Sintilimab plus chemotherapy for patients with EGFR- mutated non-squamous non-small-cell lung cancer with disease progression after EGFRtyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double- blind, randomised, placebo-controlled, phase 3 trial

Background In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit ofanti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results. Methods This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing).Findings Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12.9 months (IQR 8.2-17.8) in the sintilimab plus IBI305 plus chemotherapy group, 15.1 months (8.0-19.5) in the sintilimab plus chemotherapy group, and 14.4 months (9.8-23.8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5.5 months [95% CI 4.5-6.1] vs 4.3 months [4.1-5.3]; hazard ratio [HR] 0.72 [95% CI 0.55-0.94]; two-sided p=0.016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7.2 months [95% CI 6 & BULL;6-9 & BULL;3]; HR: 0.51 [0.39-0.67]; two-sided p<0.0001). As of data cutoff (July 4, 2022), the median overall survival was 21 & BULL;1 months (95% CI 17 & BULL;5-23 & BULL;9) for sintilimab plus IBI305 plus chemotherapy (HR 0 & BULL;98 [0 & BULL;72-1 & BULL;34]) and 20 & BULL;5 months (15 & BULL;8-25 & BULL;3) for sintilimab plus chemotherapy group (HR 0 & BULL;97 [0 & BULL;71-1 & BULL;32]) versus 19 & BULL;2 months (15 & BULL;8-22 & BULL;4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0 & BULL;79 (0 & BULL;57-1 & BULL;09) to 0 & BULL;84 (0 & BULL;61-1 & BULL;15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0 & BULL;78 (0 & BULL;57-1 & BULL;08) to 0 & BULL;84 (0 & BULL;61-1 & BULL;16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group.Interpretation This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up.