Dr Jones on Communication Between Community and Academic Oncologists in Cancer Care

Robin Jones, MD, MRCP, consultant medical oncologist, professor, Medical Oncology, head Sarcoma Unit, The Royal Marsden NHS Foundation Trust, discusses the importance of communication between community and academic oncologists in cancer care, highlighting the impact of multidisciplinary communication.

Effective communication between academic centers and community oncologists holds paramount importance, particularly in the landscape of gastrointestinal stromal tumor (GIST) research, Jones begins. The nature of GIST calls for community oncologists to proactively engage with academic institutions to explore available clinical trials that encompass the spectrum of promising novel agents and treatment approaches emerging in the field of GIST management, he states.

The evolving treatment paradigm presents an opportunity to offer patients innovative treatments, making it essential to initiate discussions about clinical trial participation, especially for those experiencing disease progression, he explains. For instance, 

the phase 3 Peak trial (NCT05208047) is investigating the TKI bezuclastinib

 (CGT9486) in combination with sunitinib (Sutent) vs sunitinib monotherapy in patients with GIST. However, part 2 of this trial is not open to patients who have received therapies beyond first-line imatinib (Gleevec), which highlights the importance of clinical trial awareness when considering treatment sequencing for patients with GIST.

, including the Peak regimen under investigation, may broaden the range of treatment options available to patients, he explains. However, despite the optimistic trajectory of current developments, challenges persist. The prevalence of community oncology practices, although beneficial for widespread health care access, poses logistical challenges for patients seeking trial participation at the academic centers Jones says. Geographical constraints may impede some patients from traveling to specialized centers offering treatments through clinical trials, he notes. Jones goes on to say that, nevertheless, there is a positive outlook regarding recruitment to the Peak trial that draws inspiration from previous successes in enrolling patients in other second-line trials.

Recognizing the historical scarcity of clinical trials in the GIST landscape, the current surge in opportunities signifies a turning point in treatment, he continues. The excitement surrounding ongoing trials and their innovative combination therapy approaches underscores the importance of effective communication regarding these trials, he imparts. Proactively spreading awareness about trials within the medical community and among patients and health care providers can illuminate the potential for a novel second-line treatment for patients with GIST. This multifaceted approach aims to bridge the communication gap between academic and community settings as well as address logistical challenges, ultimately contributing to the successful execution and impact of clinical trials, Jones concludes.

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Robin Jones, MD, MRCP, discusses the importance of communication between community and academic oncologists in cancer care.

Dr Marquina on the Importance of Referring Patients With GIST to Specialized Sarcoma Centers

Gloria Marquina, MD, PhD, Department of Medical Oncology, Hospital Universitario Clinico San Carlos, discusses the importance of referring patients with sarcoma to specialized centers, as well as the need to consider ongoing clinical trials for patients with gastrointestinal stromal tumors (GIST) vs treatment with the current second-line standard-of-care (SOC) agent sunitinib (Sutent).

GIST is a rare form of soft tissue sarcoma of the gastrointestinal tract that is characterized by high rates of malignant transformation. Patients diagnosed with sarcomas, especially GIST, should be directed to a specialized sarcoma center for treatment, Marquina begins. The primary benefit of referral is that patients will then undergo a comprehensive evaluation by an expert multidisciplinary team, ensuring an individualized and holistic approach to treatment, Marquina explains. Marquina and her colleagues at the sarcoma referral center in Hospital Universitario Clinico San Carlos are focused on providing each patient with personalized treatments that account for their unique needs while adhering to the established SOCs and guidelines for sarcoma.

Regarding the treatment of patients with GIST, sunitinib is considered the conventional second-line therapy for those who either cannot tolerate or experience disease progression on the TKI imatinib (Gleevec), Marquina continues. The medical oncology community widely acknowledges that patients may have access to emerging treatment options on a clinical trial that are not otherwise available to them. Accordingly, medical and community oncologists should stay informed about ongoing clinical trials that might provide their patients with alternative treatment choices in the second line, and they should reach out to a GIST specialist, if necessary, Marquina concludes. 

