The FDA has issued a complete response letter to the biologics license application seeking the approval of sintilimab injection in combination with pemetrexed and platinum chemotherapy in the frontline treatment of patients with nonsquamous non–small cell lung cancer.
The FDA has issued a complete response letter (CRL) to the biologics license application seeking the approval of sintilimab injection in combination with pemetrexed and platinum chemotherapy in the frontline treatment of patients with nonsquamous non–small cell lung cancer (NSCLC).1
The regulatory agency completed their review cycle but stated that they are unable to approve the application in its current form, which aligns with the outcome of the Oncologic Drugs Advisory Committee (ODAC) Meeting that was held in February 2022.2 The committee had concluded that the supporting data from the phase 3 ORIENT-11 trial (NCT03607539), which had been conducted entirely in China, could not be applied to a US population. They noted that the study population was younger, predominantly male, and included higher rates of smokers than are generally found in the United States.
The ODAC voted 14 to 1 to require Innovent Biologics (Suzhou), the drug developer, to conduct a new trial that would illustrate the efficacy of sintilimab in patients residing within the United States. They noted that “regulatory flexibility” did not apply to this case, because the agent is not filling an unmet need.
“The CRL includes a recommendation for an additional clinical study, specifically a multiregional clinical trial, comparing standard-of-care therapy for first-line metastatic NSCLC with sintilimab with chemotherapy utilizing a non-inferiority design and an overall survival end point,” according to a press release issued by Eli Lilly and Company.
The Chinese, double-blind, randomized, phase 3 trial enrolled patients with stage IIIB/C or IV disease who were not candidates to undergo surgery or receive local therapy.3 To be eligible for enrollment, patients were required to have an ECOG performance status of 0 or 1 and have a tumor sample available for PD-L1 assessment.
Study participants were randomized 2:1 to receive sintilimab at 200 mg every 3 weeks for up to 2 years (n = 266) or placebo (n = 131) in combination with pemetrexed at 500 mg/m2 every 3 weeks and platinum therapy comprised of cisplatin at 75 mg/m2 or carboplatin area under the curve 5. Those in the control arm received placebo every 3 weeks for up to 24 months plus pemetrexed at the same dose and schedule as the investigative arm. Following this time point, those on the control arm were permitted to cross over to receive sintilimab at 200 mg every 3 weeks for up to 24 months.
Patients were stratified by gender, type of platinum therapy (cisplatin vs carboplatin), and PD-L1 expression level (tumor proportion score [TPS] of less than 1% vs 1% or higher).
The primary objective of the trial was progression-free survival (PFS) per independent radiologic review committee (IRRC), and secondary end points comprised overall survival (OS), response rate, duration of response, time to response, and safety.
Efficacy was examined in the intent-to-treat population and safety findings included all patients who received at least 1 dose of the study treatment. The median age of patients included on the trial was 61 years (range, 32.5-75.0), 76.2% of patients were male, 72.7% had an ECOG performance status of 1, 90.3% had stage IV disease, and approximately 15% had brain metastases. Moreover, 74.1% of patients received carboplatin, 65.4% were either current or former smokers, and 67.2% had a PD-L1 TPS of 1% or higher.
At a median follow-up of 8.9 months, the median PFS achieved with sintilimab/chemotherapy was 8.9 months (95% CI, 7.1-11.3) vs 5.0 months (95% CI, 4.8-6.2) with chemotherapy alone, which translated to an estimated 52% reduction in the risk of progressive disease or death (HR, 0.482; 95% CI, 0.362-0.643; P < .00001). The PFS benefit achieved with the agent was observed across all key subsets that were evaluated, including age, performance status, platinum-based therapy received, smoking status, and presence of brain metastases.
Additionally, the level of PD-L1 expression was found to correlate with PFS benefit achieved with the agent. In those with a TPS of less than 1%, the median PFS with sintilimab/chemotherapy was 7.3 months (95% CI, 6.2–not reached [NR]) vs 5.1 months (95% CI, 4.6-7.8) with chemotherapy alone (HR, 0.664; 95% CI, 0.406-1.086).
In the subset of patients with a TPS ranging from 1% to 49%, the median PFS with the addition of sintilimab was 7.1 months (95% CI, 6.2-9.2) vs 4.8 months (95% CI, 2.5-8.0) with chemotherapy alone (HR, 0.503; 95% CI, 6.2-9.2). In those with a PD-L1 TPS of 50% or higher, the median PFS had not yet been reached (95% CI, 9.2-NR) with sintilimab/chemotherapy vs 5.0 months (95% CI, 4.3-6.8) with chemotherapy alone (HR, 0.310; 95% CI, 0.197-0.489).
Sintilimab also induced a nominally significant 40% reduction in the risk of death compared with chemotherapy alone (HR, 0.609; 95% CI, 0.400-0.926; P = .01921). The 6-month OS rates in the investigative and control arms were 89.6% and 80.4%, respectively.
Additionally, the combination of sintilimab and chemotherapy induced an objective response rate of 51.9% vs 29.8% with chemotherapy alone, and the disease control rates were 86.8% and 75.6%, respectively. Time to response proved to be shorter with the sintilimab combination vs chemotherapy alone, at 1.5 months vs 2.6 months, respectively.
The most common toxicities with sintilimab/chemotherapy 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.
Sintilimab (Tyvyt) has been approved in China for use in relapsed or refractory classic non-Hodgkin lymphoma following 2 lines or more of systemic chemotherapy, in combination with pemetrexed and platinum chemotherapy in the frontline treatment of squamous NSCLC, and in combination with bevacizumab biosimilar injection (Byvasda) in the frontline treatment of hepatocellular carcinoma.