, co-chairs on "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update."
Thank you for being here today, Dr. Rajdev and Dr. Shah.
Dr. Lakshmi Rajdev: Thank you.
Dr. Manish Shah: Thank you for having us. It is wonderful.
Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Rajdev and Dr. Shah, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.
So then to dive into what we are here today to talk about, Dr. Shah, I would like to start first with what prompted the update to this guideline, which was previously published in 2023, and what is the scope of this updated guideline?
Dr. Manish Shah: Yes, terrific. So even in the last few years, the pace of drug development in gastroesophageal cancers has just been astounding. So, what prompted this guideline is actually the practice-changing results for a new biomarker, CLDN18.2 hat was based on the GLOW and SPOTLIGHT studies, as well as a practice-changing study in HER2-positive disease where we added pembrolizumab to trastuzumab and chemotherapy for tumors that are HER2-positive and PD-L1 CPS 1 or greater. And then there were also new studies and new approvals in esophageal squamous cell cancer that you will hear about as well.
So there were several studies, overall more than 5,000 patients were reported on, and that led to several new therapies, new indications, and it really necessitated this guideline.
Brittany Harvey: Excellent. It is great to hear about all of these exciting updates in this space.
So then to next review the key recommendations of this guideline by clinical question that the expert panel addressed. So, Dr. Rajdev, what is the recommended first-line treatment for patients with proficient mismatch repair, microsatellite stable, HER2-negative gastroesophageal adenocarcinoma?
Dr. Lakshmi Rajdev: Thank you for that question. So historically, we have sort of used fluoropyrimidine and platinum doublets, which yielded a survival of about one year. More recently, immunotherapy and targeted therapy options have improved outcomes in patients with advanced esophageal and gastric adenocarcinoma, as well as squamous cell carcinoma. Patients with gastric and GE junction adenocarcinoma have a high rate of actionable alterations, so it is imperative that physicians test the following biomarkers upfront so that it can help guide therapy.
The markers recommended by the ASCO panel are HER2, MMR or MSI, CLDN18.2, and PD-L1. And also, it was recommended to use NGS if feasible in this patient population. HER2, as we know, is expressed in about 15% to 25% of patients; PD-L1 expression occurs in about 80% of patients; MSI-high, deficient MMR is present in about 5% to 8% of patients; and CLDN18.2 expression is present in about 40% of patients. There is, of course, biomarker overlap. About 13% to 22% of CLDN18.2 patients are also PD-L1 positive.
For patients with pMMR or microsatellite stable HER2-negative disease with PD-L1 expression greater than 1 and absence of CLDN18.2, the panel recommended a first-line therapy with fluoropyrimidine and platinum-based therapy in combination with immunotherapy. These recommendations stem from large phase 3 trials, and the agents approved in the United States are pembrolizumab, nivolumab, and tislelizumab. It has been shown that immunotherapy benefit is greater in patients with higher PD-L1 expression, and it is not possible to comment on the individual PD-L1 cutoff scores and sort of identify the optimal PD-L1 cutoff score that sort of balances benefits and harms.
But what is recommended is that immunotherapy-based treatments can be offered in patients with a CPS score of greater than 1. With regard to the choice of immunotherapy agents, that is pembrolizumab, nivolumab, or tislelizumab, these agents are considered to have similar efficacy, and the selection of an agent could be based on dosing schedule, cost considerations, toxicity, and the method of administration. Typically, clinicians should avoid withholding the start of chemotherapy while awaiting biomarker testing, depending on the clinical scenario.
Now, for patients with pMMR microsatellite stable disease that is HER2-negative with PD-L1 expression less than 1 and positive CLDN18.2 expression, zolbetuximab-based treatments or in combination with chemotherapy is recommended, and this is based on two global phase III randomized controlled trials, the GLOW and the SPOTLIGHT. And across both studies, the hazard ratio for the overall survival was 0.78, and similarly, there was also an improvement in progression-free survival favoring the zolbetuximab group compared to the chemotherapy group alone.
An important note is that nausea, vomiting is commonly associated with zolbetuximab-based treatments, and the panel recommended prophylactic antiemetics, adjusting zolbetuximab infusion rates, pausing infusion temporarily, using non-prophylactic antiemetics, and hydration intravenously prior to discontinuation of zolbetuximab-based chemotherapy. So effective handling of the GI-related symptoms with zolbetuximab is recommended prior to discontinuation of therapy.
Now, for patients with pMMR microsatellite stable HER2-negative gastric, GE junction adenocarcinoma with PD-L1 expression greater than 1 and CLDN18.2 positivity, the ones with the dual expression with CLDN18.2 as well as PD-L1 chemotherapy, the choice of therapy can be based on the degree of PD-L1 expression, the toxicity profile, the burden of symptoms, and the anticipated improvement in symptoms associated with response to treatment, the patient comorbidities, the prior medical and treatment history. So this decision needs to be made on a case-by-case basis, and these are some of the factors that we suggested that could potentially influence the choice of therapy. For patients with pMMR microsatellite stable disease that is HER2-negative and a PD-L1 expression less than 1 and an absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy is recommended. So you can see we have segmented out patients based on PD-L1 expression, pMMR and microsatellite stable disease expression, and also based on CLDN expression.
Brittany Harvey: Absolutely. And that first point you noted, I think is really important, that biomarker testing is really critical for treatment decision-making in this space.
So then the next subgroup of patients that the panel looked at, Dr. Shah, what first-line therapy is recommended for patients with proficient mismatch repair, microsatellite stable, HER2-positive gastroesophageal adenocarcinoma?
Dr. Manish Shah: So this was an update from a few years ago. So we have known for 15 years now that if you are HER2-positive, you should get trastuzumab plus chemotherapy. That was based on the ToGA trial. And the update now is based on a trial called KEYNOTE-811, where it examined the addition of pembrolizumab to trastuzumab and chemotherapy versus trastuzumab and chemotherapy, and there was a progression-free and overall survival benefit.
And again, here, the biomarkers are important. If your CPS PD-L1 is less than 1, we would not recommend Pembrolizumab in that setting, so you would still get trastuzumab and chemotherapy. But if it is 1 or greater, the PD-L1 CPS score, then we do recommend pembrolizumab unless there is a contraindication to immunotherapy. The take-home message really is from the onset of diagnosis, please check your biomarkers. And I will just, it is worth repeating, it is important to check your PD-L1 status, HER2 status, mismatch repair status, and CLDN18.2 status. And then the optimal therapy, and it is outlined in the publication, is really biomarker-driven. We know that if we are able to hit the target that is overexpressed, we are going to have a better outcome.