Gloria Marquina, MD, PhD, as well as the need to consider ongoing clinical trials for patients with gastrointestinal stromal tumors vs treatment with the current second-line standard-of-care agent sunitinib. 

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.

Part 1 of Peak investigated the combination in patients with GIST who had received at least 1 prior line of therapy.

 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 

“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.

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

: 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.

: 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 

.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].

 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 

. [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.

: 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 

: 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.

: 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.

: [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.

: 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.

: 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].

: 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?

: 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.

: 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.

: 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.

: 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?

: [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.

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

What are the next steps for this research?

: 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.

: 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?

: 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.

: 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.

: 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.

: 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.

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

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

: [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.

(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

Tap WD, Wagner AJ, Bauer S, et al. Safety, pharmacokinetics (PK), and clinical activity of bezuclastinib + sunitinib in previously-treated gastrointestinal stromal tumor (GIST): 

esults from part 1 of the phase 3 Peak study.

. 2023;41(suppl 16):11537. doi:10.1200/JCO.2023.41.16_suppl.11537

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. 

. 2021;7(9):1343-1350. doi:10.1001/jamaoncol.2021.2086

Articles

The TKI bezuclastinib plus standard-of-care sunitinib may become the new second-line standard treatment for patients with gastrointestinal stromal tumor that has progressed on imatinib.

Bezuclastinib/Sunitinib Combination Under Evaluation in Advanced GIST 

Neeta Somaiah, MD, associate professor, deputy department chair, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses enrollment criteria for the phase 3 Peak trial (NCT05208047) in patients with gastrointestinal stromal tumor (GIST) and the advantages of this trial’s design.

The Peak trial is investigating bezuclastinib (CGT9486) in combination with sunitinib (Sutent) vs sunitinib alone in patients with GIST. The first portion of part 1 of this trial enrolled patients who had received at least 1 prior line of therapy for GIST. The second evaluation of part 1 enrolled patients who had received at least 2 prior TKIs for GIST. Part 2 of this trial is enrolling patients who progressed on or are intolerant to imatinib.

Many patients with GIST receive imatinib (Gleevec) in the first line and may switch to local treatment options upon local progression, Somaiah says. Patients who progress with more diffuse disease may be eligible for enrollment in the Peak trial, Somaiah notes. GIST is a relatively easier-to-treat sarcoma because it has standard first-, second-, third-, and fourth-line therapeutic options, which patients may be referred to upon progression on imatinib, according to Somaiah. However, community oncologists should consider the Peak trial before prescribing standard lines of therapy beyond imatinib. Patients with GIST who receive treatment beyond imatinib are not eligible for enrollment in Peak and lose the chance to receive an additional line of targeted therapy, Somaiah emphasizes.

Data from part 1 of Peak, which were presented at the 2023 ASCO Annual Meeting, showed that bezuclastinib plus sunitinib was well tolerated, Somaiah notes. The safety profile of this combination supports further enrollment in this trial, Somaiah says.

Additionally, even patients in the Peak trial who are not randomly assigned to receive the investigative combination will receive sunitinib monotherapy in the control arm, Somaiah explains. This trial is distinct from placebo-controlled trials because it offers patients standard benefits in both arms, Somaiah emphasizes. Furthermore, patients who are randomly assigned to receive sunitinib monotherapy may have the option of crossing over to the investigative arm upon disease progression, Somaiah notes. Raising awareness about the advantages of this second-line trial can help more patients access a potentially beneficial treatment combination, Somaiah concludes.

Neeta Somaiah, MD, discusses enrollment criteria for the phase 3 Peak trial in patients with gastrointestinal stromal tumor and the advantages of this trial’s design.

Dr Somaiah on the Peak Trial in GIST

The combination of bezuclastinib (CGT9486, formerly PLX9486) and sunitinib (Sutent) had a tolerable safety profile and demonstrated early signals of clinical activity in patients with gastrointestinal stromal tumor (GIST), according to early findings from part 1 of the phase 3 Peak trial (NCT05208047), which were presented at the 2023 ASCO Annual Meeting.

