Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial,The Lancet Oncology

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Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial
The Lancet Oncology ( IF 51.1 ) Pub Date : 2022-07-28 , DOI: 10.1016/s1470-2045(22)00382-5
Shun Lu ₁ , Lin Wu ₂ , Hong Jian ₁ , Ying Chen ₃ , Qiming Wang ₄ , Jian Fang ₅ , Ziping Wang ₅ , Yanping Hu ₆ , Meili Sun ₇ , Liang Han ₈ , Liyun Miao ₉ , Cuimin Ding ₁₀ , Jiuwei Cui ₁₁ , Baolan Li ₁₂ , Yueyin Pan ₁₃ , Xingya Li ₁₄ , Feng Ye ₁₅ , Anwen Liu ₁₆ , Ke Wang ₁₇ , Shundong Cang ₁₈ , Hui Zhou ₁₉ , Xing Sun ₂₀ , David Ferry ₂₁ , Yong Lin ₂₂ , Shuyan Wang ₁₉ , Wen Zhang ₂₀ , Chengli Zhang ₁₉

Affiliation

Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Thoracic Medical Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Department of Oncology, Jilin Cancer Hospital, Changchun, China.
Department of Respiratory Medicine, Henan Cancer Hospital, Zhengzhou, China.
Department of Thoracic Medical Oncology, Peking University Cancer Hospital, Beijing Cancer Hospital, Beijing, China.
Department of Thoracic Medical Oncology, Hubei Cancer Hospital, Wuhan, China.
Department of Oncology, Jinan Central Hospital affiliated to Shandong University, Jinan, China.
Department of Oncology, Xuzhou Central Hospital, Xuzhou, China.
Department of Respiratory Medicine, Nanjing University Mdical School affiliated to Nanjing Drum Tower Hospital, Nanjing, China.
Department of Respiratory Medicine, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, China.
Department of Oncology, Jilin University First Hospital, Changchun, China.
Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Department of Oncology, Anhui Provincial Hospital, Hefei, China.
Department of Oncology, Zhengzhou University First Affiliated Hospital, Zhengzhou, China.
Department of Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, China.
Department of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China.
Department of Respiratory Medicine, Sichuan University West China Hospital, Chengdu, China.
Department of Oncology, Henan Provincial People's Hospital, Zhengzhou, China.
Department of Medical Science and Strategy Oncology, Innovent Biologics, Suzhou, China.
Department of Biostatistics and Information, Innovent Biologics, Suzhou, China.
Department of Oncology Medical Strategy, Eli Lilly and Company, New York, NY, USA.
Eli Lilly and Company, Indianapolis, IN, USA.

Background

VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy.

Methods

This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18–75 years with locally advanced or metastatic NSCLC and EGFR^mut who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m²) and cisplatin (75 mg/m²), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting).

Findings

Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4–13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0–9.3] vs 4·3 months [4·1–5·4]; hazard ratio 0·46 [0·34–0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause).

Interpretation

In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy.