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Background: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients., Methods: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months)., Results: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed., Conclusions: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Outcomes for patients with melanoma have improved over the past decade as a result of the development and FDA approval of immunotherapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1). However, these therapies do not benefit all patients, and an area of intensive research investigation is identifying biomarkers that can predict which patients are most likely to benefit from them. Here, we report exploratory analyses of the associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival, and overall survival in patients with advanced melanoma treated as part of the CheckMate 066 and 067 phase III clinical trials evaluating immuno-oncology therapies. In patients enrolled in CheckMate 067 receiving the anti-PD-1 inhibitor nivolumab (NIVO) alone or in combination with the anti-CTLA-4 inhibitor ipilimumab (IPI) or IPI alone, longer survival appeared to associate with high (>median) versus low (≤median) TMB and with high versus low inflammatory signature scores. For NIVO-treated patients, the results regarding TMB association were confirmed in CheckMate 066. In addition, improved survival was observed with high TMB and absence of BRAF mutation. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immune checkpoint blockade in advanced melanoma., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC)., Patients and Methods: A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared., Results: In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI., Conclusion: Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months., Competing Interests: Disclosure AAT has served as an advisor/consultant to Array BioPharma, BioNtech, Clinigen, Bristol Myers Squibb, EMD Serono, Genentech/Roche, ImmunoCore, Merck, NewLink Genetics, Novartis, Partner Therapeutics, Pfizer, and Sanofi-Genzyme/Regeneron; and has received institutional research support from Bristol Myers Squibb, Genentech/Roche, Merck, and OncoSec. KT is an employee of Precision HEOR, which was contracted by Bristol Myers Squibb for the current work. KC is an employee of Precision HEOR, which was contracted by Bristol Myers Squibb for the current work. DFM has served as a consultant to Alkermes, Bristol Myers Squibb, Eisai, Eli Lilly, EMD Serono, Iovance, Merck, and Pfizer; and has received research support from Alkermes, Bristol Myers Squibb, Exelixis, Genentech, Merck, Pfizer, and X4 Pharmaceuticals. PM has served as an advisor to Amgen, Bristol Myers Squibb, GSK, Merck KGaA, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; has worked as a speaker for Amgen, Bristol Myers Squibb, GSK, Merck KGaA, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; and has received institutional research support from Bristol Myers Squibb and MSD. JL has served as a consultant to Achilles Therapeutics, AstraZeneca, Aveo, Boston Biomedical, Bristol Myers Squibb, Covance, Eisai, EUSA Pharma, GSK, Immunocore, Imugene, Incyte, iOnctura, Ipsen, Kymab, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Pharmacyclics, Roche, Secarna, and Vitaccess; and has received research support from Achilles Therapeutics, Bristol Myers Squibb, Covance, Immunocore, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Roche, Secarna, and Vitaccess. FSH has served as an advisor/consultant to Aduro, Apricity, Bristol Myers Squibb, Checkpoint Therapeutics, Compass Therapeutics, Corner Therapeutics, Eisai, EMD Serono, Genentech/Roche, Idera, Kairos, Merck, Novartis, Pionyr, Sanofi, 7 Hills Pharma, Surface, Takeda, Torque, Rheos, Pieris Pharmaceutical, PsiOxus Therapeutics, and Zumutor; holds equity in Bicara and Pionyr; and is named on several patents and patents pending and on patents issued to or pending for Dana-Farber Cancer Institute. CL is an employee of Bristol Myers Squibb. JIR is an employee of Bristol Myers Squibb; holds stocks in Bristol Myers Squibb; and is named on a patent pending for Bristol Myers Squibb. HJ provided consultancy services to Bristol Myers Squibb related to the current work. AM is an employee of Bristol Myers Squibb and holds stock in Bristol Myers Squibb. SR is an employee of Bristol Myers Squibb. SK is an employee of Bristol Myers Squibb. MBA has served as an advisor/consultant to Agenus, Alexion, Apexigen, Arrowhead, Aveo, Bristol Myers Squibb, COTA, Eisai, Exelixis, Genentech/Roche, Idera, ImmunoCore, Iovance, Leads BioPharma, Merck, Neoleukin, Novartis, and PACT, Pfizer, Pneuma, Pyxis Oncology, Third Rock Ventures, and Werewolf; and has received institutional research funding from Bristol Myers Squibb. Data sharing Bristol Myers Squibb's policy on data sharing is available at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lower clearance of immune checkpoint inhibitors is a predictor of improved overall survival (OS) in patients with advanced cancer. We investigated a novel approach using machine learning to identify a baseline composite cytokine signature via clearance, which, in turn, could be associated with OS in advanced melanoma. Peripheral nivolumab clearance and cytokine data from patients treated with nivolumab in two phase III studies (n = 468 (pooled)) and another phase III study (n = 158) were used for machine-learning model development and validation, respectively. Random forest (Boruta) algorithm was used for feature selection and classification of nivolumab clearance. The 16 top-ranking baseline inflammatory cytokines reflecting immune-cell modulation were selected as a composite signature to predict nivolumab clearance (area under the curve (AUC) = 0.75; accuracy = 0.7). Predicted clearance (high vs. low) via the cytokine signature was significantly associated with OS across all three studies (P < 0.01), regardless of treatment (nivolumab vs. chemotherapy)., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Background: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial., Methods: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group., Results: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted., Conclusions: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)., (Copyright © 2019 Massachusetts Medical Society.)

Herein is reported the preparation of several series of symmetrical polyammonium salts that serve as cationic lipids or precursors thereof, and are structurally based on several series of parent diamines where dimethylazonia functionalities are present, separated by a central structural unit, and pendant terminal chains. The resultant materials are of significant interest for a variety of purposes, such as serving as antihydrophobic species and as transfectins, the details of which are provided in separate reports. Attempts to effect selective alkylation to provide the corresponding unsymmetrical cationic lipids were without success, always leading to relatively useless mixtures of products.

Herein is reported the preparation of several series of polyammonium salts that serve as cationic lipids or precursors thereof, and are structurally based on the parent diamine 1,4-diazabicyclo[2.2.2]octane (dabco). Through selective alkylation of dabco a variety of di- and tetracationic lipid species and precursors thereof have been prepared. The resultant materials are of significant interest for a variety of purposes, including serving as antimicrobial agents and antihydrophobic species, the details of which are provided in separate reports.