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Improving Outcomes and Quality of Life in Advanced GIST: Discussing the Patient Journey and the Latest Data

  • Authors: Sara Rothschild, MPH; Margaret von Mehren, MD; Jean-Yves Blay, MD​; Richard F. Riedel, MD; Olivia Franek, BSN, RN, OCN
  • CME / ABIM MOC / CE Released: 12/19/2022
  • Valid for credit through: 12/19/2023
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    ABIM Diplomates - maximum of 0.75 ABIM MOC points

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Target Audience and Goal Statement

This educational activity is intended for a global audience of hematologists/oncologists, gastroenterologists, pathologists, nurses, nurse practitioners, and other healthcare professionals involved in the care of patients with GIST.

The goal of this activity is for learners to better be able to apply the latest advances for the treatment of advanced GIST, including as part of a multidisciplinary team, to improve patient outcomes and quality of life.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Different safety profiles of the available treatments for advanced GIST
  • Have greater competence related to
    • Applying team-based best practices for improving quality of life of patients with GIST
  • Demonstrate greater confidence in their ability to
    • Understand the implications of the latest data for patients with advanced GIST


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  • Sara Rothschild, MPH

    Patient Advocate
    Executive Director
    The Life Raft Group
    Wayne, New Jersey, United States


    Sara Rothschild, MPH, has no relevant financial relationships.

  • Margaret von Mehren, MD

    Professor of Medical Oncology
    Chief of the Division of Sarcoma Medical Oncology
    Fox Chase Cancer Center
    Philadelphia, Pennsylvania, United States


    Margaret von Mehren, MD, has the following relevant financial relationships:
    Consultant or advisor for: Boehringer Ingelheim Pharmaceuticals, Inc.; Deciphera Pharmaceuticals, Inc.; GlaxoSmithKline   
    Research funding from:  Cogent; Deciphera Pharmaceuticals, Inc.; GlaxoSmithKline; Novartis; Solarius; Theseus; Tomito

  • Jean-Yves Blay, MD

    Professor of Medical Oncology
    President, UNICANCER
    General Director, Centre Léon Bérard
    French Sarcoma Group
    Académie Nationale de Médecine
    Lyon, France


    Jean-Yves Blay, MD, has the following relevant financial relationships:
    Consultant or advisor for: Bayer; Deciphera Pharmaceuticals, Inc.; Roche
    Research funding from: AstraZeneca Pharmaceuticals LP; Bayer; Blueprint; Bristol Myers Squibb Company; Deciphera Pharmaceuticals, Inc.; GlaxoSmithKline; Merck Sharp & Dohme GmbH; Novartis; Roche
    Executive role with: Transgene

  • Richard F. Riedel, MD

    Associate Professor of Medicine
    Duke Cancer Institute
    Duke University Health System
    Durham, North Carolina, United States


    Richard F. Riedel, MD, has the following relevant financial relationships:
    Consultant or advisor for: AADi; Blueprint; NanoCarrier; SpringWorks     
    Research funding from: AADi; AROG; Ayala; BioAtla; Cogent Biosciences; Daiichi Sankyo, Inc.; Deciphera Pharmaceuticals; GlaxoSmithKline; Karyopharm; Ignyta Inc.; Immune Design; Inhibrx; Lilly; NanoCarrier Co., Ltd.; Novartis; Oncternal; Philogen S.p.A.; Plexxikon Inc.; PTC Therapeutics; Roche; SpringWorks; Threshold Pharmaceuticals; Tracon Pharmaceuticals, Inc.; Trillium

  • Olivia Franek, BSN, RN, OCN

    Sarcoma Oncology Nurse
    Duke Cancer Institute
    Duke University Health System
    Durham, North Carolina, United States


    Olivia Franek, BSN, RN, OCN, has no relevant financial relationships.


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    ​Medical Education Director, Medscape, LLC 


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    ​Scientific Content Manager, Medscape, LLC 


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Improving Outcomes and Quality of Life in Advanced GIST: Discussing the Patient Journey and the Latest Data

Authors: Sara Rothschild, MPH; Margaret von Mehren, MD; Jean-Yves Blay, MD​; Richard F. Riedel, MD; Olivia Franek, BSN, RN, OCNFaculty and Disclosures

CME / ABIM MOC / CE Released: 12/19/2022

Valid for credit through: 12/19/2023


Activity Transcript

Segment 1: Challenges Faced by Patients During Their Treatment Journey With GIST

Sarah Rothschild: Hello, I'm Sarah Rothschild, a patient advocate and executive director of the Life Raft group. Welcome to this program titled “Improving Outcomes and Quality of Life in Advanced GIST: Discussing the Patient Journey and the Latest Data.” In this program, Margaret von Mehren, Jean-Yves Blay, Richard Riedel, and Olivia Franek will be discussing the latest advances for the treatment of advanced gastrointestinal stromal tumor (GIST). In this chapter, I'm going to discuss the challenges faced by patients during their treatment journey with GIST.

