FDA Denies Approval of Sintilimab With Chemotherapy for Nonsquamous NSCLC

The FDA has issued a complete response letter to Eli Lily and Company regarding the biologics license application (BLA) for sintilimab injection (Tyvyt) in combination with pemetrexed and platinum chemotherapy as frontline treatment for patients with nonsquamous non–small cell lung cancer (NSCLC), according to an announcement by the company.¹

In the letter, the FDA informed the company that the application has been fully reviewed but cannot be approved as is. This letter follows a 14 to 1 vote by the Oncologic Drug Advisory Committee in favor of the FDA requiring more research to support an approval of sintilimab with pemetrexed and platinum-based chemotherapy for this indication. The FDA suggested in the letter that the company conduct a multiregional clinical trial evaluating standard of care therapy for first-line metastatic NSCLC compared with sintilimab with chemotherapy following a non-inferiority design with an overall survival (OS) end point.

The BLA for the sintilimab combination was supported by results from the randomized, double-blinded, phase 2 ORIENT-11 clinical trial (NCT03607539). The study assessed treatment with 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 weeks and platinum chemotherapy every 3 weeks. The comparator arm of the study consisted of pemetrexed plus platinum chemotherapy and placebo.

A total of 397 patients with advanced or metastatic nonsquamous NSCLC were randomized 1:1 and evaluated for the primary end point of progression-free survival (PFS), and the secondary end points of OS, objective response rate, disease control rate, time to response, and duration of response.

Sintilimab with pemetrexed and platinum-based chemotherapy showed a median PFS of 8.9 months (95% CI, 7.1-11.3) 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.

In the subgroup of patients with TPS <1%, the median PFS observed was 7.3 months in the sintilimab arm 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). Also, in patients with TPS ≥ 50%, the median PFS was not reached with sintilimab versus 5.0 months in the control arm (HR, 0.310; 95% CI, 0.197-0.489).

Although the study showed positive result for the primary end point, the agency and members of the ODAC expressed that the end point was not appropriate to support an FDA approval and the population of the ORIENT-11 trial was not reflective of the U.S. patient population.

Further, multiple ODAC members expressed that there was no pressing need to approve another drug for this indication when the combination of pembrolizumab (Keytruda) and chemotherapy was already granted FDA approval for the treatment of this patient population.

“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 Jorge Nieva, MD, section head, solid tumors, University of Southern California, Norris Comprehensive Cancer Center Keck School of Medicine of USC, during the February ODAC meeting.

In the randomized, double-blind, phase 3 KEYNOTE-189 study (NCT02578680), pembrolizumab in combination with placebo demonstrated a significantly longer OS and PFS than chemotherapy alone in patient with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations.²

The programs for sintilimab with pemetrexed and platinum-based chemotherapy in the US is currently being assessed for next steps by Eli Lily and Company. While sintilimab still has no indications in the US, the indications in China include both solid tumors and hematologic malignancies.

_REFERENCES:

_{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. March 24, 2022. Accessed March 24, 2022. https://bit.ly/3umij6U}

_{2. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005}