Ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases (ABC): 7-year follow-up of a multicentre, open-label, randomised, phase 2 study.

Patients with melanoma brain metastases respond well to immunotherapy, but long-term comparative survival data are scarce. We aimed to assess the efficacy of ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases at 7 years. This open-label, randomised, phase 2 study was conducted at four sites (two research institute cancer centres and two university teaching hospitals) in Australia. Patients aged 18 years or older with active, immunotherapy-naive melanoma brain metastases and Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Asymptomatic patients with no previous brain-directed therapy were randomly assigned (5:4) using the biased-coin minimisation method (after a safety run-in of six patients) to cohort A (intravenous ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks) or cohort B (intravenous nivolumab 3 mg/kg every 2 weeks). Patients with previous brain-directed therapy, neurological symptoms, or leptomeningeal disease were assigned to cohort C (non-randomised; intravenous nivolumab 3 mg/kg every 2 weeks). The primary endpoint was best intracranial response (complete or partial response) from week 12. Secondary survival endpoints included intracranial progression-free survival and overall survival. Safety was assessed from the first dose of treatment to at least 100 days after treatment discontinuation. Analyses were performed in patients who received at least one dose of study drug. The main analysis has been reported, and this is a long-term follow up of the ABC trial. This trial is registered with ClinicalTrials.gov, NCT02374242, and is ongoing. Between Nov 4, 2014, and April 21, 2017, 89 patients were assessed for eligibility, 79 of whom were enrolled and assigned to cohort A (n=36), cohort B (n=27), or cohort C (n=16). Three patients (one in cohort A and two in cohort B) were excluded due to ineligibility. 17 (22%) of 76 patients were female and 59 (78%) were male. At data cutoff (March 26, 2024), the median follow-up was 7·6 years (IQR 6·9-8·2). Overall intracranial responses occurred in 18 (51% [95% CI 34-69]) patients from cohort A, five (20% [7-41]) from cohort B, and one (6% [0-30]) from cohort C. 7-year intracranial progression-free survival was 42% (95% CI 29-63) in cohort A, 15% (6-39) in cohort B, and 6% (1-42) in cohort C. 7-year overall survival was 48% (34-68) in cohort A, 26% (13-51) in cohort B, and 13% (3-46) in cohort C. Safety results were consistent with the primary analysis. 50 patients died, including 18 (51%) from cohort A, 18 (72%) from cohort B, and 14 (88%) from cohort C. Our findings suggest that ipilimumab plus nivolumab maintains efficacy to at least 7 years in patients with active asymptomatic brain metastasis. Upfront ipilimumab plus nivolumab should be the standard of care for patients with melanoma brain metastasis; a trial investigating the role of stereotactic surgery in this new paradigm is ongoing. Melanoma Institute Australia and Bristol Myers Squibb.

Long GV ，Atkinson V ，Lo SN ，Guminski AD ，Sandhu SK ，Brown MP ，Gonzalez M ，McArthur GA ，Menzies AM ... -  《-》

Nivolumab plus ipilimumab versus carboplatin-based doublet as first-line treatment for patients with advanced non-small-cell lung cancer aged ≥70 years or with an ECOG performance status of 2 (GFPC 08-2015 ENERGY): a randomised, open-label, phase 3 study.

Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies has shown superiority over chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC), but data for older patients (aged ≥70 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or those with an ECOG performance status of 2 are scarce. We aimed to test the superiority of the PD-1 antibody nivolumab and the CTLA-4 antibody ipilimumab over platinum-based doublet chemotherapy as first-line treatment in patients with NSCLC aged 70 years or older or with an ECOG performance status of 2. This open-label, multicentre, randomised, controlled, phase 3 trial was done at 30 hospitals and cancer centres in France. Eligible patients had stage IV histologically proven NSCLC, with no known oncogenic alterations, and were either aged 70 years or older with ECOG performance status of 0-2 or younger than 70 years with an ECOG performance status of 2. Patients were randomly assigned (1:1) centrally, using a computer-generated algorithm stratified by age (<70 vs ≥70 years), ECOG performance status (0-1 vs 2), and histology (squamous vs non-squamous) to receive nivolumab plus ipilimumab or platinum-based doublet chemotherapy (carboplatin [area under the curve ≤700 mg] plus pemetrexed [500 mg/m2 intravenous infusion every 3 weeks] or carboplatin [on day 1; area under the curve ≤700 mg] plus paclitaxel [90 mg/m2 as intravenous infusion on days 1, 5, and 15, every 4 weeks]). The primary endpoint was overall survival; secondary endpoints included progression-free survival and safety. All efficacy analyses were performed in the intention-to-treat population, which included all randomly assigned patients. Safety was analysed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study treatment and who had at least one safety follow-up. The trial is registered with ClinicalTrials.gov, NCT03351361. The trial was stopped early for futility on the basis of a pre-planned interim analysis after 33% of the expected events had occurred. Between Feb 12, 2018, and Dec 15, 2020, 217 patients were randomly assigned, of whom 216 patients were included in the final analysis, with 109 patients in the nivolumab plus ipilimumab group and 107 in the chemotherapy group; median age was 74 years (IQR 70-78). Median overall survival was 14·7 months (95% CI 8·0-19·7) in the nivolumab plus ipilimumab group and 9·9 months (7·7-12·3) in chemotherapy group (hazard ratio [HR] 0·85 [95% CI 0·62-1·16]). Among patients aged 70 years or older with an ECOG performance status of 0-1 (median age 76 years [IQR 73-79]), median overall survival was longer in the nivolumab plus ipilimumab group than the chemotherapy group: 22·6 months (95% CI 18·1-36·0) versus 11·8 months (8·9-20·5; HR 0·64 [95% CI 0·46-0·96]). Among patients with an ECOG performance status of 2 (median age 69 years [IQR 63-75]), median overall survival was 2·9 months (95% CI 1·4-4·8) in the nivolumab plus ipilimumab group versus 6·1 months (3·5-10·4) in the chemotherapy group (HR 1·32 [95% CI 0·82-2·11]). No new safety signals were reported. The most frequent grade 3 or worse adverse events were neutropenia (28 [27%] of 103 patients) in the chemotherapy group and endocrine disorders (five [5%] of 105 patients), cardiac disorders (ten [10%] patients), and gastrointestinal disorders (11 [11%] patients) in the nivolumab plus ipilimumab group. The study showed no benefit of nivolumab plus ipilimumab combination in the overall study population. As a result of early stopping, the trial was underpowered for primary and secondary endpoints; however, the finding of better survival with nivolumab plus ipilimumab compared with platinum doublet in the subgroup of older patients with NSCLC with an ECOG performance status of 0-1 warrants further study. Bristol-Myers Squibb.

Léna H ，Greillier L ，Cropet C ，Bylicki O ，Monnet I ，Audigier-Valette C ，Falchero L ，Vergnenègre A ，Demontrond P ，Geier M ，Guisier F ，Hominal S ，Locher C ，Corre R ，Chouaid C ，Ricordel C ，GFPC 08–2015 ENERGY investigators ... -  《-》

Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial.

CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In our previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, we report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines. CheckMate 8HW is a randomised, open-label, international, phase 3 trial at 128 hospitals and cancer centres across 23 countries. Immunotherapy-naive adults with unresectable or metastatic colorectal cancer across different lines of therapy and microsatellite instability-high or mismatch repair-deficient status per local testing were randomly assigned (2:2:1) to nivolumab plus ipilimumab (nivolumab 240 mg, ipilimumab 1 mg/kg, every 3 weeks for four doses; then nivolumab 480 mg every 4 weeks; all intravenously), nivolumab (240 mg every 2 weeks for six doses, then 480 mg every 4 weeks; all intravenously), or chemotherapy with or without targeted therapies. The dual independent primary endpoints were progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus chemotherapy (first line) and progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus nivolumab (all lines) in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. This study is registered with ClinicalTrials.gov (NCT04008030). Between Aug 16, 2019, and April 10, 2023, 707 patients were randomly assigned to nivolumab plus ipilimumab (n=354) or nivolumab alone (n=353). 296 (84%) of 354 patients in the nivolumab plus ipilimumab group and 286 (81%) of 353 patients in the nivolumab group were centrally confirmed to have microsatellite instability-high or mismatch repair-deficient status. At the data cutoff on Aug 28, 2024, median follow-up (from randomisation to data cutoff) was 47·0 months (IQR 38·4 to 53·2). Nivolumab plus ipilimumab treatment showed significant and clinically meaningful improvement in progression-free survival versus nivolumab (hazard ratio 0·62, 95% CI 0·48-0·81; p=0·0003). Median progression-free survival was not reached with nivolumab plus ipilimumab (95% CI 53·8 to not estimable) and was 39·3 months with nivolumab (22·1 to not estimable). Treatment-related adverse events of any grade occurred in 285 (81%) of 352 patients receiving nivolumab plus ipilimumab and in 249 (71%) of 351 patients receiving nivolumab; grade 3 or 4 treatment-related adverse events occurred in 78 (22%) and 50 (14%) patients, respectively. There were three treatment-related deaths: one event of myocarditis and pneumonitis each in the nivolumab plus ipilimumab group and one pneumonitis event in the nivolumab group. Nivolumab plus ipilimumab showed superior progression-free survival versus nivolumab across all treatment lines, with a manageable safety profile, in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These results, together with the first-line results of superior progression-free survival with nivolumab plus ipilimumab versus chemotherapy, suggest nivolumab plus ipilimumab as a potential new standard of care for patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Bristol Myers Squibb and Ono Pharmaceutical.

