Triple Combination Improves PFS in BRAF-Positive Melanoma

July 2020 Vol 11, No 7



The combination of the checkpoint inhibitor atezolizumab plus the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib improved progression-free survival (PFS) and lengthened duration of responses compared with the 2 targeted therapies plus placebo in newly diagnosed BRAF V600E/K–mutant advanced melanoma, according to results of the phase 3 IMspire150 trial presented at the 2020 virtual meeting of the American Association for Cancer Research.

Investigator-assessed median PFS was 15.1 months for the triplet versus 10.6 months for the placebo arm (P = .025). Twelve-month PFS was 54.0% versus 45.1%, respectively, and 18-month PFS was 43.5% versus 31.6%, respectively.

Interim analysis of survival favored the atezolizumabcontaining arm compared with vemurafenib/cobimetinib plus placebo.

Grant A. McArthur, PhD

“Atezolizumab combined with vemurafenib and cobimetinib showed a statistically significant and clinically significant improvement in investigator-assessed PFS versus placebo plus vemurafenib and cobimetinib. The addition of atezolizumab led to a clinically meaningful improvement in duration of response versus vemurafenib and cobimetinib alone.

“Based on these results, combination therapy with atezolizumab, vemurafenib, and cobimetinib represents a viable treatment option for this group of patients,” said lead author Grant A. McArthur, PhD, Peter MacCallum Cancer Centre, Melbourne, Australia.

The international IMspire150 trial randomized 514 treatment-naive patients with BRAF V600E–positive stage IIIc or IV advanced melanoma 1:1 to treatment with the triplet combination versus the 2 targeted therapies. Treatment in the control arm was vemurafenib 960 mg/bid plus cobimetinib 60 mg/day on days 1 to 21 of a 4-week cycle. The experimental arm received atezolizumab 840 mg on days 1 and 15 of 4-week cycles plus a similar loading dose of vemurafenib/cobimetinib for cycle 1; during cycle 2, the dose of vemurafenib was lower (720 mg). Treatment was given on days 1 and 15 of each 28-day cycle and continued until disease progression, death, or unacceptable toxicity.

Baseline demographic and clinical characteristics were well balanced between the arms. Almost all the patients (94%) had metastatic disease.

Objective response rates were similar in the groups, but atezolizumab extended median duration of response to 21.0 months versus 12.6 months, respectively. “This was a clinically meaningful difference,” Dr McArthur noted.

Independent review committee assessment of PFS did not show a significant difference between treatment arms: median of 16.1 months for the triplet versus 12.3 months for the doublet. At 6 months, 12 months, and 18 months, landmark analysis favored the atezolizumabcontaining arm over the doublet.

All subgroup analyses of PFS favored the experimental arm, including age, lactate dehydrogenase, disease burden, and extent of disease by organ site.

Overall survival data were not mature at the time of analysis, but interim analysis numerically favored the triplet.

No unexpected side effects were reported. Treatment- related adverse events in 30% or more of patients in the experimental arm versus controls, respectively, were increased serum creatinine phosphatase (CPK) levels (51.3% vs 44.8%), diarrhea (42.2% vs 46.6%), rash (40.9% in both arms), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), increased ALT (33.9% vs 22.8%), and increased lipase (32.2% vs 27.4%).

Grades 3/4 treatment-related adverse events in more than 10% of patients, respectively, were increased lipase (20.4% vs 20.6%), increased serum CPK (20.0% vs 14.9%), increased ALT (13.0% vs 8.9%), and maculopapular rash (12.6% vs 9.6%).

Commenting on this study, discussant Charles Sawyers, MD, Memorial Sloan Kettering Cancer Center, said: “To me, the biggest question is why the combination therapy [ie, plus atezolizumab] is better. Perhaps the targeted agents prime the microenvironment for immunotherapy, changing the tumor from ‘warm’ to ‘hot.’ It is also possible that the benefit of combination therapy is due to patient-to-patient variability without drug activity or synthesis; that is, the benefit is actually due to the fact that some patients respond well to drug A and some to drug B. Time will tell.”

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Last modified: August 10, 2023

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