PD-1/PD-L1 inhibitors (PDx) improve survival in ≥ 2L NSCLC, primarily in PD-L1 high pts. Combining PDx with CTLA-4 agents may address unmet medical needs by providing synergistic antitumor activity even in PD-L1 low/neg pts in this setting. This Phase 3 trial (NCT02352948) evaluated durvalumab (D) vs SoC and D plus anti-CTLA-4 tremelimumab (T) vs SoC in Stage IIIB/IV NSCLC.
Eligible pts had ≥2 prior systemic treatments (1 platinum-based CT), WHO PS 0/1, no prior PDx and were EGFR/ALK WT. From Q2 2015, in sub study A (SSA), PD-L1 TC ≥25% (Ventana SP263 assay) pts were randomized 1:1 to D 10 mg/kg IV q2w for up to 12 mo or SoC (erlotinib 150 mg QD PO, gemcitabine 1000 mg/m2 IV [day 1, 8, and 15 of a 28-day cycle] or vinorelbine 30 mg/m2 IV [day 1, 8, 15, and 22 of a 28-day cycle]). In sub study B (SSB), PD-L1 TC <25% pts were randomized 3:2:2:1 to D+T (D 20 mg/kg IV + T 1 mg/kg IV q4w for up to 12 wks then D 10 mg/kg IV q2w for 34 wks); SoC (as SSA); D (as SSA); or T 10 mg/kg IV q4w for 24 wks then q12w for 24 wks. Co-primary endpoints were OS and PFS for D+T vs SoC in SSB and D vs SoC in SSA. Secondary endpoints included 12-mo OS and PFS, ORR, safety and QoL. All 5% alpha was given to SSB (4% OS; 1% PFS); SSA was descriptive with no statistical testing.
Due to recruitment challenges 126/250 (SSA) and 469/600 (SSB) planned pts were randomized (DCO Feb 09 2018). Baseline characteristics were well balanced. In SSB, median OS was 11.5 vs 8.7 mo with D+T vs SoC (HR 0.80 [95% CI 0.61, 1.05]; p = 0.109). 12-mo OS rates were 49.5% and 38.8%. Median PFS was 3.5 vs 3.5 mo (HR 0.77 [0.59, 1.01]; p = 0.056) with 12-mo PFS rates of 20.6% and 8.0%. ORR was 14.9% D+T and 6.8% SoC. In SSA, median OS was 11.7 vs 6.8 mo with D vs SoC (HR 0.63 [0.42, 0.93]). 12-mo OS rates were 49.3% and 31.3%. Median PFS was 3.8 vs 2.2 mo (HR 0.71 [0.49, 1.04]) with 12-mo PFS rates of 19.4% and 9.9%. ORR was 35.5% D and 12.5% SoC. Grade ≥3 treatment-emergent AEs were 46.8% D+T and 54.5% SoC in SSB; 45.2% D and 66.7% SoC in SSA.
In the ≥3L setting, D monotherapy provided a clinically meaningful improvement in OS vs SoC in PD-L1 TC ≥25% pts. D+T did not significantly improve OS or PFS vs SoC in PD-L1 TC <25% pts. D+T, D and T exhibited manageable safety profiles. Further biomarker analyses may help identify pts who may benefit most from D+T, D or T in advanced NSCLC.
Clinical trial identification
NCT02352948/January 28, 2015.
Legal entity responsible for the study
Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Paul Glacken, MSc, and Elizabeth Andrew, PhD, of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca.
N. Reinmuth: Personal fees: BMS, Roche, AstraZeneca, Takeda, Novartis, Boehringer Ingelheim, MSD, Lilly. S. Sugawara: Lecture fees and research grant: AstraZeneca. D.M. Medine: Speaker and member of an advisory board: Roche; Advisory board: BMS, Boehringer Ingelheim. S. Novello: Speakers' bureau: Eli Lilly, Roche, BMS, Takeda, BI, AstraZeneca. Y. Takeda: Research funding: Taiho, Boehringer Ingelheim, Chugai, Kyowa Hakko Kirin. R.A. Soo: Honorarium and research funding: AstraZeneca; Honorarium: BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Celgene, Ignyta, Roche, Taiho. S.L. Geater: Non-financial support: Boehringer Ingelheim, AstraZeneca, Sanofi Aventis, Novartis; Grants: Boehringer Ingelheim, AstraZeneca, Novartis. M. Powell, R. May: Full-time employment: AstraZeneca. P. Stockman: Full-time employment and equity ownership: AstraZeneca. D. Planchard: Personal fees associated for advisory boards: AstraZeneca, Boehringer Ingelheim. BMS, MSD, Pfizer, Novartis, Roche, Celgene. All other authors have declared no conflicts of interest.