Elsevier

The Lancet

Volume 395, Issue 10240, 13–19 June 2020, Pages 1835-1844
The Lancet

Articles
Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(20)30934-XGet rights and content

Summary

Background

IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma.

Methods

IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc–IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients.

Findings

Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4–23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63–0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events.

Interpretation

The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma.

Funding

F Hoffmann–La Roche and Genentech.

Introduction

Immune checkpoint inhibitors and BRAF and MEK inhibitors have significantly improved treatment outcomes in patients with BRAFV600 mutation-positive metastatic melanomas.1, 2, 3, 4, 5, 6, 7, 8 Although BRAF and MEK inhibitors are associated with high objective response rates, most responses are short-lived.9 Immune checkpoint inhibitors provide more durable responses, but response rates are relatively lower.10 Because of these complementary clinical characteristics, the combination of the two approaches is appealing. A combination approach is also supported by preclinical and translational data showing the immunological effects of BRAF and MEK inhibitors, such as the influx of CD4 and CD8 T cells into tumours, the upregulation of melanoma antigens and expression of major histocompatibility complex class I and major histocompatibility complex class II on tumour cells, and a cytokine shift toward an interferon γ tumour milieu.11, 12, 13, 14 Early phase studies have shown promising antimelanoma activity and manageable safety with such combinations.15, 16, 17, 18, 19

The programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab is approved as a monotherapy or combination for selected patients with urothelial, lung, and breast cancer,20 and has shown activity as a monotherapy in advanced melanoma (objective response rate of 30%; median duration of response of 62 months in a cohort of 43 patients).21 Combination therapy with the BRAF inhibitor, vemurafenib, and the MEK inhibitor, cobimetinib, is approved for patients with BRAFV600 mutation-positive advanced or metastatic melanoma.2, 22 A phase 1b study in patients with BRAFV600 mutation-positive advanced melanoma showed that initiating vemurafenib and cobimetinib 4 weeks before atezolizumab and reducing vemurafenib dosing from 960 mg twice-daily to 720 mg twice-daily after 3 weeks was tolerable and efficacious (objective response rate of 71·8%; median duration of response of 17·4 months).16 Moreover, the initial period of targeted therapy was associated with favourable changes in the tumour immune microenvironment.16

Research in context

Evidence before this study

At the time of the drafting of these results, the approved systemic options for patients with advanced melanoma were immunotherapy (all patients) or BRAF and MEK inhibitors for the subset of patients with BRAF mutations in their tumours. Although immunotherapy provides durable responses, a substantial proportion of patients with melanoma have a poor response to immunotherapy; conversely, although most patients respond to MAPK pathway inhibitors, responses are often short-lived. It is clinically desirable to combine the higher response rates observed with targeted therapy with long-term clinical benefit associated with immune modulation, without compromising patient safety. On the basis of emerging preclinical and clinical evidence for potential synergy between immune checkpoint inhibition and BRAF and MEK inhibitors, IMspire150 explored whether a combination of atezolizumab, vemurafenib, and cobimetinib would prolong progression-free survival in patients with BRAF-mutation-positive advanced melanoma versus vemurafenib and cobimetinib. We searched PubMed for any clinical reports published until Feb 20, 2020, that explored similar systemic options. We used the search string “melanoma AND ((BRAF OR MEK inhibitor) AND (immune checkpoint inhibitor))” restricted to articles reporting on a clinical trial. We identified two previous publications reporting data from early phase clinical reports (KEYNOTE 022 and GP28384/NCT01656642) investigating this combination in melanoma, but no controlled phase 3 clinical studies.

Added value of this study

IMspire150 is the first phase 3 study to evaluate an immune checkpoint inhibitor combined with BRAF plus MEK inhibitors in patients with advanced BRAFV600 mutation-positive melanoma. The IMspire150 study met its primary progression-free survival endpoint and provided high-level evidence to show that combined inhibition with vemurafenib, cobimetinib, and atezolizumab prolongs progression-free survival in previously untreated patients with BRAF mutation-positive advanced melanoma. Reassuringly, the safety profile and treatment discontinuation rates with this combination were similar to those of the control group of vemurafenib and cobimetinib, which is an approved treatment option for patients with BRAF-mutation-positive advanced melanoma.

Implications of all the available evidence

The analysis reported here shows that atezolizumab combined with vemurafenib and cobimetinib is a safe and efficacious treatment option for patients with BRAF mutation-positive advanced melanoma. Survival data from this and other ongoing studies on treatment sequencing will inform the optimal treatment paradigm in this patient population.

We therefore did a randomised, controlled, phase 3 study that incorporated this dosing schedule to compare atezolizumab, vemurafenib, and cobimetinib versus atezolizumab placebo, vemurafenib, and cobimetinib in patients with previously untreated BRAFV600 mutation-positive advanced or metastatic melanoma.

Section snippets

Study design and participants

IMspire150 was a multicentre, phase 3, double-blind, placebo-controlled study. Eligible patients from 112 institutes in 20 countries were aged 18 years and above with histologically confirmed stage IV or unresectable stage IIIc melanoma per the American Joint Committee on Cancer's Staging Manual, 7th edn.23 Patients had documented BRAFV600 mutation-positive tumours by a locally approved test; Eastern Cooperative Oncology Group Performance Status of 0 or 1; measurable disease by Response

Results

Between Jan 13, 2017, and April 26, 2018, 514 patients were enrolled and randomly assigned to the atezolizumab group (n=256) or the control group (n=258) and comprised the intention-to-treat analysis population. Baseline demographic and disease characteristics can be seen in table 1.

The atezolizumab safety population comprised patients who received at least one dose of atezolizumab (n=230). The control safety population comprised patients who received at least one dose of study drug but no

Discussion

The addition of atezolizumab to vemurafenib and cobimetinib significantly prolonged the primary endpoint of investigator-assessed progression-free survival from 10·6 months to 15·1 months and reduced the relative risk for progression or death by 22% versus the comparator combination of vemurafenib and cobimetinib. The choice of the comparator was based on the prevailing standard-of-care at time of study design. Progression-free survival curves started to separate after 7 months and maintained

Data sharing

Qualified researchers might request access to individual patient-level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Additional details on Roche's criteria for eligible studies are available here: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx. For more details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see:

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    *

    Co-senior authors on this manuscript

    Current affiliation, Kartos Therapeutics, Redwood City, CA, USA

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