The Life Raft Group recently hosted a webinar with Dr. Hirotaka Miyashita of UC San Diego Health, who provided an update on two promising clinical studies that were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting this summer. The ASCO Annual Meeting is the world’s largest oncology conference that is hosted annually in Chicago. This event draws tens of thousands of cancer care professionals to learn about the latest oncology clinical trial data and network with the medical community.
The goal of this webinar was to inform attendees about these in-progress clinical trials, which are investigating two distinct approaches for addressing a challenging -and unfortunately common- outcome in advanced GIST.
Gastrointestinal stromal tumors (GIST) are a class of soft tissue sarcomas that can occur anywhere throughout the gastrointestinal tract. In this group of tumors, as in other cancers, transformation of healthy tissue into cancerous cells, or tumorigenesis, is initiated by accidental genetic changes called mutations. While there are various distinct mutations identified as drivers in GIST (as well as some cases wherein the driver mutation cannot be identified), most instances contain primary mutations of KIT, the gene that encodes the KIT protein.
KIT is a type of protein called a surface receptor; it transmits extracellular signals to the inside of a cell, helping to coordinate processes such as cell survival and replication. In healthy cells, it promotes functions such as cellular proliferation only in response to an appropriate biological signal. However, for the approximately 75-85% of GIST patients with a primary KIT mutation, these oncogenic, or cancer-driving, genetic changes dis-regulate this process. These mutations result in what is known as constitutive activation, or activation of KIT even without a biological “go” signal. The outcome of this is the unrestricted cell proliferation that is characteristic of tumor growth. For GIST patients, there has been great clinical success with small molecule inhibitor drugs that can block proteins such as KIT, and function as a “stop” signal to slow or suppress tumor growth. Many of the first, second, third, and fourth line drugs for GIST belong to this class of inhibitors.
Imatinib (also called Gleevec) is one such drug, and represents the standard first line of treatment for GIST patients with a primary KIT mutation. However, despite the initial success of these treatments in suppressing tumor growth and improving patient prognoses, acquired treatment resistance remains an ongoing challenge. Treatment resistance occurs when tumor cells develop secondary, or additional mutations that allow the tumor cells to continue proliferating even in the presence of an inhibitor drug. Dr. Miyashita presented compelling and concise data on the frequency of resistance, an outcome which remains all too common. About 60% of patients taking Imatinib as a first line treatment will develop some form of resistance within 24 of beginning treatment.
Despite the clear challenges associated with acquired resistance, it is often not readily possible to combine existing treatments at will to address all mutations simultaneously. Since many existing treatment options carry a similar set of side effects, providing these drugs at the same time comes with a steeper risk of overlapping reactions or more significant safety considerations. In light of this, researchers continue to explore treatments for these acquired, resistance-conferring mutations.
A viable candidate for such a treatment should cover a broader range of mutations in advanced GIST, without introducing intolerable or dangerous side effects. The two studies presented at ASCO this year are investigating distinct, complementary approaches to achieve this goal. The PEAK study involves a combination of two drugs that, together, target a greater number of mutations than each can address individually. On the other hand, the StrateGIST trial tested a new drug, developed specifically to achieve broad-spectrum coverage of a range of mutations on its own.
The PEAK study examined the combination of the drugs Bezuclastinib and Sunitinib, to achieve broader coverage of a wider array of mutations. So far, this Phase 3 trial has demonstrated that the combination did not create safety concerns or unexpected side effects, and has been successful in lowering the risk of continued cancer growth compared to sunitinib alone, or as a monotherapy. Notably, bezuclastinib is considered a next-generation inhibitor that targets KIT. It is recognized for its ability to target mutations in the exons 17 and 18 of KIT, present in certain hard-to-treat, resistant tumor cells. Bezuclastinib was also chosen for its selectivity; since it marks a precise set of targets, it can be given in conjunction with sunitinib without safety concerns. Sunitinib as a monotherapy exhibits a strong response to mutations in exons 9, 13, and 14, along with a moderate response to exon 11 mutations. Together, bezuclastinib and sunitinib cover a range of six KIT exons: 9, 11, 13, 14, 17, and 18. Earlier study data showed promise, with second-line patients experiencing a stall in tumor progression for as long as 19 months. Next, a phase 3 was designed to examine the efficacy of this novel combination in a robust, global, randomized study. The 413 patients of PEAK3 were initially randomly assigned to either the sunitinib monotherapy study group or the combination treatment group. The study aimed to balance a need validate the combination’s efficacy with providing patients ethical access to treatment. An adaptive study design allowed patients in the monotherapy group to switch to the combination treatment if tumor progression was confirmed during the study.
The key outcome evaluated by this study was a measure called progression-free survival (PFS), an indicator of how long the recipients of the combination treatment benefited from a halt in their tumor progression. Overall, the median PFS for patients on the drug combination was 16.5 months, while sunitinib alone resulted in a median PFS of 9.2 months. In other words, the combination achieved a 50% reduced risk of tumor progression compared to the standard monotherapy. As expected at the outset, safety was not a major concern with this combination, and only about 10% of those initially enrolled had to exit the study due to adverse reactions. This combination is in relatively early stages of testing and researchers are still gathering longer-term survival data. Still, the combination of bezuclastinib and sunitinib has already shown clear promise in decreasing immediate risk of tumor progression. Furthermore, the bezuclastinib and sunitinib combination achieved about a 46% rate of notable tumor shrinkage, compared to about 26% achieved by the sunitinib monotherapy.
Overall, the PEAK study was highly significant for multiple reasons. In addition to the promising results achieved so far, the study demonstrated, for the first time in GIST, that a combination of two KIT-targeting drugs could provide a clear, measurable benefit to patients.
Currently in phase 1/1b, the StrateGIST 1 Study represents another method of addressing acquired resistance in advanced GIST. This trial tested the drug, velzatinib, developed deliberately to block frequent primary mutations along with those typically seen in cases of acquired resistance. This approach directly avoids the challenge of managing potentially overlapping side effects that can occur in combination treatments. Indeed, this broad coverage drug appears to be well tolerated so far. Velzatinib was designed to target KIT mutations across exons 9, 11, 13, 14, 17, and 18: a notably broad range of coverage. It showed promising activity across exons, demonstrating a response against common driver mutations as well as secondary resistance drivers.
This study was also significant for multiple reasons. Velzatinib was tested across all lines of treatment. In addition to achieving a 65% response rate as a first line of treatment, it conferred some level of benefit to patients in all four lines of treatment. Additionally, this study incorporated liquid biopsies (ctDNA) as a measure demonstrating that this novel drug helps to clear tumor biomarkers from the blood.
The promise of the therapies examined in these two clinical trials highlights the importance of ongoing investigation into the treatment and suppression of resistance in advanced GIST.
WATCH NOW: ASCO (American Society of Clinical Oncology) is an important conference in the oncology community where new scientific research updates are shared. The Life Raft Group partnered with Hirotaka Miroshita, MD PhD of UC San Diego Health, who summarized abstracts and presentations that were presented during this conference that are relevant to the GIST patient community.
