NEW YORK – In a small Phase II trial evaluating Pfizer's encorafenib (Braftovi) and binimetinib (Mektovi), the majority of heavily pretreated, refractory multiple myeloma patients with BRAF V600 mutations saw their tumors shrink on the combination regimen, researchers reported at the American Society of Hematology's annual meeting on Saturday.
Multiple myeloma patients with relapsed or refractory disease are a difficult-to-treat group and tend not to have enduring response to treatment. Targeted treatments aren't often an option due to the lack of targetable biomarkers in this population. However, BRAF mutations have been observed in 2 percent to 4 percent of newly diagnosed multiple myeloma patients and in up to 8 percent of those with relapsed or refractory disease.
Moreover, in a 2018 case report in JCO Precision Oncology, researchers reported on two multiple myeloma patients with BRAF V600 mutations in the Vemurafenib-Basket study who had enduring response to vemurafenib (Genentech's Zelboraf) and one patient who had a shorter response. Several years earlier, in 2013, researchers led by Marc Raab, head of the translational myeloma research group at the German Cancer Research Center in Heidelberg, reported that a multiple myeloma patient with a BRAF V600E mutation who was refractory to all approved treatment options had a rapid and durable response to vemurafenib.
In the study presented at the ASH annual meeting, researchers led by Raab evaluated the combination of BRAF inhibitor ecorafenib and MEK inhibitor binimetinib in 12 relapsed or refractory multiple myeloma patients with the BRAF V600E mutation who had at least two lines of prior treatment. Researchers decided to test the combination of a BRAF and MEK inhibitor, since this strategy is approved already in melanoma and is used to doubly inhibit the RAS/RAF pathway.
In order to enroll in the study, patients had to have a BRAF V600E or V600K mutation in more than 50 percent of multiple myeloma cells as determined by both immunohistochemistry and next-generation sequencing.
Among these patients, the overall response rate, which was the primary endpoint, was 83 percent with 25 percent of patients having a near complete response or complete response, and 50 percent experiencing a partial response. The researchers noted that the responses occurred rapidly with most patients seeing a response after one 28-day cycle of treatment with the oral regimen.
Progression-free survival data was not yet available as the trial is still ongoing, but Raab noted in a presentation at the meeting that some patients have had a duration of response exceeding one year, while others were "short-lived," noted Raab.
The adverse events were in line with previous studies of encorafenib and binimetinib in melanoma, though Raab noted the adverse events observed in this trial were less severe than those recorded in the melanoma clinical trials. "We think it's even better tolerable in myeloma," he said.
With targeted therapy resistance almost always emerges. As such, researchers conducted correlative studies using whole-genome sequencing, RNAseq, and IHC to understand the resistance mechanisms in patients.
At the time of the presentation, WGS and RNASeq data from the start of treatment and relapse were available for only four multiple myeloma patients. Although these patients still had the baseline BRAF V600E mutation at relapse, they also acquired a variety of other new RAS pathway mutations.
For example, one patient developed a KRAS mutation at relapse, while a second patient developed both an NRAS and a KRAS mutation. A third patient had an NRAS mutation alongside a BRAF mutation at the start of the trial and maintained both of these mutations at relapse. Raab noted that this patient had stable disease on the MEK/BRAF inhibitor combination, but technically didn't respond. Lastly, a fourth patient did not have a RAS mutation at relapse but acquired a new BRAF translocation.
This data suggests that emerging RAS mutations and structural variants in BRAF could be the source of resistance to BRAF/MEK inhibitors, the researchers concluded. Additionally, based on the lack of response in the one patient who had an NRAS mutation at the start of the trial alongside a BRAF mutation, Raab noted that pre-existing RAS mutations may be predictive of poor response to the encorafenib-binimetinib regimen.
"We are seeing some durable responses in this patient population," he said. "But emerging RAS mutations and structural variants seem to drive relapse, similar to [studies in] melanoma. Interestingly and importantly, a pre-existing concomitant RAS mutation together with the BRAF V600E mutation may predict a poor response and may prevent patients from receiving the therapy."
Pfizer is studying the combination of encorafenib and binimetinib in several other indications, including BRAF V600E-mutated colorectal cancer and lung cancer. The two drugs were originally developed by Array BioPharma, which was acquired by Pfizer last year.