Most treatment-emergent adverse effects (TEAEs) seen with the combination were low grade and reversible, and there was a low rate of adverse effects (AEs) of grade 3 or higher.

“The combination does not appear to be adding to the overall frequencies or severity of risk known to be associated with single-agent sunitinib,” William D. Tap, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, stated in a poster presentation.

 mutations are found in approximately 80% of patients with GIST at diagnosis, most frequently in exons 11 and 9. Although the TKI imatinib (Gleevec) inhibits the primary

 mutations, 60% of GIST tumors develop resistance to imatinib within 2 years of treatment.

The investigational TKI bezuclastinib inhibits 

 Sunitinib, another TKI approved for the management of GIST, targets 

 mutations in exons 9, 11, 13, and 14. Thus, the combination of bezuclastinib and sunitinib targets the full spectrum of primary and secondary mutations in GIST.

Furthermore, in a phase 1/2 trial (NCT02401815), patients with relapsed/refractory GIST who had received a median of 3 prior lines of therapy who received the combination of bezuclastinib and sunitinib experienced clinical benefit, and the combination had an acceptable safety profile.

The objective of part 1a, which has completed enrollment, was to identify the dose for the optimized formulation of bezuclastinib in combination with sunitinib that achieved target drug exposures defined based on previous Phase 1/2 clinical data with bezuclastinib and sunitinib in patients with GIST. The primary end point of part 1a was to determine the pharmacokinetics of bezuclastinib. The objective of part 1b, which has completed enrollment, was to characterize the potential interactions between bezuclastinib and sunitinib, with primary end points of determining the pharmacokinetics of bezuclastinib and sunitinib, and the primary active metabolite of sunitinib. The objective of part 2, which is open for enrollment, is to determine the efficacy of bezuclastinib plus sunitinib vs sunitinib alone, with a primary end point of progression-free survival per mRECIST v1.1 criteria.

Part 1a of Peak was an optimized formulation lead-in with 19 patients. Cohort 1 (n = 5) received bezuclastinib at 300 mg once daily plus sunitinib at 37.5 mg once daily. Cohort 2 received bezuclastinib at 600 mg once daily plus sunitinib at 37.5 mg once daily. The expansion cohort (n = 9) also received bezuclastinib at 600 mg once daily plus sunitinib at 37.5 mg once daily, which was selected as the dose for parts 1b and 2, which will be conducted in parallel. In all part 1a cohorts, sunitinib treatment began on day 2. Part 1b, which enrolled approximately 20 patients, investigated bezuclastinib or sunitinib as monotherapy for 2 weeks followed by bezuclastinib plus sunitinib. Part 2, which aims to enroll 388 patients, is randomly assigning patients 1:1 to receive either bezuclastinib plus sunitinib at the selected dose or sunitinib monotherapy at 37.5 mg daily.

Patients with histologically confirmed GIST with at least 1 measurable lesion per mRECIST v1.1 criteria are eligible to enroll in Peak. Patients are required to have locally advanced, unresectable, or metastatic disease; documented disease progression on or intolerance to imatinib, and an ECOG performance score of 0 to 2. Part 1a enrolled patients who had received at least 1 prior line of therapy. Part 1b enrolled patients who had received at least 2 prior TKIs. Part 2 is enrolling patients who have received imatinib as their only prior therapy for GIST.

At a data cutoff date of March 29, 2023, 39 total patients had been treated in part 1: 19 patients in part 1a and 20 patients in part 1b. In part 1a, 5 patients received a starting dose of bezuclastinib at 300 mg daily, 3 of whom elected to increase their dose to 600 mg daily, and 14 patients received bezuclastinib at 600 mg daily. In part 1b, patients were randomly assigned to receive bezuclastinib at 600 mg daily or sunitinib at 37.5 mg daily for 2 weeks, followed by combination therapy with bezuclastinib plus sunitinib. Of the patients treated in part 1, 25 remained on the study treatment as of the data cutoff date.

