Activity Transcript

Michael Heinrich, MD: Hello, welcome to this educational activity. My name is Dr Michael Heinrich; I am a Professor of Medicine at the OHSU Knight Cancer Institute, located at the Oregon Health and Science University in Portland, Oregon. Welcome to this program, entitled: "Changing Paradigms in the Management of Advanced GIST: Implications and Application of New Strategies". Joining me today in this interactive discussion are Dr Ping Chi, who is the Geoffrey Beene Junior Faculty Chair, and a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City, and Dr Patrick Schöffski, head of the department of general medical oncology at the University Hospitals Leuven in Belgium; welcome to you both.

Patrick Schöffski, MD, MPH: Hello, Mike.

Ping Chi, MD, PhD: Hi; thank you.

Dr Heinrich: Today, we will discuss the key milestones in the management of locally advanced unresectable or metastatic GIST, and the new treatment algorithm, particularly what has changed with the new approvals. We will use patient cases to illustrate how to effectively treat patients and what characteristics are used to determine the optimal treatment. In particular, we have focused on the consideration of molecularly-driven, tailored, personal therapies. We will discuss the treatment options along the disease continuum of care, from front-line metastatic disease to treatment of patients in the fourth-line setting

Dr Heinrich: We also, throughout this discussion, highlight some of the unmet needs and the current challenges.

Currently in the United States, there are 6 FDA approved agents that can be used for the treatment of GIST. These include: imatinib, sunitinib, regorafenib, and the most recently approved agent, ripretinib. All of these agents are approved for treatment of GIST, but not with any particular specification for the types of GIST that could be treated.

Dr Heinrich: We now know that some of these drugs lack activity against certain subtypes of GIST. In contrast to these 4 agents, there are 2 agents which are FDA-approved and have specific indications based on a molecular subtype of GIST. These include avapritinib, which was approved earlier this year for the treatment of PDGFRA exon 18-mutant GIST, and larotrectinib, which is approved for the treatment of any pediatric or adult tumor with an NTRK-positive translocation, including the minority of GIST carcinomas that carry such a translocation. Dr Schöffski, can you update us on the current status of the EMA authorizations for these agents?

Dr Schöffski: Well, the status of the agents that you mentioned in the US, Dr Heinrich, is very similar in Europe. We, of course, have routine access to imatinib, sunitinib, and regorafenib. In some European countries, other mentioned agents are available through compassionate use or off-label programs, and some of the files are in advanced stage for regulatory approval.

Dr Heinrich: Okay; then that would match up well the United States approvals quite nicely.

The first case we like to consider represents a continuum of care; our case journey begins with a 60-year-old woman who presents with iron deficiency anemia, which is one of the more common presentations for patients with GIST. Imaging to define the cause of iron deficiency anemia showed a large small bowel tumor with multiple liver metastasis; a liver biopsy was performed, which revealed the presence of metastatic GIST. Dr Schöffski, now that we have a diagnosis of metastatic GIST, what additional workup would be desirable?

Dr Schöffski: I think apart from conventional staging with imaging, that is via CT scan of the abdomen as a minimum requirement, I think it's very important that we have mutational data. That means we should perform biopsies and analyze which mutations may be drivers of this GIST tumor. This is important because we know that the drugs that are available are not active across all mutational subtypes. Therefore, it's very important to have at least some genomic information on the KIT and PDGFRA mutational status.

Dr Heinrich: I would completely agree with that. My real estate friends like to say, "it's all about location, location, location". I tell my GIST patients: "it's all about mutation, mutation, mutation". In this case, the molecular workup showed a KIT exon 11 mutant GIST. Dr Chi, having this information. What would you now consider for initial therapy choices?

Dr Chi: Sure; in this setting standard of care first-line therapy is imatinib 400 mg, once daily. This is based on the parallel phase 3 clinical trials in North America, Europe, and Australia which compared two doses of imatinib, 400 mg and 800 mg, in patients with advanced GIST. The RECIST response rates were about 45% to 57%, respectively, and the progression-free survival were between 20 months to 24 months with the 2 doses, respectively, with there being no statistically significant differences. The overall survival with both doses is about 46.8 months; very similar. Thus, in this setting, I think we would use 400 mg, once daily. Now, if this patient were to have an exon 9 mutant GIST, we would consider starting imatinib at 400 mg, once daily, and titrate up to 800 mg, once daily, if the patient can tolerate the adjustment. This is based on the fact that the parallel phase 3 clinical trials comparing 2 different doses of imatinib demonstrated significantly higher response rates, and also longer progression-free survival with the 800 mg dose of imatinib compared to the 400 mg dose of imatinib.