Being diagnosed with cancer feels like a loss of control, and patients may start facing challenges in both their medical and quality of life journeys. This is especially true for someone diagnosed with a rare cancer like gastrointestinal stromal tumor, or GIST. Being aware of the unmet needs of GIST patients and the impact on their quality of life is an important part of the doctor-patient partnership for survival.

The questions that arise in the beginning of the patient journey are multiple, and it is vital that the physician listens carefully to the patient concerns so that they can establish a partnership for survival. Each of these key areas are important in the patient journey. First, one of the most important areas we emphasize to our patients is to ask their doctor if they have received biomarker or mutational testing, as this is a standard of care and mentioned in the guidelines. It is important that patients receive this type of testing. Additionally, it's important for doctors to assess the risk of recurrence for the patient and have honest conversations at the beginning of their journey. The second area that we emphasize for our patients is to see a specialist or go to a sarcoma reference center. The ability to engage with a specialist in a convenient location is obviously ideal, but if there's access to telehealth visits, and if they're covered by insurance, it's also important to examine that further.

An important stage for patients in the treatment planning process is to please consider the patient preferences and demographics. Patients’ eligibility for surgery, medication, a clinical trial, and routine surveillance are important factors in patient survivorship. Paired with treatment tends to come adverse events, both short-term and long-term effects. Taking a personalized approach, especially evaluating if a patient is able to take his or her medication, can help optimize the treatment plan they are on. Does the patient have a support system? Does a caregiver or family member accompany them to their appointment? That's an important part of the patient's holistic journey. How are their emotional needs being met? Are they members of a patient organization? Do they attend support groups? Do they receive professional counseling?

Next, the financial and economic burden can also weigh heavily on the patient. How is insurance covering their treatment, and are there patient assistance programs to cover such treatments? There's a high risk for survivors to retire early or not return to work due to their therapy. Health behaviors have a long-term impact on survival, so it is important to pay attention to nutrition and exercise to help enhance the survivorship of your patients. Physical activity improves general quality of life, fatigue, sleep, cognitive function, et cetera. And finally, coordinating all this care with oncology specialists, other medical specialists, and primary care professionals (PCPs) is important to ensure all needs are met, especially when managing comorbidities and other chronic conditions.

Although GIST patients face many similar challenges in their medical and psychosocial treatment journey, each patient is an individual and should be considered unique. In this example of a patient timeline taken from our patient registry, the following are some of the key challenges this patient faced over the course of his 12-year GIST journey. The patient was 57 years old when he presented with abdominal pain and fatigue and went to the ER in 2009. After surgical resection and confirmation of GIST he was placed on imatinib and seen by a non-GIST specialist. Once he had progression, he switched to a specialist and received mutational testing. Over the span of years, he was on 5 different tyrosine kinase inhibitors (TKIs). With each, he faced adverse events that resulted in dose interruptions as well as hospitalizations. The adverse events impacted his quality of life and left him unable to work and thus apply for disability. Additionally, he missed traveling to milestones in his family's life, like the birth of a grandchild or a wedding, because it was too difficult to travel. He became depressed. Eventually with progression, he entered hospice and passed away in 2021. And I'm sharing this with you because you may be looking through the medical lens, but there's an important quality of life lens that's important to consider.

The primary tool for successful navigation for a GIST patient is open and honest communication with their GIST specialists and other members of a multidisciplinary team. Having their provider be able to hear what's most important to the patient and how the disease impacts the individual patient through various quality of life aspects will help them navigate their care and take a forward-thinking approach to help patients be better informed in enhancing their survivorship.

Common side effects or adverse events can appear in all phases of the patient's journey. Patients with a high number of adverse events are more likely to experience treatment interruptions or issues with adherence. So as part of the listening process, it’s important to determine what side effects or adverse events are they experiencing. Have they ever skipped medications to alleviate the symptoms? How severe are the symptoms, and how is that affecting their quality of life?

Neither the patient nor the physician have to navigate this journey alone. By taking a team approach and empowering the patient with multiple resources, the journey is less daunting, so ensure that you have a multidisciplinary team that you're working with. Utilize experts for treatment challenges through virtual tumor boards. Empower the patient with sources of knowledge about their disease and treatment. Utilize nurse navigators to help with side effect management. Rely on patient advocacy organizations for support and advice and coordinate with the patient's other physicians to address comorbidities in other chronic conditions and develop or join a group of specialists for collaboration.

