FDA’s ODAC Votes No to Approval of Frontline Sintilimab/Chemotherapy in Nonsquamous NSCLC


The FDA’s Oncologic Drug Advisory Committee has voted against approval of the biologics license application for sintilimab plus pemetrexed and platinum-based chemotherapy for the treatment of nonsquamous non–small cell lung cancer without further clinical trial research.

The FDA’s Oncologic Drug Advisory Committee (ODAC) voted 14 to 1 that the FDA should require additional clinical trial(s) demonstrating applicability to patients in the United States (US) and US medical care before making a regulatory decision on the biologics license application (BLA) for sintilimab (Tyvyt) injection in combination with pemetrexed and platinum chemotherapy for the first-line treatment of patients with nonsquamous non–small cell lung cancer (NSCLC).1

A biologics license application (BLA) was submitted to the FDA for this indication on May 18, 2021. The application is supported by findings from the phase 3 ORIENT-11 clinical trial (NCT03607539). In the study, treatment with sintilimab led to improved survival and responses in patients with locally advanced or metastatic nonsquamous NSCLC.

ORIENT-11 is a randomized, double-blinded, phase 2 study of pemetrexed plus platinum-based chemotherapy with or without sintilimab as frontline treatment of advanced or metastatic nonsquamous NSCLC. In the study’s experimental arm, sintilimab doses of 100 mg, or 200 mg every 3 weeks were administered in combination with pemetrexed 500 mg/m2 every 3 week and platinum chemotherapy every 3 weeks. The experimental combination was compared with pemetrexed plus platinum chemotherapy and placebo. The study followed a 1:1 randomized, enrolling 266 patients to the experimental arm and 131 patients were enrolled to the comparator arm.2

An independent radiographic review committee assessed the primary end point of progression-free survival and the secondary end point of overall survival, objective response rate (ORR), disease control rate, time to response, and duration of response.

A total of 397 patients were enrolled. Patients were eligible if they were ineligible for surgery or local therapy, had no EGFR or ALK genetic alterations, and had an ECOG performance status of 0 or 1 met the study’s criteria for inclusion. At baseline, the median age of the study population was 61 years (range, 30-75 years), and about 75% of patients were male and had an ECOG performance status of 1. The majority of the patients had stage IV disease, were current or former smokers, had PD-L1 expression in terms of a tumor proportion score (TPS) ≥1%, and received carboplatin.

The median PFS observed with the sintilimab combination was 8.9 months (95% CI, 7.1-11.3) with sintilimab compared with 5.0 months (95% CI, 4.8-6.2) with placebo (HR, 0.482; 95% CI, 0.362-0.643; P < .00001). The PFS benefits were consistently favorable across the subgroups evaluated, which were patients with high or low PD-L1 expression.

The median PFS in the subgroup of patients with TPS <1% was 7.3 months in the sintilimab versus 5.1 months in the control arm (HR, 0.664; 95% CI, 0.406-1.086). In the TPS 1% to 49% group, the median PFS was 7.1 months with sintilimab versus 4.8 months with the control (HR, 0.503; 95% CI, 0.276-0.918). Lastly, in patients with TPS ≥50%, the median PFS was not reached with sintilimab compared with 5.0 months in the control arm (HR, 0.310; 95% CI, 0.197-0.489).

Despite the study meeting its primary end points, the more important question was whether a trial conducted in a single foreign country was sufficient for an approval in the US, according to Harpreet Singh, MD, director, Division of Oncology, Office of Oncologic Diseases, at the FDA.3

Although the ORIENT-11 trial is 1 of a growing number of single-country clinical trials, for an FDA approval the data must be applicable to a US patient population, the study must be performed by investigators of recognized competence, and the FDA must validate the trail through on-site inspection and other practices. Another key issue is whether the study design is appropriate in the US.