Dr Chi: Alternatively, one can also consider clinical trials, considering that about 50% of the patients would progress within 2 years, and more than 90% of patients would progress, I imagine, within 10 years. For example, we have recently presented our single arm phase 2 trial of the combination of imatinib with binimetinib at ASCO 2020, based on compelling preclinical data demonstrating synergy between the two drugs in preclinical models. The combination trial demonstrated a recessed response rate of 67% and a progression-free survival of 30 months in the front-line setting. While this is promising, I would only consider this option in the clinical trial setting for now, pending further randomized controlled trial data.

Dr Chi: Now, in addition to tyrosine kinase inhibitor treatment, we should also consider supportive care since the patient, depending on the severity of the iron deficiency, could potentially consider intravenous iron to help boost the iron stores and facilitate the recovery of anemia. In general, imatinib 400 mg once daily dosing is well-tolerated. Additionally, I would typically scan the patient every 8 weeks to confirm efficacy, and then we can stretch it out to longer, say every 3 to 4 months. When in doubt, I would also use a patch to help adjudicate responses in progression.

Dr Heinrich: Thank you. The patient was in fact treated with imatinib which was well-tolerated, and the patient fortunately had an objective response for RECIST. At this point, Dr Schöffski, would you consider surgery in a responding patient, or under what circumstances would you think about that?

Dr Schöffski: I think at this point in, this is still a very controversial issue. There are many experienced colleagues treating many GIST patients who consider surgery in responding patients, especially if the number of lesions is somewhat limited and you have a good probability that you can get rid of the majority of the malignant cells and malignant deposits. Other colleagues would prefer to continue TKI treatment until the patient stops responding to the treatment. Then the question remains, does the patient have focal progression or multifocal progression? I think the strongest evidence for surgery we have in patients with focal progression on treatment with a TKI is where we have some data showing that removal of the focal progression of the lesion seems not to be responding anymore; this can be a reasonable approach. What is important is that you continue TKI treatment after performing the type of surgery you elect to do.

Dr Heinrich: Yes; it's fortunate that randomized studies of the role of surgery combined with TKI therapy have just not been successful in either being launched or being successful in approval. In this case, after 2 years of imatinib treatment, the CT scan showed clinically relevant progression. Now, back to you, Dr Schöffski, what would be the potential causes of this imatinib resistance?

Dr Schöffski: Well, of course, we know multiple causes for imatinib resistance. What you are describing here in this case is a very typical finding. After a period of 2 to 2.5 years, patients start developing resistant lesions which are progressing on images on CT scans or on PET scans, showing increased metabolic activity. We know that there are only a few cases of GIST which show primary resistance mutations; that is very uncommon. What is much more common is secondary resistance occurring on treatment with a tyrosine kinase inhibitor, most likely due to the selective pressure on the tumor cells with effective inhibition of specific clones of the tumor. Resistance mutations are a very common phenomenon in GIST, and they are actually genetic changes that are occurring within exons and coding regions of the tyrosine kinase domains, causing a reactivation of the KIT or the PDGFRA. These changes typically occur in exons in coding for the ATP binding site, or the activation loop of the gene of the receptor.

Dr Heinrich: Now, that we have this progression and presumed resistance due to secondary mutations, what would be treatment strategies that we would consider, Dr Chi, for this patient?

Dr Chi: The treatment strategies are really 3-fold, but before that, I think while it's still investigational, but as Dr Schöffski mentioned, figuring out what type of resistance mechanisms are involved. What would be of particular importance is to know the types of secondary resistance mutations involved to imatinib therapy in this setting would be potentially significant, especially since there are many mutation specific tyrosine kinase inhibitors that can be used for treatment. In this case, for now, I would consider surgery first, as Dr Schöffski mentioned earlier, if there is limited disease progression refractory to imatinib for example, a solitary resistant deletion, or oligoclonal progression, surgery can be utilized. This would really prolong the effect of imatinib.

Dr Chi: This is more, as Dr Heinrich mentioned, there isn't randomized trial to support this at this point. However, I think in general, from a philosophical standpoint, and also common practice prolonging the utility of imatinib is key. Now, the standard of care second-line therapy includes one, dose escalation of imatinib from 400 to 600 or 800 mg, daily dosing. This is based on the long-term follow-up study that compared the 2 doses of imatinib which had demonstrated a clinical benefit of prolonging the progression-free survival by about 11 to 12 weeks; the second option would be to use the second-line and FDA approved therapy sunitinib. Sunitinib is a multi-targeted tyrosine kinase inhibitor that blocks the KIT, PDGFRA, and VEGF receptors.

