Bezuclastinib/Sunitinib Combination Under Evaluation in Advanced GIST

The TKI bezuclastinib (CGT9486) plus standard-of-care (SOC) sunitinib (Sutent) may become the new second-line standard treatment for patients with gastrointestinal stromal tumor (GIST) that has progressed on imatinib (Gleevec), according to Robin Jones, MD, MRCP, and Neeta Somaiah, MD.

The randomized phase 3 Peak trial (NCT05208047) is evaluating the efficacy and safety of bezuclastinib plus sunitinib vs sunitinib alone in patients with GIST. Part 2 of this trial, which is open for enrollment, will investigate the combination in patients who have progressed on or are intolerant to imatinib.¹

Part 1 of Peak investigated the combination in patients with GIST who had received at least 1 prior line of therapy.² Findings from part 1 presented at the 2023 ASCO Annual Meeting demonstrated a disease control rate (DCR), defined as stable disease or better at 16 weeks, of 54.8% including a partial response rate of 12.9% and a 100% DCR in the efficacy-evaluable second line patients who had received prior imatinib only. Furthermore, most adverse effects (AEs) observed with the combination were grade 1/2 and reversible, and few patients required dose reductions or treatment discontinuations because of AEs.

“From a study design standpoint, it’s in the patients’ best interest to be offered this study,” Somaiah said in an interview with OncLive^®.

“For patients, the opportunity to have a novel treatment earlier in the treatment of advanced disease is probably better,” Jones added in the interview.

In the interview, Jones and Somaiah discussed the rationale for the Peak trial, findings seen so far with bezuclastinib plus sunitinib in patients with GIST, and the importance of raising awareness about the unique benefits of this trial’s design.

Jones is a consultant medical oncologist, a professor of medical oncology, and the head of the Sarcoma Unit at The Royal Marsden NHS Foundation Trust in London, United Kingdom. Somaiah is an associate professor and the deputy department chair of the Department of Sarcoma Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: Could you describe the clinical need in the GIST population that led to the development of the Peak trial?

Somaiah: We are making advances in the treatment of patients with metastatic GIST. However, we are running into trouble where patients, once they progress on imatinib, develop a variety of resistance mechanisms, some early and some as secondary resistance. Once they develop those mechanisms of resistance, [their treatment] becomes increasingly challenging because subsequent therapies tend not to last or provide as much long-term benefit, [so we] run out of treatment options.

The focus of the research community has been: How do we target these resistance mutations better to get more long-term benefit, even past imatinib. [In the past, we have tried different combinations of] TKIs, but now with more specific inhibitors, it has become feasible to [investigate this combination] because the targeted inhibitors don’t have as many overlapping toxicities, and hence can be combined more easily. That’s what we’re seeing, and that’s what led to the Peak study.

Jones: Very often, single-agent TKIs don’t result in durable clinical benefit for patients. The early clinical data that led to the Peak trial show promise regarding the efficacy and tolerability of using combination therapy. That’s a bonus, and many oncologists have been heartened by that, particularly given the challenges sometimes in administering sunitinib and the toxicity that can be experienced. The initial data regarding the combination [of bezuclastinib and sunitinib] have been published in JAMA Oncology.3 This was a nonrandomized clinical trial, but it showed that it was safe to co-administer the 2 drugs, and the promising efficacy data have led to the development of the Peak trial, [which is] randomizing [patients to] combination therapy vs sunitinib [monotherapy].

Somaiah: KIT exon 11 mutations [are] 1 of the most common mutations in patients with GIST. Approximately 60% to 70% [of patients with GIST] have exon 11 mutations in KIT. [Most of these patients], once they develop resistance to imatinib, [tend to develop] clones with additional mutations, usually in exons 13 or 17, but [clones are] also seen in exons 14 and 18. [Of] the subsequent treatments that we currently have as SOC, some, such as sunitinib, target exon 13 secondary mutations well, but don’t target exon 17 as well. Then, we have subsequent lines [of therapy, such as] regorafenib [Stivarga] and ripretinib [Qinlock], that have shown that they might have a predilection for targeting exon 17 mutations.

Sometimes, patients might have combination mutations, not just 1. They could have multiple secondary mutations. The need for this combination that has been in the field for a long time has been to try and broaden the inhibition of the variety of mutations we see in these patients. [The phase 1b/2a trial included] a small number of patients, but it showed that [bezuclastinib], a more specific inhibitor of exon 17, can be combined safely with sunitinib. That was a big step forward, [indicating that] we can [administer] this combination and maybe get broader coverage. There were hints of efficacy in that small group. Some patients [who benefited from this combination] were heavily pretreated and had previously progressed on sunitinib.

Jones: That point regarding broad coverage is important in patients with advanced disease, given the heterogeneity and the need to cover a broad range of resistance mutations.

