In an interim analysis of the Chinese phase III ORIENT-31 trial reported in The Lancet Oncology, Lu et al found that the addition of sintilimab and the bevacizumab biosimilar IBI305 to chemotherapy prolonged progression-free survival in patients with advanced EGFR-mutated nonsquamous non–small cell lung cancer (NSCLC) who had experienced disease progression on EGFR tyrosine kinase inhibitor therapy.

Study Details

In the double-blind multicenter trial, 444 patients with locally advanced or metastatic disease were randomly assigned 1:1:1 between July 2019 and July 2021 to receive either sintilimab, IBI305, and chemotherapy with pemetrexed/cisplatin (n = 148), sintilimab plus chemotherapy (n = 145), or chemotherapy alone (n = 151), with matching placebo in the latter two groups. At the time of analysis, efficacy results in the sintilimab-plus-chemotherapy group were immature and thus were not reported. All study drugs were given on day 1 of 3-week cycles. Sintilimab was given at 200 mg and IBI305 at 15 mg/kg; all patient groups received pemetrexed at 500 mg/m² and cisplatin at 75 mg/m². Cisplatin was given for four cycles, with all other drugs given for 24 months or until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival on independent radiographic review in the intention-to-treat population.

Progression-Free Survival

Median follow-up at interim analysis was 9.8 months (interquartile range = 4.4–13.3 months). Median progression-free survival was 6.9 months (95% confidence interval [CI] = 6.0–9.3 months) in the sintilimab/IBI305–plus-chemotherapy group vs 4.3 months (95% CI = 4.1–5.4 months) in the chemotherapy group (hazard ratio = 0.46, 95% CI = 0.34–0.64, P < .0001).  Estimated rates at 6 and 12 months were 59% vs 30% and 28% vs 12%, respectively. 

An objective response was observed in 65 patients (44%, 95% CI = 36%–52%) vs 38 patients (25%, 95% CI = 19%–33%). Disease control rates were 83% vs 72%. Median durations of response were 8.3 months (95% CI = 5.4–12.1 months) vs 7.0 months (95% CI = 4.1–8.3 months).

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 51% of patients in the sintilimab/IBI305–plus-chemotherapy group vs 45% of the chemotherapy group, with the most common in the sintilimab/IBI305–plus-chemotherapy group being decreased neutrophil count (20% vs 18% in chemotherapy group), anemia (12% vs 10%), and decreased white blood cell count (11% vs 9%). Grade 3 hypertension occurred in 9% vs 3%. Treatment-related serious adverse events occurred in 28% vs 25% of patients. Death considered potentially related to treatment occurred in six patients (4%) in the sintilimab/IBI305–plus-chemotherapy group, due to unknown causes in three and intestinal obstruction, gastrointestinal hemorrhage, and myelosuppression in one patient each. Potentially treatment-related death occurred in one patient in the chemotherapy group (due to unknown cause).

The investigators concluded, “In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC [whose disease] progressed after receiving EGFR tyrosine kinase inhibitor therapy.”

Shun Lu, MD, PhD, of Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Innovent Biologics and the National Natural Science Foundation of China. For full disclosures of the study authors, visit thelancet.com.