GIST patients will be challenged at each stage of their treatment journey, and the key to helping them survive and thrive is to openly communicate and listen to the important information that they provide. Understanding the whole patient is vital to developing effective treatment. Encouraging patients to be their own advocate and providing them with resources to educate and support them helps both the patient and the treating physician. And lastly, patient organizations like the Life Raft Group provide the resources for both patients and physicians alike, providing a true partnership for survival. Thank you for participating in this activity. Please continue and listen to the next chapter in this program.

Segment 2: Digesting the Data From the Latest Congresses

Jean-Yves Blay, MD: Hello. Welcome to this session entitled “Digesting the Data from the Latest Congresses on Gastrointestinal Stromal Tumors.” My name is Jean-Yves Blay. I am a professor of medical oncology working in Lyon, France, and I have the pleasure to share with you some of the more recent data on gastrointestinal stromal tumors, GIST.

Starting maybe with something which is very important: the nature of mutations observed in GIST. We know that GIST is not a single entity. They are actually characterized by a variety of mutually exclusive mutations, most often on the KIT oncogene, but also within the KIT oncogene as a variety of different mutations on different parts of the molecule. All leading to the activation of the kinase. When KIT is not mutated, the most frequently mutated gene is PDGFRA receptor alpha, with similar activating mutations in different parts of the molecule. Rarer forms of GIST are affected with mutations on other genes and proteins: succinate dehydrogenase, SDH, NF1, and sometimes BRAF translocation involving NTRK.

Altogether, these are different tumors in terms of natural history and, more importantly, in terms of response to the different treatments. These will have an impact in terms of the treatment given to the patient. We know that patients with high-risk GIST after surgery can be proposed to receive adjuvant treatment. Patients may need a treatment, but of course the mutation needs to be sensitive to the inhibitor.

Ten-year follow-up of a 3-year randomized study, a randomized study testing 1 year vs 3 years of adjuvant treatment of imatinib, showed an improvement in overall survival, putting 3 years as a standard treatment in patients with high-risk GIST with sensitive mutations. This points to the importance of having a good characterization and early characterization of the nature of the molecular alteration driving the GIST in order to best guide treatment.

In patients that have relapsed, different treatments are going to be used sequentially first. When the patient is progressing, after imatinib, sunitinib, then regorafenib, then ripretinib are the second-, third-, and fourth-line treatment recommended by both the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), because actually all guidelines around the world have integrated these different treatments because of the demonstration of an improvement in progression-free survival in randomized studies where they were investigated.

We are going to discuss some recent randomized studies, but first what I would like to do is to focus on a recently reported ESMO 2022 publication at the ESMO congress, starting with the results presented by our colleagues from Poland, exploring a large series of patients treated with imatinib in a situation of GIST with molecular characterization conducted in all patients. What is very interesting is the observation that the nature of mutation, and more precisely the nature of mutation in terms of point mutation, codon mutation, is impacting patient outcomes and natural history. The risk of relapse is different with a similar mutation observed in gastric GIST and in bowel GIST, and whether it is KIT or PDGFRA receptor alpha, everything counts. So, to best describe the natural history of the disease, we need everything. We have to have the information on the nature of the oncogene mutated, the site of mutation, the site of the tumor, the nature of the mutation. Mutations are very important.

Another important presentation was a report within ESMO 2022 of a clinical study which explored deep learning to analyze mutations and predictors of patient outcome by reading hematoxylin and eosin (H&E) slides in GIST. This was conducted in 2 centers whose objective was to evaluate the efficacy of deep learning models to predict patient prognosis and mutational profile of GIST using, very simply, the digitized H&E stain whole slide images. It’s quite an original study. This has been done already in other tumor models, but this was the first time in GIST, and actually, very interestingly, what was observed was that we were able to improve the prediction of relapse obtained by classical Miettinen classification, which shows, as we all know, the site, the size and the mitotic index of the primary tumor. What we can see is the analysis of the image by deep learning is very much completing the Miettinen classification with an improved capability to predict patient outcomes. Relapse prediction was shown to be different in particular, with a combination of deep learning and Miettinen classification, which could enable to completely distinguish very low and very high-risk tumors, thus improving our capacity to best guide the treatment decision. And this was observed in all patients and also for patients with high-risk and intermediate-risk tumors. So, we really are now able to distinguish 2 patient populations: lower and high risk.

Next part of this analysis was the prediction of mutation, and it's important, as we have discussed, to predict mutation. In this case, the tool was found to be able to predict the nature of mutation on exon 11 with the details of the codon mutation, but the prediction which was not 100% accurate, and that's something we need to work further on. What is interesting again is that we can describe the histological features of the GIST which are predictive of the mutational profile. In a reverse learning way, in a sense, we learn that what we've been learning from the machine, and that's something which is a very nice example of the power of deep learning approaches, which refines the deep Miettinen classification, as they call it, and refines our capacity to predict the mutation and also instruct the expert on the analysis of the classical H&E slides.

