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Background: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy., Methods: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete., Findings: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8-15·1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11·5%, 90% CI 1·2-21·8] of 26 patients) and the low-dose radiotherapy group (two [7·7%, 0·0-16·3] of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three [11·5%, 1·2-21·8] of 26 patients; p=0·99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy., Interpretation: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting., Funding: The US National Institutes of Health and the Dana-Farber Cancer Institute., Competing Interests: Declaration of interests JDS declares research support paid to their institution from Merck, BMS, Regeneron, Debiopharm, and the NCI; consulting or participation on a scientific advisory board, and travel fees and payment for lectures from Genentech, Immunitas, Debiopharm, BMS, Nanobiotix, Tilos, AstraZeneca, LEK, Catenion, ACI Clinical, Astellas, Stimit, and Merck; expert witness fees from Pearson Doyle Mohre and Pastis, Kline and Specter, and Heidell, Pittoni, Murphy and Bach; stock options from Immunitas; and equity in Doximity. SMA declares research support paid to her institution from Merck, Exilixis, Abbvie, Kura Oncology, Amgen, and Nektar. RDG declares support for the present manuscript from a grant from the NCI of the National Institutes of Health (NIH); grants or contracts (to his institution) from Pfizer, Mirati, Daiichi Sankyo, Jounce Therapeutics, Helsinn, BMS, Merck, Janssen, and Takeda; honoraria from Rockpointe CME, Targeted Oncology, OncLive, and the Society for Immunotherapy of Cancer; reimbursement for travel for meetings from Pfizer and AstraZeneca; participation on advisory boards for Mirati, Daiichi Sankyo, AstraZeneca, Sanofi, Oncocyte, Jazz Pharmaceuticals, BluePrint Medicines, and Pfizer; and that he is co-chair of the Hoosier Cancer Research Network Thoracic Clinical Trial Working Group. CL declares honorarium for chairing the data and safety monitoring board for Delcath. JH declares participation on advisory boards for Bayer and Merck, and research funding from Merck, Boston Biomedical, Treos Bio, Senhwa Biosciences, Bayer, Incyte, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene, Taiho Pharmaceutical, Effector Therapeutics, and G1 Therapeutics. JLA declares research support from Pfizer; scientific advisory board membership for the Lustgarten Foundation, Stand Up to Cancer, Moleculin Biotech, Bessor Pharma, and Fujifilm; stock options from Bessor Pharma and Moleculin Biotech; and honoraria for data and safety monitoring board membership from Panbela Therapeutics and the Pancreatic Cancer Action Network. SKJ declares grant funding to her institution from the NCI and the Cancer Therapy Evaluation Program, and is a consultant and adjudication committee member for Merck, IMX Medical, and Syntactx. NVU has consulted for QED, Ipsen, Taiho, Incyte, AstraZeneca, and Astellas, and declares research funding from Taiho, Eli Lilly, Ipsen, and EMD Serono, and long position holdings in Natera and Exact Sciences. KLS is a member of the data and safety monitoring committee for the Case Comprehensive Cancer Center. JMJ declares consulting for Foundation Medicine. HP declares research grants or funding to their institution from Adlai Nortye USA, Alpine Immune Sciences, Ambrx, Amgen, Aprea Therapeutics, ArrayBioPharma, Bayer, BeiGene, BJ Bioscience, BMS, Daiichi Pharmaceutical, Eli Lilly, Elicio Therapeutics, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Medimmune, Medivation, Merck, Millennium, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, RePare Therapeutics, Seattle Genetics, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, TurningPoint Therapeutics, Vedanta Biosciences, and Xencor, and reimbursement for meetings or travel from Daiichi Sankyo and Vedanta. LCV declares consulting fees for Janssen, BMS, Takeda, Jazz, and Daiichi Sankyo. JLW declares research support from the NCI of the NIH. RHM declares research support from ViewRay and AstraZeneca; scientific advisory board participation for ViewRay and AstraZeneca; and expert witness fees from the US Attorney's Office Northern District of New York. MarMA has consulted for Genentech, BMS, Merck, AstraZeneca, Maverick, Blueprint Medicine, Syndax, Ariad/Takeda, Nektar, Gritstone, ArcherDX, Mirati, NextCure, Novartis, EMD Serono, and Panvaxal/NovaRx; declares research funding (to their institute) from AstraZeneca, Lilly, Genentech, BMS, and Merck; and declares participation on a data safety monitoring board and advisory board for BMS and Apollomics. SJR declares research support from BMS, Merck, Affimed, and KITE/Gilead, is on the Scientific Advisory Board of Immunitas Therapeutics, and has equity in Immunitas Therapeutics. AMM declares research support from Merck, BMS, Transgene, Incyte, Trisalus, Genentech, and the