Dr Chi: There was a phase 3 randomized clinical trial comparing patients on sunitinib at 50 mg, using a dosing schedule of 4 weeks on, 2 weeks off vs placebo. In this trial, results demonstrated a significant improvement in the median progression-free survival compared to placebo, and the objective response rate was only 7%. The dose tested in the clinical trial was 50 mg, once daily, 4 weeks on, 2 weeks off. At that dose, many patients suffered hand-foot syndrome, and hypertension. Following this, there was a phase 2 clinical trial comparing 50 mg, once daily dosing, 4 weeks on, 2 weeks off with a continuous building up of sunitinib to 37.5 mg once daily. Here, the data revealed better tolerability, and also equivalent efficacy. Currently, in the GIST community, the 37.5 mg once daily dosing is frequently practiced.

Dr Heinrich: I agree, but I think Dr Schöffski, you might prefer the original schedule?

Dr Schöffski: I tend to follow the original label and dosing schedule for sunitinib and start with the 50 mg dose, and give the drug 4 weeks on, 2 weeks off. Also, in my practice, I of course learned that not many patients tolerate the original schedule. There is a lot of variation to the theme; you see that patients switch early to continuous dosing at lower doses, longer intervals, longer treatment breaks. I've seen a lot of variation and I think our task is to find the dose and schedule that is suitable for the individual patient.

Dr Chi: I just wanted to mention, what's worth mentioning is in the second-line setting one should also consider clinical trials if available, which we will go into a little bit more detail. Currently, there is the INTRIGUE clinical trial comparing a new drug, ripretinib, vs sunitinib at the traditional dosing schedule, using a 1:1 randomization design.

Dr Heinrich: To continue with the case, the patient as predicted by Dr Chi, did have mild, moderate hand-foot skin reaction accompanied by some diarrhea. Fortunately, this was medically optimized with supportive care. Despite compliance after 5 months of therapy, unfortunately, progression was noted on a follow-up scan. At this point we have a patient with both imatinib and sunitinib resistant GIST. Dr Schöffski, what treatment strategies would you consider at this point?

Dr Schöffski: First of all, I would like to mention that this is a very typical evolution of such a GIST patient with an exon 11 mutation with a relatively long duration of disease control with first-line imatinib, and the unsatisfactory duration of disease control with the second-line sunitinib; this is poorly tolerated in many patients. Therefore, this is very typical and also in line with my own personal experience.

Dr Schöffski: Well, after failure of a second-line treatment with sunitinib, we would of course consider treatment with regorafenib, which is the approved standard of care in that setting.

Dr Heinrich: Regarding regorafenib, there's quite a bit of controversy concerning dosing strategies to ensure optimal tolerance. Do you have a preferred way of starting the drug?

Dr Schöffski: I, again, tend to follow the official label and the official dosing instructions, but my experience also tells me that again, many patients who start on the full dose require early dose modifications; I think that's more common practice that the exception to the rule.

Dr Heinrich: Dr Chi, what's your strategy for starting regorafenib?

Dr Chi: Initially, I think 160 mg 3 weeks on, 1 week off, however, in the trial many patients actually required a dose reduction. Additionally, there has been a recent study in the colon cancer group where regorafenib is also FDA-approved, comparing 2 dosing strategies. In that study they demonstrated that starting at a dose of regorafenib at 80 mg once daily, and with weekly escalation by 40 mg equivalent to 160 mg per day, 3 weeks on, 1 week off, really helped the patients to tolerate at least 2 cycles, and significantly more patients made it through the first cycle. Of course, in that study, they have also used additional supportive care, like using topical steroids such as clobetasol to help with the hand-foot syndrome; this is actually the current strategy that we're using now amongst most of my practice and my colleagues' practice.

Dr Schöffski: If I may add here, I think it would be a fair statement to say that every patient receiving standard second and third-line therapies require does modifications or schedule modifications, or at least the vast majority would eventually.

Dr Chi: I agree; I think in my practice, at least two-thirds of them would require those reduction.

Dr Heinrich: I think another takeaway point would be that these side effects often occur and can become severe within the first 10 days of treatment in patients who are on high dose. As a result, early intervention and early follow-up with your patients is important. You can't start the drug and tell people to come back in 4 weeks because they may not make it even 2 weeks on the dose they're prescribed. Therefore, supportive care and dose adjustments are very important when using this drug.

