The following article features coverage from the American Association for Cancer Research (AACR) 2020 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Atezolizumab in combination with cobimetinib and vemurafenib prolonged progression-free survival (PFS) — and responses were more durable than placebo and BRAF/MEK inhibition — among patients with previously untreated unresectable or metastatic melanoma, according to results from the phase 3 IMspire150 trial.

Immune checkpoint inhibitors and BRAF/MEK inhibitors are approved for the treatment of melanoma, but both have their limitations. Immune checkpoint inhibitors elicit lower response rates, whereas responses to BRAF/MEK inhibition are less durable. The aim of this study was to determine if combining these 2 approaches would improve efficacy.

The randomized, phase 3 IMspire150 trial assigned 514 patients with previously untreated stage IIIc/IV melanoma to receive cobimetinib-vemurafenib during the first cycle, followed by vemurafenib plus vemurafenib placebo (atezolizumab group) or vemurafenib (placebo group) leading up to the second cycle. Beginning with the second cycle, patients received either atezolizumab plus cobimetinib and vemurafenib or placebo plus cobimetinib and vemurafenib until disease progression or unacceptable toxicity.

The primary endpoint was investigator-assessed PFS, and key secondary endpoints included PFS by an independent review committee, objective response rate (ORR), duration of response (DOR), and overall survival (OS).

Baseline demographics were similar between arms, with a median age of 54 years, and 58% male. The majority of the population was enrolled in Europe (79%), followed by Australia/New Zealand/other (16%), and North America (5%). Most patients had stage IV disease (94%) and 33% had elevated lactate dehydrogenase levels.

After a median follow-up of 18.9 months, investigator-assessed PFS was significantly prolonged in the atezolizumab combination arm with a median of 15.1 months (95% CI, 11.4-18.4 months) compared with 10.6 months (95% CI, 9.3-12.7 months) in the placebo arm (hazard ratio [HR], 0.78; 95% CI, 0.63-0.97; P =.0249). This benefit was observed across all subgroups.

The 12- and 24-month PFS was 54% and 43.6% with the atezolizumab combination, respectively, compared with 45.1% and 31.6% with the placebo arm, respectively. PFS by independent review favored the atezolizumab combination, but was not significant (median, 16.1 vs 12.3 months; P =.1607).

The objective response rate was similar between arms (data not reported). The atezolizumab combination resulted in a longer DOR at 21.0 months compared with 12.6 months in the placebo arm.

Although the OS data were not yet mature, the interim analysis estimated the median OS was 28.8 months in the atezolizumab arm compared with 25.1 months in the placebo arm. 

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“There was no difference in OS at 12 months, however, by 24 months the OS favored the atezolizumab arm,” Grant A. McArthur, MB, PhD, of Peter MacCallum Cancer Centre in Australia, who was first author and presenter of the study, said. “Ongoing follow-up is critical to determine if these curves will continue to separate with time,” he added.

The rates of treatment-related adverse events were similar between arms; however, patients in the atezolizumab combination arm were more likely to experience pyrexia, arthralgia, aspartate aminotransferase or alanine aminotransferase increase, hypothyroidism, and hyperthyroidism. Discontinuation due to AEs occurred in 12.6% of patients in the atezolizumab combination arm compared with 15.7% in the placebo arm.

In conclusion, Dr McArthur said that “overall, atezolizumab combined with vemurafenib and cobimetinib did provide a statistically significant and clinically meaningful improvement in PFS that was investigator-assessed when compared with placebo that was combined with vemurafenib and cobimetinib.”

Disclosures: Some of the study authors disclosed financial relationships with pharmaceutical and/or medical companies. For a full list of disclosures, please refer to the study abstract.

Read more of Cancer Therapy Advisor‘s coverage of AACR 2020 meeting by visiting the conference page.

Reference

McArthur GA, Stroyakovskiy D, Gogas H, et al. Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFv600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. Presented at: American Association for Cancer Research Virtual Annual Meeting I; April 27-28, 2020. Abstract CT012.