Another important study was a phase 1b/2 study of selinexor, a single agent and in combination with imatinib in patients with advanced GIST. This study presented by Dr Serrano included patients with unresectable GIST in progression after at least imatinib in advanced phase, with 2 cohorts. Cohort A with imatinib 400 per QD (daily) with selinexor at a dose of 60, 80 or 100 milligram of selinexor again twice weekly. Primary endpoint was maximum tolerated dose (MTD) and for cohort B, the clinical benefit rates. Safety profile was found acceptable for cohort A and enabled to define a recommended dose of imatinib of 400 together with selinexor at 80 as a recommended dose. Looking at the efficacy, cohort A was actually associated with a significant level of activity with 2 partial responses, which is quite unusual in this patient population. Cohort B was associated with tumor control but not significant tumor shrinkage. Median progression-free survival (PFS) in cohort A was 3.6 months, which is in more contrast with and, I might say, quite superior to, what is generally observed with imatinib single agent in this patient population. For cohort B, it was close to 3 months. So probably we can conclude here that selinexor plus imatinib has an interesting tumor control rate and response rate. Looking at the clinical benefit rate over 16 weeks, close to 40%, this is an interesting combination worth to be explored further.

To conclude, I would like to spend a few minutes on the ripretinib vs sunitinib, INTRIGUE, randomized open label phase 3 study, which was reported at American Society of Clinical Oncology (ASCO) 2022 and also in the Journal of Clinical Oncology in August. This study randomized in a 1:1 manner, ripretinib vs sunitinib in patients progressing after imatinib in advanced phase. Primary end point was PFS, and the study aimed for superiority. This was not what was observed. Ripretinib was found associated with similar PFS as compared to sunitinib in all subgroups of patients with a possible exception of exon 9 KIT mutations, where sunitinib seemed to do slightly better. But what probably is more important is the observation that grade 3-4 treatment-emergent adverse events (TEAEs) were very different in the 2 arms, with ripretinib being significantly better tolerated than sunitinib for a wide variety of different side effects. Hypertension, hand-foot syndrome, where there were more grade 3 and more grade 4 in patients treated with sunitinib. And on top of that, the tolerance profile, all along the patient pathway during the treatment, favored ripretinib in particular for skin toxicity all over the treatment. And this was actually observed for all parameters according to the quality-of-life questionnaire from the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ C30). Sunitinib was less well tolerated than ripretinib with more side effects, including fatigue, diarrhea, and a wide variety of different side effects more frequently observed with sunitinib. So here there is a challenge for sunitinib being equivalent to ripretinib in this randomized study, but ripretinib being much better tolerated. This addresses, of course, the question of sunitinib intolerance, which is not unusual in this patient population. Something to be discussed further on.

So, in conclusion, molecular characterization of GIST is still ongoing, and we have more fragmentation and adaptation of the treatment according to the molecular profile. Deep learning is able to predict relapse and mutations of GIST. It's intriguing and needs to be further evaluated. It could help general practice in a variety of different countries. We have a new combination with selinexor and imatinib, which requires further evaluation. Ripretinib was found to be equivalent to sunitinib and actually superior according to the tolerance profile. So, this will definitely impact in the long-term clinical practice guidelines that we're going to discuss. And overall, ESMO 2022 and ASCO 2022 were a very rich source of new information for gastrointestinal stromal tumors. Thank you very much for your attention, and please continue to listen to the next section on selecting and sequencing treatments in gastrointestinal stromal tumors. Thank you very much for your attention.

Segment 3: Selecting and Sequencing Treatment in GIST: What Are The Latest Recommendations?

Margaret von Mehren, MD: Hello, and welcome to “Selecting and Sequencing Treatment in GISTs: What Are the Latest Recommendations?” My name is Margaret von Mehren, and I'm joined by Jean-Yves Blay. Dr Blay, you were recently at ESMO. Can you share with us some of the abstracts and maybe the significance of those presentations that you saw there?

Jean-Yves Blay, MD: Yeah, there were several interesting abstracts at ESMO and then also at ASCO earlier on. Actually, in ESMO, one of the first presentations which attracted attention was the use of image learning approaches to try to better describe the prognosis and features of GIST. And basically, the idea was, can we use artificial intelligence to analyze the image of H&E staining slides for gastrointestinal stromal tumor and improve the prediction of the natural history of the GIST? Can we improve the prediction of relapse, progression, and metastatic progression?