What distinguishes the new formulation of bezuclastinib from the old formulation that was tested in the phase 1b/2a trial, findings from which were published in JAMA Oncology?

Somaiah: The initial formulation that was tested required patients to take many pills for the dose that was tested. The new formulation [is also] oral, but the way it’s formulated, [patients need to take fewer pills]. The active ingredient is the same, but the formulation, the way it’s made to get a higher dosage is different.

Jones: In terms of the practicalities and being pragmatic, the essential point to take home is that [the new formulation of bezuclastinib is] easier to take.

What are the design and methods of Peak?

Somaiah: [Peak is being conducted in] 2 different parts. Part 1, because of the newer formulation [of bezuclastinib], was run almost like a phase 1a/1b trial [using] a dose-escalation strategy where the investigators tried a lower dose of bezuclastinib along with sunitinib. The dose escalation for bezuclastinib was up to the target dose of 600 mg daily, along with sunitinib at 37.5 mg daily.

This study is using the 37.5 mg daily dosing of sunitinib, which is a preference for most oncologists who treat patients with GIST because it gives more continuous coverage. We realize the 50-mg dose is difficult to tolerate, so that’s an accepted continuous dosing strategy that we have used. Even if [patients] start with 50 mg, many times in clinical practice, we reduce the dose and try to keep them on [therapy] continuously.

Part 1a was the dose-escalation part. In part 1b, the strategy was starting 1 drug for 2 weeks and then introducing the other drug, so they could study how 1 drug might affect the pharmacokinetics of the other drug. In part 1a and 1b, all patients got both drugs.

Jones: Part 2 is the randomized component of the trial, with progression-free survival as the primary end point. The trial randomizes patients pretreated with imatinib to receive either the combination of sunitinib and bezuclastinib or sunitinib alone.

Somaiah: Previously, [in the] part 1a and part 1b portion, patients [received multiple prior lines of therapy]. However, we’re now in the randomized phase, which is post-imatinib. Patients should have only had 1 prior line of therapy. It’s a nice design that even the investigators like because [although] it randomizes patients to either get a single agent or a combination, there is a crossover, so if a patient does not end up on the combination [arm with the] new drug initially, if they progress on sunitinib, they can cross over [to receive bezuclastinib].

Jones: That’s an important point for patients, as well as important regarding recruitment to the trial, because [all enrolled] patients have access to the novel agent.

What barriers to enrollment do you expect with this trial, and does the fact that this is a second-line trial affect potential enrollment challenges?

Somaiah: All of us have patients in our practice who are on imatinib. They are followed, and if they progress, if it’s focal, we sometimes have other strategies, such as local treatments. Once they progress truly with more diffuse disease, we’re offering them this study.

However, GIST is a sarcoma that is easier to treat because there are first-, second-, third-, and fourth-line treatments that are already SOC. Often in the community, patients get exposed to some of these drugs. Sometimes they’re exposed to these drugs in the wrong order. If they go past imatinib, they won’t be eligible for the study, and they will lose out on the chance for this added line targeting their tumors. That’s 1 of the biggest challenges.

In the United Kingdom, [enrollment] might be a little less disjointed, but in the United States [US], we have so many sites and community centers, and patients can be treated anywhere. Trying to streamline them to an available trial can be a challenge. Beyond that, when part of a study, patients need to travel. The study provides some travel support in the US, so that makes that a little easier [for patients to] come in every couple weeks for their protocol-scheduled appointments.

Jones: The fact that there are so many community oncology practices [in the US] can be a challenge regarding patients receiving other treatments and not being considered for the trial. The geography can [make it] difficult for patients to travel to centers to receive treatment within a clinical trial. I’m optimistic that recruitment will be relatively good and rapid. Many other second-line trials have recruited well recently, and everybody’s excited about this trial and the use of combination therapy. Part of it is communication and spreading the word about the trial and the fact that it gives patients another novel option in the second-line setting.

Somaiah: We saw at the 2023 ASCO Annual Meeting [and are noticing as we enroll patients in the trial] that the safety profile is well tolerated. [Patients are not] getting placebo. They’ll either get sunitinib, which is the next-line SOC, or they might get the combination. If they [are enrolled in] the single-agent arm, they still have the option of crossing over if they progress. Hopefully, by spreading the word and [letting people know] about this second-line option, we can ensure that patients are offered [this trial] and more patients can get access to it.

Jones: Everybody’s excited that the combination is well tolerated. [It also targets a broad range of] resistance mutations. It’s exciting and important that we let everybody know about this trial. The fact that there is crossover means it’s a good choice for patients.

What stood out about the findings from part 1 of Peak?

