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AACR Studies in BRAF-Mutated Melanoma Show Benefit of Combo Treatment, Continuous Dosing Strategies

NEW YORK – Results from two studies presented during the American Association for Cancer Research's Virtual Annual Meeting on Monday shed light on the efficacy of a new three-drug cocktail and of intermittent dosing of targeted drugs for patients with BRAF V600 mutation-positive advanced melanoma.

First, results from the Phase III IMspire 150 trial showed that combining the immune checkpoint inhibitor atezolizumab (Genentech's Tecentriq) with the MEK inhibitor cobimetinib (Genentech's Cotellic) and the BRAF inhibitor vemurafenib (Genentech's Zelboraf) prolonged progression-free survival compared with cobimetinib and vemurafenib alone among patients with BRAF V600 mutation-positive advanced melanoma.

Then, results from the Phase II SWOG S1320 study in the same molecularly defined subset of patients showed that contrary to a hypothesis favoring intermittent dosing based on preclinical studies, continuous dosing of the BRAF inhibitor dabrafenib (Novartis's Tafinlar) and the MEK inhibitor trametinib (Novartis's Mekinist) demonstrated improved progression-free survival compared with intermittent dosing.

Lead author Grant McArthur of the Victorian Comprehensive Cancer Centre presented the results of the IMspire 150 trial. Out of 514 patients with previously untreated, unresectable stage IIIc/IV BRAF-mutated melanoma, 246 patients who received a three-drug combination of atezolizumab, cobimetinib, and vemurafenib achieved a median progression-free survival of 15.1 months compared with 10.6 months for patients who received cobimetinib and vemurafenib plus a placebo. The results demonstrated an improved duration of response in the atezolizumab group as well; patients treated with the three-drug combination achieved a median duration of response of 21 months compared to 12.6 months in the comparator group.

Overall survival data were not available in time for the presentation, but McArthur said that so far overall survival looked as though it would "favor the atezolizumab group."

The primary endpoint of progression-free survival was assessed by the investigators — who found a significantly significant benefit with the addition of atezolizumab — but a central review committee reported a progression-free survival that, though likewise improved, was not statistically significant. A follow-up discussion led by Charles Sawyers of Memorial Sloan Kettering highlighted that the investigators will need to reconcile this difference in these findings.

During the discussion, Sawyers also wondered whether the improved response with the combined regimen was due to a synergy between the checkpoint inhibitor and targeted therapies, or if it was due to inter-patient variability — meaning some patients responded to the checkpoint inhibitor and some responded to the targeted treatments — without drug synergy?

After the IMspire 150 presentation, Alain Algazi of the University of California, San Francisco presented the results of the 206-patient Phase II SWOG S1320 study. These results demonstrated that among the patients who received dabrafenib and trametinib continuously had a median progression-free survival of 9 months compared to 5.5 months among those who received the drugs on an intermittent dosing schedule of 5 weeks of treatment interspersed with three week-long breaks. The two separate dosing regimens began after an 8-week period during which all patients received continuous dosing. Only the patients who demonstrated objective response or stable disease after those initial 8 weeks were randomized to one of the two dosing arms.

The researchers had originally hypothesized that progression-free survival would improve to 14.1 months with intermittent dosing, but this study flipped that theory on its head. And although overall survival was not originally part of the study design, Algazi noted that the overall survival curves were very similar in the two treatment arms. Following disease progression, though, overall survival was improved in the intermittent dosing arm, an outcome that Algazi said should be considered "hypothesis generating" going forward.

The original, disproven hypothesis that the intermittent dosing arm would experience improved progression-free survival was based in part on the notion that intermittent dosing could prevent cells from developing drug resistance. The reversal seen in the actual findings raised the question as to why the clinical outcomes differed from preclinical findings. Algazi offered several potential explanations, including the possibility that the patients who received intermittent dosing wound up having a decreased exposure to the drugs; that it may take longer than 8 weeks for resistant clones to develop; that the long half-life of trametinib kept drug levels high even during the off-weeks; and that non-MAPK resistance pathways may overshadow beneficial signals from the intermittent therapy.

During the study's follow-up discussion, Sawyers asked with regard to the last suggestion whether the study design might have benefitted from enrolling a narrower group of patients to ensure that the mechanism of acquired resistance would not be due to something other than BRAF-amplification. This is the mechanism the researchers originally thought led to resistance via the restoration ERK signaling and they had hoped to overcome this with intermittent dosing. While roughly 80 percent of acquired resistance to these drugs is due to restored ERK signaling, Sawyers pointed out that BRAF amplification is responsible only about a third of the time. The other two-thirds of the time, ERK signaling is restored due to splice variants and RAS pathway mutations.  

"Is it possible that by enrolling [BRAF-mutated] all comers, that a beneficial signal, which might have been just restricted to the BRAF amplified patients, could have been missed?" Sawyers asked, acknowledging that it would have been difficult to design the enrollment otherwise, since the mechanism of acquired resistance before the patient develops said resistance was unknown. "You'd have to do a much larger trial in which you had enough patients who would represent each of these three categories and then do a subset analysis after the fact," he said, referring to the three molecular mechanisms known to restore ERK signaling.

Sawyers also pondered why so few clinical studies have looked into intermittent dosing in the context of targeted therapies. One explanation he gave is that the overwhelming majority of targeted drugs have long half-lives, which don't allow for an assessment of a large pulsed dose due to the slow decay curve of the drug. "It is unlikely that we could incentivize drug developers to go for shorter half-life drugs," Sawyers said.

"Because all stakeholders, myself included, would want to know, 'What is the maximum tolerated dose when you inhibit a target continuously?' It's a critical data point in planning future clinical development, [and] adding an additional Phase I cohort to receive pulsatile dosing would be considered an expensive luxury," he added.

A final lingering question that Algazi touched on during his presentation was the fact that, in both the continuous and intermittent treatment arms of the study, roughly 30 percent of patients had received prior immune checkpoint inhibitor therapy.  At the American Society of Clinical Oncology's Annual Meeting in May, the researchers will share data from an exploratory analysis looking at the potential effect of this prior checkpoint inhibitor treatment on progression-free survival.