Zurich, Switzerland—For regimens joining BRAF and MEK inhibition in BRAF-mutated melanoma, recent clinical trial data showing unequivocal overall survival (OS) improvements effectively “close the book” on defining clinical benefit, according to Keith T. Flaherty, MD, Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, Boston. Increases in complete response (CR) rates, added Dr Flaherty at the 2014 Society for Melanoma Research International Congress, suggest that with longer-term follow-up, increases in durable responses will also be demonstrated.
The call to explore 2-pathway solutions went out even before phase 3 clinical trial data were available on BRAF monotherapy inhibition, when translational research suggested reactivation of the MAP kinase pathway for BRAF and MEK, Dr Flaherty said in an interview. “That immediately pointed to the concept of BRAF/MEK combination therapy as a strategy, given the ready availability of numerous MEK inhibitors that were already reasonably far along in clinical development.”
Preclinical evidence supported the idea that BRAF/MEK inhibition is safer and more tolerable than either monotherapy, taking advantage of BRAF inhibitors having a very different effect on MAP kinase pathway signaling in tumor tissue versus normal tissue without BRAF mutations. Dr Flaherty noted that this separates a BRAF-MEK combination from other 2-drug pairings that could be used in different cancers. “This is a unique phenomenon that we’re taking advantage of,” he said. With dabrafenib (Tafinlar) monotherapy, the rates of cutaneous squamous-cell carcinoma, skin papilloma, and hyperkeratosis were 19%, 15%, and 30%, respectively, versus 7%, 4%, and 9%, respectively, for patients receiving dabrafenib plus trametinib (Mekinist).
Combined BRAF/MEK inhibition improved response rates, progression-free survival (PFS), and, according to new data recently presented at the 2014 European Society for Medical Oncology annual congress, OS in evidence accrued in the past year. “It is the overall survival finding that closes the book,” Dr Flaherty said. “It’s what we celebrated regarding BRAF monotherapy compared with standard therapy.” In the phase 3 BRIM-3 trial of vemurafenib (Zelboraf) versus dacarbazine (DTIC), with 336 patients in each arm, the hazard ratio (HR) for OS favoring vemurafenib was 0.37.
Dr Flaherty’s research comparing BRAF-MEK combination with dabrafenib monotherapy showed delayed resistance for the combination, with PFS duration of 9.4 months and 5.9 months, respectively (HR, 0.39).
The best evidence for synergy between BRAF and MEK inhibitors is the near doubling of CR rates, said Dr Flaherty. In the phase 2 trial data on which the FDA had based its accelerated approval for the dabrafenib-trametinib combination in BRAF-mutated unresectable or metastatic melanoma, the CR rates for the combination and for dabrafenib monotherapy were 9% and 4%, respectively. In a recent study, the CR rates with dabrafenib plus trametinib versus vemurafenib were 13% and 8%, respectively (Robert C, et al. N Engl J Med. 2014 Nov 16. Epub ahead of print).
Dr Flaherty acknowledged that there are doubters who, pointing to the immaturity of the current data, posit that combination therapy may merely be a “temporizing strategy” that fails to create more durable responses. “The counter argument, however, is that we know that complete responders to BRAF inhibitor monotherapy have the most durable responses. So it’s reasonable to expect, based on dabrafenib/trametinib data showing that complete responders shine through as the patients not only who maintain response the longest, but clearly also who survive the longest, that another year of follow-up data will likely assuage this concern.”
Dr Flaherty concluded that combined BRAF/MEK inhibition delays the emergence of resistance and improves OS.