André T ，Elez E ，Lenz HJ ，Jensen LH ，Touchefeu Y ，Van Cutsem E ，Garcia-Carbonero R ，Tougeron D ，Mendez GA ，Schenker M ，de la Fouchardiere C ，Limon ML ，Yoshino T ，Li J ，Manzano Mozo JL ，Dahan L ，Tortora G ，Chalabi M ，Goekkurt E ，Braghiroli MI ，Joshi R ，Cil T ，Aubin F ，Cela E ，Chen T ，Lei M ，Jin L ，Blum SI ，Lonardi S ... -  《-》

Overall survival and quality of life with [(177)Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): secondary outcomes from a multicentre, open-label, randomised, phase 2 trial.

Interim analysis of the ENZA-p trial showed improved prostate-specific antigen (PSA) progression-free survival with the addition of lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 to enzalutamide as first-line treatment of metastatic castration-resistant prostate cancer. Here, we report the secondary endpoints of overall survival and health-related quality of life (HRQOL) with longer follow-up. ENZA-p was a multicentre, open-label, randomised, phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older who had not previously been treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga PSMA-PET-CT-positive disease, an Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, early docetaxel, and previous treatment with abiraterone. Treatment was oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks. The primary endpoint was prostate-specific antigen (PSA) progression-free survival, which has been previously reported. Overall survival, defined as the interval from the date of randomisation to date of death from any cause, or the date last known alive, and HRQOL were key secondary endpoints. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the Patient Disease and Treatment Assessment Form. For HRQOL analyses, deterioration-free survival was measured from randomisation until the earliest occurrence of death, clinical progression, discontinuation of study treatment; or a worsening of 10 points or more from baseline in physical function, or in overall health and QOL. Analyses of these secondary endpoints were prespecified and are by intention to treat. The trial is registered with ClinicalTrials.gov, NCT04419402, and follow-up is complete. Between Aug 17, 2020, and July 26, 2022, 79 patients were randomly assigned to enzalutamide and 83 to enzalutamide plus [177Lu]Lu-PSMA-617. 96 deaths was reported after a median follow-up of 34 months (IQR 29-39): 53 (67%) in the enzalutamide group and 43 (52%) in the enzalutamide plus [177Lu]Lu-PSMA-617 group. Overall survival was longer in the enzalutamide plus [177Lu]Lu-PSMA-617 group than the enzalutamide group (median 34 months [95% CI 30-37] vs 26 months [23-31]; HR 0·55 [95% CI 0·36-0·84], log-rank p=0·0053). HRQOL was rated by 154 (95%) of 162 participants. Deterioration-free survival at 12 months and stratified log-rank p values favoured enzalutamide plus [177Lu]Lu-PSMA-617 for both physical function (median 10·64 months [95% CI 7·66-12·42] vs 3·42 months [3·19-7·89]; HR 0·51 [95% CI 0·36-0·72], log-rank p<0·0001) and overall health and QOL (8·71 months [6·41-11·56] vs 3·32 months [3·09-5·26]; HR 0·47 [95% CI 0·33-0·67], log-rank p=0·0001). Mean scores for pain until progression favoured enzalutamide plus [177Lu]Lu-PSMA-617 over enzalutamide (difference 7·3 [95% CI 1·6-12·9]; p=0·012). Mean scores for fatigue until progression favoured enzalutamide plus [177Lu]Lu-PSMA-617 over enzalutamide (difference 5·9 [95% CI 1·1-10·7]; p=0·016). The frequency of self-rated xerostomia was lower in the enzalutamide group than in the enzalutamide plus [177Lu]Lu-PSMA-617 group (43 [57%] of 75 vs 58 [74%] of 78; p=0·039), and scores were not significantly different between groups for all other domains. Grade 3-5 adverse events occurred in 35 (44%) of 79 patients in the enzalutamide group and 37 (46%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group. No deaths were attributed to study treatment in either group. The addition of [177Lu] Lu-PSMA-617 to enzalutamide was associated with improved survival and some aspects of HRQOL in patients with high-risk metastatic castration-resistant prostate cancer. Our findings warrant phase 3 evaluation of adaptive-dosed [177Lu] Lu-PSMA-617 in combination with androgen receptor pathway inhibitors in people with metastatic prostate cancer. The Prostate Cancer Research Alliance initiative (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, RoyMorgan, AdAcAp (a Novartis company), and Astellas.

