PURPOSE: Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma. MATERIALS AND METHODS: All patients with... Show morePURPOSE: Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma. MATERIALS AND METHODS: All patients with advanced melanoma treated with first-line anti-PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to BRAF and NRAS status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS. RESULTS: In total, 1764 patients received anti-PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti-PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for BRAF-mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with NRAS-mutant (4.8 months; 95% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95% CI, 3.6 to 7.1). In multivariable analysis, BRAF-mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for BRAF-mutant melanoma compared with NRAS-mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens. CONCLUSION: Ipilimumab-nivolumab-treated patients with BRAF-mutant melanoma display improved PFS and OS compared with patients with NRAS-mutant and double wild-type melanoma. BRAF mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma. Show less
As a subset of advanced melanoma patients derive long-term benefit from anti-PD-1 therapy, early identification of non-responsiveness would enable an early switch to next line therapies. This study... Show moreAs a subset of advanced melanoma patients derive long-term benefit from anti-PD-1 therapy, early identification of non-responsiveness would enable an early switch to next line therapies. This study assessed if an early increase in S100B or lactate dehydrogenase (LDH) could be predictive for non-responsiveness to anti-PD-1. We retrospectively analysed advanced melanoma patients treated with anti-PD-1 monotherapy. Serum S100B and LDH levels were measured at baseline and before every infusion. Non-response was defined as progression or death at 6 months. Marker cut-offs were defined based on > 95% specificity and feasibility in clinical practice. For validation an independent cohort was analysed. In total, 313 patients were included (166 patients in training cohort, 147 patients in validation cohort). Increase of > 50% in LDH or > 100% in S100B above upper limit of normal at week 6 compared to baseline was determined as criterion to positively test for non-responsiveness. In the validation cohort, obtained specificity of the combination test was > 95% with a positive predictive value of 82%; obtained sensitivity was lower (21%), with a negative predictive value of 55%. Early increase in S100B or LDH is a strong parameter for non-responsiveness to anti-PD-1 in advanced melanoma. Prospective confirmation is needed before clinical implementation. Show less
Serra-Bellver, P.; Versluis, J.M.; Oberoi, H.K.; Zhou, C.; Slattery, T.D.; Khan, Y.; ... ; Lorigan, P. 2022
Purpose: To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma.Pat...Show morePurpose: To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma.Patients and methods: This retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated.Results: A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval [CI] 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6-26.5). Median PFS was 7.9 months (95% CI 5.8-10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3-4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded.Conclusion: The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials. Show less
