The FDA's Oncologic Drugs Advisory Committee stated that additional clinical research demonstrating applicability within the United States is necessary to support the biologics license application for a sintilimab combination regimen for non–small cell lung cancer.
The FDA's Oncologic Drugs Advisory Committee voted 14-to-1 in favor of gathering more data rather than relying on single-country assessment of frontline sintilimab (Tyvyt), pemetrexed, and platinum-based chemotherapy for non-squamous non–small cell lung cancer (NSCLC) to back a biologics license application (BLA), citing a need for additional clinical research to demonstrate the regimen’s utility for a United States population.1
“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.,” according to Paz J. Vellanki, MD, PhD, a clinical assistant professor at the University of Maryland School of Medicine.
The FDA accepted a BLA for sintilimab plus pemetrexed and platinum-based chemotherapy for patients with non-squamous NSCLC in May 2021.2 The application was based on findings from the phase 3 ORIENT-11 trial (NCT03607539), which assessed the use of sintilimab compared with a combination of placebo and pemetrexed/platinum-based chemotherapy.
“We had hoped that sintilimab could have played a positive role for patients and the U.S. healthcare system through an aggressive pricing strategy. We acknowledge that the landscape has changed dramatically on a number of fronts since the ORIENT-11 study was conducted and the sintilimab application was initiated. Lilly wholeheartedly agrees with the importance of ethics in clinical trial conduct and clinical trial diversity. We have long-standing initiatives in place to advance diversity and inclusion in Lilly-conducted clinical trials. Along with Innovent, we will continue to work with the FDA as it completes its review of the sintilimab application,” according to a statement from drug developer Eli Lilly.
Findings from the ORIENT-11 trial indicated that after a median follow-up of 8.9 months, patients in the sintilimab cohort had a significantly longer median progression-free survival of 8.9 months compared with 5.0 months in the placebo group (HR, 0.482; 95% CI, 0.362-0.643; P <.00001).3 Moreover, the confirmed objective response rate was 51.9% (95% CI, 45.7%-58.0%) and 29.8% (95% CI, 22.1%-38.4%) in the sintilimab and placebo cohorts, respectively.
A total of 397 patients enrolled on the study and were randomized 2:1 to received either 200 mg of sintilimab or placebo plus pemetrexed and platinum-based chemotherapy once every 3 weeks for 4 cycles. This was followed by sintilimab or placebo plus pemetrexed.
In terms of safety, 61.7% of those in the sintilimab arm and 58.8% of those in the placebo arm experienced grade 3 or higher adverse effects.
“[The] FDA stated that as ORIENT-11 was conducted solely in China, the BLA submission must demonstrate how the study population adequately represents US patients in terms of disease characteristics, sex, race, ethnicity, age, and standards of care per 21 CFR 314.50. In another meeting, the FDA indicated the impact of intrinsic and extrinsic ethnic factors on the exposure, efficacy, and safety of sintilimab must also be addressed,” Vellanki stated.