The addition of the PD-L1 inhibitor atezolizumab to the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib induced a high response rate for patients with BRAF-mutant unresectable melanoma.
Ryan J. Sullivan, MD
The addition of the PD-L1 inhibitor atezolizumab (Tecentriq) to the MEK inhibitor cobimetinib (Cotellic) and the BRAF inhibitor vemurafenib (Zelboraf) induced a high response rate for patients with BRAF-mutant unresectable melanoma, according to findings from a phase Ib study presented at the 2016 Society for Melanoma Research Annual Meeting.1
At the data cutoff of June 15, 2016, 30 patients had received ≥1 dose of atezolizumab. The response rate with the triplet was 83%, which included 3 complete responses (10%) and 21 partial responses. Overall, 29 of the 30 patients were evaluable for response, with just 1 patient experiencing primary progressive disease. At the time of the analysis, median duration of response and progression-free survival were not yet reached.
"The great majority of patients are benefiting, and benefiting a lot. Five patients had a 100% reduction in target lesion volume, 2 were complete responders and 3 were partial responders," said lead investigator Ryan J. Sullivan, MD, from the Massachusetts General Hospital, during a presentation of the data.
In the triplet arm (cohort 4) of the phase Ib study, patients with metastatic or unresectable BRAF-mutant melanoma were treated with atezolizumab in combination with cobimetinib and vemurafenib. Patients in the study were at a median age of 50 years and had not received a prior PD-1 or BRAF/MEK inhibitor. A majority of patients had a normal LDH (81.5%) and an ECOG performance status of 0 (83%). The stage of disease ranged from IIIc (27%) to M1c (20%).
During a 28-day run-in period, vemurafenib was administered at 960 mg twice daily on days 1 to 21. After the run-in, the vemurafenib dose was reduced to 720 mg twice daily and atezolizumab was administered at 800 mg every 2 weeks. Cobimetinib was given at 60 mg daily on days 1 to 21 across both phases of the study.
The median follow-up for safety was 3.9 months. The most common treatment-related adverse events were arthralgia, elevated liver enzymes, nausea, fatigue, flu-like symptoms, maculopapular rash, mucosal inflammation, and photosensitivity.
"The triple combination of atezolizumab, cobimetinib, and vemurafenib had a manageable safety profile in patients with BRAF V600-mutant melanoma," said Sullivan. "The AEs that we observed with the triple combination were similar to those with atezolizumab and vemurafenib."
Grade 3/4 AEs were experienced by 40% of patients treated with the combination, of which 27% were deemed atezolizumab related. There were 3 treatment-related serious AEs, which included 1 patient with elevated creatine phosphokinase, 1 case of sepsis, and 1 patient with diarrhea and ALT/AST elevation. These events were resolved with dose interruptions and/or dose reductions, Sullivan noted.
"Interestingly, elevation of ALT and AST were the most frequent toxicities both when we looked at all grades and grade 3/4," said Sullivan. "We did biopsies on these patients, and what we found was this was not a lymphocytic infiltration of the liver but rather it looked like a toxic necrosis picture that you might expect from vemurafenib or Tylenol or any other hepatotoxic drug."
Based on these findings, a phase III study labeled TRILOGY was developed to further explore cobimetinib, vemurafenib, and atezolizumab versus cobimetinib, vemurafenib, and placebo for patients with previously untreated BRAF-mutant metastatic melanoma. The study, which is expected to launch in early 2017, plans to enroll 500 participants, and the primary endpoint is PFS (NCT02908672).
Prior to the triplet study, atezolizumab was assessed in combination with single-agent cobimetinib. In this phase Ib study,2 patients received cobimetinib and atezolizumab at various doses. Cobimetinib was escalated from 20 mg daily to 60 mg daily for the first 21 days of a 28-day cycle. Atezolizumab was given at 800 every 2 weeks. The 60 mg daily dose of cobimetinib was discovered to be the maximum tolerated dose.
The study included 2 patients with ocular melanoma and 20 with non-ocular melanoma, of which 10 patients were BRAF-mutant and 10 were BRAF wild-type. In those with non-ocular melanoma, the ORR was 45% and the disease control rate was 75%. The median duration of response was 14.9 months. Response rates were similar regardless of BRAF status.
The median PFS was 12 months in those with non-ocular melanoma. In those with wild-type BRAF melanoma, the median PFS was 15.7 months and in those with BRAF mutations the median PFS was 11.9 months. After a median follow-up of 18.9 months, the median overall survival (OS) had not yet been reached.
Based on these findings, a phase III study was developed to explore the combination of atezolizumab and cobimetinib compared with the PD-L1 inhibitor alone in patients with untreated BRAF wild-type unresectable melanoma. The study is expected to open in 2017, according to a statement from the companies developing the drugs, Genentech and Exelixis.
In an earlier cohort of the same phase Ib study that assessed the triplet regimen,3 atezolizumab was combined with vemurafenib alone in patients with BRAF-mutant metastatic melanoma. In this study, patients received atezolizumab with vemurafenib concurrently (n = 3) or after a vemurafenib run-in period of 56 days (n = 8) or 28 days (n = 6). In this examination, the 28-day run-in was found to be superior, Sullivan noted.
Across all 17 patients in this portion of the study, the ORR was 76% with the doublet, which included 3 complete responses. In the concurrent group, the ORR was 33%. With the 56-day run-in, the ORR was 75% and for the 28-day run-in the ORR was 100%. Across all patients, the PFS was 10.9 months and the duration of response was 20.9 months.
"During the dose escalation of this combination, it was shown to be well tolerated and had promising efficacy. Given the changing landscape of combined BRAF/MEK inhibitors, this combination of vemurafenib, cobimetinib, and atezolizumab was added," noted Sullivan. "The lead-in from the study was found to be the best way of giving these drugs together."
In the phase III coBRIM study4 that led to the approval of vemurafenib plus cobimetinib for melanoma in November 2015, the ORR with cobimetinib/vemurafenib was 69.6% compared with 50% for vemurafenib alone. In the combination arm, 15.8% of patients had complete responses versus 10.5% with single-agent vemurafenib. The median duration of response was 13 months versus 9.2 months, respectively.
The 3-year OS rate was 37.4% with cobimetinib and vemurafenib compared with 31.1% for patients treated with vemurafenib alone. The median OS was 22.5 versus 17.4 months, for the combination and single-agent, respectively.