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Adding the PD-L1-directed immunotherapy atezolizumab (Tecentriq) to a targeted combination improved progression-free survival (PFS) for advanced melanoma patients with a BRAF V600 mutation, a phase III trial showed.

In over 500 patients receiving the BRAF/MEK inhibitor combination of vemurafenib (Zelboraf) plus cobimetinib (Cotellic) as initial therapy, those randomized to atezolizumab achieved a median investigator-assessed PFS of 15.1 months, as compared with 10.6 months for those assigned to placebo (HR 0.78, 95% CI 0.63-0.97, P=0.025), reported Grant McArthur, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia.

Findings from IMspire150, presented at the American Association for Cancer Research (AACR) virtual meeting, showed superior investigator-assessed PFS favoring the triplet over the doublet at both 12 months (54.0% vs 45.1%) and 18 months (43.6% vs 31.6%).

"Patients with advanced BRAF-mutant melanoma can be treated with combinations of BRAF and MEK inhibitors that offer the advantage of high response rates -- however, for many patients these responses are short-lived," McArthur said. "Immune checkpoint inhibitors, in contrast, provide more durable responses, but have a lower response rate."

While response rates in the trial were similar between the two arms (66.3% with the triplet and 65.0% with the doublet), the median duration of response was 21.0 months with atezolizumab and 12.6 months with placebo -- a "clinically meaningful improvement," said McArthur. At 1 year, 69.4% versus 50.8%, respectively, had maintained their responses.

An interim overall survival analysis favored the atezolizumab arm numerically (28.8 vs 25.1 months), and at 2 years, 60.4% of patients assigned to atezolizumab were alive versus 53.1% of those on placebo.

However, PFS as assessed by an independent review committee -- a key secondary endpoint -- failed to show statistical significance (median 16.1 months with the triplet vs 12.3 months with the doublet). Landmark analyses favored the atezolizumab arm at all time points analyzed:

• 6 months: 77.6% vs 75.3%
• 12 months: 54.8% vs 51.1%
• 18 months: 45.2% vs 36.9%

AACR invited discussant Charles Sawyer, MD, of Memorial Sloan Kettering Cancer Center in New York City, questioned whether the BRAF/MEK inhibitor control arm in IMspire150 was still relevant.

"Since the time this trial was initiated, the standard of care for these patients has changed and that's based upon the remarkable benefit of giving combined checkpoint blockade," he said, pointing to , which demonstrated a 5-year PFS rate of 38% for advanced melanoma patients with BRAF mutations treated upfront with the PD-1-directed agent nivolumab (Opdivo) plus ipilimumab (Yervoy), a CTLA-4-directed checkpoint inhibitor.

Unclear from the IMspire150 data, said Sawyer, is whether the targeted agents are indeed priming the tumor microenvironment for immunotherapy, thereby improving outcomes. He suggested the possibility that no synergy exists between the agents, and that patient-to-patient variability could simply be playing a role.

Study Details

IMspire150 was an international trial that randomized 514 patients with previously untreated advanced BRAF-mutant melanoma to the doublet or triplet regimens. In the doublet arm, patients received the BRAF inhibitor vemurafenib (960 mg, twice daily) plus the MEK inhibitor cobimetinib (60 mg, once daily on days 1-21 of a 4-week cycle).

In the triplet arm, patients received a similar vemurafenib-cobimetinib loading dose during cycle one, and starting at cycle two received a lower dose of vemurafenib (720 mg), plus cobimetinib (same dose) and intravenous atezolizumab (840 mg on days 1 and 15 of 4-week cycles).

Baseline characteristics were well balanced. Patients had a median age of 54 years, 58% were men, all had good performance status, and most were treated in Europe (79%). Nearly all patients had metastatic disease (94%), with the majority having more than three involved organs, and about one-third in each arm had elevated lactate dehydrogenase (LDH).

Common treatment-related toxicities were similar between the two arms, but several occurred with greater frequency in the triplet arm: pyrexia (38% vs 26% in doublet), arthralgia (39% vs 28%), increased alanine aminotransferase (34% vs 23%) and aspartate aminotransferase (30% vs 20%), hypothyroidism (17% vs 6%), and hyperthyroidism (16% vs 8%).

Treatment discontinuation for toxicity occurred in 12.6% of patients on the triplet and 15.7% of those on the doublet. In all, 14 treatment-related deaths occurred (seven in each arm).

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