From MedPage Today

Cold Water For Anti-PD-1 Candidate

FDA Staff Dumps Cold Water on Anti-PD-1 Candidate for NSCLC.

Despite positive trial results, it looks like an uphill path to FDA approval for the investigational checkpoint inhibitor sintilimab as a treatment for non-small cell lung cancer (NSCLC), suggested agency briefing documents released ahead of an advisory meeting.

On Thursday, the FDA’s Oncologic Drugs Advisory Committee will discuss whether data that come solely from a Chinese clinical trial are sufficient to support a U.S. marketing application for sintilimab, an anti-PD-1 monoclonal antibody. But FDA staff cited other major hurdles to the drug’s approval, including the “lesser” endpoint used in the phase III trial supporting the application, along with an already crowded field of PD-1/L1 inhibitors in this setting.

Anti-PD-1 Candidate Gets Cold Water Treatment

“Sintilimab does not fulfill an unmet need for U.S. patients with NSCLC, limiting the degree of regulatory flexibility that is warranted regarding the acceptability of this data to support FDA approval,” agency staff asserted.

Sintilimab’s developers Innovent Biologics and Eli Lilly will present results from ORIENT-11, a phase III study that tested sintilimab in combination with pemetrexed (Alimta) and platinum-based chemotherapy as an initial treatment for adults with metastatic NSCLC.

The study is an ongoing, randomized, double-blind trial that enrolled 397 patients from August 2018 to July 2019 exclusively in China. Patients received chemotherapy plus pemetrexed and either sintilimab or placebo. The trial met its primary endpoint of progression-free survival (PFS) at the interim efficacy analysis. Median PFS was 8.9 months with sintilimab compared to 5.0 months with placebo (HR 0.48, 95% CI 0.36-0.64, P<0.00001).

FDA Staff Critical of Findings

But FDA staff was critical of the PFS findings, calling it “a lesser endpoint” compared to “endpoints used for approval of currently available therapies in this space,” noting that all approvals of first-line immunotherapy-based regimens for metastatic NSCLC have been based on a statistically significant overall survival improvement.

Still, other outcome measures in ORIENT-11 favored the sintilimab arm as well, including objective response rate (51.9% vs 29.8% in the placebo arm) and disease control rate (86.8% vs 75.6%). Median duration of response was not reached in the sintilimab arm versus 5.5 months in the placebo arm.

The investigators called the safety profile of sintilimab in combination with pemetrexed and platinum-based chemotherapy acceptable, with toxicities that were tolerable and generally manageable with dose interruptions and supportive care.

Yet FDA staff contended that sintilimab “offers no advantage in safety or mode of administration to the U.S. patient population.”

But in large part, agency reviewers trained their focus on the trial’s population. ORIENT-11 “raises significant questions regarding data from a single foreign country to support a U.S. approval and its generalizability to a diverse American population” as it “enrolled a patient population which lacks the racial and ethnic diversity of the U.S. population, notably with regards to currently underserved groups,” they wrote.

FDA staff also observed that the trial doesn’t adhere to the most recent and relevant guidelines for global, harmonized drug development through the strategic use of multi-regional clinical trials.