CCTG BR.34: A randomized trial of durvalumab and tremelimumab +/- platinum-based chemotherapy in patients with metastatic (Stage IV) squamous or nonsquamous non-small cell lung cancer (NSCLC).

9502 Background: First-line therapy for advanced NSCLC includes PD-1 checkpoint inhibitor (ICI) monotherapy, and in combination with chemotherapy. Combination ICI have also demonstrated better survival compared to chemotherapy (CM-227). In CCTG BR.34, we compared overall survival (OS) in patients with advanced NSCLC receiving first-line durvalumab plus tremelimumab (DT) with or without platinum doublet chemotherapy (CT). Methods: This international, open-label, randomized trial accrued 301 participants from Canada and Australia, with stage IV NSCLC, EGFR/ALK wildtype, ECOG PS 0/1. Patients were randomized to DT for 4 cycles or DT+CT (pemetrexed- or gemcitabine-platinum), with ongoing D or D + pemetrexed (non-squamous) maintenance until disease progression. Stratification factors included histology, stage IVA v. IVB and smoking status. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR = CR + PR) and adverse events (AEs). Results: At a median follow up of 16.6 months, no significant difference in OS was seen between the two treatment arms, with a median OS of 16.6 months with DT+CT v. 14.1 months with DT, (estimated HR 0.88, 90% CI 0.67-1.16). PFS was significantly improved in the DT+CT arm (stratified HR 0.67, 95% CI 0.52-0.88; medians 7.7 v. 3.2 months). ORR was higher in the DT+CT arm, 28% v. 14%, (odds ratio 2.1, p=0.001). Preplanned subgroup analysis demonstrated no significant differences in treatment outcomes by plasma TMB (<20 v. ≥20 mut/Mb, Guardant OMNI), age, sex, or smoking status. There was a trend to improved OS with DT+CT in the subgroup with PD-L1 TPS≥50%, (HR 0.64, 95% CI 0.40-1.04, p=0.07). Plasma TMB<20 mut/Mb was associated with shorter survival in both treatment groups (HR 1.99, 95% 1.3-3.1). Toxicity was greater in the DT+CT arm, with grade≥3 adverse events in 82% v. 70%, (p=0.02), most commonly dyspnea, nausea and cough. The incidence of immune-related adverse events was similar between arms (colitis 11%, pneumonitis 6%, endocrinopathy 21%). Grade 5 events occurred in 2.7%, (5 with DT+CT, 3 with DT). Conclusions: The addition of CT to first-line DT did not improve OS in advanced NSCLC. CT+DT improved ORR and PFS, and was associated with greater toxicity. No differential effects were seen by PD-L1 TPS nor bTMB. These data suggest that adding chemotherapy to ICI may be beneficial in those with PD-L1 TPS >=50%, and warrant further analysis in independent datasets. Clinical trial information: NCT03057106 .

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