FDA Grants Sintilimab/Pemetrexed Review for Frontline Nonsquamous NSCLC

A biologics license application for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer has been accepted for FDA review.

Yongjun Liu, MD, PhD

A biologics license application (BLA) for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer (NSCLC) has been accepted for FDA review, according to an announcement from Innovent Biologics, Inc.1

The application, which was submitted to the regulatory agency in March 2021, was based on data from the phase 3 ORIENT-11 trial (NCT03607539), which demonstrated that the regimen significantly improved progression-free survival vs chemotherapy alone in the frontline treatment of patients with locally advanced or metastatic nonsquamous NSCLC.2

At a median follow-up of 8.9 months, the median PFS with sintilimab was 8.9 months (95% CI, 7.1-11.3) per an independent radiologic review committee (IRRC) vs 5.0 months (95% CI, 4.8-6.2) with chemotherapy alone; this translated to an estimated 52% reduction in the risk of disease progression or death (HR, 0.482; 95% CI, 0.362-0.643; P <.00001).

Under the Prescription Drug User Fee Act, the FDA is slated to make a decision on the BLA in March 2022. The regulatory agency did not identify any potential review issues in its acceptance letter, and it will be holding an Advisory Committee meeting to further discuss the application.

“The acceptance of this application – the first for sintilimab in the United States and outside of China – is an important milestone in Innovent’s global commercialization strategy and in our collaboration with Lilly,” Yongjun Liu, MD, PhD, president of Innovent, stated in a press release. “We look forward to working closely with the FDA to potentially bring this sintilimab/pemetrexed/platinum chemotherapy combination as a treatment option in the United States, following the regimen’s regulatory approval in China earlier this year.”

The Chinese, double-blind, randomized phase 3 ORIENT-11 study examined the safety and efficacy of sintilimab in combination with pemetrexed and platinum-based chemotherapy as a frontline treatment in a total of 397 patients with nonsquamous NSCLC.

To be eligible for enrollment, patients had to have stage IIIB/C or IV disease and not be candidates for surgery or local therapy. They also needed to have an ECOG performance status of 0 or 1 and have a provision of a tumor sample for PD-L1 assessment. Stratification factors included gender, type of platinum therapy (cisplatin vs carboplatin) and PD-L1 expression level (tumor proportion score [TPS] less than 1% vs 1% or higher).

In the trial, study participants were randomized 2:1 to receive either sintilimab at 200 mg (n = 266) or placebo (n = 131) in combination with pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 or carboplatin area under the curve (AUC) 5, every 3 weeks for 4 cycles.

Patients in the investigative arm were given sintilimab at 200 mg every 3 weeks for up to 2 years plus pemetrexed at 500 mg/m2 every 3 weeks, while those in the control arm were given placebo every 3 weeks for up to 24 months plus pemetrexed at the 500 mg/m2 every-3-week dosing schedule. Following this time point, patients on the control arm were allowed to cross over to receive sintilimab at 200 mg every 3 weeks for up to 24 months.

The primary objective of the trial was PFS per IRRC, while secondary end points comprised overall survival (OS), response rate, duration of response (DOR), time to response, and safety. Efficacy was evaluated in the intent-to-treat population and safety data included all patients who were given at least 1 dose of the study treatment.

The median age of study participants was 61 years (range, 32.5-75.0) and the majority (76.2%) were male. Moreover, 72.7% had an ECOG performance status of 1, 90.3% had stave IV disease, and about 15% had brain metastases. More patients received carboplatin (74.1%) vs cisplatin, and 65.4% were either current or former smokers. More than half, or 67.2%, of patients had a PD-L1 TPS of 1% or higher.

At a median follow-up of 8.0 months, a total of 198 PFS events were reported. Moreover, 31.3% (n = 35) of patients who were on the control arm crossed over to receive sintilimab. Additional data indicated that the PFS benefit achieved with sintilimab was noted across key subgroups analyzed, including age, performance status, platinum-based therapy, smoking status, and presence of brain metastases.

Notably, PFS benefit was found to correlate with level of PD-L1 expression. The median PFS in patients with a TPS of less than 1% was 7.3 months (95% CI, 6.2–not reached [NR]) and 5.1 months (95% CI, 4.6-7.8) with sintilimab and chemotherapy alone, respectively (HR, 0.664; 95% CI, 0.406-1.086). In the subgroup of patients with a TPS of 1% to 49%, the median PFS in the sintilimab and chemotherapy-alone arms was 7.1 months (95% CI, 6.2-9.2) and 4.8 months (95% CI, 2.5-8.0), respectively (HR, 0.503; 95% CI, 6.2-9.2). In the subset of patients with the highest PD-L1 TPS of 50% or greater, the median PFS had not yet been reached (95% CI, 9.2–NR) with sintilimab vs 5.0 months (95% CI, 4.3-6.8) with chemotherapy alone (HR, 0.310; 95% CI, 0.197-0.489).

Moreover, sintilimab resulted in an approximate 40% reduction in the risk of death compared with chemotherapy alone, and this was determined to be nominally significant (HR, 0.609; 95% CI, 0.400-0.926; P = .01921). The OS rates at 6 months in the investigative and control arms were 89.6% and 80.4%, respectively.

The sintilimab regimen elicited an objective response rate (ORR) of 51.9% vs 29.8% with chemotherapy alone. The disease control rates achieved in the investigative and control arms were 86.8% and 75.6%, respectively. The median OR had not yet been reached (95% CI, 8.0-NR) with sintilimab vs 5.5 months (95% CI, 4.1-10.9) with chemotherapy alone. Time to response also proved to be shorter in the sintilimab arm vs the chemotherapy-alone arm, at 1.5 months and 2.6 months, respectively.

Rates of adverse effects (AEs) were comparable between the 2 treatment arms, with grade 3 to 5 toxicities experienced by 61.7% and 58.5% of those on the investigative and control arms, respectively. Serious AEs were reported by 28.2% of those given the sintilimab regimen vs 29.8% of those who received chemotherapy alone. Six patients on the investigative arm experienced AEs that resulted in death vs 9 patients on the control arm.

Toxicities that led to discontinuation of treatment were reported in 6.0% and 8.4% of those on the investigative and control arms, respectively. Moreover, slightly more immune-related AEs were experienced by those who received the sintilimab regimen vs chemotherapy alone, at 43.2% and 36.6%, respectively; these effects were grade 3 to 5 in 5.6% and 6.1% of patients, respectively.

The most frequently experienced toxicities included anemia, reduced neutrophil count, reduced white blood cell count, reduced platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, nausea, reduced appetite, asthenia, vomiting, constipation, and pyrexia.

Currently, 2 indications for sintilimab have been approved in China, while 3 regulatory submissions remain under review.


  1. US 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. Innovent Biologics, Inc. May 18, 2021. Accessed May 18, 2021. https://prn.to/2RsrJOD
  2. Zhang Li, Yang Y, Wang Z, et al. ORIENT-11: sintilimab + pemetrexed + platinum as first-line therapy for locally advanced or metastatic non-squamous NSCLC. J Thorac Oncol. 2020;15(10). doi:10.1016/j.jtho.2020.08.002

This article was originally posted on OncLive as, "Sintilimab/Pemetrexed Regimen in Frontline Nonsquamous NSCLC Accepted for FDA Review."