ORIENT-31: Novel Four-Drug Regimen Evaluated in EGFR-Mutated NSCLC

Get Permission

A four-drug combination of the anti–PD-1 antibody sintilimab, the bevacizumab biosimilar IBI305, plus pemetrexed and cisplatin chemotherapy significantly improved progression-free survival compared with chemotherapy alone in patients with advanced nonsquamous non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. These results from the global phase III ORIENT-31 trial were presented during the 2021 ESMO Virtual Plenary by Shun Lu, MD, PhD, Director of the Oncology Department of Shanghai Chest Hospital, China.1

In May 2021, a biologics license application for the front-line use of sintilimab injection plus pemetrexed and platinum-based chemotherapy in patients with nonsquamous NSCLC was accepted for review by the U.S. Food and Drug Administration.

The regimen of sintilimab plus IBI305 and chemotherapy reduced the hazard ratio for disease progression by 53.6%, and the curves separated soon after treatment initiation, suggesting early response.
— Shun Lu, MD, PhD

Tweet this quote

“To my knowledge, this is the first randomized, placebo-controlled study that indicates a significant progression-free survival benefit with platinum-based double chemotherapy plus an anti–PD-1/PD-L1 antibody and VEGF inhibitor vs chemotherapy alone,” Dr. Lu said.

In the first interim analysis of ORIENT-31, the primary endpoint, median progression-free survival, was 6.9 months with this novel approach vs 4.3 months with chemotherapy alone (hazard ratio [HR] = 0.464; P < .0001). “The regimen of sintilimab plus IBI305 and chemotherapy reduced the hazard ratio for disease progression by 53.6%, and the curves separated soon after treatment initiation, suggesting early response,” Dr. Lu said.

The prespecified progression-free survival futility analysis comparing the addition of the bevacizumab biosimilar to sintilimab/chemotherapy, vs sintilimab/chemotherapy, did not cross the futility stopping boundary (HR = 0.726; 95% confidence interval [CI] = 0.528–0.998); a numerical benefit was observed, but the data are immature.

As Dr. Lu pointed out, immunotherapy has generally not proven effective for patients with advanced NSCLC and EGFR mutations, but when it is given along with bevacizumab, some benefit has been seen. This is presumed to occur because of the immunomodulatory effects of vascular endothelial growth factor (VEGF) inhibitors: the T-cell–mediated cancer cell killing ability of checkpoint inhibitors may be enhanced through the reversal of VEGF-mediated immunosuppression, Dr. Lu explained.

The subgroup analysis of IMpower150 bears this out, by showing that outcomes were significantly improved with the atezolizumab combined with bevacizumab and chemotherapy over atezolizumab/chemotherapy alone in patients with EGFR-mutated disease who had not responded to targeted treatment.2 Although encouraging, this approach has lacked prospective evidence, Dr. Lu said.

About ORIENT-31

ORIENT-31 aimed to provide prospective data. The study randomly assigned 444 patients (primarily Asian) with EGFR-mutated nonsquamous NSCLC to one of three treatment arms:

  • Arm A: Sintilimab (200 mg), IBI305 (15 mg/kg), pemetrexed (500 mg/m2), and cisplatin (75 mg/m2) every 3 weeks for four cycles followed by maintenance with sintilimab/IBI305/pemetrexed for up to 24 months total
  • Arm B: Sintilimab, pemetrexed/cisplatin, and placebo (as above) followed by maintenance with sintilimab and pemetrexed for up to 24 months total
  • Arm C: Pemetrexed plus cisplatin and two placebos (as above) followed by maintenance with pemetrexed, with conditional crossover to sintilimab monotherapy allowed upon disease progression.

The median age of all 444 patients was 57 years; 36% had brain metastasis; and 29% had T790M mutations. Two-thirds of patients received a first- and/or second-generation tyrosine kinase inhibitor, and one-fourth received these drugs followed by a third-generation agent; 6% received a third-generation tyrosine kinase inhibitor.

The primary endpoint was progression-free survival assessed by independent radiographic review. Secondary endpoints will be tested sequentially pending success of the primary endpoint.

The statistical design for the first interim analysis called for testing the superiority of arm A vs arm C (α = 0.0146) and for futility testing for arm A vs arm B (HR = 0.840). The second interim analysis will be a superiority test of arm A vs arm C, and the final analysis will be a superiority test of arm A vs arm B. This final analysis will determine the benefit of adding bevacizumab to immunotherapy plus chemotherapy.

Secondary Endpoints Improved

The first interim analysis occurred after 9.8 months of median follow-up. The superiority of the novel regimen over chemotherapy was shown, and a trend toward benefit was observed for the novel regimen (arm A) vs sintilimab/chemotherapy (without bevacizumab; arm B). Although the data are immature for arm B vs arm C (chemotherapy alone), the numerical benefit has been observed, Dr. Lu said.


  • The global phase III ORIENT-31 trial evaluated the anti–PD-1 antibody sintilimab plus the bevacizumab biosimilar IBI305 given with chemotherapy in 444 patients randomly assigned to one of three treatment arms.
  • The primary endpoint was progression-free survival for the four-drug combination vs chemotherapy alone.
  • In the first interim analysis, the novel regimen improved median progression-free survival from 4.3 months to 6.9 months (HR = 0.464; P < .0001).
  • The addition of bevacizumab to the immunotherapy/chemotherapy combination will be statistically tested in a future analysis.

The progression-free survival benefit of the four-drug regimen, a 54% reduction in risk, was consistent across subgroups, including age, gender, performance status, brain metastases at baseline, smoking status, and prior lines of EGFR tyrosine kinase treatment, he added.

ORIENT-31 also met significantly improved objective response rates over chemotherapy (43.9% [95% CI = 35.8%–52.3%] vs 25.2% [95% CI = 18.5%–32.9%]) and median duration of response (8.3 vs 7.0 months, respectively).

The regimens were all generally well tolerated, with no new safety signals. The incidence of grade ≥ 3 treatment-emergent adverse events was 54.7% for arm A, 39.3% for arm B, and 51.0% for arm B. These side effects led to discontinuation of any study drug in 17%, 8%, and 7%, respectively. Most events in all arms were low grade and manageable, he said. 

DISCLOSURE: Dr. Lu has received speaker fees from or served as an advisor or consultant to AstraZeneca, Roche, Hansoh, Hengrui Therapeutics, Pfizer, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Zai Lab, GenomiCare, Yuhan Corporation, PrIME Oncology, Menarini, and Roche.


1. Lu S, Wu L, Jian H, et al: 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. 2021 ESMO Virtual Plenary. Abstract VP9-2021. Presented November 19, 2021.

2. Nogami N, Barlesi F, Socinski MA, et al: IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups with EGFR mutations or metastases in the liver or brain. J Thorac Oncol. October 6, 2021 (early release online).


Related Articles

Expert Point of View: Myung-Ju Ahn, MD, PhD

Myung-Ju Ahn, MD, PhD, Professor in the Department of Hematology and Oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine, South Korea, said the novel regimen of sintilimab, IBI305, and chemotherapy is a promising approach in EGFR-mutated nonsquamous non–small cell lung...