Somaiah: [The investigators] escalated the dose up to 600 mg of bezuclastinib with 37.5 mg of sunitinib. The safety profile was not different from [the expected safety profile of] sunitinib alone. [Although sunitinib] wasn’t the comparator, both the parts 1a and 1b safety data were tolerable.

We saw some amount of grade 3 hypertension. This is why knowing the AE profile and being aggressive at managing it early is important. We saw some cytopenias that we’ve seen with sunitinib alone, but the rate was not high. [The safety profile was well tolerated in] my own experience [of treating patients] as well. Early data [showed] signals of efficacy as well. It was exciting to see the data put together.

Jones: The safety and tolerability of the combination are promising. Everybody’s excited about that.

What are the next steps for this research?

Somaiah: Crossing the finish line with this study will be important. It will change the way we sequence drugs. [If the trial is positive, bezuclastinib plus sunitinib] will probably be the first combination treatment. That would be exciting.

The field in general is moving toward recognizing the heterogeneity of secondary mutations. Those data are also being collected as part of the study because it’s important to [understand which] patients are responding and [which] patients are not responding and see what in their tumor profile we need to work on in future lines. This would open the door for combination [therapies for GIST] and investigating specific mutations.

Jones: The first step is to get the trial done, to complete enrollment and get the results. If the trial is positive, it will change our treatment approach to advanced GIST and result in a change in the SOC. It will also open the door regarding the feasibility of combination therapy and potentially combination therapy in different settings and for different molecular subgroups of GIST. Advanced GIST becomes increasingly heterogeneous and complex in its mutational profile. This trial is a starting point for combination therapy and trying to get that broad coverage of mutational heterogeneity.

What is your main message for your academic and community partners regarding this research?

Somaiah: If you have patients with GIST and they’re on imatinib but have a disease burden that is stable to slowly progressing, reach out to a center that’s close to you that has the study open. [Oncologists] worry when patients are progressing on imatinib and need to get to [different] centers. They usually like to start a new [regimen].

One strategy that I have told oncologists is they could escalate the dose of imatinib if [the patient is] tolerating it well. Put them on [twice-daily dosing] and send them to us so we can figure out whether this trial will be the right fit for them. We can partner with them and ensure the patient, if they go on the study or not, can transition back to their oncologist at home. Keep this in mind, so if your patients are getting close to the point where you’re worried about how well their disease is controlled with imatinib, we can start plugging them in.

Jones: The major thing is communication between academic centers and community oncologists. It’s always good to reach out and contact academic centers regarding clinical trials, [including] this trial and other trials in GIST, because now is an exciting time with several promising novel agents and novel approaches in GIST. That communication is important. It’s always good to offer patients the opportunity to have access to a novel treatment. Reach out and ask whether there is a trial for patients with disease progression. Patients will also appreciate the opportunity to receive a new drug and increase their number of treatment options.

Somaiah: We haven’t had a frontline study [in GIST], except some small ones. However, there was a time when there was a dearth of studies for GIST, and now, there are many. It’s good to get the word around that GIST studies are out there, so [community oncologists can] contact academic centers sooner rather than later. If [patients get] broader coverage [with a regimen] and can stay on the same agent for longer, that helps morale, rather than needing to switch from 1 drug to the other, [which makes them] feel like they’re running out of options.

Jones: Other trials are in the pipeline. It’s an exciting time. It’s important to have early communication and be able to offer patients as many options as possible, increasing the number of [available] lines of therapy.

Somaiah: If patients don’t end up [enrolling in this trial for their] second-line [treatment], we still have options after.

Jones: There’s been a dearth of clinical trials over the past few years, but now, [the landscape is] changing. Communication is crucial.

Somaiah: [GIST] is a rare disease, so I don’t expect [oncologists] to be on top of the trials in GIST. Sharing information through patient advocacy sites is also helpful because sometimes patients are empowered with the knowledge themselves and ask [about trials].

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

References

1. (Peak) a phase 3 randomized trial of CGT9486+sunitinib vs. sunitinib in subjects with gastrointestinal stromal tumors. ClinicalTrials.gov. Updated August 22, 2023. Accessed August 28, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05208047
2. Tap WD, Wagner AJ, Bauer S, et al. Safety, pharmacokinetics (PK), and clinical activity of bezuclastinib + sunitinib in previously-treated gastrointestinal stromal tumor (GIST): results from part 1 of the phase 3 Peak study.J Clin Oncol. 2023;41(suppl 16):11537. doi:10.1200/JCO.2023.41.16_suppl.11537
3. Wagner AJ, Severson PL, Shields AF, et al. Association of combination of conformation-specific KIT inhibitors with clinical benefit in patients with refractory gastrointestinal stromal tumors: a phase 1b/2a nonrandomized clinical trial. JAMA Oncol. 2021;7(9):1343-1350. doi:10.1001/jamaoncol.2021.2086