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).

Abstract

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 .

Selection of optimal first-line immuno-related therapy based on specific pathological characteristics for patients with advanced driver-gene wild-type non-small cell lung cancer: a systematic review and network meta-analysis

“…Twenty-six trials 3 , 4 , 9 – 19 , 24 , 28 – 38 were included involving 16,977 patients and a total of 18 treatment regimens ( Table 1 ). They are (a) ICI-free treatments, including platinum-based doublet CT, CT/Mpem, CT/BEV, or CT/BEV with maintenance of pemetrexed (CT/BEV/Mpem); (b) ICI-containing treatments, including mono-ICI, namely PEM, nivolumab (NIV), ATE, durvalumab (DUR); (c) ICI-combination treatments, including ICIs plus CT (PEM/CT, NIV/CT, ATE/CT, camrelizumab (CAM)/CT, ipilimumab (IPI)/CT), ATE plus CT and BEV (ATE/CT/BEV); (d) doublet ICIs including NIV/IPI, DUR plus tremelimumab (DUR/TRE); and (e) dual ICIs plus CT (NIV/IPI/CT or DUR/TRE/CT).…”

“…ICI functions slowly but persistently to make up for the shortcomings of CT. Synergy leads to long-term patient survival. As CT is indispensable but has inevitable toxicities, it is especially important to pinpoint the precise position of CT. As designed in CheckMate 9LA, 17 by reducing the CT cycles and performing CT at the beginning of the treatment course, 37 short-term CT may avoid possible early progressions with simultaneous decreasing toxicity, finally obtaining the maximum clinical benefit combined with immunotherapy. Therefore, in the era of immunotherapy, it is worth exploring how to reasonably apply CT in combination to maximize efficacy and synergy.…”

“…Twenty-six trials 3,4,[9][10][11][12][13][14][15][16][17][18][19]24,[28][29][30][31][32][33][34][35][36][37][38] were included involving 16,977 patients and a total of 18 treatment regimens (Table 1). They are…”

Comparison of Efficacy and Safety of Single and Double Immune Checkpoint Inhibitor-Based First-Line Treatments for Advanced Driver-Gene Wild-Type Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

“…According to the study screening process in Figure 1, 20 RCTs were eligible for our NMA, including 13,032 patients and 17 different treatments. They are SICI regimens, including PEM (7,8,36), CEM (10), NIV (37), ATE (9), and DUR (28); SICI+CT regimens, including PEM+CT (11)(12)(13)(14)(15)(16), sintilimab (SIN)+CT (19,20), ATE+CT (21)(22)(23)(24), IPI+CT (25,26), camrelizumab (CAM) +CT (18), and NIV+CT (17); DICI regimens, including DUR +TRE (28) and NIV+IPI (27,38); DICI+CT regimens, including DUR+TRE+CT (28,30) and NIV+IPI+CT (29); and CT as control group, including CT with maintenance with pemetrexed (Mpem) and platinum-based doublet CT. The baseline characteristics of the studies were shown in Table 1.…”

“…CheckMate 9LA was the first study proving that DICI combined with CT (DICI+CT) significantly improved efficacy; NIV+IPI+CT gained longer OS and PFS over CT (29). While in CCTG BR.34, DUR+TRE+CT failed to obtain OS advantage in contrast to DICI (30).…”