Authors: Natasha B. Leighl, Scott Andrew Laurie, Glenwood D. Goss, Brett Gordon Maxwell Hughes, Martin R. Stockler, Ming Sound Tsao, Swati Kulkarni, Normand Blais, Anil A. Joy, Mihaela Mates, Punam Rana, Sunil Yadav, Craig Underhill, Christopher W. Lee, Penelope Ann Bradbury, Andrea Hiltz, Janet Dancey, Keyue Ding, Francisco Emilio Vera Badillo, Canadian Cancer Trials Group, Australasian Lung Cancer Trials Group; Princess Margaret Cancer Centre, Toronto, ON, Canada; Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada; Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medical Oncology, The Prince Charles Hospital, Department of Medical Oncology, Royal Brisbane & Women’s Hospital, and School of Medicine, University of Queensland, Brisbane, QLD, Australia; NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Windsor Regional Hospital, Windsor, ON, Canada; Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC, Canada; Cross Cancer Institute, University of Alberta, NW Edmonton, AB, Canada; Cancer Centre of Southeastern Ontario, Kingston, ON, Canada; Humber River Regional Hospital, Toronto, ON, Canada; Saskatoon Cancer Centre, University of Saskatchewan, Saskatoon, SK, Canada; Albury-Wodonga Regional Cancer Centre, Albury-Wodonga, Australia; BC Cancer Agency, Surrey, BC, Canada; Canadian Cancer Trials Group, Kingston, ON, Canada; Queen’s University, Kingston, ON, Canada
Research Funding: Canadian Cancer Society Research Institute, Pharmaceutical/Biotech Company
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.