Bezuclastinib/Sunitinib Shows Early Promise in Second-Line GIST

Antonio Ucar, MD

Relapse after frontline treatment with imatinib (Gleevec) is common in patients with gastrointestinal stromal tumors (GIST) because of secondary KIT mutations, according to the investigators of the phase 3 Peak study (NCT05208047). However, the exploration of a novel second-line combination, bezuclastinib (PLX 9486) plus sunitinib (Sutent), may be safe and effective in these patients.¹

Phase 1a findings from the study were presented in June at the American Society of Clinical Oncology 2023 Annual Meeting (ASCO 2023). The combination was found to be safe and tolerable with no new safety signals.

In 19 patients total, once daily bezuclastinib was administered at a starting dose of 300 mg with sunitinib 37.5 mg. Treatment with bezuclastinib was escalated to 600 mg with 14 patients receiving the highest dose of bezuclastinib plus sunitinib 37.5 mg. The patient population assessed had a median age of 60 years (range, 42-77 years), were predominantly male (68%), had an ECOG performance status of 0-1 (95%), metastatic disease (95%), and locally advanced disease (5%).

Results showed that the most common treatment-emergent adverse events (TEAEs) were low-grade. No grade 4 or higher TEAEs occurred. The most common treatment-related AEs were diarrhea (37%), neutropenia (37%), and alanine aminotransferase (32%) and aspartate aminotransferase (26%) increases. There was 1 patient with a serious AEs of grade 2 neutropenia and pyrexia, as well as grade thrombocytopenia. There was also 1 case of dose reduction in the study, which resulted from grade 3 diarrhea.

“The hope is that the combination will be superior to single-agent sunitinib. We're trying to cover the gaps that are present with the current treatment by adding activity against certain mutations, especially KIT mutations in exon 17 and 18 that are currently not addressed by the use of sunitinib. The hope is that that it will be more efficacious, that they will maintain disease control for longer, and that the toxicity will not be worse than what we're used to seeing with sunitinib, therefore, allowing patients to maintain a good quality-of-life,” Antonio Ucar, MD told Targeted Oncology™ about the Peak study, in an interview.

In the interview, Ucar, oncologist/hematologist at Miami Cancer Institute of Baptist Health South Florida, discussed the evolving role of sunitinib for the second-line treatment of GIST, and the Peak study.

TARGETED ONCOLOGY: Can you explain the current role of sunitinib in the treatment of previously treated GIST?

Ucar: Sunitinib is multitarget tyrosine kinase inhibitor that has been approved for the second-line treatment of GIST. That is for tumors that progress after initial treatment with imatinib. There was a large, randomized study that included 312 patients where a group of patients receiving sunitinib were compared to patients taking placebo. The main objective of this study was to evaluate the median time to progression, which was significantly better for patients taking sunitinib compared with the placebo arm. The study allowed for crossover, so patients in the placebo arm that had progressive disease were allowed to receive sunitinib eventually. The results of overall survival are not as impressive for that reason, because most of the patients ended up getting sunitinib anyway, but numerically, the results were better for the patients getting sunitinib. For several years, this was the only option we had for imatinib progressive disease, and now, a number of other drugs have appeared in the market for subsequent lines of treatment.

GIST under the microscpe | Image Credit: © MdBabul -www.stock.adobe.com

Why is there a continued need for new therapies?

Imatinib in the first-line is an effective drug usually. Obviously, it depends on the mutational status of the GIST, because there are certain mutations that are more responsive to the imatinib. I would say the majority of them are there are other mutations that cause resistance to imatinib. Most of my patients getting imatinib in first-line respond for approximately 18 to 24 months. But after that time, there is the disease progression. That is caused by a change in the mutational status of a tumor. New mutations appear in the tumor that render the tumor resistant to treatment. There are also some cases where patients are intolerant to imatinib, and they need an alternative drug to try to maintain a response or to get a good response. But in general, the main problem has always been the development of new mutations, which is something common, and that evolves throughout the progression of the disease over time.

