VP9-2021: ORIENT-31: Phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy

Treatment option for nonsquamous non-small cell lung cancer (nsqNSCLC) with epidermal growth factor receptor mutations (EGFRm) is limited upon progression after tyrosine kinase inhibitors (TKIs). ORIENT-31 is a randomized, double-blind, phase 3 study of sintilimab (sint, anti-PD-1 antibody) with or without IBI305 (bevacizumab biosimilar) plus chemotherapy (chemo) in patients (pts) with EGFRm nsqNSCLC who progressed after EGFR TKI therapy (NCT03802240). Pts with EGFRm nsqNSCLC who had progressed afterEGFR-TKI therapy were randomized (1:1:1) to Arm A (sint + IBI305 + chemo), Arm B [sint + placebo 2 (pb2) + chemo] or Arm C (pb1 + pb2 + chemo), stratified by sex (male vs female) and brain metastasis (yes vs no). Sint / pb1 (200 mg), IBI305 / pb2 (15 mg/kg), pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) were administered IV Q3W for 4 cycles, followed by maintenance treatment of sint / pb1, IBI305 / pb2 and pemetrexed. Conditional crossover to sint monotherapy was allowed for pts in Arm C. Primary endpoint is progression-free survival (PFS) by independent radiographic review committee (IRRC). By data cutoff (31 Jul, 2021, median follow up of 9.8m) of first interim analysis, 444 pts were randomized (Arm A / B / C 148 / 145 / 151). Median age was 57 y. 36.0% pts had brain metastasis. Previously, 63.7% pts received 1st or 2nd generation (G) TKI with T790M-, 28.2% pts received 1st or 2nd and then 3rd G TKI with T790M+, 8.1% pts received first-line 3rd G TKI. Median PFS (95%CI) by IRRC was 6.9m (6.0, 9.3) in Arm A, 5.6m (4.7, 6.9) in Arm B, 4.3m (4.1, 5.4) in Arm C. PFS was significantly prolonged in Arm A vs. Arm C (HR 0.464, 95%CI: 0.337, 0.639; p<0.0001). Arm B showed trend of PFS benefit vs. Arm C (HR 0.750, 95%CI: 0.555, 1.013; p=0.0584). The futility analysis of Arm A vs. B did not cross the futility boundary (HR 0.726, 95%CI: 0.528, 0.998). Confirmed ORR were 43.9%, 33.1% and 25.2% in Arm A, B and C respectively. Incidence of grade ≥3 treatment-emergent AEs were 54.7%, 39.3% and 51.0% respectively. In pts with EGFRm nsqNSCLC who progressed after EGFR-TKIs, sint combined with IBI305 and chemo has significantly improved PFS compared with chemo alone.