According to Singh, ORIENT-11 could not have been conducted in the US because the study. The study would have had lack of investigator support because the comparator arm offered substandard chemotherapy. Further, FDA-approved therapies conferred a survival advantage. According to a presentation by Innovent Biologics,4 the company only consulted with regulatory authorities in China about an approval for the sintilimab combination. Singh stated, that if the company had consulted with the FDA, they would have likely been advised to perform a direct comparison of sintilimab to an approved anti-PD-L1/chemotherapy regimen with OS as the primary end point.3

David Ferry, MD, PhD, vice president, Oncology Medical Strategy Eli Lilly and Company, who presented data to show the applicability of ORIENT-11 in the US shared that the FDA suggested a noninferiority trial in a recent meeting. However, due to the need to accrue more than 2,000 patients to such a study and the likeness that it would take 7 years to complete, the company proposed a post-marketing trial with a diverse patient population instead. The trial would be a non-comparative dose-finding study with a primary end point of ORR.

Another expert at the FDA, Paz J. Vellanki, MD, PhD, clinical reviewer, Thoracic and Head and Neck Cancer, highlighted that the standard of care for nonsquamous NSCLC had already changed in the US before the BLA for sintilimab in combination pemetrexed and platinum-based chemotherapy had been submitted. Pembrolizumab (Keytruda) combined with chemotherapy as seen in the KEYNOTE-189 (NCT02578680) clinical trial. The study showed a statistically significant in OS, an end point that the ORIENT-11 trial was not powered for.2

Further assessment of the applicability of ORIENT-11 data to support an FDA approval of sintilimab/pemetrexed/platinum for the treatment of nonsquamous NSCLC showed that Chinese clinical practice standards are not in line with US standards, there was insufficient pharmacokinetic data to show similarity to a diverse US population, and the retrospective, exploratory analyses suggest potential differences between the patient population in China and that of the US.

Race and ethnicity were also key concerns of the FDA experts. Although China is ethnically diverse, in the United States, patients with nonsquamous NSCLC are roughly 79% White, 15% Black, and 6% Asian. The population of ORIENT-11 was 100% Asian.

“While the pharmaceutical industry has championed a renewed commitment to inclusion and diversity in clinical trials, acceptance of for data from a single country is antithetical to the concept of racial and ethnic diversity. Alternatively, enrollment of a diverse study population in an international trial may help improve representation of underrepresented groups in drug development. Improved diversity and representation and clinical trials will require a continuing commitment and effort from FDA, the pharmaceutical industry, professional societies, patient advocacy groups, and health care providers,” said Vellanki, during the presentation.

There was also an imbalance between males and females in ORIENT-11 (76% male) compared with the US population where patients with nonsquamous NSCLC are only 50% male. The patient population in the US is also older than the population of patients in the ORIENT-11 study.

Although the ODAC meeting was not weighing efficacy and safety data as it traditionally would, efficacy was of concern with the voting members. Both Jorge J. Nieva, MD, and Antoinette J. Wozniak, MD noted their concerns during the question-and-answer session and during the advisory board discussion.1

“It would be very hard today in North America to discuss with a patient, the results of ORIENT-11 and how that would apply to that patient’s treatment with lack of survival data when we have survival data in the United States, based upon the KEYNOTE-189 trial, explained Nieva, section head, Solid Tumors, University of Southern California, Norris Comprehensive Cancer Center Keck School of Medicine of USC.

During the open public hearing, Diana Zuckerman, MD, president of the National Center for Health Research, stated: “There are many problems with the data supporting this application. But let's start with the first mistake. Number one, the sponsor did not consult with the FDA regarding the trials design or conduct...The result is a very inadequate trial design, including a non-representative group of patients. Number two most important to me, the study relied on progression-free survival, rather than overall survival. We agree with FDA scientists that other drugs in the same class have shown highly significant improvement in overall survival.”


1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. Accessed February 10, 2022. https://bit.ly/3Bdwluu 

2. 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

3. Singh, H and Vellanki P. Sintilimab for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). Presented at: Oncologic Drugs Advisory Committee (ODAC) Meeting February 10, 2022.

4. Shui L, Socinski MA, Gasal E, et al. Sintilimab BLA in non-squamous NSCLC. Presented at: Oncologic Drugs Advisory Committee (ODAC) Meeting February 10, 2022.

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