And Dr. Rajdev did mention where there is overlap, there can be a lack of data, and that is where we are with both PD-L1 positive and CLDN positive. Here we do have data in HER2-positive cases where if you are both HER2-positive and PD-L1 positive, you would combine trastuzumab and pembrolizumab for the best outcomes.
Brittany Harvey: Understood. I really appreciate you detailing what is most important for each individual biomarker combination that patients may have.
So then following that, Dr. Rajdev, what does the expert panel recommend for first-line treatment for patients with esophageal squamous cell carcinoma that is not amenable to definitive chemoradiation?
Dr. Lakshmi Rajdev: There are three phase III randomized clinical trials that have influenced practice in patients with esophageal squamous cell carcinoma examining the benefit of immunotherapy in this patient population. The RATIONALE-306 was a randomized trial of tislelizumab plus chemotherapy with platinum and fluoropyrimidine or paclitaxel versus placebo with chemotherapy. And then you have the KEYNOTE-590, which compared pembrolizumab plus chemotherapy versus chemotherapy alone. And then you have CheckMate-648, which included comparisons of nivolumab plus chemotherapy versus nivolumab plus ipilimumab or chemotherapy.
And the primary endpoints for these studies were overall survival, and they did look at subgroups with PD-L1 expression. They used TPS score greater than 1% in CheckMate-648 and PD-L1 CPS greater than 10 in KEYNOTE-590. The bottom line is that the overall hazard ratio for overall survival across this patient population was 0.72. So clearly, there is benefit in patients that express PD-L1 CPS greater than 1 for benefit for the addition of immunotherapy.
Now, the benefit again in patients with a PD-L1 expression less than 1 remains limited, and so the panel has made a recommendation for using immunotherapy in combination with platinum-based chemotherapy in patients with a PD-L1 greater than 1. Again, we know that it is hard to make recommendations on what PD-L1 cutoffs are recommended in this patient population, meaning that should it be limited to patients with a PD-L1 of 1 to 4 or greater than 10? I think that the general consensus that has been gleaned from the data is that the higher the PD-L1 expression, the greater the benefit.
I do want to comment on another option that is available in patients with squamous cell carcinoma compared to adenocarcinoma, and that is the combination of nivolumab and ipilimumab. Now, in CheckMate-648, nivolumab with ipilimumab was also recommended as a treatment option in patients that have a PD-L1 score of greater than 1. There was a survival benefit demonstrated with this combination compared to chemotherapy alone.
And an important observation in this study is that, although there was a slightly increased rate in early death, but there was really no significant difference in PFS and OS compared to chemotherapy alone. Importantly, the treatment appeared to be pretty well tolerated by the study population. There was a notable difference in the objective response rate, which was 35% in the nivolumab plus ipilimumab group compared to patients receiving nivolumab and chemotherapy, where it was 53%. So superiority is, so the importance of chemotherapy in patients with esophageal squamous cell carcinoma is to be noted. However, there is no difference in overall survival and progression-free survival when using the combination of nivolumab and ipilimumab, and thus it affords a chemotherapy-free option for this patient population with esophageal squamous cell carcinoma and a CPS with a score of greater than 1.
Brittany Harvey: Understood. I appreciate you reviewing the evidence underpinning those recommendations as well.
So then the next patient population that the guideline panel addressed, what first-line therapy is recommended for patients with deficient mismatch repair, microsatellite instability-high, gastroesophageal adenocarcinoma or esophageal squamous cell carcinoma?
Dr. Lakshmi Rajdev: The rate of MSI-high expression is about 3% to 7% across different studies. Now, the KEYNOTE-158 was a tumor-agnostic study in patients with non-colorectal cancers, and again, the problem with the MSI-high population, given that it is so rare, the numbers in the individual studies are fairly small. But consistent outcomes do emerge, indicating high response to immunotherapy. So in KEYNOTE-158, a response rate of about 46% was noted. The number of patients was small, it was about 24.
In CheckMate-649, which is a study of chemotherapy plus or minus nivolumab in patients with advanced gastric adenocarcinoma, there was again a very small number of patients, and patients that were MSI-high or deficient MMR did experience substantial benefits with the addition of immunotherapy, with hazard ratios in the order of about 0.38. In KEYNOTE-062, again, it was a very small number of patients, again about 6% or so, and similar to CheckMate-649, a substantial benefit was noted in combination with chemotherapy, but also there were benefits noted with pembrolizumab alone.
The RATIONALE-305 again was a study of tislelizumab in combination with chemotherapy and similarly showed benefits to the combination of chemotherapy plus immunotherapy in this patient population. I think that we are all aware of the dramatic benefits of immunotherapy in this particular subset of patients, deficient MMR MSI-high, and also we have seen in CheckMate-649 they did have a subset of patients that received nivolumab and ipilimumab. And in this patient population, they noted unstratified hazard ratio of 0.28.
So I think that the overall consensus is that immunotherapy is a very important treatment modality in patients with deficient MMR MSI-high disease, given that a lot of the trials in gastroesophageal adenocarcinoma have utilized chemotherapy-based options, that is certainly a recommendation of the panel to use chemotherapy in combination with immunotherapy. However, on a case-by-case basis, the panel recommended immunotherapy alone as well, and given the high response rates noted in trials across different diseases as well as noted in this disease as well.
Brittany Harvey: Certainly. And I appreciate you both for reviewing these first-line recommendations.
So moving to later lines of therapy, Dr. Rajdev, what recommendations did the expert panel make for second or third-line therapy for gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma?
Dr. Lakshmi Rajdev: So, I think that the RAINBOW trial that investigated the utility of the addition of ramucirumab as second-line therapy has been around since 2014, and those results have led to the addition of ramucirumab to taxane-based therapy in the second-line setting. Based on the utilization of oxaliplatin and platinum-based therapy in the front-line setting, there may be patients that have an underlying neuropathy, and so we wanted to really include treatment options for this patient population so that an agent that is less neurotoxic could also be recommended in combination with ramucirumab.
