SUMMARY We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multidimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.
BACKGROUND Approximately 50% of melanomas harbor activating (V600) mutations in the serine–threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600–mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600–mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600–mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann–La Roche; ClinicalTrials.gov number, NCT00949702.)
Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).
Summary Background Dabrafenib plus trametinib (D+T) improves outcomes in BRAF V600–mutant metastatic melanoma without brain metastases; however, activity of D+T has not been studied in active melanoma brain metastases (MBM). Here, we report results from the phase 2 trial COMBI-MB. Our aim was to build upon the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of D+T in patients with BRAF V600–mutant melanoma brain metastases. Methods This ongoing open-label, phase 2 study (NCT02039947) evaluated dabrafenib 150 mg twice daily plus trametinib 2 mg once daily in four melanoma patient cohorts: (A) BRAF V600E, asymptomatic MBM, no prior local brain therapy; (B) BRAF V600E, asymptomatic MBM, prior local brain therapy; (C) BRAF V600D/K/R, asymptomatic MBM, with or without prior local brain therapy; and (D) BRAF V600D/E/K/R, symptomatic MBM, with or without prior local brain therapy. The primary objective was to assess intracranial response rate (IRR) in cohort A in the all-treated-subjects population. Secondary endpoints included IRR in cohorts B–D; extracranial and overall response rates; disease control rates; duration of intracranial, extracranial, and overall response; progression-free survival; overall survival; and safety. Findings A total of 125 patients were enrolled (A: n=76; B: n=16; C: n=16; D: n=17). At the data cutoff (November 28, 2016; median follow-up 8·5 months) investigator-assessed IRR was 58% (n=44/76) in cohort A. Intracranial response by investigator assessment was also achieved in 9 (56%) of 16 patients in cohort B, 7 (44%) of 16 patients in cohort C, and 10 (59%) of 17 patients in cohort D. Safety results were consistent with prior D+T studies, with 60 (48%) of 125 patients across cohorts experiencing grade 3/4 adverse events. The most common serious adverse events across cohorts were pyrexia (n=9/125; 7%) and ejection fraction decreased (n=5/125; 4%). Interpretation D+T was active with a manageable safety profile in patients with BRAF V600–mutant MBMs, but the median duration of response was relatively short. These results provide evidence of clinical benefit with D+T and support the need for additional research to further improve outcomes in patients with MBMs. Funding Novartis.
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