ODAC Recommends New Trial Data of Sintilimab in US Population of Frontline NSCLC


The FDA’s Oncologic Drugs Advisory Committee voted against using single-country foreign data to support a biologics license application for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer.



The FDA’s Oncologic Drugs Advisory Committee voted against using single-country foreign data to support a biologics license application (BLA) for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer (NSCLC).

ODAC concluded that supporting data from the phase 3 ORIENT-11 trial (NCT03607539), conducted entirely in China, could not be applied to the US population.

The committee voted 14-1 to require drug maker Innovent Biologics (Suzhou) to conduct a new trial demonstrating the efficacy of sintilimab, an anti–PD-1 monoclonal antibody, in the United States. Committee members concluded that “regulatory flexibility” was unnecessary in this case because sintilimab is not filling an unmet need.

Unlike usual ODAC hearings which focus on a drug’s efficacy and safety, the committee was tasked with determining whether data from a trial conducted in China was applicable for US patients. Committee members noted that the study population was younger, predominantly male, and included higher rates of smokers than are generally found in the United States.

“While it is not inconceivable that data would, in the end, apply to the United States or Western populations and generate same outcomes as we’ve seen with other studies in this space, I think we don’t have the data at hand," Ibiayi Dagogo-Jack, MD, a thoracic oncologist at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School, said during the hearing. “The data that were presented to us don't directly draw the conclusion that this is generalizable.”

Innovent Biologics filed the BLA in 2021 based on findings from ORIENT-11 demonstrating that the regimen significantly improved progression-free survival (PFS) compared with chemotherapy alone in the frontline treatment of patients with locally advanced or metastatic nonsquamous NSCLC.1

At a median follow-up of 8.9 months, the median PFS with sintilimab was 8.9 months (95% CI, 7.1-11.3) per an independent radiologic review committee vs 5.0 months (95% CI, 4.8-6.2) with chemotherapy alone; this translated to an estimated 52% reduction in the risk of disease progression or death (HR, 0.482; 95% CI, 0.362-0.643; P = .0000004).2,3

Moreover, sintilimab induced a nominally significant 40% reduction in the risk for death compared with chemotherapy alone (HR, 0.609; 95% CI, 0.400-0.926; P = .01921). The overall survival (OS) rates at 6 months in the investigative and control arms were 89.6% and 80.4%, respectively.

In the ODAC briefing document, the following were noted as objections to relying on the submitted BLA:4

  • The patient population in ORIENT-11 does not reflect the diversity of the American population, with both known and unknown differences in intrinsic and extrinsic factors;
  • Sintilimab does not fulfill an unmet need for US patients with NSCLC, limiting the degree of regulatory flexibility that is warranted regarding the acceptability of this data to support FDA approval;
  • ORIENT-11 was powered for PFS, without statistical testing for OS. All FDA approvals of first-line immunotherapy-based regimens for metastatic NSCLC have been based on a statistically significant improvement in OS;
  • ORIENT-11 lacked FDA consultation and oversight;
  • The treatment paradigm is not reflective of US standard of care and would not have been able to enroll patients in the US where immune checkpoint inhibitors have been approved since 2017 in this indication.

Massimo Cristofanilli, MD, chief of breast medical oncology at Weill Cornell Medicine, noted that no country, including China, would accept data collected in a single foreign country. Committee members also expressed their discomfort with approving sintilimab in part because patients in ORIENT-11 did not receive pembrolizumab (Keytruda), an agent approved for use in 2016 and has been demonstrated to extend overall survival (OS).

Richard Pazdur, MD, the director of the FDA’s Oncology Center of Excellence did not have a vote. However, Pazdur, who is the 2019 Giants of Cancer Care® award winner for Community Outreach, noted the lack of diversity in the trial. All patients in ORIENT-11 were Asian, which comprises 7% of the US population.

“We as a public agency, the FDA, have to adhere to what patients want in the United States. We've heard clearly from all patient groups that they want faces like theirs presented in their clinical trials,” he said. “Single country submission is a step backward in achieving the racial diversity that we need in the United States. I just want people to understand that this is going to be a major, goal of not only oncology submissions, but also submissions throughout the FDA.”

Jorge J. Nieva, MD, associate professor of clinical medicine at the University of Southern California Comprehensive Cancer Center, was the only committee member to vote to rely on single-country data, and argued on the idea that the ORIENT-11 population was not representative of US patients. He pointed out that patients in clinical trials conducted in the United States tend to be younger, wealthier, and more urban than the general US population.

“It seems that the applicant has committed is not doing things the way the FDA would like it to have been done,” Nieva said. “They failed to show proper process, not that they failed scientifically. I think the FDA should be in the business of evaluating their science and not the process, unless the process used compromise the science.”

In ORIENT-11, eligible patients had to have stage IIIB/C or IV disease and not be candidates for surgery or local therapy. They also needed to have an ECOG performance status of 0 or 1 and have a provision of a tumor sample for PD-L1 assessment. Stratification factors included gender, type of platinum therapy (cisplatin vs carboplatin) and PD-L1 expression level (tumor proportion score [TPS] less than 1% vs 1% or higher).3

Investigators randomly assigned patients to 200 mg sintilimab (n = 266) or placebo (n = 131) in combination with 500 mg/m2 pemetrexed and 75 mg/m2 cisplatin or carboplatin area under the curve (AUC) 5, every 3 weeks for 4 cycles. Patients on the control arm were later allowed to cross over to receive sintilimab at 200 mg every 3 weeks for up to 24 months.

The primary objective of the trial was PFS. Secondary end points included OS, response rate, duration of response, time to response, and safety. Efficacy was evaluated in the intent-to-treat population and safety data included all patients who were given at least 1 dose of the study treatment.

The median age of patients was 61 years (range, 32.5-75.0) and the majority (76.2%) were male. A total 72.7% had an ECOG performance status of 1, 90.3% had stage IV disease, and approximately 15% had brain metastases. More patients received carboplatin (74.1%) vs cisplatin, and 65.4% were either current or former smokers. More than half, or 67.2%, of patients had a PD-L1 TPS of 1% or higher.

Regarding safety, the adverse effects (AEs) rates were comparable between the 2 treatment arms; grade 3 to 5 toxicities were experienced by 59% and 53% of those on the investigative and control arms, respectively.4 Serious AEs were reported by 28% of those given the sintilimab regimen vs 34% of those who received chemotherapy alone. Six patients on the investigative arm experienced AEs that resulted in death vs 11 patients on the control arm.

Toxicities that led to discontinuation of treatment were reported in 5% and 9% of those on the investigative and control arms, respectively.


  1. US 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; May 18, 2021. February 10, 2022.
  2. Innovent releases the ORIENT-31 phase 3 study first interim analysis results of sintilimab plus BYVASDA (bevacizumab biosimilar injection) and chemotherapy in patients with EGFR-mutated nonsquamous non-small cell lung cancer who progressed after EGFR-TKI therapy at ESMO Virtual Plenary 2021. News release. Innovent Biologics; November 21, 2021. Accessed November 22, 2021.
  3. Zhang Li, Yang Y, Wang Z, et al. ORIENT-11: sintilimab + pemetrexed + platinum as first-line therapy for locally advanced or metastatic non-squamous NSCLC. J Thorac Oncol. 2020;15(10). doi:10.1016/j.jtho.2020.08.002.
  4. FDA Briefing Information for the February 10, 2022, Meeting of the Oncologic Drugs Advisory Committee. Accessed February 10, 2022.
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