NIH; consulting fees from Zosano; advisory board participation for BMS, AstraZeneca, Incyte, and Dynavax; and stock options in MultiplexThera. CJW declares equity in BioNTech, U24 research support from the NCI of the NIH, and research funding from Pharmacyclics. FSH declares research support from the NCI of the NIH, BMS, Novartis, and Genentech; royalties or licenses from BMS and Novartis; consulting fees from BMS, EMD Serono, Surface, Sanofi, Genentech, Gossamer, Trillium, Immunocore, Merck, Novartis, Compass Therapeutics, Pieris, Bioentre, Iovance, Catalym, and Amgen; patents for the methods for treating MHC class I polypeptide-related sequence A disorders (number 20100111973; with royalties paid), tumour antigens and uses thereof (number 7250291; issued), angiopoiten-2 biomarkers predictive of anti-immune checkpoint response (number 20170248603; pending), compositions and methods for the identification, assessment, prevention, and treatment of melanoma using PD-L1 isoforms (number 20160340407; pending), therapeutic peptides (number 20160046716; pending), therapeutic peptides (number 20140004112; pending), therapeutic peptides (number 20170022275; pending), therapeutic peptides (number 20170008962; pending), therapeutic peptides (number 9402905; issued), methods of using pembrolizumab and trebananib (pending), vaccine compositions and methods for restoring NKG2D pathway function against cancers (number 10279021; issued), antibodies that bind to MHC class I polypeptide-related sequence A (number 10106611; issued), and anti-galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses (number 20170343552; pending); data safety monitoring board and advisory board participation for Aduro and Checkpoint Therapeutics; scientific advisory board leadership for Bicara and Apricity; and stock options in Checkpoint Therapeutics, Pionyr, Apricity, and Bicara. AL is currently an employee of Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Both innate and adaptive immune responses are important components of anticancer immunity. The CD47-SIRPα interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours., Methods: We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks) until disease progression, voluntary withdrawal from the study, or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities during the first cycle, and was assessed in all patients who had received at least one dose of evorpacept. Secondary outcomes included the safety, tolerability, and antitumour activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety, and tolerability were assessed in all patients who had received at least one dose of evorpacept, and antitumour activity was assessed in those who recieved at least one dose of study treatment and underwent at least one post-baseline tumor assessment. This trial is registered with ClinicalTrials.gov, NCT03013218., Findings: Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept (n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30), and were included in the safety analysis. Median follow-up was 29·1 months (95% CI not calculable [NC]-NC) in the single-agent cohort, 27·0 months (25·1-28·8) in the evorpacept plus pembrolizumab cohort, and 32·7 months (27·0-32·7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received single-agent evorpacept; neutropenia with an associated infection in one patient with gastroesophageal junction cancer who received 3 mg/kg once per week, and thrombocytopenia with associated bleeding in one patient with pancreatic cancer who received 30 mg/kg once every other week. No maximum tolerated dose was reached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg once every other week. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with single-agent evorpacept (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received single-agent evorpacept, four treatment-related serious adverse events were reported. Five serious treatment-related adverse events related to evorpacept plus pembrolizumab were reported, and one serious adverse event related to evorpacept plus trastuzumab was reported. In response-evaluable patients in the dose-escalation phase (n=15) receiving single-agent evorpacept once per week, four (27%) had a best overall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg, and one received 10 mg/kg); in the 11 patients who received single-agent evorpacept at the highest dose of 30 mg/kg once every other week, two (18%) had stable disease. In the dose-expansion cohort, overall responses were recorded in four (20·0%; 95% CI 5·7-43·7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab, in one (5·0%; 0·1-24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab, and in four (21·1%; 6·1-45·6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab., Interpretation: The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC., Funding: ALX Oncology., Competing Interests: Declaration of interests NJL reports research funding from ALX Oncology, Ascentage, BeiGene, Constellation