In total, 17.9% (n = 7), 28.2% (n = 11), and 53.8% (n = 21) of patients in part 1 had received 1, 2, and at least 3 prior TKIs. Additionally, 23.1% (n = 9) and 87.2% (n = 34) of patients had received prior radiotherapy and prior anticancer surgery, respectively. The primary tumor locations at diagnosis included the stomach (20.5%; n = 8), small intestine (56.4%; n = 22), and other abdominal locations (23.1%; n = 9). Patients in part 1 had primary mutations in exon 9 (23.1%; n = 9), exon 11 (69.2%; n = 27), and other or unknown locations (10.3%; n = 4). One patient in part 1b had primary mutations in both exon 9 and exon 11.

The most common any-grade TEAEs of all causalities were diarrhea (44%), fatigue (41%), nausea (33%), hair color changes (23%), hypertension (21%), taste disorder (21%), GERD (18%), abdominal pain, headache, and rash (each in 15%). In part 1a, the most common TEAEs of grade 3 or higher were diarrhea and hypertension (each in 11%). In part 1b, the most common TEAE of grade 3 or higher was hypertension (10%).

The most common any-grade laboratory TEAEs were neutropenia and increased aspartate aminotransferase (AST)(each in 39%), increased alanine transaminase (ALT) and decreased white blood cell (WBC) counts (each in 36%), anemia (21%), hypophosphatemia (18%), increased blood creatinine levels, hyponatremia, and thrombocytopenia (each in 15%). In part 1a, the most common laboratory TEAEs of grade 3 or higher were increased AST, anemia, and thrombocytopenia, occurring in 5% of patients each. In part 1b, the most common laboratory TEAEs of grade 3 or higher were neutropenia (10%), increased ALT and decreased WBC counts (each in 5%).

TEAE-related dose reductions of any study drug occurred in 23% (n = 9) of patients. Treatment discontinuations because of TEAEs occurred in 2 patients, 1 with grade 2 rash and 1 with grade 1 abdominal pain and grade 3 diarrhea.

Two patients experienced serious AEs that were possibly associated with the study drugs. One of these patients had grade 2 decreased neutrophil counts and pyrexia, as well as grade 3 decreased platelet counts, and the other patient had grade 2 bacterial peritonitis and grade 3 febrile neutropenia.

Regarding pharmacokinetics, the steady state exposure of bezuclastinib increased in an approximately dose-proportional manner from 300 mg to 600 mg after once-daily administration of bezuclastinib and 37.5 mg of sunitinib.

“Part 1a data support the selection of 600 mg bezuclastinib and 37.5 mg sunitinib as the dose for part 1b and part 2 of the Peak study,” Tap said.

Of the efficacy evaluable subset of patients in part 1 who had received either prior imatinib only (n = 6) or at least 2 prior TKIs (n = 25), the disease control rate (DCR) was 54.8% (n = 17/31), including a 100.0% DCR in the prior imatinib only group, which is the population being enrolled in part 2 of Peak, and a 44.0% (n = 11) DCR in the 2 or more prior therapies group. In total, 12.9% (n = 4), 71.0% (n = 22), and 16.1% (n = 5) of patients achieved best overall responses of partial response (PR), stable disease (SD), and progressive disease (PD), respectively. In the group of patients with prior imatinib only, the PR, SD, and PD rates were 16.7% (n = 1), 83.3% (n = 5), and 0%, respectively. In the group of patients with at least 2 prior TKIs, the PR, SD, and PD rates were 12.0% (n = 3), 68.0% (n = 17), and 20.0% (n = 5), respectively. The median time to response was 4.2 cycles (range, 2.0-8.0). 

“Although not mature enough to estimate median progression-free survival, the efficacy data obtained thus far support potential for durable disease control in imatinib-resistant GIST, including heavily pretreated tumors,” Tap concluded.

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 

Gramza AW, Corless CL, Heinrich MC, et al. Resistance to tyrosine kinase inhibitors in gastrointestinal stroma tumors. 

. 2009;15(24):7510-7518. doi:10.1158/1078-0432.CCR-09-0190

The combination of bezuclastinib and sunitinib had a tolerable safety profile and demonstrated early signals of clinical activity in patients with gastrointestinal stromal tumor. 

