By: Len Kusdra, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
The pace of treatment in metastatic melanoma has significantly accelerated in the past couple of years. What was once a disease beset by toxic and largely ineffective treatments now enjoys a number of effective agents that have reduced the mortality of this aggressive disease. Yervoy® (ipilimumab, Bristol-Myers Squibb), a CTLA-4 antagonist, was the first of these effective immunotherapy agents that showed a significant and clinically relevant improvement in survival and led to its approval by the U.S. Food and Drug Administration (FDA) in 2011 for both first- and second-line metastatic melanoma. With the pervasive excitement of immunotherapy in the field of oncology (for which Yervoy provided proof-of-concept in melanoma), it was only a matter of time that more of these agents would make their way into melanoma. As a result, Opdivo® (nivolumab, Bristol-Myers Squibb) and Keytruda (pembrolizumab, Merck) have been added to the armamentarium for physicians in treating metastatic melanoma. The age of targeted therapy further emerged between 2012 and 2015 with approval of four agents that target the RAS-BRAF-MAPK pathway: Zelboraf® (vemurafenib, Roche/Genentech), Tafinlar® (dabrafenib, Novartis), Mekinist® (trametinib, Novartis) and Cotellic® (cobimetinib, Roche/Genentech/Exelixis, in combination with Zelboraf). All four agents are indicated for use in metastatic melanoma patients whose tumors harbor BRAF mutations.
For BRAF-mutant patients, the approval of BRAF and MEK inhibitors ushered in an era of patient segmentation and the resulting personalized medicine in melanoma; however, it is now appreciated (as is the case with other tumor types) that other mutations exist that provide niche opportunities for development of novel agents. One such mutation type is in NRAS, which occurs in about 15% of patients and is associated with more aggressive disease and poorer prognosis.1,2 Until recently, no active clinical development existed for this population, representing a major unmet need in the treatment of metastatic melanoma. This has changed with the development of binimetinib (Array Biopharma), a novel MEK inhibitor that showed promising clinical activity in a Phase II trial (NCT01320085) in patients demonstrating a 20% response rate in patients with NRAS mutations and in 20% of BRAF-mutant patients.3 Based on these promising results, Novartis decided to move binimetinib forward into late-stage development with the initiation of the NEMO clinical trial.
NEMO (NCT01763164) is an open-label, Phase III trial evaluating binimetinib versus dacarbazine in patients with advanced, unresectable (Stage IIIC) or metastatic NRAS melanoma who were either untreated or who had progressed on or after immunotherapy. Patients were randomized 2:1 to receive either 45 mg twice a day or dacarbazine at 1000 mg/m2 intravenously every three weeks. The primary endpoint is progression-free survival (PFS) with secondary endpoints including overall survival (OS), response rates, and disease control rate. In December 2015, Array Biopharma announced top-line results from NEMO demonstrating that the trial had met the primary endpoint of improving PFS (HR = 0.62, p<0.001). The median PFS for patients in the binimetinib arm was 2.8 months versus 1.5 with dacarbazine (Array BioPharma, press release, December 2015).
Today at the American Society of Clinical Oncology annual meeting, attendees were presented with more detailed findings from NEMO.3 At this interim analysis, 269 patients had received binimetinib and 133 patients had received dacarbazine. The PFS did not change from that announced in the press release, and, at this interim analysis, there was no improvement in OS (11.0 months in the binimetinib arm versus 10.1 in the dacarbazine arm); however, the data is not mature and longer-term follow-up is required before final assessment. The confirmed overall response rate was 15% (95% CI: 11% to 20%) and disease control rate was 58% (95% CI: 52%-64%) for binimetinib, respectively, compared with 7% (95% CI: 3%-13%) and 25% (18%-33%) for dacarbazine (p-value for response=0.015; p-value for the disease control rate <0.001). An intriguing piece of data arises in the prespecified subset analysis between patients who had received prior immunotherapy versus patients who had received no prior immunotherapy, although the data should be interpreted with caution given the small patient population in the prior immunotherapy arm (n=57 and 28 in the binimetinib and dacarbazine cohort, respectively). While the PFS benefit was seen in both subgroups, the benefit appeared to be greater in patients who had received prior immunotherapy (5.5 months in the binimetinib arm versus 1.6 months in the dacarbazine arm in patients who had prior immunotherapy, HR=0.46; 2.8 months in the binimetinib arm versus 1.5 months in the dacarbazine arm in patients with no prior immunotherapy). The trend favoring binimetinib in patients who had received prior immunotherapy was observed regardless of whether patients received Yervoy or a PD-1 agent. Of some concern is the side effect profile: 21% of patients discontinued treatment due to adverse events in the binimetinib group and 6% discontinued treatment in the dacarbazine arm due to side effects. Overall, binimetinib was associated with increased incidence of Grade 3/4 adverse events (68% binimetinib versus 46% dacarbazine). The most common Grade 3-4 adverse event was elevation of blood CPK (19% with binimetinib versus 0% with dacarbazine), hypertension (7% with binimetinib versus 2% with dacarbazine), and rash (4% with binimetinib versus 0% with dacarbazine).
Data from NEMO paves the way for regulatory approval of binimetinib in NRAS-mutant melanoma patients, a population with a high unmet need, making it first to market in this niche setting. While not being evaluated directly in this patient population, Keytruda, Opdivo and Yervoy may pose a competition for binimetinib. The activity seen with checkpoint inhibitors in both BRAF-mutant and BRAF-wildtype patients has raised the debate on whether to administer immunotherapy as first-line therapy in all subtypes regardless of mutational status or whether to reserve immunotherapy for the relapsed setting following failure of BRAF inhibitors in BRAF-mutant patients. Indeed, while the majority of BRAF-mutant patients will receive Zelboraf or Tafinlar with or without Mekinist, physicians also will administer Opdivo with or without Yervoy in a fraction of patients.5 With the subset analysis showing a greater efficacy benefit in patients with prior immunotherapy treatment, physicians may push binimetinib treatment to the second line, preferring to utilize immunotherapy upfront as a treatment paradigm for NRAS patients. In addition, while the PFS improvement in the entire population is significant, physicians may question the benefit-to-cost ratio given the increased rate of Grade 3/4 adverse events, thus posing a challenge to uptake. Countering that viewpoint is that NRAS patients suffer from a lack of effective clinical options, and the unmet need justifies binimetinib’s use.
Another question that inevitably arises is whether combination therapy will yield improved outcomes as seen with Tafinlar and Mekinist. As such, Array has initiated a Phase III trial evaluating binimetinib in combination with their BRAF inhibitor encorafenib (NCT01909453; COLUMBUS). This trial recently completed enrollment, and initial data readout and regulatory filing are expected to occur sometime in 2016 (Array BioPharma Investor Report, January 13, 2016).
Despite the challenges discussed, binimetinib represents the first major therapeutic option for NRAS-mutant melanoma and has offered a ray of hope in the dark muddy waters of this deadly and aggressive disease.
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