Martin Reck

Purpose ENTRÉE Lung (NCT03739710) was a global, open-label, platform study investigating novel immunotherapy combinations in advanced non-small cell lung cancer (NSCLC) following progression on anti-PD-(L)1 and platinum-based treatment. We report findings with dostarlimab (anti-PD-1) plus belrestotug (anti-TIGIT) with or without nelistotug (anti-CD96). Patients and Methods The study included safety cohorts with dose escalation and expansion: Arm 4 safety cohort (Arm4-safety), dostarlimab 500 mg plus belrestotug 200–1000 mg (initial dose level: 400 mg); Arm5-safety, dostarlimab 500 mg plus belrestotug 400 mg and nelistotug 210–1400 mg (initial dose level: 700 mg); study treatments were administered intravenously every 3 weeks. A randomized cohort was added to Arm 5 (Arm5-randomized), assigning patients to nelistotug 210 or 1400 mg in the triplet combination. Primary endpoints were safety and tolerability. Results Sixty-two patients were enrolled (n=24 Arm4-safety; n=17 Arm5-safety; n=21 Arm5-randomized [n=11, 200 mg; n=10, 1400 mg]). Grade ≥3 treatment-related adverse events occurred in 4 (17%), 1 (6%) and 3 (14%) patients in Arm4-safety, Arm5-safety and Arm5-randomized, respectively. There were few treatment discontinuations due to adverse events. Most patients exhibited progressive disease as best response. There was one partial response (Arm5-randomized, 210 mg); stable disease ≥12 weeks was experienced by 4 (17%), 5 (29%) and 2 (10%) patients in Arm4-safety, Arm5-safety and Arm5-randomized, respectively. Conclusions Dostarlimab plus belrestotug, with or without nelistotug, was well tolerated but demonstrated no clinically meaningful activity in previously treated advanced NSCLC. Further research is required to identify patients who may benefit from other immunotherapy combinations.

PURPOSE: Tiragolumab plus atezolizumab has shown encouraging survival outcomes in metastatic non–small cell lung cancer (NSCLC), primarily in patients with PD-L1–high tumors. We further evaluated the combination of tiragolumab plus atezolizumab in the phase III SKYSCRAPER-01 study. METHODS: Patients with untreated, locally advanced unresectable/metastatic PD-L1–high (by central laboratory testing) NSCLC were randomly assigned 1:1 to receive either tiragolumab (600 mg) plus atezolizumab (1,200 mg) or placebo plus atezolizumab (1,200 mg) intravenously in 21-day cycles until disease progression, loss of clinical benefit, or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (INV-PFS) and overall survival (OS) in the primary analysis set (PD-L1–high per 22C3 assay). RESULTS: Five hundred twenty-one patients were randomly assigned to either the tiragolumab plus atezolizumab group (n = 262) or the placebo plus atezolizumab group (n = 259). At the primary PFS analysis (Mar 12, 2022; median follow-up 9.9 months [IQR, 6.2-13.8]), median INV-PFS was 7.0 months (95% CI, 5.6 to 9.8) with tiragolumab plus atezolizumab and 5.6 months (95% CI, 4.4 to 7.0) with placebo plus atezolizumab (hazard ratio [HR], 0.78 [95% CI, 0.63 to 0.97]; P = .02 [nonsignificant]). At the final OS analysis (Sept 24, 2024; median follow-up 17.9 months [IQR, 6.7-39.0]), median OS was 23.1 months (95% CI, 17.7 to 28.8) with tiragolumab plus atezolizumab and 16.9 months (95% CI, 14.6 to 21.3) with placebo plus atezolizumab (HR, 0.87 [95% CI, 0.7 to 1.1]; P = .22 [nonsignificant]). Overall, 41.2% (n = 110/267) and 33.8% (n = 89/263) of patients experienced grade 3-4 adverse events with tiragolumab plus atezolizumab and placebo plus atezolizumab, respectively. Four and two treatment-related deaths occurred in each group, respectively. CONCLUSION: Tiragolumab plus atezolizumab did not demonstrate a statistically significant INV-PFS or OS benefit over atezolizumab in patients with previously untreated PD-L1–high NSCLC.

In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival (EFS) and pathologic complete response in patients with resectable non–small cell lung cancer (R-NSCLC), with a safety profile consistent with the individual agents. We report EFS from a second planned interim analysis, interim disease-free survival (DFS) and overall survival (OS), and safety, after all patients completed/discontinued treatment. In this phase III, double-blind, placebo-controlled study, patients with treatment-naïve R-NSCLC (stage II–IIIB [N2]) were randomly assigned (1:1) to neoadjuvant platinum-based chemotherapy plus durvalumab/placebo (once every 3 weeks, four cycles) presurgery and then adjuvant durvalumab/placebo (once every 4 weeks, 12 cycles). Efficacy was analyzed in the modified intention-to-treat population (n = 740; for DFS, its resected subpopulation), which excluded patients with documented EGFR / ALK aberrations. As of May 10, 2024 (median follow-up, 25.9 months [censored patients]), EFS benefit favoring the durvalumab arm remained consistent (hazard ratio [HR], 0.69 [95% CI, 0.55 to 0.88]). Numerical improvement in DFS (HR, 0.66 [95% CI, 0.47 to 0.92]) and OS (HR, 0.89 [95% CI, 0.70 to 1.14]) favored the durvalumab arm. Maximum grade 3/4 adverse events occurred in 15.4% and 10.6% of the durvalumab and placebo arms, respectively, during adjuvant treatment. These results further support perioperative durvalumab plus neoadjuvant chemotherapy as a new treatment option.