FDA to Review BLA for Frontline Sintilimab/Pemetrexed in Nonsquamous NSCLC

Update: The FDA's Oncologic Drug Advisory Committe voted against approval of this combination on February 10, 2020. Read more >>

The FDA has accepted a 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), according to a press release issued by the developer, Innovent Biologics, Inc.¹

The BLA for the PD-L1 inhibitor under this indication is the first U.S. regulatory submission of sintilimab. The application is supported by data from the phase 3 ORIENT-11 clinical trial. In the study, treatment with sintilimab led to improved survival and responses in patients with locally advanced or metastatic nonsquamous NSCLC.

A total of 397 patients with previously untreated nonsquamous stage IIIB/C NSCLC were enrolled in the study. Patients who 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. These patients (N = 397) were randomized 1:1 to receive either sintilimab in combination with chemotherapy (n = 266) or chemotherapy with placebo (n = 131). Baseline characteristics were comparable between the 2 treatment arms.

Patients in the study were a median age of 61 years (range, 30-75 years), and about 75% of patients were male and had an ECOG performance status of 1. Most of the study 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.

Sintilimab 200 mg plus pemetrexed 500 mg/m² and cisplatin75 mg/m² or AUC 5 carboplatin every 3 weeks for a total of 4 cycles were administered to patients in the experimental arm. Patients then received sintilimab 200 mg and pemetrexed 500 mg/m² administered every 3 weeks for up to 2 years. In the control arm, patients received matching chemotherapy, and placebo was administered for up to 2 years. Following the 2 years, crossover to the sintilimab arm was allowed.

The primary end point of the study was progression-free survival (PFS) by independent radiologic review committee (IRRC), and the secondary end points were overall survival (OS), objective response rate (ORR), duration of response (DOR), time to response, and safety.

Results from the study showed a median PFS of 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.²

Looking at patients according to their PD-L1 status, 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). Finally, 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).

The median OS was not reached in either of the treatment arms (HR, 0.609; 95% CI, 0.400-0.926; P = .01921). Sintilimab did however achieve a 6-month OS rate of 89.6% compared with 80.4% in the chemotherapy arm.

Treatment with sintilimab also achieved an ORR of 51.9%, with a complete response in 1 patient, compared with 29.8% in the control arm, for a DCR of 86.8% versus 75.6%, respectively. Median DOR was not reached with sintilimab plus chemotherapy compared with 5.5 months in the chemotherapy plus placebo arm. The median time to response was 1.5 months in the experimental arm versus 2.6 months in the control arm.

In terms of safety, all but 1 patients experienced adverse events (AEs). Events that were grade 3 to 4 were observed in 61.7% of patients treated with the sintilimab plus chemotherapy compared with 58.8% of patients who received chemotherapy and placebo. Serious AEs were reported in 28.2% of the sintilimab arm versus 29.8% of those who received the control.

The most common AEs observed were anemia, decreased neutrophil counts, decreased white blood cell counts, decreased platelet counts, increased aspartate aminotransferase (AST) levels, increased alanine aminotransferase (ALT) levels, nausea, decreased appetite, asthenia, vomiting, constipation, and pyrexia. There were notably 6 deaths in the experimental arm compared with 9 in the control arm. In addition, treatment discontinuation due to AEs was reported in 6.0% of the sintilimab arm versus 8.4% of the control arm

The study of sintilimab in this patient population in the randomized, double-blind phase 3 trial ORIENT-11 trial is ongoing but no longer recruiting paients. Further study of the agent is underway in patients with previously untreated metastatic squamous NSCLC in the phase 2 ORIENT-12 trial.

_References:

_{1. U.S. 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. May 18, 2021. Accessed May 18, 2021. https://prn.to/3yvRsGK}

_{2. Xu N, Ying K, Wang Z, et al. Phase Ib study of sintilimab in combination with chemotherapy for 1L advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15):e20546. doi:10.1200/JCO.2019.37.15_suppl.e20546}