The RAMIRIS trial is one such trial where ramucirumab was combined with FOLFIRI, and it demonstrated benefit in combination with ramucirumab. So we have listed that as a potential treatment option for patients in the second-line setting who may have an underlying neuropathy or even for whatever reason that based on the toxicity profile, that needs to be the preferred option by a physician, that recommendation is new from the older guidelines that we have.
With regard to the utility of PD-1 inhibitors, there really has been no benefit noted in the second-line setting with regard to overall survival or progression-free survival, so no recommendation is made for that option. I think an important study that has been recently presented is the DESTINY-Gastric04 trial, which really has been practice-changing and has led to the recommendation for trastuzumab deruxtecan in patients that have HER2-positive metastatic gastric or GE junction adenocarcinoma. Now, this is a phase III trial in patients who retained HER2-positive disease after progressing on front-line trastuzumab-based treatments, and the comparator for this trial was trastuzumab deruxtecan versus ramucirumab plus paclitaxel.
There was significant improvement and progression-free survival in patients that received trastuzumab deruxtecan. The patients that were excluded from the trial are patients that have pulmonary problems, interstitial lung disease; that is one of the toxicities of this particular agent, and close monitoring and prompt initiation of therapy such as glucocorticoid treatment in patients who develop this toxicity was also highlighted by the panel. So to summarize, the new guidelines highlight the possibility of FOLFIRI plus ramucirumab as a second-line option and then trastuzumab deruxtecan as a later-line option in patients that still retain HER2 expression. And that is very important because the trial did retest patients whether they expressed HER2. As we know, in a substantial number of patients, there is downregulation of HER2, and there is emerging data that the benefit for subsequent HER2-directed therapies is best noted in patients that still retain HER2 expression.
Brittany Harvey: Great. So as our listeners have heard, there are many recommendations and new treatment options for advanced gastroesophageal cancer.
Dr. Shah, earlier you highlighted the importance of biomarker testing, but I would like to hear in your view, what is the importance of this guideline and how will it impact both clinicians and patients with gastroesophageal carcinoma?
Dr. Manish Shah: So as we have discussed throughout this podcast, the treatment for gastroesophageal cancer, both adenocarcinoma and squamous cell cancer, is increasingly complex, increasingly biomarker-driven. And I think the value of the guideline is to place all of that into context. So it provides the data for why certain biomarkers are important, what therapies should be indicated. Not only that, but if you are able to review the guideline, it provides the details of each of these studies and summarizes them in a meta-analysis fashion to sort of give you the context, because sometimes the individual studies can be maybe a little bit discordant or confusing and the guideline attempts to harmonize all that.
And then also, I think the tables are very, very interesting because they give you actual numbers in terms of how many patients over a thousand would this benefit or how many patients over a thousand would this cause harm in terms of nausea, vomiting, or other things like that. So it gives you context for helping clinicians and patients weigh the potential benefits of the novel treatment strategies against the potential adverse events. And then finally, the guideline does also provide an algorithm that you are able to follow based on the biomarkers, and those are in figures 4 and 5.
So I think overall, it is a very comprehensive guideline. It intends to make more manageable a very complex subject, and you know, I really encourage our listeners to review it after listening to the podcast.
Dr. Lakshmi Rajdev: If I can add to that, I think that what is also really good about the guidelines is there are quick summaries. So if someone is busy in the clinic, of course, there is the opportunity to review the data supporting the guidelines in great depth in the manuscript, but what is also really good is that there are good summaries. In the event that you are very busy, you can easily identify what the recommendations should be for that particular patient based on these summaries.
Brittany Harvey: Absolutely. Listeners are encouraged to review the full guideline, including those tables and figures that may be more helpful when they are looking for something quick to look at in the clinic as well.
So, as you both mentioned, there have been a number of recent practice-changing trials in this area. So I imagine there is still a lot of ongoing research as well. So Dr. Shah, what are the outstanding questions regarding treatment options for patients with locally advanced unresectable, advanced, or metastatic gastroesophageal carcinoma?
Dr. Manish Shah: I think we touched upon it a little bit. The guidelines are based on the data available, and they are primarily examining one novel therapy with chemotherapy in a specific biomarker population. But as you know, the biomarkers are not either/or; you are not either CLDN18.2 positive or PD-L1 positive. A portion of patients could have dual biomarkers, and you know, I think that we are generating data on how to manage those patients.
At the recent GI Symposium in January this year, the ILUSTRO trial was presented by Dr. Shitara, which looked at combining zolbetuximab and chemotherapy with immunotherapy for dual-positive biomarkers, and that is leading to a phase III study that has begun to enroll. So unanswered questions are: how do we manage dual-positive biomarkers? The other thing that was mentioned is that the current data for mismatch repair deficiency involve chemotherapy plus immunotherapy. Only squamous cell cancer is there a study with a positive non-chemotherapy kind of backbone, that is CheckMate-648 that Dr. Rajdev mentioned. As we move forward, it will be good to get data on non-chemotherapy options in certain biomarker-positive populations.
And then finally, another update, which is likely to be practice-changing, is the HERIZON-GEA-01 study that looked at zanidatamab, which is another biparatopic antibody that targets HER2, and that is likely to change practice. And as that data gets published, we may look to even do a rapid update for the current immunotherapy and targeted therapy guideline that is just being published.
Dr. Lakshmi Rajdev: So, if I can add to that, there are numerous ADCs that look very interesting. There are bispecific antibodies; in fact, the zanidatamab is a bispecific antibody showing improved activity in patients with HER2-positive disease. So I think there are studies from Asia looking at CLDN CAR T-based therapies. So, I think that there are a lot of novel agents and a lot of excitement in the field.
We know that the bemarituzumab study, unfortunately, the FGFR2 inhibitor failed to demonstrate any benefit, but I think that there are other agents that are being explored, so there are newer targets, newer agents, ADCs, bispecifics that could potentially change the field in the future.
Brittany Harvey: Yes, we will look forward to the data to address these unanswered questions and new agents and inform future guideline updates.
So, I would like to thank you both for all of your work to review the evidence here and update this important guideline, and for your time today, Dr. Rajdev and Dr. Shah.
Dr. Lakshmi Rajdev: Thank you.
Dr. Manish Shah: Thank you.
Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast.
