IMspire 150 trial

Background

Phase III double-blind RCT of 514 randomised patients (777 screened) with unresectable stage IIIc-IV BRAF V600-mutant melanoma, testing addition of the anti-PD-L1 atezolizumab to vemurafenib plus cobimetinib.

Interventions and follow up

Arm A: Cycle 1: vemurafenib 960mg BID d1-21 then 720mg BID + cobimetinib 60mg/d d1-21. Cycle 2+: atezolizumab 840mg q2wk + vemurafenib 720mg + cobimetinib 60mg
Arm B: Cycle 1: vemurafenib 960mg BID + cobimetinib 60mg/d d1-21. Cycle 2+: placebo q2wk + vemurafenib 720mg + cobimetinib 60mg
Primary endpoint: investigator-assessed PFS
Median follow up: 18.9mo

Results

mPFS: 15.1mo vs 10.6mo (A vs B); HR 0.78, 95%CI 0.63-0.97, P=.025
Treatment discontinuation: 45% vs 51%
Discontinuation due to death: 36% vs 43%
OS: immature at primary report

Adverse events

Overall (A vs B): any-grade 99% vs 99%, grade ≥3 79% vs 74% (difference not statistically significant)
Common (combination): elevated LFTs, lipase elevation, photosensitivity rash, CPK elevation, nausea
Immune/infusion-related: infusion reactions and immune-mediated events more frequent with atezolizumab

Conclusions

Adding atezolizumab to vemurafenib plus cobimetinib significantly prolonged PFS in BRAF V600-mutant melanoma without a significant increase in grade ≥3 toxicity, establishing a first triplet targeted-immunotherapy regimen.

Key Limitations

Modest absolute PFS gain; immature OS; restricted to BRAF V600 disease; complex dosing schedule; no comparison against checkpoint inhibitor doublets, leaving the optimal first-line sequence uncertain.

Clinical Context

Supported FDA and EMA approval of atezolizumab plus vemurafenib and cobimetinib for BRAF V600-mutant melanoma. ASCO and ESMO recognise targeted-immunotherapy triplets as an option within the broader first-line landscape.

References