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Observational Study
. 2018 Jul 3;18(1):705.
doi: 10.1186/s12885-018-4618-9.

Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma

M Amini-Adle  1 , N Khanafer  2 , M Le-Bouar  3 , G Duru  4 , S Dalle  3 , L Thomas  3
Affiliations
Observational Study

Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma

M Amini-Adle et al. BMC Cancer. .

Abstract

Background: Anti-PD-1 and BRAF-inhibitors (BRAFi) have been approved as first-line treatments in advanced melanoma. To date, no prospective data are available to give the best sequence of treatment. The objective of this study was to evaluate in real-life the efficacy of anti-PD-1 after BRAFi, ipilimumab, or chemotherapy failure.

Methods: This was a single institution cohort analysis in patients treated with anti-PD-1 right after BRAFi, ipilimumab, or chemotherapy failure. Melanoma evolution after anti-PD-1 initiation was analyzed in BRAF-mutated and BRAF wild-type patients. The efficacy of treatment was evaluated by Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).

Results: Seventy-four patients were included: 33 wild-type and 41 BRAF-mutated melanoma. ORR to anti-PD-1 was significantly lower in BRAF-mutated patients (12.2% vs. 45.5%, p = 0.002). After anti-PD-1 initiation, the median PFS and OS was significantly shorter in the BRAF mutated group (2 vs. 5 months and 7 vs. 20 months, p = 0.001). The hazard ratio for disease progression was of 2.3 (95%CI:1.3-3.9; p = 0.003) and 2.5 (95%CI:1.3-4.5; p = 0.005) for death. Thirty-nine percent of BRAF-mutated-patients died within 3 months after anti-PD-1 initiation. Rapid death (≤3 months) was significantly higher in BRAF-mutated patients (55.2% vs. 20.0%, p = 0.014).

Discussion: This is the largest series of unselected patients treated in real-life with anti-PD-1 as second-or-higher line of treatment. Anti-PD-1 was less effective in BRAF-mutated cases as a majority of patients presented aggressive tumor evolution after BRAFi discontinuation. These data are consistent with previous studies suggesting a negative impact of BRAFi prior to immunotherapy.

Keywords: Anti PD-1; BRAF inhibitor; Immunotherapy; Melanoma; Treatment sequence.

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Conflict of interest statement

Ethics approval and consent to participate

The Ethics committee from Hospices Civils de 390 Lyon has approved this retrospective study. Eligible patients were selected from two 391 prospective studies: “MELBASE” and “PAIR”. Melbase is a French multicenter prospective 392 database following patients starting first-line treatment for stage IV melanoma (NCT 393 02828202). PAIR (Programme d’Actions Intégrées de Recherche) is a single center cohort of 394 patients treated with nivolumab as second line of therapy (NCT 02626065). All patients gave 395 their written informed consent to participate in these databases.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests. However, several authors have received funding for work not related to this manuscript.

Dr Mona Amini-Adle is co-investigator in several clinical trials conducted by Roche Genetech, BMS, Merck Serono, Novartris. She received travel costs covered by BMS, AMGEN.

Dr Nagham Khanafer reports a PhD grant from Sanofi Pasteur, non-financial support (travel expenses) from Alere, Astellas and Sanofi Pasteur and personal fees from Astellas.

Pr Stéphane Dalle is either principal investigator or co-investigator in several clinical trials conducted by Roche Genetech, BMS, Merck Serono, Novartris. He received a research grant (not related with the present work) and travel costs covered by Roche Genetech, BMS.

All authors declare that they have sufficiently participated in the submitted work to deserve authorship, all have had access to clinical material and have revised the manuscript before submission.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Survival analysis according to BRAF mutational status. a Kaplan Meier curve of Progression free survival (PFS) according to BRAF status. b Kaplan Meier curve of overall survival (OS) according to BRAF status
See this image and copyright information in PMC

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