Pharma, Forty Seven, Alpine, Merck, Pfizer, Regeneron, Apexian, Formation Biologics (Forbius), Symphogen, CytomX, InhibRx, Incyte, Jounce, Livzon, Northern Biologics, Innovent Biologics, Ikena, Odonate, Loxo, Alpine Biosciences, Mersana, Astellas, Celgene, Seagen, Samumed, Sapience Therapeutics, Epizyme, and Mersana; and personal fees from Innovent Biologics, all outside the submitted work. LQMC reports receiving research funding from ALX Oncology; participation on an advisory board for Merck; and receipt of medical writing services from Merck, all outside the submitted work. JFG reports research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array, Merck, Adaptimmune, Novartis, and ALX Oncology; consulting fees from Genentech-Roche, Bristol-Myers Squibb, Takeda, Loxo-Lilly, Blueprint, Oncorus, Regeneron, Gilead, Moderna, AstraZeneca, EMD Serono, Pfizer, Novartis, Merck, GlydeBio, and Karyopharm; payment or honoraria from Pfizer for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and having a spouse who owns stock and has other ownership interests in Ironwood Pharmaceuticals, all outside the submitted work. PL reports participation on advisory boards or data safety monitoring boards for AbbVie, Agios, Five Prime, GenMab, Halozyme, Roche-Genentech, Genentech, CytomX, Takeda, Cybrexa, Agenus, Tyme, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GlaxoSmithKline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical Development, Kineta, Zentalis Pharmaceuticals, Molecular Templates, ABL Bio, STCube Pharmaceuticals, Bayer, and I-Mab; and was a consultant for SOTIO, SK Life Science, and I-Mab, all outside the submitted work. K-WL reports research support to their institution from ALX Oncology, AstraZeneca, Ono Pharmaceutical, Merck Sharp & Dohme, Merck, Pfizer, BeiGene, Astellas Pharma, Zymeworks, Five Prime Therapeutics, Macrogenics, Seagen, Bolt Biotherapeutics, Trishula Therapeutics, Oncologie, Pharmacyclics, LSK BioPharma, MedPacto, Green Cross, ABLBIO, Y-BIOLOGICS, Genexine, Daiichi Sankyo, Taiho Pharmaceutical, InvetisBio, Leap Therapeutics; and personal fees from ISU ABXIS, Bayer, Daiichi Sankyo, Bristol-Myers Squibb (consultation), Ono Pharmaceutical, and Boryung Pharmaceutical (honorarium), all outside the submitted work. JL reports receiving consulting fees from Mirati, Seattle Genetics, Oncxerna, and AstraZeneca, all outside the submitted work. Y-JB reports receiving research support paid to their institution from AstraZeneca, Novartis, Genentech-Roche, Merck Sharp & Dohme, Bayer, Merck Serono, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Eli Lilly, Curis, Taiho, Takeda, Ono Pharmaceutical, Daiichi Sankyo, Astellas, BeiGene, Green Cross, and Genexine; and consulting fees from AstraZeneca, Novartis, Genentech-Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Merck Serono, Daiichi-Sankyo, Astellas, BeiGene, Green Cross, Samyang Biopharm, Hanmi, and ALX Oncology, all outside the submitted work. FSH reports research support to their institution from ALX Oncology, Bristol-Myers Squibb, Novartis, and the National Institutes of Health; consulting fees from Bristol-Myers Squibb, Novartis, EMD Serono, Genentech, Sanofi, Bicara, Apricity, Surface, Compass, Aduro, Pionyr, 7 Hills Pharma, Checkpoint, Bioentre, Gossamer, Iovance, Trillium, Catalym, Immunocore, Amgen, and Rheos; and ownership of stock or stock options in Pionyr, Apricity, Bicara, Checkpoint, and Torque, all outside the submitted work. RS-D reports receiving grants or contracts through his institution from ALX Oncology outside the submitted work. PF reports employment at ALX Oncology, and owning stock or stock options in ALX Oncology. PS is employed by IDDI, and reports research support from ALX Oncology outside the submitted work. FJ reports having a consulting or advisory role at ALX Oncology. HIW reports employment at ALX Oncology, receiving support for travel expenses from ALX Oncology, and owning stock and having other ownership interests in ALX Oncology outside the submitted work. JP reports employment at ALX Oncology, owning stock and having other ownership interests in ALX Oncology, research funding from ALX Oncology, patents planned, issued, or pending at ALX Oncology, and reports a leadership or fiduciary role at Tallac Therapeutics, all outside the submitted work. SSR is employed by and is on the board of directors at ALX Oncology, and reports owning stock and having other ownership interests in ALX Oncology, all outside the submitted work. WAM reports receiving research funding from ALX Oncology outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial., Methods: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058., Findings: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A)., Interpretation: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests HAT worked in a consulting/advisory role for Array BioPharma, Bristol Myers Squibb (BMS), Genentech/Roche, Merck, and Novartis; participated in a scientific advisory board for