What rationalizes the addition of the novel drug bezuclastinib to sunitinib as an approach to treat previously treated GIST?

Sunitinib has activity against primary KIT mutations. It also has activity against some of the secondary KIT mutations. To explain a little bit about the mutations, there are 2 major mutations that we identify in tumors in GIST. When it's a KIT mutation, which is the most common one seen in about 70% to 80% of the cases, there is a PDGFRA mutation in 5% to 10% of patients. Then, there's a 10% to 15% chance where both the KIT and the PDGFRA mutation are wild type. So, there's no mutation basically.

Sunitinib, as I mentioned, has activity against the primary KIT mutations and secondary KIT mutations. But there are other mutations in particular KIT exon 17 and 18 mutations that are resistant to sunitinib, and this mutation is of very poor prognosis because it renders the tumor resistant. The tumor continues to grow despite a multitude of treatments. With the addition of this new medication, bezuclastinib, it targets that KIT exon 17/18 mutation. The idea is to cover as many mutation options as possible. There is no escape to the activity of the disease. Like in many other diseases, including cancer, we use a multitude of drugs that work by different mechanisms of actions that have different targets, to try to optimize the control and the response of the tumor.

What should oncologists know about the bezuclastinib’s mechanism of action and earlier results?

The main importance of bezuclastinib is that it doesn't target other kinases that are in the family of KIT. The activity is basically concentrated towards the KIT exon 17/18 mutations, which is not necessarily 1 of the most common, but it's 1 of the types with the worst prognosis. This is how it covers the gap that existed before when you're dealing with single-agent sunitinib. We’re trying to cover all the possible mutations, or as many mutations that we can. We also want to find a medication that is not only effective, but it's also safe and tolerable, and it seems like bezuclastinib fits that profile.

Can you explain the phase 3 results presented at ASCO 2023?

This was a big study of bezuclastinib sunitinib vs single-agent in patients with imatinib-resistant or intolerant GIST. The study had 3 phases. The first 2 phases were basically to evaluate the maximum-tolerated dose. It was a dose-finding phase and also used to evaluate the safety of the combination. It seems that the combination of bezuclastinib and sinitinib did not add a lot of toxic adverse effects or did not worsen the toxic adverse effects that were already known to be caused my single-agent sunitinib, so the safety profile is comparable to sunitinib, which is a good thing to not see excessive toxicity.

The most common adverse effects include the possibility of anemia and neutropenia, elevation of liver function test, thrombocytopenia, and patients also had fatigue, diarrhea, nausea, and some skin toxicity. The combination appears to be safe. The other aspect, of course, is the efficacy, and it seems that there has been 100% disease control up to now. That means that there are partial responses. Although the partial responses were few, there is also lack of tumor growth or progression of disease. That's a good thing because patients are able to maintain the same quality-of-life and avoid the need for additional medications in the future. Also, some of the responses that they saw were kind of late, meaning that patients received several cycles of the combination before they saw a partial response or a significant reduction in the size of the tumor. This is always encouraging because we're hopeful that with more treatments, perhaps we will continue seeing more responses to this combination.

In summary, it seems to be safe, and we're optimistic that the efficacy will be improved over what we see with sunitinib alone. There is an ongoing part 2 to this study, which is basically the randomized portion where we are trying to compare these 2 arms.

How you think this drug could fit into the treatment landscape in the future, if granted FDA approval?

The hope is that the combination will be superior to single-agent sunitinib. We're trying to cover the gaps that are present with the current treatment by adding activity against certain mutations, especially KIT mutations in exon 17 and 18 that are currently not addressed by the use of sunitinib. The hope is that that it will be more efficacious, that they will maintain disease control for longer, and that the toxicity will not be worse than what we're used to seeing with sunitinib, therefore, allowing patients to maintain a good quality-of-life.

_REFERENCES:

_{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):11537-11538. doi:10.1200/JCO.2023.41.16_suppl.11537}