Actually, this proved to be the case in this study where the analysis provided higher capacity of this tool to describe high-risk patients, overall improving the classical Miettinen classification that we often use. It was also able, and that's very interesting, able to predict to some extent the nature of the molecular alterations of certain GISTs. But strangely, it was not fully correlated, and actually we will still need molecular analysis if we want to be accurate in defining treatment options because we need that, don't we, Meg? But what do you think?

Dr von Mehren: We certainly do, and I think as we look at some of the studies that have been recently published and changed our standard of care, it's become increasingly important to know what the molecular characterization of the GIST that we're treating is in terms of making choices about the next therapy for our patients.

There were several studies, of course, presented at ASCO having to do with ripretinib, which was studied in the second-line setting. What was your take on the outcome of the INTRIGUE trial?

Dr Blay: Actually, the INTRIGUE trial was intriguing in the sense that we expected, given the molecular inhibitor profile of ripretinib, we may have expected that ripretinib would be superior to sunitinib in the second-line setting. Actually, this is not what was observed. The 2 agents in this rigorously conducted randomized trial did not provide different results in terms of progression free. We are waiting for overall survival, obviously.

Interestingly, it seems to be the case for the majority of mutations which were screened in this study and possibly with the exception of exon 9, where, as usual, sunitinib seems to do a bit better. It's a small proportion of patients, about 10%, but still sunitinib seems to have specific activity. I think at ASCO as well, data on quality of life was presented, and this is probably where we see a big, big difference actually, for all parameters of patient tolerance, it seems that ripretinib clearly does better than sunitinib, maybe with one exception, which I think is constipation, but for all the rest. So ripretinib is superior, or should I say, provides less side effects than sunitinib. So, the patient has seen that. We have seen that, and this is of course intriguing in terms of how we select our second-line treatment. There’s going to be discussion about the standards. So, I was wondering, Meg, what's your practice on using this data in a routine setting?

Dr von Mehren: Right. It's with that information, my takeaway is that in terms of efficacy, if with the exception of exon 9 patients that you mentioned, there probably is not a big difference in outcomes, at least from the data that we have available. But certainly, with certain patients who may have more underlying comorbidities or have maybe a poorer performance status, ripretinib might be a safer and more feasible and more tolerable agent for specific patients. I think in my practice I still think of sunitinib as the standard but look to patients to see if there is perhaps a reason where the alternative might be in their best interest because it's safer for them. How has that played out in your practice?

Dr Blay: Actually, exactly like you, we have kind of a flexibility if the patient has not tolerated the agents well. And yesterday, actually, I saw a patient who is not able to tolerate sunitinib at a dose over 12.5mg every other day. So of course, she's underdosed and probably if the next computed tomography (CT) shows progression, that will be one of the proposals I will give to our end. We have this capacity in view of these results in some European countries to provide a switch earlier on if we have demonstrated that the other agents are not that well tolerated. This actually is probably very useful information, and I don't know what's your feeling, Meg, but I'm certainly looking for a long-term overall survival impact on each agent in second line. I'm very curious of the results. What do you think?

Dr von Mehren: I am as well. Because certainly we think of using an agent that maybe has broader activity the way we believe ripretinib has compared to sunitinib as hopefully providing longer disease control. But I think always with GIST, which we know as we give patients additional therapies, their tumors become more diverse in terms of the individual clones that have different mutations. And so how as we look forward are we going to be able to manage those patients, and is adding regorafenib after ripretinib going to be as efficacious as was documented in the INVICTUS trial, where ripretinib was added as fourth- or fifth-line therapy? And I think that's still an unanswered question and something that the data will be very informative on when it's available.

Dr Blay: And actually, the order of prescription is a question which is typically academic but that we probably would need to address together. That's a very complicated question. Which order, and what is the impact on selection of resistant clones? Could we reuse treatments that were used previously? And actually, on this perspective, the selinexor plus imatinib study, which was presented at ESMO, it was a phase 1/2, but it is quite interesting because it seems that the author showed the feasibility first, but also similar activity. I don't know how you interpret these results. Meg?

Dr von Mehren: It was very intriguing, and I think we'll need more data to really understand what these early signals mean. But I think the sequencing question is really an interesting one. We have, when we think about resistance, sort of this thought that there's the exon 13/14 mutations and the 17/18 mutations, and we think of those as of 2 different groups. In all likelihood they probably are present together. And so, what does that mean?

And I think one of the studies that's ongoing now, which will be intriguing in terms of its potential information, is the PEAK study. Bezuclastinib has been studied with sunitinib in a small number of patients, and so it'll be interesting to see what we find in a larger study comparing it to sunitinib alone.

