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.

BACKGROUND: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION NUMBER: NCT03668119.

Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC.

BACKGROUND: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg. METHODS: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing. RESULTS: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %). CONCLUSIONS: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications. CLINICAL TRIAL REGISTRATION: NCT03600883.

Use of Different Anti-PD-1 Checkpoint Combination Strategies for First-Line Advanced NSCLC Treatment-The Experience of Ion Chiricuța Oncology Institute.

PURPOSE: Different combination modalities between an anti-PD-1/PD-L1 agent and a platinum-based chemotherapy or another checkpoint inhibitor (with or without a short course or full course of a platinum doublet) proved superior to chemotherapy alone in multiple clinical trials, but these strategies were not directly compared. The aim of this study is to report the real-world data results with different immunotherapy combinations in a series of patients treated in consecutive cohorts at the Ion Chiricuța Oncology Institute. METHODS: A total of 122 patients were successively enrolled in three cohorts: (1A) nivolumab + ipilimumab (18 patients), (1B) nivolumab + ipilimumab + short-course chemotherapy (33 patients), and (2) pembrolizumab plus full-course chemotherapy (71 patients). Endpoints included overall survival (OS), progression-free survival (PFS), objective response (ORR), and univariate and multivariate exploratory analysis of prognostic factors. RESULTS: Median follow-up in the consecutive cohorts 1A, 1B, and 2 was 83 versus 59 versus 14.2 months. Median OS and PFS for all patients were 22.2 and 11.5 months, respectively, and 2-year actuarial OS and PFS were 49% and 35%, respectively. For the nivolumab + ipilimumab (cohorts 1A and 1B) versus pembrolizumab combinations (cohort 2), median OS was 14 vs. 24.8 months (p = 0.18) and 2-year actuarial survival 42% vs. 53%; median PFS was 8.6 vs. 12.7 months (p = 0.41) and 2-year actuarial PFS 34% vs. 35%; response rates were 33.3% vs. 47.9% (p = 0.22). Older age, impaired PS (2 versus 0-1), corticotherapy in the first month of immunotherapy, and >3.81 neutrophils to lymphocytes ratio were independent unfavorable prognostic factors in the multivariate analysis of survival (limited to 2 years follow-up). The 5-year long-term survival was 30.5% and 18.8% for cohorts 1A and 1B, respectively (not enough follow-up for cohort 2). CONCLUSIONS: Efficacy results using different immunotherapy combination strategies were promising and not significantly different between protocols at 2 years. Real-world efficacy and long-term results in our series were in line with those reported in the corresponding registration trials.

Perioperative Nivolumab in Resectable Lung Cancer.

BACKGROUND: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes. METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety. RESULTS: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. CONCLUSIONS: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.).

Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial.

BACKGROUND: In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy. METHODS: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting. RESULTS: With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed. CONCLUSIONS: In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.