Bezuclastinib Plus Sunitinib Shows Encouraging Safety and Efficacy Profile in R/R Second-Line GIST

Combination therapy targeting multiple exons where mutations commonly develop in gastrointestinal stromal tumor (GIST) may represent a promising treatment approach to increase efficacy when patients develop resistance to therapies such as imatinib (Gleevec).

 mutations, which are present in approximately 70% of patients with GIST,

 encompass imatinib in the first line, sunitinib (Sutent) in the second line, regorafenib (Stivarga) in the third line, and ripretinib (Qinlock) in the fourth line. Despite having several therapies available including the 

 inhibitor imatinib, approximately 50% of patients will develop resistance following 2 years of imatinib treatment.

 mutations are most frequently found in exons 9 or 11 of tumors, resistance to imatinib which is driven by additional mutations involving the ATP binding domain exons 13/14 or activation loop exons 17/18, requires agents to target several mutations.

“Approximately 60% to 70% [of patients with GIST] have exon 11 mutations in 

. [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,” Neeta Somaiah, MD, explained in an interview with 

. 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.

“[Of] the subsequent treatments that we currently have as standard of care, some, such as sunitinib, target exon 13 secondary mutations well, but don’t target exon 17 as well,” she noted. “Then, we have subsequent lines [of therapy, such as] regorafenib and ripretinib, that have shown that they might have a predilection for targeting exon 17 mutations.”

As secondary mutations can occur for many patients, combination treatment regimens targeting a variety of mutations remain key areas of research. The investigational tyrosine kinase inhibitor (TKI) bezuclastinib (CGT9486) targets KIT exons 9, 11, 17, and 18 and sunitinib inhibits KIT exons 9, 11, 13, and 14, ensuring all primary and secondary mutations are targeted.

 The phase 3 Peak trial (NCT05208047) aims to evaluate this combination in the second line, with part 1a and part 1b already complete, and part 2 currently enrolling patients.

“It has become feasible to [investigate the combination] because targeted inhibitors don’t have as many overlapping toxicities, hence, they can be combined more easily. That’s what we’re seeing, and that’s what led to the Peak study,” Somaiah said, adding that the phase 1b/2a portion of the trial included “a small number of patients, but 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.”

Robin Jones, MD, MRCP, added in an interview with 

 that because “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.”

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.

Early Data Sets the Stage for Peak Part 2

Findings from part 1 of the Peak trial presented at the 2023 American Society of Clinical Oncology Annual Meeting demonstrated the clinical activity and tolerable safety profile of the bezuclastinib plus sunitinib combination in patients with GIST.

Data from part 1a and part 1b revealed that patients who received prior TKI therapy with imatinib only (n = 6) experienced a disease control rate (DCR) of 100.0% and patients who previously received 2 or more prior TKI therapies (n = 25) achieved a DCR of 44.0%; the total DCR was 54.8%. As of the March 29, 2023, data cutoff, in the imatinib only group 1 patient had an unconfirmed partial response (PR), the stable disease (SD) rate was 83.3%, and no patients experienced progressive (PD). Of those who received 2 or more prior therapies, 12.0% had a PR, 68.0% had SD, and 20.0% experienced PD.

The most common any grade treatment-emergent adverse effects (AEs) that occurred in the part 1a safety population (n = 19) and part 1b safety population (n = 20) were diarrhea (58% vs 30%), fatigue (53% vs 30%), nausea (47% vs 20%), neutropenia (47% vs 30%), increased aspartate aminotransferase (47% vs 30%), increased alanine transaminase (42% vs 30%), decreased white blood cell count (37% vs 35%), respectively. Grade 3 events occurring in more than 1 patient included diarrhea (11% vs 0%), hypertension (11% vs 10%), and neutropenia (0% vs 10%), respectively.

Importantly, it was noted that the combination therapy did not appear to add to the severity of AEs associated with sunitinib monotherapy; there were limited dose reductions (9/39) due to AEs and only 2 patients discontinued treatment due to AEs which included a patient with grade 2 rash and a patient with grade 1 abdominal pain as well as a grade 3 diarrhea.