Dr Blay: That's indeed one of the key questions that will have some results in the coming years, which may change the landscape very much. So, our guidelines are going to be modified probably. What do you think?

Dr von Mehren: The NCCN guidelines this year really started to do that in its most recent update, and I guess maybe last year as well, where we have broken out the PGFRA mutations, particularly those that are not sensitive to imatinib, to really indicate that we need to think about these tumors as a distinct entity. We've also tried in the guidelines coming out shortly to ensure that we talk about SDH-deficient GIST, which are also a completely different type of gastrointestinal stromal tumor that don't have the common KIT and PGFRA mutations. And we do indicate that for some that have the even rarer mutations, such as the N track translocations or NF1 type mutations, that there are alternative therapies that we might be thinking about. I believe the ESMO guidelines have similar recommendations.

Dr Blay: Yes, exactly. We always start with imatinib, with the exception of the mutations which are known to be resistant, where there are more open options, I would say even though we do not have that many options, by the way, of course NTRK inhibitors, BRAF inhibitors, it's even rarer, and NF1 and SDH are probably going to be the next big challenge. And then in second line it comes to sunitinib, regorafenib, fourth line of ripretinib, even though as we said it’s possible to use it earlier for those patients who do not have good tolerance with the first agents. So, we are evolving towards fragmentation, a split of what used to be homogenous disease, which is certainly not the case. That’s like non-small cell lung cancer. Right? We have more and more subtypes.

Dr von Mehren: Exactly. I still remember the first meeting I had to discuss imatinib for GIST, and we thought of it as one disease, and that was 22-plus years ago, and it's so interesting to see where we've come today. So, Jean-Yves, it's been a pleasure to speak with you about GIST; I know it's one of my favorite tumors and one of yours. Thank you so much for this discussion. And I want to thank you, the audience, for your attention. Please continue on to listen to the next section on safety profile, adverse management, and patient considerations in GIST.

Segment 4: Safety Profile, Adverse Event Management, and Patient Considerations: Applying Best Practices in GIST

Margaret Von Mehren, MD: Hello. Joining me in this chapter is Rich Riedel, Associate Professor of Medicine at Duke Cancer Institute, Duke University Health System in North Carolina in the United States. We're going to now discuss the “Safety Profiles, Adverse Event Management, and Patient Considerations: Applying Best Practices in GIST.” Dr Riedel, there are a variety of agents that we have for managing our patients. Can you talk about the differences in the safety profiles between these different agents? How do you think about this?

Richard F. Riedel, MD: Now we're fortunate, because we currently have 5 FDA-approved agents for the treatment of GIST: imatinib, which was approved in 2000; sunitinib, in the mid 2000s; regorafenib around 2012; and then more recently, the approvals of ripretinib and avapritinib in 2020. Each of these are multitargeted tyrosine kinase inhibitors, and there are some similar toxicities across all groups, but each of them also has some unique side effects.

Imatinib, for example, the most common side effects include things like periorbital or ankle edema, fatigue, nausea, rash, diarrhea, for example. Sunitinib and regorafenib are somewhat similar, in the sense that they have activity against vascular endothelial growth factor receptor, and as a result, things like hypertension, stomatitis, hand-foot syndrome, for example, can be seen preferentially in those agents. Ripretinib is somewhat unique in the sense that about half of patients will have alopecia, which is somewhat unique when compared to previously approved TKIs. Avapritinib, which is fairly unique in the sense that it's approved for patients with PDGFRA exon 18 mutations, also has very similar side effects to the other agents. One side effect that's fairly unique is cognitive or memory impairment, which can be seen in about 30% or 40% of patients. I think it's important to recognize that while there are some similar toxicities, there are some toxicities that can be unique between agents.

Dr Von Mehren: How do you see these side effects reflected in the quality of life, either in what's published or what you see in your patients?

Dr Riedel: Yeah, I think historically, at least when we look at previously published data, the use of quality of life or patient-reported outcome measures have been somewhat limited to nonexistent. That has changed in recent years, particularly with some of the studies involved with ripretinib, both in the fourth-line setting compared to placebo, as well as in the recently reported INTRIGUE study, in which ripretinib was compared to sunitinib in the second line.

In both of those studies, things like physical functioning, role functioning, as well as specific treatment-related symptoms were assessed. And at least in those studies, in the fourth-line setting, the quality of life was fairly stable for patients who were on ripretinib, whereas it declined in patients on placebo. And similarly in the second-line setting for ripretinib versus sunitinib, the quality of life was less diminished for ripretinib when compared to sunitinib. I think it's important to recognize that not only do these agents have efficacy with respect to the disease, but they also have potential side effects and quality-of-life implications for the patients.

