Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden.

Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB). Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab. In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals. Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab. NCT03668119.

Schenker M ，Burotto M ，Richardet M ，Ciuleanu TE ，Gonçalves A ，Steeghs N ，Schoffski P ，Ascierto PA ，Maio M ，Lugowska I ，Lupinacci L ，Leary A ，Delord JP ，Grasselli J ，Tan DSP ，Friedmann J ，Vuky J ，Tschaika M ，Konduru S ，Vemula SV ，Slepetis R ，Kollia G ，Pacius M ，Duong Q ，Huang N ，Doshi P ，Baden J ，Di Nicola M ... -  《Journal for ImmunoTherapy of Cancer》

Blood-based tumor mutational burden impacts clinical outcomes of immune checkpoint inhibitor treated breast and prostate cancers.

Breast and prostate tumors are known to be less responsive to immune checkpoint inhibitors (ICIs). Tissue-based tumor mutation burden (tTMB) has emerged as a predictive biomarker of response to ICIs, including in these "cold tumors". In clinical practice, when tTMB is not available, blood-based TMB score (bTMB) can be used to consider treatment with ICIs. This retrospective, real-world study included a final cohort of metastatic breast and prostate cancer patients treated with an ICI following a liquid biopsy test. Multiple bTMB-High cut-offs were assessed. Clinical, genomic, and outcomes data were collected. We hypothesized that a cut-off of bTMB ≥10 mut/Mb is not a strong predictor of response to ICIs in this setting. The Guardant Health genomic database (GHGD) was then queried (N = 13,992) for associations of bTMB with genomic alterations. In the clinical cohort (N = 48), ICI treatment is offered after a median of 3 (1-9) lines of treatment. The median bTMB is 16.4 (10-186) mut/Mb. The median time on ICI and PFS is 2.1 (0-1.7) and 3.1 months (95%CI, 1.6-4.6) respectively; no difference by MSI/MMR status (p = 0.152). Response rate among eligible patients (n = 36) is 16.7%; only N = 1/6 in bTMB <16 mut/Mb. High bMSI is associated with higher bTMB (correlation test, r = 0.66, p = 0.000). In the GHGD, patients with bTMB high have significantly more alterations than bTMB low and TP53, PIK3CA, ATM, ESR1, NF1, BRCA2, ARID1A, and APC were the most frequently altered genes. In this study, the practice of offering an ICIs based on bTMB was uncommon and did not independently predict ICI benefits in patients with refractory, advanced breast and prostate cancers.

Barnett RM ，Jang A ，Lanka S ，Fu P ，Bucheit LA ，Babiker H ，Bryce A ，Meyer HM ，Choi Y ，Moore C ，Garje R ，Gao X ，Kim DW ，Chang RY ，Gulhati P ，Ramaker R ，Bansal R ，Zhang T ，Oliver Sartor A ，Armstrong AJ ，Bilen MA ，Barata P ... -  《-》

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 in Microsatellite-Instability-High Metastatic Colorectal Cancer.

Patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) metastatic colorectal cancer have poor outcomes with standard chemotherapy with or without targeted therapies. Nivolumab plus ipilimumab has shown clinical benefit in nonrandomized studies of MSI-H or dMMR metastatic colorectal cancer. In this phase 3 open-label trial, we randomly assigned patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status according to local testing to receive, in a 2:2:1 ratio, nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The dual primary end points, assessed in patients with centrally confirmed MSI-H or dMMR status, were progression-free survival with nivolumab plus ipilimumab as compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab as compared with nivolumab alone in patients regardless of previous systemic treatment for metastatic disease. At this prespecified interim analysis, the first primary end point (involving nivolumab plus ipilimumab vs. chemotherapy) was assessed. A total of 303 patients who had not previously received systemic treatment for metastatic disease were randomly assigned to receive nivolumab plus ipilimumab or chemotherapy; 255 patients had centrally confirmed MSI-H or dMMR tumors. At a median follow-up of 31.5 months (range, 6.1 to 48.4), progression-free survival outcomes (the primary analysis) were significantly better with nivolumab plus ipilimumab than with chemotherapy (P<0.001 for the between-group difference in progression-free survival, calculated with the use of a two-sided stratified log-rank test); 24-month progression-free survival was 72% (95% confidence interval [CI], 64 to 79) with nivolumab plus ipilimumab as compared with 14% (95% CI, 6 to 25) with chemotherapy. At 24 months, the restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer with nivolumab plus ipilimumab than with chemotherapy, a finding consistent with the primary analysis of progression-free survival. Grade 3 or 4 treatment-related adverse events occurred in 23% of the patients in the nivolumab-plus-ipilimumab group and in 48% of the patients in the chemotherapy group. Progression-free survival was longer with nivolumab plus ipilimumab than with chemotherapy among patients who had not previously received systemic treatment for MSI-H or dMMR metastatic colorectal cancer. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 8HW ClinicalTrials.gov number, NCT04008030.).