“The safety and tolerability of the combination are promising,” Jones said. Somaiah added that “we saw some grade 3 hypertension [which] 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 estimated enrollment of the randomized, open-label, part 2 portion of the trial is 388 patients.4 Patients will be assigned 1:1 to receive either combination therapy with bezuclastinib and sunitinib or sunitinib monotherapy. Sunitinib will be given at 37.5 mg once daily with or without bezuclastinib given at the selected starting dose of 600 mg once daily. Bezuclastinib will be administered in its optimized formulation that was used in part 1a and 1b which has improved bioavailability and was developed to reduce pill burden.

“The active ingredient is the same but the formulation—the way it’s made to get a higher dosage—is different,” Somaiah explained.

Part 2 of the trial will include patients with locally advanced, unresectable, or metastatic GIST who are intolerant to or have failed prior treatment with imatinib only. The international, multicenter trial is enrolling patients with at least 1 measurable lesion according to mRECIST 1.1 criteria and an ECOG performance status of 0 to 2. The study will be opening and recruiting at 130 study locations globally.

Those with PDGFR driving mutations or succinate dehydrogenase deficiency; clinically significant cardiac disease; active, uncontrolled, systemic bacterial, fungal, or viral infections at screening; and gastrointestinal abnormalities that would preclude adequate absorption will be excluded from the study. Additionally, patients who are seropositive for HIV 1 or 2 or positive for hepatitis B surface antigen or hepatitis C virus antibody; have active bleeding; received a major surgery within 4 weeks of the first study dose; received strong CYP3A4 inhibitors or inducers; or received prior anti-cancer therapy other than imatinib are ineligible as well.

“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,” Somaiah said. “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 plus sunitinib].”

“Crossing the finish line with this study will be important,” Somaiah said. “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,” Somaiah continued. “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 added that communication between academic centers and community oncologists is key moving forward. “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.”

Khosroyani HM, Klug LR, Heinrich MC. TKI Treatment sequencing in advanced gastrointestinal stromal tumors. 

. 2023;83(1):55-73. doi:10.1007/s40265-022-01820-1.

Hu X, Wang Z, Su P, Zhang Q, Kou Y. Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors. 

. 2022;12:933248. doi:10.3389/fonc.2022.933248.

(Peak) a phase 3 randomized trial of CGT9486+sunitinib vs. sunitinib in subjects with gastrointestinal stromal tumors. ClinicalTrials.gov. Updated August 22, 2023. Accessed September 19, 2023. bit.ly/45XYdBj

Combination therapy targeting multiple exons where mutations commonly develop in gastrointestinal stromal tumor may represent a promising treatment approach to increase efficacy when patients develop resistance to therapies such as imatinib.

Dual Inhibition With Bezuclastinib/Sunitinib Aims to Fill an Unmet Need in GIST 

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, sponsored by Cogent Biosciences, we had the pleasure of speaking with Robin Jones, MD, MRCP, and Neeta Somaiah, MD, about the phase 3 Peak trial (NCT05208047) in patients with gastrointestinal stromal tumor (GIST). Dr 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. Dr 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.

The 2-part Peak trial is evaluating the TKI bezuclastinib (CGT9486) plus sunitinib (Sutent) vs sunitinib alone in patients with GIST. The first evaluation of part 1 included patients who had received at least 1 prior line of therapy for GIST. The second evaluation of part 1 included patients who had received at least 2 prior TKIs for GIST. Part 2 of this trial is enrolling patients with disease progression on or intolerance to the TKI imatinib (Gleevec).

In our exclusive interview, Drs Jones and Somaiah discussed unmet needs in GIST that the Peak trial seeks to answer; the advantages of the methods and design of this trial; and how the tolerable safety profile of bezuclastinib plus sunitinib supports further research with this combination.

That’s all we have for today! Thank you for listening to this episode of 

, sponsored by Cogent Biosciences. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

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Drs Jones and Somaiah discuss unmet needs in GIST that the Peak trial seeks to answer; the advantages of the methods and design of this trial; and how the tolerable safety profile of bezuclastinib plus sunitinib supports further research with this combination.