I would ask you then, Meg, what do you think some of those implications are clinically when it comes to assessing side effects for patients in the clinic?

Dr Von Mehren: Well, I think first of all, each individual patient comes with their own health history and potential comorbidities. Certainly, when I’m starting a patient, say, on sunitinib or regorafenib, and to some extent ripretinib, if they have a history of hypertension, we always discuss the importance of monitoring their blood pressure at home and being aware of when they need to contact us to potentially make those adjustments or increase their blood pressure medications.

Certainly, patients who have been on sunitinib, who might have had hand-foot syndrome, the likelihood that they will experience that with regorafenib is probably higher, and to some extent also may be seen with ripretinib. And so, for hand-foot syndrome in particular, prevention is really important. It's a key way of managing these patients, and so you must ensure they understand how to take care of hand-foot syndrome and also how to prevent it. And lastly, also, when to call and to call early at the first signs of any issues.

I think with avapritinib, one of the things that is different in some patients is cognitive dysfunction. That can come in the form of memory issues, word-finding issues and, in some patients, changes in mood, even some depressive-type symptoms. For that drug, I talk to the patient, but I also make sure that the patient's loved ones or people who are around that patient, living with that patient, are aware to look for these symptoms. Certainly, again, prevention is the key in that case and stopping the medication, reducing the dose of avapritinib can help lessen that side effect.

And I guess lastly with ripretinib, the alopecia, which is something that we don't see in most of these agents, maybe a little bit with some of the other ones, is really education of the patients so that they're aware that this can happen, and aware that this is something that's reversible, and will go away when and if they need to change their medication. I think being aware that this can happen, their hair not only can fall out, but it can become coarser, curlier, really have a different look, and prevention. I guess the other thing with ripretinib that I also make sure patients are aware, is that they need to be followed by a dermatologist because there can be some skin lesions that should be monitored by a dermatologist, and just to have that as part of their routine care.

Dr Riedel: You mentioned prevention, particularly as it relates to hand-foot syndrome for sunitinib and regorafenib. Can you speak to what you specifically do in clinic, what you recommend for patients?

Dr Von Mehren: In clinic, especially after they've started their therapy, I make sure that we're examining their hands and feet. If they're not having these symptoms, I don't always make them take off their shoes, but certainly if they're describing anything, we take a look.

In terms of how we educate them: First, especially for the feet, making sure that you're wearing comfortable shoes, things that are not going to cause a lot of friction on the feet. That if there are any calluses, part of prevention is trying to lessen those callouses with a pumice stone, or seeing a podiatrist, getting a manicure. And then, the use of good emollient lotions or creams. If patients start having more problems, there is a cream that you can prescribe, with urea, which can also be helpful and help mitigate some of those things. I don't know if you do anything differently.

Dr Riedel: Similarly, we will recommend twice-daily lotioning with a good moisturizing lotion. We will consider steroid creams if we see the callous formation, or sensitivity in the palm or the soles that are affecting their activities of daily living, for example. But very similar, we try to be proactive with respect to the hand-foot syndrome for both sunitinib and regorafenib.

For ripretinib, at least in my experience, after patients are on sunitinib or regorafenib, if they transition to ripretinib, it's almost a bit of a welcome change in part because the side effect profile is favorable and the alopecia, at least in my experience, is less of an issue for patients. Although you are right, it's important to make them aware of it because we don't see it often with the first-, second-, or third-line agents that we typically use.

Dr Von Mehren: Yeah. No, I completely agree. I think for some of my patients, the symptom that stands out with ripretinib is sometimes the muscle cramps, which I feel like patients report more frequently. And then, just educating patients about the importance of hydration, the importance of making sure they're getting good electrolytes, potassium, magnesium, calcium, phosphorus. I also will share with them things that my other patients have shared with me they find useful. There are some magnesium sprays, topical sprays that can be useful. I have a patient who swears by pickle juice, probably because it has a lot of salt and other electrolytes. That is one of the things I share with my patients, but that for some patients can, particularly patients who are very active, be a symptom that is bothersome.

Dr Riedel: Then you mentioned the cognitive impairment with avapritinib. As you mentioned, and we will do this similarly, we will engage family members early and recognize that some of the memory or cognitive issues that can develop can be at least somewhat subtle and may require probing questions. Or issues that might otherwise be dismissed by family members really could potentially be early warning signs. That's really important, to engage with the family in addition to the patient, to make them aware of those findings.

Dr Von Mehren: Yeah. No, I mean as we get older, we all have issues forgetting where we put our keys and things like that. But if it becomes a pattern that is much more frequent, if they're recording more issues with word finding, those are the subtle points that are really important to pick up early. They seem minor, but they can compound and become more significant.

