The past decade of drug discovery has brought a dramatic expansion in the number of new therapies to treat patients with advanced or metastatic melanoma in 2 modalities: checkpoint blockade immunotherapies and molecularly targeted drugs.
Antoni Ribas, MD, PhD
The past decade of drug discovery has brought a dramatic expansion in the number of new therapies to treat patients with advanced or metastatic melanoma in 2 modalities: checkpoint blockade immunotherapies and molecularly targeted drugs. In both areas, these therapeutic categories have grown from single-agent regimens into combination strategies.
Now, investigators are seeking to determine whether triplet regimens that combine an immunotherapy that targets the PD-1/PD-L1 pathway with small molecules that inhibit BRAF and MEK signaling would be more effective than single- or dual-agent approaches.
The rationale for the multipronged strategy has been building for several years, according to Antoni Ribas, MD, PhD, a leading melanoma investigator who discussed clinical trial findings at recent conferences. Ribas, a 2015 Giants of Cancer Care® award winner, is a professor of medicine, surgery, and molecular and medical pharmacology at the University of California, Los Angeles.
Overall, approximately 65% of melanomas harbor mutations that activate signaling in the RAS/RAF/ MEK/ERK pathway, Ribas has observed.1 These mutations cause aberrations within the melanoma cell that in turn spark interactions with T lymphocytes whose activity is controlled by immune checkpoints such as PD-1 (FIGURE).1
The triplet strategies combine a monoclonal antibody targeting either PD-1 or PD-L1 with drugs that inhibit BRAF and MEK kinases, which are key components of the protein signaling pathway within the melanoma cell.
The safety and efficacy of such combinations have been explored in phase I studies, Ribas noted during a presentation at the Ninth World Congress of Melanoma, held in Brisbane, Australia, in October 2017. The regimens proved to be safe, and most patients had either stable disease or a response, a level of efficacy that Ribas called “surprising.” In these studies, very few patients did not demonstrate some level of clinical benefit, he said. These early results led to several ongoing later-stage studies, which are now enrolling participants, representing a potential new standard of care on the horizon (TABLE).
“Three phase I trials attest to the overall safety of combined full-dose therapy with a BRAF and a MEK inhibitor with anti—PD-1/PD-L1 and provide early encouraging evidence of combined efficacy,” Ribas said. “There are toxicities, but they are usually responsive to stopping the targeted therapies for a little bit of time and then restarting.”
In preclinical models, the triplet combination of dabrafenib (Tafinlar), trametinib (Mekinist), and pembrolizumab (Keytruda) demonstrated superior antitumor activity in mouse models of BRAF V600E-mutated melanoma.2 Dabrafenib is a BRAF inhibitor, trametinib is a MEK inhibitor, and pembrolizumab targets PD-1.
Mechanistically, treatment with BRAF plus MEK inhibition was found to increase T-cell accumulation at the site of the tumor. “The triple therapy, but also the doublet of the BRAF and MEK inhibitor, had the highest accumulation and expansion of the T-cell intratumor,” Ribas noted.
In RNA sequencing data, the BRAF/MEK combination was found to increase CD8, interferon gamma, granzyme B, and the PD-1:PD-L1 ratio, resulting in a more immunogenic microenvironment. Additionally, BRAF inhibition was found to increase PD-L1 expression.
“Those who received the doublet of dabrafenib and trametinib had increased immune signaling in the tumor,” Ribas said. “Another thing that was important was an upregulation of PD-L1 with dabrafenib inside of the tumor and not in the spleen. It was localized to where the targeted therapy has activity.”
These triplet regimens are among the emerging melanoma combinations that are generating excitement throughout the field, noted Michael A. Postow, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, in an interview with OncologyLive®. “The world is moving to 2- and 3-drug combinations and, if those show benefit in randomized studies, we will all be happy about that,” he said. “We need to keep in mind that we should be conservative with our thinking until we have the data to support what could be more expensive and toxic regimens.”In the KEYNOTE-022 study, which was updated at the ESMO 2017 Congress,3 the combination of pembrolizumab, dabrafenib, and trametinib was assessed in 15 patients with metastatic BRAF-mutated melanoma. The confirmed response rate was 67%, and the confirmed plus unconfirmed response rate was 73%. This included a complete response (CR) rate of 13%.
The median duration of response was not yet reached at the time of assessment (95% CI, 1.6-26.5 months). After a median follow-up of approximately 20 months, 7 of the 11 (64%) responding patients had not yet progressed, including the 2 patients with a CR. Of those with a CR, 1 continued to receive the triplet, and the other had discontinued dabrafenib and trametinib at 18 months and continued pembrolizumab monotherapy.