To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Bishal Gyawali and Dr. Tessa Cigler share the new, comprehensive, evidence-based update of the ASCO guideline on the use of hematopoietic colony-stimulating factors in patients with cancer. They discuss recommendations on primary prophylaxis, secondary prophylaxis, and treatment of febrile neutropenia along with stem cell mobilization, efficacy, safety, duration, dosing, and administration of CSFs – including biosimilars. They highlight where it is appropriate to use a CSF, and importantly, when not to use a CSF. They touch on the significance of individual patient considerations and cost implications, and future work to refine the risk factors for the development of complications of febrile neutropenia.

Read the full guideline, "White Blood Cell Growth Factors: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines
TRANSCRIPT
This guideline, clinical tools and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02938    
Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.
My name is Brittany Harvey, and today I'm interviewing Dr. Bishal Gyawali from Queen's University in Kingston, Ontario, Canada, and Dr. Tessa Cigler from Weill Cornell Medicine in New York, New York, co-chairs on "White Blood Cell Growth Factors: ASCO Guideline Update." Thank you for being here today, Dr. Gyawali and Dr. Cigler.
Dr. Bishal Gyawali: Thank you very much for having me. It's a pleasure.
Dr. Tessa Cigler: Hi there. Nice to be here as well.
Brittany Harvey: Great. And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Cigler and Dr. Gyawali, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.
So then I'd like to dive into the guideline that we're here today to talk about. So first, what prompted an update to this guideline on the use of hematopoietic colony-stimulating factors in patients with cancer, and what is the scope of this updated guideline?
Dr. Bishal Gyawali: The last version of the guidelines from ASCO on this topic was back in 2015, so it has been more than a decade since ASCO had a guideline on the use of G-CSF in patients with cancer receiving treatment. So it was due for an update because there has been a lot more evidence based on not necessarily new drugs, but evidence for proper timing of these agents and the duration of these agents, as well as there have been a lot of new biosimilars, and there are questions about are these biosimilars equivalent or how do we choose among these different options. One is that content of the evidence that has evolved over time in the last decade, but also I think the last time we had these guidelines, the ASCO guidelines were not incorporated to have those evidence GRADE tables. So the quality of the ASCO guidelines itself has evolved over the years, so we wanted to have a new version of the guideline that includes not only the new evidence, but also contains those evidence GRADE tables that will help to quantify the benefits. And so I think it was high time, and even more than that, the newer ASCO guidelines for any guideline, they also include considerations of cost, access, equity, and all these factors that were not included in the previous version of the guideline. So I think it's only natural that with time the guideline should also evolve.
Dr. Tessa Cigler: I agree completely, and just as a framework, as we all know, neutropenia and its complications, including febrile neutropenia and infections, are still an important toxicity of many myelosuppressive chemotherapies. And these neutropenic complications do require prompt evaluation and treatment and often hospitalization, and we know that hematopoietic colony-stimulating factors, which I'm going to refer to as growth factors, can reduce the duration and severity of neutropenia and the risk of febrile neutropenia, so it remains an important topic in the practice of clinical oncology.
Brittany Harvey: Absolutely. It's an important topic for both clinicians and for patients who are receiving treatment for their cancer. And as you said, there was a substantial amount of literature to review here and updating everything to be in line with the GRADE evidence rating system, so there was a lot of work that you both put into this.
So then next, I'd like to review the key recommendations of this guideline by clinical question. So first, what factors did the expert panel identify that should influence the decision to administer primary prophylaxis of febrile neutropenia with a CSF?
Dr. Bishal Gyawali: Yeah, so I think that constitutes one of the most important recommendations in our guidelines about primary prophylaxis with G-CSF. And this is important because not only it's about when to use it, it's also about when not to use it, as in the ASCO "Choosing Wisely" campaign has also made some recommendations about this. So our guideline recommendations are also aligned with that.
So first of all, we recommend that primary prophylaxis with G-CSF is recommended when the risk of febrile neutropenia because of the chemotherapy regimen is equal to or more than 20% unless an alternative chemotherapy regimen with comparable efficacy and safety that does not need G-CSF is available. And the quality of evidence to make this recommendation is high, so we give a strong strength of recommendation for this. Having said that, even for patients where the risk of febrile neutropenia is not necessarily 20%, it's a little lower, but because of other patient-related factors, the patient is at a higher risk of complications from febrile neutropenia, such as age, comorbidities, and other factors, in such case primary prophylaxis with G-CSF should be offered. And we also make a recommendation that if G-CSF is not affordable or available, then antibiotic prophylaxis can also be offered, but the evidence quality for this is low, and the strength of recommendation is very conditional.
A couple of things to highlight here would be that, I think Dr. Cigler can attest to that, we ran into lots of problems about finding the data for the evidence base to say what are the patient-related factors that actually make them at a higher risk of febrile neutropenia, you know, like how did that 20% benchmark come about? Why 20%? Or when we say even if it's less than 20%, if based on other comorbidities, if the risk is higher, we tried to dig into that evidence. For example, we're talking about our "Box 1" in the guideline, what is the evidence for each item we have included under that "Box 1"? And we tried to do a lot of search to find the evidence for that, and some of them do have strong evidence, and that will tie into our future research ideas as well. And some of them actually don't have such solid evidence too, so that was one of the reasons why we ran into lots of problems about how do we quantify whether someone is at a high risk of febrile neutropenia and where that 20% benchmark comes from.
Dr. Tessa Cigler: And definitely, because there's not very clear data, our guidelines definitely leave room for physician discretion in all these situations.
Brittany Harvey: Absolutely. I find that in a lot of these guidelines the key point is that there's a lot of shared decision-making with patients after talking through what risk factors they may have and what is best for them in their individual clinical scenario.
So then moving on to secondary prophylaxis, what factors did the expert panel identify that should influence the decision to administer secondary prophylaxis of febrile neutropenia with a CSF?
Dr. Tessa Cigler: So for patients who've already experienced a neutropenic complication from a previous cycle of chemotherapy, the question is which patients should then receive prophylactic G-CSF for subsequent cycles of chemotherapy. And without a lot of evidence again to guide us, the panel really felt strongly that secondary prophylaxis should be used when a treatment delay or when a reduced dose of chemotherapy would be thought to compromise cure rates or survival outcomes. We do note that in many situations, certainly a dose reduction or a delay would be a very reasonable alternative or an additional strategy to G-CSF administration.