Dr Heinrich: Continuing on in the evolution and journey of this case. The patient did tolerate regorafenib and did require a dose reduction to 120 mg per day, which was required because of a hand-foot skin reaction, and somewhat lesser for her diarrhea. However, after 5 months of therapy, progression was noted on scan. At this point, there's a new agent we'd like to discuss. Dr Chi, could you start us off by talking about the new agent ripretinib and talk about its novel mechanism of action?

Dr Chi: Sure; ripretinib was just been FDA-approved in May of this year. It is a switch control tyrosine kinase inhibitor that binds to the switch pocket and locks the tyrosine kinase into its inactive form; it broadly inhibits those KIT and PDGFRA signaling through this dual mechanism of action. It can also potentially inhibit a broad spectrum of KIT and PDGFRA mutations, not only primary mutations, but also secondary resistance mutations in exon 13, 14, as well as 17 and 18.

Dr Heinrich: Following up on that, could you talk about the testing of the agent, and in particular the phase 3 results?

Dr Chi: Sure; ripretinib has actually demonstrated pretty promising efficacy initially in the phase 1 study with an objective response rate of about 9%. This was further confirmed in a phase 3 randomized placebo-controlled study, which included a crossover out of the placebo arm upon progression. The oral ripretinib was given 150 mg, once daily, and that's the FDA-approved the dose. In this study, called the INVICTUS study, results demonstrated a significant improvement in progression-free survival. For the ripretinib of arm, the median progression-free survival is 6.3 months, and the placebo arm showed a median progression-free survival of 1.0 month. Ripretinib therapy also demonstrated with crossover, a promising overall survival benefit, despite this not being their primary endpoint.

Dr Heinrich: Yes, I found the INVICTUS results were exciting. Dr Schöffski, would you like to comment as well?

Dr Schöffski: I agree that the data are very exciting, and this is a very important treatment option for our patients with prior exposure to other tyrosine kinase inhibitors. What I think has not been mentioned yet is that the safety profile of the drug differs a little bit from the tyrosine kinase inhibitors that we have been using over the past 20 years. There is a higher incidence of ri associated with the use of this drug. I think this is something that we should inform patients about when starting this fourth-line treatment.

Dr Heinrich: Yes, that is certainly is not medically significant, but a personally and psychologically significant side effect. I was very impressed with the INVICTUS results in terms of that there was a very low rate of dose reductions from the starting dose of 150 mg, and there was a very low rate of patients discontinuing due to side effects. I think it also was impressive from the standpoint that, in my personal opinion, I view the side effects of ripretinib as being milder and easier to manage than sunitinib and regorafenib. We, therefore, now have a fourth-line therapy that yields at least as good, or if not longer progression-free survival results compared to earlier agents, and in my opinion has fewer side effects.

Dr Heinrich: Overall, I think in our discussion of case one so far, we've highlighted that this is a very typical patient journey for a patient with KIT exon 11 mutant GIST. Some patients would not do as well as this and some would do better in terms of individual lines of therapy. Overall, we see diminishing returns with each of the lines of therapy, although interestingly, ripretinib at 6 months of progression-free survival is at least as good as what we saw in the second-line setting.

Dr Heinrich: Now, let's discuss the intrigue study, which you refer to the phase 3 study is ongoing. Accrual has been somewhat affected by the global pandemic, but we're hopeful that accrual would be completed in 2021, and that we would possibly have the results of that study later in 2021; something to look forward to because, that again, would change our paradigm of treatment.

Dr Heinrich: I'd like to shift gears now to a second case to highlight some different points relative to management of advanced GIST. This case is a 62-year-old male who presents with abdominal pain. The patient underwent upper endoscopy as well as imaging which revealed a 12-centimeter gastric mass, and unfortunately, at least 5 liver metastases were detected on imaging. The pathology showed an epithelioid GIST. At this point, Dr Schöffski, is there additional workup that we would need to consider?

Dr Schöffski: I think as in the case of patient number one that we discussed earlier, there is clearly a need for a genetic workup of the tumor material from this patient, especially because of the anatomical localization. We know that 1 in 5 gastric GISTs carry a mutation that is highly resistant to standard first-line treatment with imatinib, the PDGFRA mutation D842V. It's absolutely mandatory to have full genetic information here to exclude the possibility that it could be such a case, especially also because of the morphology of the tumor cells, the epithelioid character that you describe in the case. We want to obtain the full genetic information on the case to select the right drug for first-line treatment.

Dr Heinrich: Yes, the epithelioid nature is a big tip off that it may not respond to imatinib, so I absolutely agree. Knowing that it has a PDGFRA D842V mutation, which would be very common in the gastric GIST, what should we think about therapy wise here?