There were no late or unexpected toxicities with the triplet therapy during the follow-up period. Grade 3/4 treatment-related adverse events (AEs) were experienced by 73% of patients, with the most common being alanine aminotransferase increase (20%), aspartate aminotransferase increase (20%), pyrexia (20%), gamma-glutamyltransferase increase (13%), neutropenia (13%), and white blood cell count decrease (13%). There were no treatment-related deaths. Due to AEs, 27% of patients discontinued at least 1 of the therapies.
A randomized phase II portion of the KEYNOTE022 study is ongoing (NCT02130466), with a primary endpoint of progression-free survival (PFS). This portion of the study has enrolled 120 patients, and results are expected in the second quarter of 2018, according to Ribas.Two phase III studies are exploring other combinations of BRAF and MEK inhibition with a PD-1 or PD-L1 inhibitor. The TRILOGY trial is investigating the MEK inhibitor cobimetinib (Cotellic) plus the BRAF inhibitor vemurafenib (Zelboraf) and the PD-L1 inhibitor atezolizumab (Tecentriq), and the COMBI-i trial is examining dabrafenib plus trametinib with the investigational PD-1 inhibitor spartalizumab (PDR001), which is being developed by Novartis.
In the TRILOGY trial, the triplet will be compared with cobimetinib, vemurafenib, and placebo for patients with previously untreated BRAF-mutant metastatic melanoma. The study, which is currently accruing patients, hopes to enroll 500 participants, and the primary endpoint is PFS. Results are expected by the end of 2019 (NCT02908672).
The COMBI-i trial has a similar schema, with the immunotherapy-containing triplet being compared with dabrafenib, trametinib, and placebo. The trial is currently accruing with a goal of enrolling about 500 patients. The primary endpoint is PFS, and the results are expected to report in the fourth quarter of 2020, Ribas said (NCT02967692).
Additionally, several smaller phase I trials are exploring novel combinations. The National Cancer Institute is testing several experimental regimens in an 8-arm trial that seeks to enroll 40 participants with metastatic or unresectable melanoma (NCT01940809). The regimens include dabrafenib plus trametinib followed by ipilimumab (Yervoy), a CTLA-4 checkpoint inhibitor; dabrafenib plus trametinib followed by both nivolumab (Opdivo), a PD-1 inhibitor, and ipilimumab; and trametinib or dabrafenib with nivolumab plus ipilimumab.
In a phase Ib study, Genentech is examining the combination of atezolizumab with vemurafenib and cobimetinib in an expansion cohort of patients with BRAF-mutant metastatic melanoma who have experienced disease progression after receiving prior checkpoint inhibitor therapy (NCT01656642). The study, which is active but not recruiting participants, has an estimated completion date of November 2018, according to ClinicalTrials. gov. Meanwhile, MedImmune, which is part of AstraZeneca, is conducting a phase I/II study with a cohort in which participants received dabrafenib plus trametinib and durvalumab (Imfinzi), a PD-L1 inhibitor (NCT02027961). The trial also is active but no longer recruiting participants.Although the prospect of triplet therapy for patients with melanoma remains experimental, dual regimens have become the standard of care in recent years.
The combination of nivolumab plus ipilimumab was initially approved in October 2015 to treat patients with BRAF V600 wild-type, unresectable or metastatic melanoma, which was based on findings from the phase II CheckMate-069 study. This indication was expanded in January 2016 to include patients with BRAF V600 mutations.
In updated analyses presented at the 2017 American Association for Cancer Research Annual Meeting, the combination was associated with a 12% reduction in the risk of death versus nivolumab monotherapy in patients with treatment-naïve advanced melanoma. The median overall survival (OS) was not reached in the nivolumab/ipilimumab arm or for patients who received nivolumab alone and was 20 months for those who were treated with ipilimumab.4 Toxicities have been a concern with the combination. Grade 3/4 treatment-related adverse events were reported in 58.5% of patients in the combination arm, 20.8% in the nivolumab arm, and 27.7% in the ipilimumab arm.
In 2014, the FDA granted accelerated approval to the combination of dabrafenib and trametinib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation after demonstrating a higher objective response rate of 76% and a duration of 10.5 months compared with 54% and 5.6 months, respectively, for singleagent dabrafenib. The following year, the agency approved vemurafenib and cobimetinib for the same patient population based on gains over single-agent vermurafenib in progression-free survival (12.3 vs 7.2 months, respectively) and median OS (not reached vs 17 months).
Meanwhile, the FDA is scheduled to make a decision by June 30, 2018, on a new drug application for the combination of encorafenib, a BRAF inhibitor, and binimetinib, a MEK inhibitor. Dual use of the experimental therapies demonstrated an OS improvement compared with single-agent vemurafenib, according to updated findings from the phase III COLUMBUS trial.
The combination of encorafenib at 450 mg daily and binimetinib at 45 mg twice daily reduced the risk of death by 39% versus vemurafenib monotherapy (HR, 0.61; 95% CI 0.47-0.79; P <.001). The median OS was 33.6 months versus 16.9 months, respectively.5