Thanks for this great discussion, Rich, and thank you for participating in this activity. Please continue and listen to the next chapter in this program.

Segment 5: Communicating With the Patient: Discussing the Role of the Clinician and The nurse

Richard F. Riedel, MD: Hello, I'm Dr Richard Riedel from the Duke Cancer Institute. I'm a sarcoma medical oncologist, and joining me in this chapter is Olivia Franek, a sarcoma oncology nurse within the Duke Cancer Institute at Duke University Health System in Durham, North Carolina. We are going to now discuss the role of the clinician and nurse when communicating with the patient. So, Olivia, we see a number of patients on a daily basis within our clinic, both newly diagnosed and established patients. You and your nursing colleagues are often at the front line and meeting these patients before we, as the physician providers, are. What are some of the concerns that they express to you?

Olivia Franek, BSN, RN, OCN: I think a lot of our patients have a lot of concerns about their journey and where this will take them. A lot of them are totally unfamiliar with the diagnosis. They're not sure where to start. They're not sure what this journey will look like, so a lot of their concerns revolve around the treatment, what that will involve, how that will impact their family, and then other logistical matters such as coming to and from the clinic, support, and what that will look like for each individual patient and their family members. So how do you go about discussing treatment decisions and goals with our patients?

Dr Riedel: So certainly, 2 really important topics. I actually will begin first with some general education to the patient regarding the disease state. I think it's important that patients understand their diagnosis, that they understand the extent of the disease, that they understand what we are trying to do with our particular therapy. For many patients with advanced disease, we are dealing with palliative treatment or noncurable treatment. I think it's important that patients understand that. I think it's also important for them to understand the importance of communicating with us as their clinic providers to try to maintain their quality of life while dealing with potential side effects related to treatment.

Ms Franek: And what might the typical initial conversation look like versus a refractory patient?

Dr Riedel: I think those are 2 different conversations. For patients with an initial diagnosis, a lot of the information surrounding a cancer diagnosis can be overwhelming. So, I think it's, again, important to set expectations early about what our therapies can and cannot do. I think it's important to set expectations regarding the importance of communication, and particularly as it relates to side effects regarding treatment. For patients with relapsed refractory disease, we need our patients to understand that treatment options may become increasingly limited and understanding from their standpoint what their goals are with respect to aggressiveness of care, with respect to whether or not they want to consider additional treatment or not. And for some patients, moving away from a treatment strategy to one that focuses on quality of life. So, we obviously share a lot of information with patients that can be overwhelming. What are some measures that you use to assess whether or not a patient has an understanding of what the treatment recommendations are?

Ms Franek: So, I definitely think it can be very overwhelming for our patients, and typically what I would do is have them do something called a teach back method, where I ask them to repeat back to me what they have heard from you to make sure that they properly [understand] all the information. It can be overwhelming for them; it can be overwhelming for their family. So, I also want them to have the time to process that and to give them the space to come back to me with any questions. So, they might do that by calling our nurse triage line, and I will answer any questions that I can once they think of them or I might present them to you, to have a further discussion with the patient if needed. A huge part of my role is just being an advocate for the patient, making sure that their wishes are seen and heard, and also that any concerns that they have during their treatment period and during their disease process while they're under our care are met.

So sometimes that involves our huge team of people behind the scenes, which include our family medical therapists for emotional support as well as our social worker for more logistical support, travel, and things like that. We might need to get our dietician involved where patients who are on drugs like imatinib, who might have a lot of nausea or diarrhea, need more support than we can give them in clinic. So, we might ask the dietician to reach out to them and be able to work with them as well. So, I like to make sure that our patients know that we have an open line of communication, they're able to reach out to us, and we can help with any needs that they might have, that we're here for them during this difficult journey.

Dr Riedel: And certainly, for some patients who are struggling with treatment decisions or are struggling with side effects related to the medications, how can you help support them in that regard?

Ms Franek: So, I think when patients are struggling with the side effects and symptoms, a lot of it is discussing with them and giving them education regarding symptom management. So, making sure that they have the proper things at home to help take care of their symptoms, such as with making sure they have antidiarrheal medications, antiemetics, and making sure that they know that they can reach out any time that they have questions or concerns.

Dr Riedel: And I think a critical component of that is actually almost at a preventative stage, for example, meeting with our clinic pharmacist early on to set expectations regarding potential side effects. So, when or if they occur, they're prepared. The other thing that we often consider doing if there's a significant symptom burden is referring to a palliative care specialist or a symptom management specialist who really partners well with us to help deal with issues that arise with these patients.

Ms Franek: Correct. Yes, I agree. Thank you so much for this great discussion.

Dr Riedel: Well, thank you and thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.

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