FDA Issues Complete Response Letter for Sintilimab Plus Chemo in First-Line Treatment of Nonsquamous NSCLC

A biologics license application for sintilimab plus chemotherapy in first-line nonsquamous non–small cell lung cancer was not approved by the FDA and a complete response letter was issued to the drug developer.

The FDA has issued a complete response letter for a biologics license application for sintilimab plus pemetrexed and platinum chemotherapy in patients with nonsquamous non–small cell lung cancer receiving treatment in the frontline setting, according to a press release from the agent’s co-developer Eli Lily Company.1

Although the review cycle has been completed, the application could not be approved in its current form. The response letter recommends an additional multiregional clinical trial comparing the experimental regimen vs standard of care with a noninferiority design and overall survival as an end point.

The application was based on findings from the phase 3 ORIENT-11 trial (NCT03607539), which assessed sintilimab compared with placebo and pemetrexed/platinum-based chemotherapy in the indicated patient population.2 During an Oncologic Drugs Advisory Committee meeting in February, a 14-to-1 vote indicated that more data on sintilimab was needed as the currently available information relying on a single-country assessment was not robust enough to support FDA approval.3

“While [the] FDA acknowledges the reported safety and efficacy of sintilimab and ORIENT-11, acceptance of foreign data is predicated on applicability to the U.S. population and U.S. medical practice. The applicant did not consult with [the] FDA until study completion and selected an end point and control arm not applicable to current U.S. regulatory standards. As we will further discuss, given the timing of this trial and standard of care therapies, ORIENT-11 would not have been feasible to conduct in the U.S. A critical issue is the study population, comprised entirely of Asian patients from a single country. While China is a multi-ethnic country, the ORIENT-11 study population is not reflective of the racial and ethnic diversity of patients with lung cancer in the U.S.,” Paz J. Vellanki, MD, PhD, a clinical assistant professor at the University of Maryland School of Medicine, stated in a press release.

Findings from the study, which were presented at the 2020 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer Virtual Presidential Symposium and published in the Journal of Thoracic Oncology, indicated that patients who were treated with the experimental regimen experienced a median progression-free survival (PFS) of 8.9 months (95% CI, 7.1-11.3) vs 5.0 months (95% CI, 4.8-6.2) in the placebo arm (HR, 0.482; 95% CI, 0.362-0.643; P <.00001).4 Moreover, a median PFS of 7.3 months (95% CI, 6.2–not reached [NR]) and 5.1 months (95% CI, 4.6-7.8) in the sintilimab and placebo arms, respectively, were reported in a population of patients with a tumor proportion score of less than 1%.

The sintilimab regimen also yielded an objective response rate of 51.9% and a complete response rate of 1.1% compared with 29.8% and 0%, respectively, in the placebo arm. The median duration of response was NR in the experimental arm (95% CI, 8.0-NR) compared with 5.5 months (95% CI, 4.1-10.9) in the placebo arm.

Both regimens had comparable safety profiles, with 61.7% of patients in the experimental arm experiencing grade 3 or high adverse effects compared with 58.5% in the placebo arm. Serious AEs were reported in 28.2% and 29.8% of patients, respectively.


  1. Lilly announces complete response letter for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of people with nonsquamous non-small cell lung cancer. News release. Eli Lily. March 24, 2022. Accessed March 24, 2022. https://bit.ly/3JCFuA1
  2. U.S. FDA Accepts Regulatory Submission for Sintilimab in Combination with Pemetrexed and Platinum Chemotherapy for the First-Line Treatment of People with Nonsquamous Non-Small Cell Lung Cancer. News release. Innovent Biologics, Inc. and Eli Lilly and Company. May 18, 2021. Accessed March 24, 2022. https://bit.ly/3u0iSAS
  3. Lilly Statement on sintilimab Oncologic Drugs Advisory Committee (ODAC) Meeting. News release. Eli Lilly. February 10, 2022. Accessed March 24, 2022. https://bit.ly/3sweFpT
  4. Yang Y, Wang Z, Fang J, et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020;15(10):1636-1646. doi:10.1016/j.jtho.2020.07.014
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