Triplet Therapy on Horizon for BRAF+ Melanoma

Antoni Ribas, MD, PhD

The combination of anti—PD-1/PD-L1 immunotherapy with BRAF plus MEK inhibitors is advancing rapidly following early promising results for patients with BRAF-mutant advanced melanoma, according to a presentation by Antoni Ribas, MD, PhD, at the 2017 World Congress of Melanoma.

In phase I studies, not only were the triplet regimens safe but most patients had either stable disease or a response, a level of efficacy that Ribas labeled “surprising.” In these studies, very few patients did not demonstrate some level of clinical benefit, he explained. These early results have led to several ongoing phase III studies, which are now enrolling participants, representing a potential new standard of care on the horizon.

"Three phase I trials attest to the overall safety of combined full dose therapy with BRAF and MEK inhibitor with anti—PD-1/L1 and provide early encouraging evidence of combined efficacy," said Ribas, professor of medicine, surgery, and Molecular and Medical Pharmacology at the University of California, Los Angeles (UCLA). "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.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."

In the KEYNOTE-022 study, which was recently updated at the 2017 ESMO Congress,² 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 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, this included 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 ALT increase (20%), AST increase (20%), pyrexia (20%), GGT increase (13%), neutropenia (13%), and white blood cell count decrease (13%). There were no treatment-related deaths. Twenty-seven percent of patients discontinued at least 1 of the therapies due to AEs.

Two phase III studies are also exploring other combinations of BRAF and MEK inhibition with a PD-1 or PD-L1 inhibitor. The TRILOGY trial is exploring 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 PDR001, which is being developed by Novartis.

In the TRILOGY trial, the immunotherapy combo 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, wherein the immunotherapy-containing triplet is being compared with dabrafenib, trametinib, and placebo. The trial is currently accruing with a goal of enrolling 500 patients. The primary endpoint is PFS and the results are expected to report in the fourth quarter of 2020, Ribas said (NCT02967692).

References:

1. Hu-Lieskovan S, Mok S, Moreno BH, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Sci Transl Med. 2015;7(279):279ra4
2. Ribas A, Hodi FS, Lawrence D, et al. KEYNOTE -022 Update: Phase 1 Study of First of First -Line Pembrolizumab Plus Dabrafenib and Trametinib for BRAF-Mutant Advanced Melanoma. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract 1216O.

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A randomized phase II portion of the KEYNOTE-022 study is ongoing (NCT02130466), with a primary endpoint of PFS. There are 120 patients enrolled to this portion of the study and results are expected in the second quarter of 2018, according to Ribas.