Kayopharm; received research/grant support from BMS, Celgene, Genentech/Roche, GlaxoSmithKline (GSK), and Merck; and received honoraria from Eisai. PAF worked in a consulting role for AbbVie, Boehringer Ingelheim, NCI Neuro-Oncology Branch Peer Review, Novellus, Physical Sciences Oncology Network, Tocagen, and Ziopharm; received honoraria from BTG, NCRI, Tocagen, and Ziopharm; worked in an advisory role for Bayer, Inovio, Novocure, and BTG; and received research/grant support from CDMRP, NIH/NCI, Department of Defense, Pfizer, State of Florida Bankhead Coley, and Moffitt Center of Excellence Celgene Project. FSH worked in a consulting role for BMS, Corner Therapeutics, Eisai, EMD Serono, Genentech/Roche, Gossamer, Idera, Kairos, Merck, Novartis, Psioxus Therapeutics, Pieris Pharmaceutical, Takeda, and Sanofi; worked in an advisory role for 7 Hills Pharma, Aduro, Apricity, Bicara, Checkpoint Therapeutics, Pionyr, and Torque; received research/grant support from BMS and Novartis; received royalties from BMS and Novartis; and holds equity in Apricity. APA worked in an advisory role for Array BioPharma, OncoSec Medical, and Regeneron; received research/grant support from Acerta, Amgen, AstraZeneca, BMS, Dynavax, Genentech, Idera, Incyte, ISA, LOXO, Merck, Novartis, OncoSec Medical, Regeneron, Sensei, and Tessa; received travel/accommodations/expenses support from OncoSec Medical; and holds stock in OncoSec Medical and Valitor Biosciences. OH worked in a consulting role for and received research/grant support from Aduro, Akeso, Amgen, Beigene, Bioatla, BMS, Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, NextCure, Novartis, Pfizer, Sanofi Regeneron, Seagen, Tempus, and Zelluna; received research/grant support from BMS; and served as a speaker for BMS, Novartis, Pfizer, and Sanofi Regeneron. CDL received research/grant support from Novartis and Merck; worked in an advisory role for BMS and Immunocore; and received travel/accommodations/expenses support from BMS and Immunocore. SJM received research/grant support from Amgen, Merck, and Syndax Pharmaceuticals; worked in a consulting role for iTeos Therapeutics and EMD Serono; and participated in a Data Safety Monitoring board for IQVIA. MBA worked in a consulting role for Adagene, Agenus, AstraZeneca, Calithera, Exelixis, Idera, Immunocore, Iovance, Neoleukin, Sanofi, SeaGen, and Takeda; and worked in an advisory role for Apexigen, Aveo, BMS, Eisai, Elpis, Genentech/Roche, Leads Biopharma, Merck, Novartis, Pfizer, PACT, Pyxis Oncology, and Werewolf Therapeutics. KL received research/grant support from BMS, Merck, Roche/Genentech, Pfizer, and Regeneron; and worked in a consulting role for Merck, Roche/Genentech, and Pfizer. MAP worked in a consulting/advisory role for Aduro, BMS, Eisai, Incyte, Merck, NewLink Genetics, Novartis, and Pfizer; received research/grant support from Array BioPharma, AstraZeneca, BMS, Infinity, Merck, Novartis, and RGenix; and received honoraria from BMS and Merck. SJ worked in a consulting/advisory role for Array Biopharma, BMS, EMD Sorono, Genentech, Novartis, Sanofi, Sun Biopharma, and Pfizer. NIK worked in an advisory role for Array BioPharma, BMS, EMD Serono, Genentech, HUYA Bioscience International, Immunocore, Merck, Regeneron, and Jounce; received research/grant support from Amgen, BMS, Celgene, GSK, HUYA Bioscience International, Merck, Novartis, Replimmune, and Regeneron; received honoraria from BMS and Sanofi; holds stock in Amarin Corporation, Bellicum Pharmaceuticals, Mazor Robotics, and Asensus Surgical (formerly TransEnterix); participated in a Data Safety Monitoring board for AstraZeneca and Incyte; and participated in the Scientific Review Committee for NCCN (from Pfizer) and study steering committees for BMS, Regeneron, and Nektar. ACP worked in a consulting/advisory role for BMS, Merck, Regeneron, and Sanofi/Regeneron; received research/grant support from BMS, Merck, Regeneron, and Replimune; and worked on a speaker's bureau for BMS. MSE participated in a Data Safety Monitoring board for BMS; and holds stock or stock options in BMS. DAR worked in a consulting/advisory role for AbbVie, Advantagene, Agenus, Amgen, Bayer, BMS, Boston Biomedical, Celldex, DelMar, EMD Serono, Genentech/Roche, Inovio, Medicenna, Merck, Merck KGaA, Monteris, Oncorus, Oxigene, Novocure, Regeneron, Stemline, and Taiho; and received research/grant support from Tragara, Acerta Pharmaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, and Omniox. RK worked in a consulting/advisory role for Array BioPharma, BMS, Immunocore, Merck, Novartis, Pfizer, and Regeneron; received research/grant support from BMS, Merck, and Regeneron; received honoraria from Array BioPharma and BMS; and received travel/accommodations/expenses support from BMS. AT worked in a consulting/advisory role for Array Biopharma, BioNTech, BMS, Clinigen, EMD Serono, Genentech/Roche, Immunocore, Merck, NewLink Genetics, Novartis, Partner Therapeutics, Pfizer, and Sanofi-Genzyme/Regeneron; and received research/grant