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A Phase III Study of Spartalizumab in Combination with Dabrafenib and Trametinib Did Not Meet Primary Endpoint in BRAF V600–Mutated Metastatic Melanoma

Findings from the COMBI-I study
20 Jan 2022
Cancer Immunology and Immunotherapy;  Melanoma and other skin tumours;  Personalised medicine

COMBI-i did not show a statistically significant difference in investigator-assessed progression-free survival (PFS) in the broad population of patients with BRAF V600–mutated metastatic melanoma treated in this phase III study of spartalizumab in combination with dabrafenib and trametinib versus placebo in combination with dabrafenib and trametinib. Spartalizumab in combination with dabrafenib plus trametinib was associated with higher rates of adverse events and dose modifications than dabrafenib plus trametinib alone. The study findings are published by Prof. Reinhard Dummer of the University Hospital Zürich Skin Cancer Center in Zürich, Switzerland and colleagues on 14 January 2022 in the Journal of Clinical Oncology.

Preclinical data suggest the combination of an anti–PD1 antibody plus dabrafenib and trametinib has superior antitumour activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutated metastatic melanoma. 

COMBI-i is a global, randomised, phase III study evaluating the safety and efficacy of the anti–PD-1 antibody spartalizumab in combination with dabrafenib and trametinib. Findings from the open-label part 1 of safety run-in with 9 patients and part 2 of biomarker cohort with 27 patients showed the regimen has an acceptable safety profile and promising efficacy. The objective response rate (ORR) was 78% (28 of 36 patients), including a complete response rate of 44% (16 of 36 patients). 

Now, the study team report the primary analysis of the randomised, double-blind, placebo-controlled part 3, comparing spartalizumab in combination with dabrafenib and trametinib against placebo plus dabrafenib and trametinib in patients with BRAF V600–mutated unresectable or metastatic melanoma.

Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo plus dabrafenib and trametinib. The study participants were age ≥18 years with unresectable or metastatic BRAF V600–mutated melanoma. The primary endpoint was investigator-assessed PFS. Overall survival (OS) was a key secondary endpoint.

At data cut-off of 1 July 2020, the median PFS was 16.2 months (95% confidence interval [CI] 12.7 to 23.9 months) in the spartalizumab in combination with dabrafenib and trametinib arm versus 12.0 months (95% CI 10.2 to 15.4 months) in the placebo in combination with dabrafenib and trametinib arm (hazard ratio [HR] 0.82, 95% CI 0.66 to 1.03; p = 0.042, one-sided; non-significant).

The ORR rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively.

Although OS cannot be formally tested because the primary endpoint was not met, patients remain in follow-up, and future exploratory OS analyses are planned. 

Preplanned exploratory subgroup analyses suggested a greater PFS benefit with spartalizumab combined with dabrafenib and trametinib in patients with features indicative of higher disease burden, such as ≥3 sites of metastasis or a median sum of lesion diameters ≥66 mm, which may warrant further risk-benefit analyses. Numerically lower PFS HRs were also observed in patients with PD-L1–positive tumours or high tumour mutational burden, features that have previously been associated with improved clinical outcomes with first-line anti–PD-1 monotherapy.

Grade ≥3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the spartalizumab in combination with dabrafenib and trametinib arm and 33% (88 of 264) in the placebo in combination with dabrafenib and trametinib arm.

The authors commented although the results of COMBI-i do not support broad first-line use of spartalizumab in combination with dabrafenib and trametinib in patients with BRAF V600–mutated melanoma, the study findings provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutated metastatic melanoma. Further biomarker-driven analyses may help to determine whether there are subpopulations that could benefit from upfront immunotherapy plus targeted therapy combination.

In an accompanied editorial, Dr. Margaret K. Callahan of the Memorial Sloan Kettering Cancer Center and Prof. Paul B. Chapman of the Weill Cornell Medical College, both based in New York, NY, US, wrote that consistently with two previous randomised studies, the addition of anti–PD1 or anti–PD-L1 antibodies to combination treatment of RAF inhibitor plus MEK inhibitor is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, there is some evidence of harm, as the additional toxicity of triplet combination limited the delivery of combination of RAF inhibitor plus MEK inhibitor treatment in COMBI-i study. Focus should be instead on optimising doses and schedules of combination of RAF inhibitor plus MEK inhibitor and immune checkpoint inhibitor (ICI), developing treatment strategies to overcome resistance, and determining how best to sequence combination of RAF inhibitor plus MEK inhibitor and ICI. 

Professors Reinhard Dummer and Georgina V. Long contributed equally to this work and share the position of first author, Antoni Ribas and Dirk Schadendorf contributed equally to this work and share the position of senior author.

The data were presented previously in part at the ESMO 2020 Virtual Congress.

The study was supported by Novartis Pharmaceuticals Corporation.

References

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