Andre T ，Elez E ，Van Cutsem E ，Jensen LH ，Bennouna J ，Mendez G ，Schenker M ，de la Fouchardiere C ，Limon ML ，Yoshino T ，Li J ，Lenz HJ ，Manzano Mozo JL ，Tortora G ，Garcia-Carbonero R ，Dahan L ，Chalabi M ，Joshi R ，Goekkurt E ，Braghiroli MI ，Cil T ，Cela E ，Chen T ，Lei M ，Dixon M ，Abdullaev S ，Lonardi S ，CheckMate 8HW Investigators ... -  《-》

Nivolumab plus relatlimab and nivolumab plus ipilimumab for patients with advanced renal cell carcinoma: results from the open-label, randomised, phase II FRACTION-RCC trial.

The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1. The open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries. Patients were enrolled in track 1 (IO-naive) or track 2 (IO-experienced). IO-naive patients were stratified by previous tyrosine kinase inhibitor therapy and randomised to NIVO (240 mg) + RELA (80 mg) intravenously once every 2 weeks or NIVO (3 mg/kg) + IPI (1 mg/kg) intravenously once every 3 weeks for four doses, followed by NIVO (480 mg) once every 4 weeks, each up to ∼2 years. The primary endpoints were objective response by investigator (RECIST version 1.1), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Safety was a secondary endpoint; biomarker analyses were exploratory. FRACTION-RCC enrolled patients between 2 February 2017 and 23 January 2020. In track 1, 30 patients each were treated with NIVO + RELA or NIVO + IPI (clinical database lock, 1 November 2021). With NIVO + RELA [median follow-up, 48.6 months; interquartile range (IQR) 46.9-51.7 months], objective response was 30% [95% confidence interval (CI) 15% to 49%], with 33 weeks (95% CI 16-53 weeks) median DOR. The PFS rate at 24 weeks was 43% (95% CI 25% to 60%). With NIVO + IPI (median follow-up, 48.7 months; IQR 47.1-52.0 months), the objective response was 20% (95% CI 8% to 39%), with the median DOR not reached (95% CI 33 weeks-not estimable). The PFS rate at 24 weeks was 49% (95% CI 29% to 66%). Higher baseline lymphocyte activation gene 3 (LAG-3) and programmed death-ligand 1 (PD-L1) expression levels were detected among track 1 NIVO + RELA responders. Grade 3-4 treatment-related adverse events were reported in 4/30 (13%) patients treated with NIVO + RELA and 10/30 (33%) patients treated with NIVO + IPI. No deaths were attributed to study treatments. Results showed antitumour activity and manageable safety with NIVO + RELA. Findings also support NIVO + IPI as an effective combination regimen in IO-naive patients with aRCC.

Choueiri TK ，Kuzel TM ，Tykodi SS ，Verzoni E ，Kluger H ，Nair S ，Perets R ，George S ，Gurney H ，Pachynski RK ，Folefac E ，Castonguay V ，Lee CH ，Vaishampayan U ，Miller WH Jr ，Bhagavatheeswaran P ，Wang Y ，Gupta S ，DeSilva H ，Lee CW ，Escudier B ，Motzer RJ ... -  《ESMO Open》