Dr. Bishal Gyawali: Yeah, I think it's more like if there is going to be compromise in outcomes without using G-CSF, as in if we can't maintain the dose intensity and that's going to lead to inferior outcomes, then we should. But if we can reduce the dose intensity and treatment frequency and still have the same outcomes, then I guess in simple words, we're just trying to say use it when it's absolutely needed, or you can also look into other alternatives that might not need G-CSF but you could maintain the same outcomes.
Brittany Harvey: Understood. It's helpful to review those options for clinicians and showing that there's not just one way to address potential neutropenic complications for later cycles of chemotherapy.
So then following those recommendations for prophylaxis, what does the expert panel recommend regarding CSFs for the treatment of febrile neutropenia?
Dr. Bishal Gyawali: This is an important question because this ties strongly with the "Choosing Wisely" campaign. In other words, primary and secondary prophylaxis we talked about when CSF should be used; here we make a sort of negative recommendation in that we say when CSF should not be used, because this is where we see most overuse or overtreatment with G-CSF. So first, we say that we should not be using a CSF routinely simply because a patient has neutropenia. If they are afebrile but they only have neutropenia, we recommend against using CSF just to boost neutrophil counts; that's not a meaningful metric. Then the second recommendation we make is CSF should not be routinely used as an adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. So the first one was neutropenia, no fever, don't use it. The second one is okay, there is neutropenia and fever, but the treatment for that is use of antibiotic therapy, and so in such situations routinely we should not be using G-CSF just to boost the neutrophil count. And that is tied on to the third recommendation where if the patient has fever and neutropenia but is also at a very high risk for infection-related complications or who have other prognostic factors that we think will lead to poor outcomes for the patient, then in such situations, a CSF can be used as an adjunctive treatment. But we talk about the data in the manuscript, but the data show that the most that this will do is reduce the days of hospitalization by a couple of days. It actually does not have any data that it's going to improve the mortality rates.
So as of now, we use the word "may be offered," it's not "should be offered," it's "may be offered" if there are other factors that we think will make the patient at the very poor risk of mortality outcomes, and the evidence quality here therefore is low and our strength of recommendation is conditional. And we also have a box that lists those items that we think might be associated with poor prognosis for the patients, but again the data for those, are they really hard evidence? No. And that is also tied with our future research recommendation that we should study more about these factors that might lead to these poor outcomes.
Dr. Tessa Cigler: And again, allowing for discretion of the treating physician.
Brittany Harvey: Absolutely. It's just as important to know when not to use CSFs routinely, and those risk factor boxes that you mentioned are available in the full manuscript along with the full list of recommendations, and our listeners can refer to that; a link will be in the show notes of the episode .
Dr. Tessa Cigler: Just so you know, the panel, we really discussed those criteria a lot and agonized over them and gave you our best recommendations.
Brittany Harvey: Definitely, and it sounds like there was varying degrees of evidence to support a lot of those risk factors, and so it's really important that the evidence supports those, but also there was expert consensus of the panel in reviewing each of those factors individually to come up with recommendations that can be applicable for all clinicians.
Dr. Bishal Gyawali: If I may add, we're proud of our panel because I think our panel is quite inclusive of people representing different specialties within cancer care, as in we had radiation oncologist, we had infectious disease expert, pharmacists, and most importantly, we also had patient partners.
Brittany Harvey: Absolutely. Having a multidisciplinary panel is really important for each and every guideline.
So then, this is probably relevant now, but addressing a few more specific sections addressed in the guideline, what is the role of CSFs as adjuncts to progenitor cell transplantation?
Dr. Tessa Sigler: Great question, and so, as solid tumor oncologists, Dr. Gyawali and I really leaned heavily on our hematology experts within the panel. The panel decided that a CSF should be used alone after chemotherapy or in combination with a CXCR4 inhibitor to mobilize peripheral blood progenitor cells. Clearly the choice of mobilization strategy depends on the type of cancer and the type of transplantation. The panel noted that a CSF should be routinely administered after autologous stem cell transplantation to reduce the risk of severe neutropenia, and that a CSF may be administered after allogeneic stem cell transplant to reduce the duration of severe neutropenia. Again, this last recommendation has not a lot of evidence to support it, and so we kind of tempered our language that it may be administered or can be considered based on clinical judgment of the physician and the clinical status of the patient.
Brittany Harvey: And that really highlights the need for a multidisciplinary panel, because as you are solid tumor oncologists, you need the hematologists to make recommendations for all sorts of patients and make sure that these guidelines are comprehensive.
 
So then moving on to another smaller subset population, for patients receiving concomitant chemotherapy and radiation therapy, are CSFs recommended?
Dr. Bishal Gyawali: I think there is very little evidence for patients who are receiving radiation therapy alone, so there is no evidence to suggest the use of CSF in patients with radiation therapy alone. The bigger question is in patients who are receiving both chemo and radiation together, chemoradiotherapy. In those patients, up until now, the classical recommendation has been to avoid G-CSF use. I think in our updated guidelines we discuss a couple newer trials that are trying to address this issue, but in the totality of evidence, we still stick with the same recommendation as before, which is CSFs are not recommended in patients receiving concomitant chemotherapy and radiation therapy, especially those involving the mediastinum because the biggest evidence of harm is for these patients.
Dr. Tessa Cigler: I agree completely.
Brittany Harvey: Definitely. It's important to recognize when that balance of benefits and harms leans more towards harms, and so that this should not be recommended for those patients.
So there are several different CSFs that are recommended in the guideline, including biosimilars. So do the recommended CSFs differ in efficacy or safety?
Dr. Tessa Cigler: So as supported by evidence, and the panel all agreed, that the various forms of CSFs, including the biosimilars, really have the same evidence for efficacy and for safety, and that the choice of agent really should depend on cost, availability, accessibility, patient convenience, and sometimes disease subtypes and treatment regimens. But, in essence, these can be used interchangeably without concern for efficacy or toxicity differences.
