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
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.