Emmett L ，Subramaniam S ，Crumbaker M ，Joshua AM ，Sandhu S ，Nguyen A ，Weickhardt A ，Lee ST ，Ng S ，Francis RJ ，Goh JC ，Pattison DA ，Tan TH ，Kirkwood ID ，Gedye C ，Rutherford NK ，Kumar ASR ，Pook D ，Ramdave S ，Nadebaum DP ，Voskoboynik M ，Redfern AD ，Macdonald W ，Krieger L ，Schembri G ，Chua W ，Lin P ，Horvath L ，Bastick P ，Butler P ，Zhang AY ，McJannett M ，Thomas H ，Langford A ，Hofman MS ，Martin AJ ，Davis ID ，Stockler MR ，ENZA-p Trial Investigators ，Australian and New Zealand Urogenital and Prostate Cancer Trials Group ... -  《-》

Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): a prospective, multicentre, open-label, randomised, phase 3a trial.

Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff. This prospective, multicentre, open-label, randomised, phase 3a trial (explorer8) was conducted at 69 investigational sites in 31 countries. Eligible patients were male, aged 12 years or older, and had congenital severe haemophilia A or moderate or severe haemophilia B without inhibitors and with documented treatment with clotting factor concentrate in the 24 weeks before screening. The trial was paused because of non-fatal thromboembolic events in three patients (two from this trial [explorer8] and one from a related trial in haemophilia with inhibitors [explorer7; NCT04083781]) and restarted with mitigation measures, including a revised dosing regimen of subcutaneous concizumab at 1·0 mg/kg loading dose on day 1 and subsequent daily doses of 0·20 mg/kg from day 2, with options to decrease to 0·15 mg/kg, stay on 0·20 mg/kg, or increase to 0·25 mg/kg on the basis of concizumab plasma concentration measured after 4 weeks on concizumab. Patients recruited after treatment restart were randomly assigned 1:2 using an interactive web response system to receive no prophylaxis and continue on-demand clotting factor (group 1) or concizumab prophylaxis (group 2). The primary endpoints were the number of treated spontaneous and traumatic bleeding episodes for patients with haemophilia A and haemophilia B separately, assessed at the confirmatory analysis cutoff in randomly assigned patients. Analyses were by intention-to-treat. There were two additional groups containing non-randomly-assigned patients: group 3 contained patients who entered the trial before the trial pause and were receiving concizumab in the phase 2 trial (explorer5; NCT03196297), and group 4 contained patients who received previous clotting factor concentrate prophylaxis or on-demand treatment in the non-interventional trial (explorer6; NCT03741881), patients randomly assigned to groups 1 or 2 before the treatment pause, and patients from explorer5 enrolled after the treatment pause. The safety analysis set contained all patients who received concizumab. Superiority of concizumab over no prophylaxis was established if the two-sided 95% CI of the treatment ratio was less than 1 for haemophilia A and for haemophilia B. This trial is registered with ClinicalTrials.gov, NCT04082429, and its extension part is ongoing. Patients were recruited between Nov 13, 2019 and Nov 30, 2021; the cutoff date for the analyses presented was July 12, 2022. 173 patients were screened, of whom 148 (86%) were randomly assigned or allocated to the four groups in the study after trial restart on Sept 30, 2020 (nine with haemophilia A and 12 with haemophilia B in group 1; 18 with haemophilia A and 24 with haemophilia B in group 2; nine with haemophilia A in group 3; and 46 with haemophilia A and 30 with haemophilia B in group 4). The estimated mean annualised bleeding rate ratio for treated spontaneous and traumatic bleeding episodes during concizumab prophylaxis versus no prophylaxis was 0·14 (95% CI 0·07-0·29; p<0·0001) for patients with haemophilia A and 0·21 (0·10-0·45; p<0·0001) for patients with haemophilia B. The most frequent adverse events in patients who received concizumab were SARS-CoV-2 infection (19 [13%] of 151 patients), an increase in fibrin D-dimers (12 [8%] patients), and upper respiratory tract infection (ten [7%] patients). There was one fatal adverse event possibly related to treatment (intra-abdominal haemorrhage in a patient from group 4 with haemophilia A with a long-standing history of hypertension). No thromboembolic events were reported between the trial restart and confirmatory analysis cutoff. Concizumab was effective in reducing the bleeding rate compared with no prophylaxis and was considered safe in patients with haemophilia A or B without inhibitors. The results of this trial suggest that concizumab has the potential to be one of the first subcutaneous treatment options for patients with haemophilia B without inhibitors. Novo Nordisk.

Chowdary P ，Angchaisuksiri P ，Apte S ，Astermark J ，Benson G ，Chan AKC ，Jiménez Yuste V ，Matsushita T ，Høgh Nielsen AR ，Sathar J ，Sutton C ，Šaulytė Trakymienė S ，Tran H ，Villarreal Martinez L ，Wheeler AP ，Windyga J ，Young G ，Thaung Zaw JJ ，Eichler H ... -  《Lancet Haematology》