Dr. Bishal Gyawali: I completely agree. I think in terms of efficacy outcomes, I don't think there is anything to choose between these agents. The choice between these agents would largely depend on different patient and treatment-related factors: cost, availability, affordability, feasibility. We even discuss things like where does the patient live, as in how frequently the patient can commit to the cancer center, and we also discussed things like even for the daily shots of filgrastim, patients can be taught and they can get it by themselves at home. So we discussed all these factors, but in a nutshell, the choice within these agents primarily depends not on efficacy factors, but simply based on all these other factors that are equally important but which can lead to informed decision-making about what is best for a given patient. But we mention it explicitly that the biosimilars, there is nothing to choose between them, especially the biosimilars; it's about price competition and what you can get at an affordable rate.
Brittany Harvey: Understood. It's great to have many different options for patients so that there's something that can work for them based off access, cost, and all these factors that you listed. As you mentioned, it may be easier for some patients to get their treatment at home rather than in clinic, and so having different options and reviewing those with patients is very important.
Dr. Bishal Gyawali: As we are having this conversation, I'm thinking that we might be a very unique guideline in that I don't think in many other settings you have this many options that you are asking about, you know, choices between equally good options and making decisions based on cost. I don't think there are any other areas in oncology where we have the privilege of making these decisions based on cost and convenience and all these factors, as well as we might be one of those guidelines where we have, as discussed before, so many recommendations about when not to do things and trying to promote judicial use of treatments.
Dr. Tessa Cigler: As you might imagine, our panel discussions were very lively.
Dr. Bishal Gyawali: Yes. But Dr. Cigler, do you recall any other guideline where there is so much discussion about when not to use things and how we have so many biosimilar options and we can choose the one that's most appropriate? I don't recall any other.
Dr. Tessa Cigler: I agree with you.
Brittany Harvey: It's certainly a unique guideline in that regard.
So we'll move into the last clinical question that the expert panel addressed. But what does the expert panel recommend for the initiation, duration, dosing, and administration of CSFs?
Dr. Bishal Gyawali: Yeah, I think there has been some new data in this regard that were not available in the previous guideline. For example, we have new trials testing a shorter duration of filgrastim injections compared to the standard of care. So we have some data, we call this 'de-escalation of treatment'. So we have more data supporting de-escalation of treatment. We have some data for lower dose of pegfilgrastim, we have data for lower duration of filgrastim, we have also some new data about timing of treatment, as in there has been some newer data presented about the relationship of timing of the drug and the frequency of adverse events from G-CSF such as bone pain. There is also the question about, for patients who don't live near the cancer center, can they get their pegfilgrastim shot on the day of chemo while they are in the cancer center? So all these questions that are very pragmatic and important questions, but were not answered before, we're glad that we had more evidence to talk about all these factors and give a more solid recommendation to our users of the guideline.
Brittany Harvey: Definitely. And listeners can review the full list of dosing and administration recommendations in Table 2 in the guideline, and that will be linked in the show notes of the episode.
So then I really want to thank you both for reviewing all of these recommendations. There's certainly a large amount of clinical questions and recommendations that you went through.
I'd like to next ask, in your view, what is the importance of this updated guideline and how will it impact both clinicians and patients?
Dr. Bishal Gyawali: I think the importance of this updated guideline is that, as mentioned before, we talk about newer data that have come up with regards to not just the most important two questions as in when to use it as primary prophylaxis and when to use it as secondary prophylaxis and when to use it as treatment, but also with regards to the duration and timing and dosing and multiple options and how these all factors as well as patient-related factors should be combined to make an informed decision, the most appropriate decision for the patient. And as mentioned before, we have the GRADE tables that were not in the previous version of this guideline. So I think even those users that are familiar with the 2015 guideline, I think they will find very novel content in this new updated guideline, and they will find it useful for their practice.
I would encourage the readers to not only read the headlines of the box recommendations, but also read the full text of these guidelines because we have worked really hard to incorporate the latest evidence and also interpret them contextually. The discussion regarding de-escalation, patient considerations, cost implications; usually, people just skip these portions when they read a guideline. But I think these are also one of the most important paragraphs in our guideline, so they have been written with very careful thought, and I think reading the whole guideline is very much worth your time.
Dr. Tessa Cigler: As you can imagine, I agree completely, having just spent several months thinking about these guidelines and all their nuances.
Brittany Harvey: Certainly, this guideline is definitely a very comprehensive update, and that nuance in the manuscript is really important for clinicians to understand and read through and understand when it's appropriate to make certain decisions.
So then to wrap us up, I'd like to ask, what are the outstanding questions and active research areas regarding the use of white blood cell growth factors in patients with cancer?
Dr. Tessa Cigler: As you all know from clinical practice and that we've said several times already in this podcast is that the risk factors for the development of complications of febrile neutropenia are still not clearly worked out. And one of the things that is, I think, really needed in clinical practice is the development of predictive algorithms or biomarkers to really allow us to understand who might be more at risk and to allow for the clinician to be able to tailor the use of G-CSF as needed.
Brittany Harvey: Yes, and so we'll look forward to future updates in this space to inform new recommendations and an updated guideline in the future.
So I want to thank you both so much for your work to develop this comprehensive guideline. It was certainly a lot of effort, and thank you for your time today, Dr. Gyawali and Dr. Cigler.
Dr. Tessa Cigler: Oh, my pleasure. It's nice to be here and to speak with you all.
Dr. Bishal Gyawali: Yeah, it was great to speak with both of you but also through you to the audience, and we had a great time. Thank you.
Brittany Harvey: And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Sonam Puri discusses the full update to the living guideline on stage IV NSCLC with driver alterations. She shares a new overarching recommendation on biomarking testing and explains the new recommendations and the supporting evidence for first-line and subsequent therapies for patients with stage IV NSCLC and driver alterations including EGFR, MET, ROS1, and HER2. Dr. Puri talks about the importance of this guideline and rapidly evolving areas of research that will impact future updates.

Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines
TRANSCRIPT
This guideline, clinical tools and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02822   
Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.
My name is Brittany Harvey, and today I'm interviewing Dr. Sonam Puri from Moffitt Cancer Center, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2026.3.0." It's great to have you here today, Dr. Puri.
Dr. Sonam Puri: Thanks, Brittany.
Brittany Harvey: And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Puri, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.
So then, to dive into the content that we're here today to talk about, Dr. Puri, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is updated on an ongoing basis. So, what data prompted this latest update to the recommendations?
