Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES)
Publication Year 2021-10, Volume 9, Issue #10, Page e002995
Journal Title
Journal for Immunotherapy of Cancer
BACKGROUND: Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. METHODS: Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAF(V600) mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAF(V600) mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. RESULTS: Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value <0.05, false discovery rate (FDR) <0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). CONCLUSIONS: Second-line ipilimumab-nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab-nivolumab showed enrichment of the IPRES gene signature.
BMJ Journals
central nervous system neoplasms; immunotherapy; melanoma; tumor microenvironment; support for meeting attendance (Merck Sharp and Dohme). DKe has received honoraria; (Merck Sharp and Dohme, and Bristol Myers Squibb), support for meeting attendance; (MSD) and fees for advisory board (Novartis and Merck). PB has received honoraria; (Novartis) and received support for meeting attendance (Merck Sharp and Dohme). DKo; has received support for meeting attendance (Merck and Pfizer). PS has received; grants (Bristol-Myers Squibb, Roche/Genentech, Allergan, Compugen, Beigene and; Crispr Therapeutics), support for meeting attendance (Bristol-Myers Squibb,; Roche/Genentech and Astra Zeneca) and advisory board (Bristol-Myers Squibb). BS has; received honoraria and fees for advisory board (Bristol-Myers Squibb, Merck Sharp; and Dohme, AstraZeneca, Pfizer, Roche/Genentech, Amgen, Lilly, Amgen and; Sanofi/Regeneron) SS has received grants (Novartis, Advanced Accelerator; Applications, AstraZeneca, Merck Sharp and Dohme, Amgen and Genentech) and personal; fees donated to the institution (AstraZeneca, Merck Sharp and Dohme, Bristol Myers; Squibb and AstraZeneca) outside the submitted work. GAM has been a consultant or; advisor (Provectus), received research funding from (Pfizer, Celgene, and Ventana); and has had travel accommodation and expenses paid (Roche and Novartis). No stated; competing interests: BF, LS, AL, RM, KS, AW, CA, BL, RJY, AI, HAY, IAV, KD, KES and; TP.
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Creation Date: 2021-10-26 10:03:49
Last Modified: 2021-10-26 10:31:46
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