Dr Chi: Traditionally prior it's well known that PDGFRA D842V is completely resistant to imatinib. Crenolanib has been tested in the clinical setting, but more recently there's really exciting data from a phase 1 navigator study of avapritinib, a new receptor tyrosine kinase inhibitor that was specifically designed to target KIT and PDGFRA, especially the exon 17, 18 mutations, as well as the PDGFRA D842V mutant. In this phase 1 study, it demonstrated a significant overall response rate of 86%, and showed 95% of the patients with tumor shrinkage; the medium progression-free survival has not been reached. This really exciting based on this phase 1 results, avapritinib has recently been FDA-approved for the front-line setting in patients with PDGFRA D842V and other exon 18-mutant GIST.

Dr Heinrich: Dr Schöffski, I know that you've been involved in the early studies of avapritinib, would you like to additionally comment?

Dr Schöffski: Well, the only additional comment I would like to give is if you look at the waterfall plot of shrinkage of pre-identified target lesions of patients with D842V mutation in that trial, the vast majority of patients responded to this treatment with significant volume metric responses. This is significant because we have never seen before in the past 20 years of using tyrosine kinase inhibitors in GIST. This is really exciting data, and it's so important that we now have finally a treatment option for patients with this mutational variant of GIST.

Dr Heinrich: Yes, and I think it's really exciting. Over the last 20 years as we've had the TKI revolution it's been frustrating when we see patients with D842V-mutant GIST to have to say, "although you may have heard that GIST is treatable, unfortunately, the type of GIST you have is not very treatable." Now we have something that's highly active in this disease space and it's very exciting. In some ways I think it's very similar to 20 years ago when we first started developing imatinib for KIT-mutant GIST. Dr Chi, would you like to offer some concluding thoughts about the changing paradigm?

Dr Chi: Sure; I think we have come a long way of treating patients with advance GIST since the initial FDA-approval of imatinib in 2002, followed by sunitinib, regorafenib, and most recently ripretinib and avapritinib. The obvious clinical challenges that we will be facing are how to treat patients who have progressed on ripretinib or avapritinib, and how to leverage molecular data to optimize a treatment paradigm. While there has been tremendous progress, some fundamental challenges remain, and that is imatinib resistance. We know that for the majority of the patients, more than 90% of the patients can benefit from imatinib, but this benefit is not indefinite. Once their disease develops resistance to imatinib, their responses to subsequent lines of receptor tyrosine kinase inhibitor therapies, including newer generations of TKIs that we have discussed here, have really limited clinical benefit.

Dr Chi: I think the next phase of clinical investigations should focus on not only the molecular refractory setting, but also focusing on intervening early and developing therapeutic strategies to transform TKI-mediated cytostatic effects, meaning suppressing cell growth as a favorable toxic effect, which could lead to killing of cancer cells. Some of these strategies could involve novel combination therapies or outside of the box of novel therapeutic targets; for example, targeting the tumor microenvironment.

Dr Chi: On top of all of these, I think there are still significant unmet needs for the subset of patients with KIT and PDGFRA wild-type GIST. We usually include the SDH-deficient GIST mainly affecting the pediatric and young adult population with life-long mutant GIST that occurs in both the sporadic and the syndromic settings associated with neurofibromatosis 1, RAF mutations, et cetera. I think these groups of patients shall be considered differently from the KIT and PDGFRA mutant cases, and therapeutic development should be tailored to their particular genetic defects and potential molecular vulnerabilities.

Dr Heinrich: You've given us a good roadmap for the future. Dr Schöffski, do you have any additional comments?

Dr Schöffski: I think there is nothing much to add to what Dr Chi just said. My personal experience or my personal impression is that over the past 2 decades we have made tremendous progress in a disease that was untreatable until the year 2000. We have transformed this aggressive malignancy by developing and exploring a series of tyrosine kinase inhibitors in the clinic into a chronic disease status; this is really impressive. What is even more impressive is the fact that we added 2 additional lines of treatment options for GIST patients only this year. I of course hope that our treatment results will improve further in the near future by additional clinical testing and clinical trials, leading to development of new treatment strategies for GIST.

Dr Heinrich: This has certainly been a very exciting year for the GIST field, and it's been great for the international collaboration. I'd like to thank Dr Chi and Dr Schöffski for their participation. I'd like to thank the audience for participating in this educational activity. Please continue on and answer the following questions and complete the evaluation.

This transcript has been edited for style and clarity.