Dr. Sonam Puri: So Brittany, non-small cell lung cancer is one of the fastest-moving areas in oncology right now, particularly when it comes to targeted therapy for driver alterations. New data are emerging continuously from clinical trials, regulatory approvals, real-world experience, which is exactly why these are living guidelines. The goal is to rapidly integrate important advances as they happen, rather than waiting for years for a traditional update.
Since the last full update of the ASCO Stage IV Non-small Cell Lung Cancer Guideline with Driver Alterations published in 2024, there have been seven new regulatory approvals and changes in first-line therapy for some driver alterations. [This version] of the "Stage IV Non-small Cell Lung Cancer Guidelines with Driver Alterations" represents a full update, which means that the panel reviewed and refreshed every applicable section of the guideline to reflect the most current evidence across therapies including sequencing and clinical decision-making. This is to ensure that clinicians have up-to-date practical guidelines that keep pace with how quickly the field is evolving.
Brittany Harvey: Absolutely. As you mentioned, this is a very fast-moving space and this full update helps condense all of those versions that the panel reviewed before into one document, along with additional approvals and new trials that you reviewed during this time period.
So then, the first aspect of the guideline is there's a new overarching recommendation on biomarker testing. Could you speak a little bit to that updated recommendation?
Dr. Sonam Puri: Yeah, definitely. So the panel has discussed and provided recommendations on comprehensive biomarker testing and its importance in all patients diagnosed with non-small cell lung cancer. Ideally, biomarker testing should include a broad-based next-generation sequencing panel, rather than single-gene tests, along with immunohistochemistry for important markers such as PD-L1, HER2, and MET.
These results really drive treatment decisions, both in frontline settings for all patients diagnosed with non-small cell lung cancer and in subsequent line settings for patients with non-small cell lung cancer harboring certain targetable alterations. Specifically in the frontline setting, it helps determine whether a patient should receive upfront targeted therapy or immunotherapy-based approach. We now have strong data that shows that complete molecular profiling results before starting first-line therapy is associated with better overall survival and actually more cost-effective care.
Using both tissue and blood-based testing can improve likelihood of getting actionable results in a timely way, and we've also provided guidance on platforms that include RNA sequencing, which are specifically helpful for identifying gene fusions that might be otherwise missed with other platforms. On the flip side, outside of a truly resource-limited setting, single-gene PCR testing really should not be routine anymore. This is what the panel recommends. It's less sensitive and inefficient and increases the risk of missing important actionable alterations.
Brittany Harvey: Understood. I appreciate you reviewing that recommendation. It really helps identify critical individual factors to match the best treatment option to each individual patient.
So then, following that recommendation, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer with a driver alteration?
Dr. Sonam Puri: Since the last full update in 2024, there have been four additional interim updates which were published across 2024 and 2025. Compared to the last version, there have been several updates which have been included in this full update. One of the most important shifts has been in first-line treatment of patients with non-small cell lung cancer harboring the classical, or what we call as typical, EGFR mutation.
The current version of the recommendation is based on the updated survival data from the phase III FLAURA2 and MARIPOSA studies, based on which the panel recommended to offer either osimertinib combined with platinum-pemetrexed chemotherapy or the combination of amivantamab plus lazertinib in the first-line treatment of classical EGFR mutations. And these recommendations, as I mentioned, are grounded in the results of the FLAURA2 and MARIPOSA trials, both of which demonstrated improvement in progression-free survival and overall survival compared to osimertinib alone in patients with common EGFR mutations.
That being said, the panel actually spent significant time discussing the toxicities associated with these treatments as well. These combination approaches come with higher toxicity, longer infusion time, increased treatment frequency. So while combination therapy is now recommended as preferred, the panel has recommended that osimertinib monotherapy remains a reasonable option, particularly for patients with poor performance status and for those who are not interested in treatment intensification after knowing the risks and benefits.
Brittany Harvey: Absolutely. It's important to consider both those benefits and risks of those adverse events that you mentioned to match appropriately individualized patient care.
So then, beyond those recommendations for first-line therapy, what is new for second-line and subsequent therapies?
Dr. Sonam Puri: So this is a section that saw several major updates, particularly again in the EGFR space. The first was an update on treatment after progression on osimertinib for patients with classical EGFR mutation. Here the panel recommends the combination of amivantamab plus chemotherapy, and this recommendation was based on the phase III MARIPOSA-2 trial, which compared amivantamab plus chemotherapy with chemotherapy alone with progression-free survival as the primary endpoint.
The study met its primary endpoint, showing an improvement in median PFS with the combination of amivantamab plus chemotherapy compared to chemotherapy alone. And as expected, the combination was associated with higher toxicity. So, although the panel recommends this regimen, the panel emphasizes that patients should be counseled on the side effects which may be moderate to severe with the combination therapy approach.
In addition, a new recommendation was added for patients who are not candidates for amivantamab plus chemotherapy. In those cases, platinum-based chemotherapy with or without continuation of osimertinib may be offered, and the option of continuing osimertinib with chemotherapy was recommended and supported by data from a recently presented phase III COMPEL study, which randomized 98 patients with EGFR exon 19 deletion or L858R-mutated advanced non-small cell lung cancer who had experienced no CNS progression on first-line osimertinib, and these patients were randomized to receive platinum-pemetrexed chemotherapy with osimertinib or placebo. Although this study was small, it demonstrated a PFS benefit with continuation of osimertinib with chemotherapy, and this approach may be appropriate for patients without CNS progression who prefer or require alternatives to more intensive treatment strategies.
Next was an update on options for patients with EGFR-mutated lung cancer after progression on osimertinib and platinum-based chemotherapy. Here the panel recommended that for patients whose disease has progressed after both osimertinib and platinum-based chemotherapy, a new drug known as datopotamab deruxtecan can be offered as a treatment option. And this treatment recommendation was based on evaluation of pooled data from the TROPION-Lung01 and TROPION-Lung05 study, in which in the pooled analysis about 114 patients with EGFR-mutant non-small cell lung cancer were treated with Dato-DXd, 57% of whom had received three or more prior lines of treatment, and what was observed was an overall response rate of 45% with a median duration of response of 6.5 months. So definitely promising results.
