NEW YORK – Pan-cancer responses to the MEK inhibitor binimetinib (Pfizer/Array Biopharma's Mektovi) can vary depending on the NRAS codon that is altered, according to findings from a Phase II basket trial presented at the American Association for Cancer Research's Virtual Annual Meeting this week.
As part of the National Cancer Institute's Molecular Analysis for Therapy Choice, or NCI-MATCH study, researchers enrolled more than four dozen cancer patients with NRAS-mutated cancers on the binimetinib treatment sub-protocol. Of those, 47 individuals with advanced, treatment-refractory solid tumors, myelomas, or lymphomas were eligible for the study and had NRAS codon 12, codon 13, or codon 61 mutations in their tumors following testing on Thermo Fisher Scientific's Oncomine AmpliSeq panel.
"This sub-protocol of the MATCH trial was designed to test the hypothesis that single-agent MEK inhibition could be effective in NRAS-driven tumors," James Cleary, a medical oncologist specializing in gastrointestinal cancers at the Dana-Farber Cancer Institute, explained during his online talk at the AACR conference. "In this trial, we treated patients with the binimetinib MEK inhibitor, which is a nanomolar inhibitor of MEK1 and MEK2."
The participants ranged in age from 30 to 84 years old, and most had had three or more lines of treatment in the past, he noted. Patients with melanoma were not eligible to participate in the current analysis, since MEK inhibitor trials have already been done for NRAS-mutated melanoma.
More than half of the participants had colorectal adenocarcinoma, and 13 of the 24 CRC patients had mutations to NRAS codon 12. Across all 47 patients profiled, though, codon 61 mutations turned up most frequently, occurring in nearly 47 percent of the tumors, followed by codon 12 mutations in around 36 percent of tumors, and codon 13 mutations in 17 percent.
The study arm overall did not meet its primary endpoint of 16 percent objective response rate, Cleary reported, with just one patient showing a confirmed, partial response to the MEK inhibitor treatment. That individual — who had a rare NRAS codon 61-mutated indolent malignant ameloblastoma of the jaw — remained on treatment for around two years before dropping the drug due to toxicity concerns.
A second patient with NRAS codon 61-mutated colorectal cancer had an unconfirmed partial response to binimetinib, while two NRAS codon 61-mutated colorectal cancer patients stayed on treatment for more than a year before experiencing disease progression.
Progression-free survival, a secondary endpoint for the trial, came in at 3.5 months, on average, while the average overall survival was 10.5 months across all of the NRAS-mutated cases considered.
But the investigators saw more promising results when they focused on the patients with codon 61-mutated tumors in an exploratory post-hoc analysis. For patients in that subgroup, overall survival and progression-free survival stretched out compared to the cases with codon 12- or codon 13-mutated tumors, particularly when the team focused on the subset of patients with colorectal cancer.
It remains to be seen whether codon 61 mutations in NRAS may serve as a marker for response to binimetinib or other MEK inhibitors, and further research will be needed to explore how different NRAS mutations affect the broader biology of tumors, Cleary explained.
Although the broad findings argue against using the binimetinib MEK inhibitor as a monotherapy for advanced NRAS-mutated colorectal cancers, he suggested that allelic differences may be informative in future studies of MEK inhibitors in combination with other targeted treatments such as CDK4/6 inhibitors.
"I'd love to get a better mechanistic understanding of why this difference occurred," Cleary said.
Likewise, the team wants to take a look at whether there are mutation type-related toxicity differences, since close to 30 percent of participants on the binimetinib sub-protocol ended up stopping treatment due to adverse events such as rash, diarrhea, or retinal abnormalities, and more than 40 percent needed to dial down the drug dose.
Still, the findings may edge researchers closer to understanding some of the features that may correspond to MEK inhibitor treatment response in individuals with RAS-mutated cancers, which has been an area of active research in recent years.
"Development of targeted therapies directed against RAS-mutated cancers is one of the great challenges in the treatment of cancer patients," Cleary noted. "While recently there has been some progress in developing G12C KRAS inhibitors, by and large, efforts to directly target RAS have been unsuccessful."
In an effort to circumvent such roadblocks, he explained, there has been increased interest in attempting to target players downstream of RAS proteins, including MEK, that prompt cell division and proliferation in response to RAS signaling.
That approach has been stymied so far for cancers driven by KRAS mutations, Cleary noted, though there have been preclinical hints that single-agent MEK inhibitor treatment might be more beneficial for tumors containing NRAS mutation drivers, which make up some 8 percent of cancers.
In Phase II and Phase III trials reported previously, for example, binimetinib appeared to stretch out both progression-free survival and overall survival in NRAS-mutated melanomas — a cancer type in which some 20 percent of tumors have NRAS mutations, with most of those alterations occurring in codon 61 of the gene.
In particular, Cleary pointed out that the Phase III NEMO trial, which set binimetinib up against dacarbazine for NRAS codon 61-mutated melanoma, met its primary survival endpoint of progression-free survival. That study reported a 15 percent response rate in the binimetinib-treated group, though a significant subset of patients stopped taking binimetinib due to adverse events and the overall survival rate was not significantly increased.