support from BMS, Genentech/Roche, OncoSec Medical, Merck, Sanjofi-Genzyme, Regeneron, Clinigen, and CheckMate. CC received research/grant support from Siemens Healthineers and Raysearch Laboratories; and received honorarium from Elekta. CR and PD are employees of BMS and hold BMS stock or stock options. MA is an employee of BMS. IP worked in a consulting role for Amgen, Merck, and Nouscom. KAM worked in a consulting/advisory role for ImaginAb, Oncosec, Werewolf, Xilio, and Tentarix; participated in a Data Safety Monitoring board for CheckMate Pharmaceuticals; and received research/grant support from ImaginAb. RPT and JG report no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study., Methods: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAF V600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505., Findings: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44-0·67; p<0·0001) and for nivolumab versus ipilimumab was 0·65 (0·53-0·79; p<0·0001). Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 (95% CI 0·35-0·51; p<0·0001) and for nivolumab versus ipilimumab was 0·53 (0·44-0·64; p<0·0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis., Interpretation: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma., Funding: Bristol-Myers Squibb., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab., Methods: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity., Findings: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93)., Interpretation: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway., Funding: Merck & Co, Inc., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma., Methods: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF V600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients., Findings: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis., Interpretation: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients., Funding: Bristol-Myers Squibb., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy., Methods: We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3-5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients., Findings: Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3-5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37·6-62·4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31·1-55·3] of 70 patients). The most common treatment-related grade 3-4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4-53·8] vs 14 [20%; 11·4-31·3]). Progression was reported in 26 (38%; 95% CI 26·7-50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0-72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7-50·8) and 42 (60%; 47·6-71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8-25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7-not reached), whereas over a median follow-up of 14·7 months (IQR 5·6-23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2-26·5; HR 0·48 [95% CI 0·29-0·80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64-85 vs 54%; 42-65)., Interpretation: Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events., Funding: Bristol-Myers Squibb., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma., Methods: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients., Findings: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy., Interpretation: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma., Funding: Merck Sharp & Dohme., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma., Methods: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746., Findings: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred., Interpretation: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need., Funding: Bristol-Myers Squibb., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Neurocognitive function, neurological symptoms, functional independence, and health-related quality of life are major concerns for patients with brain metastases. The inclusion of these endpoints in trials of brain metastases and the methods by which these measures are assessed vary substantially. If functional independence or health-related quality of life are planned as key study outcomes, then the reliability and validity of these endpoints can be crucial because methodological issues might affect the interpretation and acceptance of findings. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, and collaborative effort to improve the design of clinical trials in patients with brain tumours. In this report, the second in a two-part series, we review clinical trials of brain metastases in relation to measures of clinical benefit and provide a framework for the design and conduct of future trials., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases., Methods: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766., Findings: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis., Interpretation: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population., Funding: Bristol-Myers Squibb., (Copyright © 2012 Elsevier Ltd. All rights reserved.)