Next, we focused on updates to subsequent therapy options for patients with another type of EGFR mutation known as EGFR exon 20 insertion mutations. In this section, the panel added sunvozertinib as a subsequent line option after progression on platinum-based chemotherapy with or without amivantamab. Sunvozertinib is an oral, irreversible, and selective EGFR tyrosine kinase inhibitor with efficacy demonstrated in the phase II WU-KONG6 study conducted in Chinese patient population. In this study, amongst 104 patients with platinum-pretreated EGFR exon 20 mutated non-small cell lung cancer, the observed response rate was 61%.
Staying in the EGFR space, the panel added a recommendation for patients with acquired MET amplification following progression on EGFR TKI therapy. In these situations, the panel recommended that treatment may be offered with osimertinib in combination with either tepotinib or savolitinib. As our listeners may know, MET amplification occurs in approximately 10% to 15% of patients with EGFR-mutated non-small cell lung cancer when they progress on third-generation EGFR TKIs, and detection of MET amplification is done with various methods, such as tissue-based methods like FISH, NGS, and IHC, as well as ctDNA-based NGS with variable cut-offs.
Over the last few years, several studies have informed this recommendation. I'm going to be discussing some of them. In the phase II ORCHARD trial, 32 patients with MET-amplified non-small cell lung cancer after progression on first-line osimertinib were evaluated, where the combination of osimertinib plus savolitinib achieved an overall response rate of 47% with a duration of response of 14.5 months.
More recently, the phase II SAVANNAH trial reported outcomes in 80 patients with MET-amplified tumors after progression on osimertinib, and in this patient population, the combination of savolitinib and osimertinib achieved an overall response rate of 56% with a median PFS of 7.4 months.
And lastly, the phase II single-arm INSIGHT 2 trial assessed the efficacy of osimertinib plus tepotinib in patients with advanced EGFR-mutant non-small cell lung cancer who had disease progression following first-line osimertinib therapy. And in this study, in a cohort of 98 patients with MET-amplified tumors confirmed by central testing, the overall response rate with the combination was 50% with a duration of response of 8.5 months. So definitely informing this guideline recommendation.
Next, we had an update on recommendation in patients with ROS1-rearranged non-small cell lung cancer. For patients with ROS1-rearranged non-small cell lung cancer, the panel recommended specifically for patients who progressed after first-line ROS1 TKIs, the addition of taletrectinib as a new option alongside repotrectinib. And this recommendation was based on analysis of the results of the TRUST-I and TRUST-II studies, which showed that amongst 113 tyrosine kinase inhibitor-pretreated patients, taletrectinib achieved a confirmed overall response rate of 55.8% with a median duration of response of 16.6 months and a median PFS of 9.7 months, a very promising agent.
Finally, for patients with HER2 exon 20 mutated non-small cell lung cancer, the panel added two new oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib, as options in addition to T-DXd and after exposure to T-DXd. These recommendations are based on early phase data from two trials: the phase I Beamion LUNG-01 study, which evaluated zongertinib, and the phase I/II SOHO-01 study that evaluated sevabertinib. In this study, zongertinib demonstrated an overall response rate of 71% in previously treated patients, with an overall response rate of 48% amongst patients who had received prior HER2-directed ADCs including T-DXd. Sevabertinib in its early phase study showed an overall response rate of 64% in previously treated but HER2 therapy-naive patients, and an overall response rate of 38% in patients previously exposed to HER2-directed therapy. The panel believes that both agents had manageable toxicity profile and represent meaningful new options for this patient population.
Brittany Harvey: Certainly, it's an active space of research, and I appreciate you reviewing the evidence underpinning all of these recommendations for our listeners.
So, it's great to have these new options for patients in the later-line settings. And given all of these updates in both the first and the later-line settings, what should clinicians know as they implement this latest living guideline update, and how do these changes impact patients with non-small cell lung cancer?
Dr. Sonam Puri: Some great questions, Brittany. I think for clinicians when implementing this update, I think about two practical steps. First is reiterating the importance of comprehensive biomarker testing. That is the only way to identify key drivers and resistance mechanisms that we are now targeting. And second, picking a first-line strategy that balances efficacy and toxicity and patient preference for your specific patient. I think informed decision-making, shared decision-making is more important than any time right now. It has always been important, but definitely very important now.
For patients, this guideline brings recommendations on more personalized treatment options for both first-line and post-progression settings, which potentially means better outcomes. But it is also very important for our patients to continue to have informed conversations about side effects, time commitment, and what matters most to them with their providers. The panel in this version of the guideline specifically acknowledges the real-world barriers that prevent patients from receiving guideline-concordant therapy, including challenges with access to comprehensive molecular testing and treatment availability, and the panel emphasizes on the importance of shared decision-making, and we provide practical discussion points to help clinicians navigate these conversations with the patient.
In addition, the panel has also addressed common real-world clinical complexities, such as treating elderly or frail patients, managing multiple chronic conditions, considerations around pregnancy and fertility, and certain disease scenarios such as oligoprogression or oligometastatic disease. And where available, the guideline summarizes this existing data to support informed individual decision-making in these complex situations.
Brittany Harvey: Shared decision-making is really paramount, especially with all of the options and weighing the risks and benefits and considering the individual circumstances of each patient that comes before a clinician.
We've talked a lot about all of the new studies that the panel has reviewed, but what other studies or areas of research is the panel examining for future updates to this living guideline as it continues to be updated on an ongoing basis?
Dr. Sonam Puri: Yes, definitely, so much to look forward to, right? Looking ahead, the panel is closely monitoring several rapidly evolving areas that are likely to shape future updates of the guideline. This includes emerging data from ongoing later-phase studies, particularly the studies that are evaluating these new targeted agents moving to earlier lines of therapy, alongside studies evaluating additional combination strategies or more refined approaches to treatment sequencing.
We're also closely watching advances in biomarker testing, the evolving understanding of resistance mechanisms, development of new targets, and promising therapeutic agents. I think ultimately the living guideline exists to help clinicians and patients navigate this rapidly evolving field, and we would like to ensure that scientific advances are rapidly translated into better, more personalized patient care.
Brittany Harvey: Definitely. We'll look forward to those updates from those ongoing trials and future areas of research that you mentioned to provide better options for patients with non-small cell lung cancer and a driver alteration.
So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Puri.
Dr. Sonam Puri: Thanks so much. Thanks so much for the opportunity.
Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. There's also a companion episode with Dr. Reuss on the related living guideline on stage IV non-small cell lung cancer without driver alterations that listeners can find in their feeds as well. And if you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.
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