The addition of sintilimab to a bevacizumab biosimilar and pemetrexed/cisplatin resulted in a statistically significant and clinically meaningful improvement in progression-free survival vs chemotherapy alone in patients with EGFR-mutated, nonsquamous non–small cell lung cancer who progressed after an EGFR TKI.
The addition of sintilimab (Tyvyt) to a bevacizumab biosimilar (Byvasda) and pemetrexed/cisplatin resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs chemotherapy alone in patients with EGFR-mutated, nonsquamous non–small cell lung cancer (NSCLC) who progressed after an EGFR TKI, according to data from the first interim analysis of the phase 3 ORIENT-31 trial (NCT03802240).1
Findings, which were presented during the 2021 ESMO Virtual Plenary, showed that the median PFS with the novel sintilimab combination regimen was 6.9 months (95% CI, 6.0-9.3) per independent radiographic review committee (IRRC) assessment vs 4.3 months (95% CI, 4.1-5.4) with chemotherapy alone (HR, 0.464; 95% CI, 0.337-0.639; P < .0001).
Moreover, the prespecified PFS futility analysis that compares the addition of the biosimilar to sintilimab/chemotherapy with sintilimab/chemotherapy alone was not found to cross the futility stopping boundary (HR, 0.726; 95% CI, 0.528-0.998). However, the data are still immature, and a numerical benefit was observed with the addition of the biosimilar.
The addition of sintilimab to the bevacizumab biosimilar and chemotherapy also resulted in an improved objective response rate (ORR) and duration of response (DOR) vs chemotherapy alone. Investigator-assessed PFS, ORR, and DOR was found to be consistent with the IRRC assessment.
“Globally, ORIENT-31 is the first prospective, double-blind phase 3 study to demonstrate significant PFS benefit of combination therapy of PD-1 and VEGF inhibitors and chemotherapy compared to standard care of therapy in this patient population,” Shun Lu, MD, PhD, principal investigator of ORIENT-31 and director of the Oncology Department of Shanghai Chest Hospital, stated in a press release. “The study has shown the clinical value of adding sintilimab plus bevacizumab biosimilar injection to platinum-based chemotherapy…This modified regimen brings forth a new and more effective treatment option and provides clinically meaningful benefits to patients with EGFR-mutated nonsquamous NSCLC following treatment with an EGFR TKI.”
To be eligible for enrollment to ORIENT-31, patients needed to have experienced progressive disease after a first- or second-generation EGFR TKI and have confirmed T790M negativity, be T790M positive but further progressed on a third-generation EGFR TKI, or progressed after a third-generation EGFR TKI as their frontline treatment.2
Study participants were randomized 1:1:1 to receive sintilimab plus bevacizumab biosimilar injection and pemetrexed/cisplatin, sintilimab plus pemetrexed/cisplatin, or just pemetrexed/cisplatin. Following 4 cycles of treatment, patients went on to receive maintenance therapy with sintilimab plus the biosimilar and pemetrexed, sintilimab plus pemetrexed, or just pemetrexed, respectively.
Treatment was administered until radiographic disease progression, intolerable toxicity, or any other conditions that necessitate treatment discontinuation.
The target accrual for the trial is 480 patients, and at the time of the data cutoff date for the first interim analysis, a total of 444 patients had been enrolled.
The primary end point of the trial was PFS per BIRRC based on RECIST v1.1 criteria, and key secondary end points comprised overall survival (OS), investigator-assessed PFS, ORR, and safety.
In May 2021, a biologics license application for the frontline use of sintilimab injection plus pemetrexed and platinum-based chemotherapy in patients with nonsquamous NSCLC was accepted by the FDA for review.3
The application was based on data from the phase 3 ORIENT-11 trial (NCT03607539), which showed that the combination significantly improved PFS vs chemotherapy alone in this population.4 At a median follow-up of 8.9 months, the IRRC-assessed median PFS in the investigative and control arms was 8.9 months (95% CI, 7.1-11.3) and 5.0 months (95% CI, 4.8-6.2), respectively (HR, 0.482; 95% CI, 0.362-0.643; P < .00001).
The Chinese, double-blind, randomized phase 3 ORIENT-11 study examined the safety and efficacy of sintilimab plus pemetrexed and platinum-based chemotherapy as a frontline treatment in 397 patients with nonsquamous NSCLC.
To be eligible for enrollment, patients needed to have stage IIIB/C or IV disease and could not be candidates for surgery or local therapy. Other eligibility criteria included an ECOG performance status of 0 or 1 and a tumor sample available 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 this trial patients were randomized 2:1 to 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 at area under the curve (AUC) 5, every 3 weeks for 4 cycles.
Those 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, and those in the control arm were administered placebo every 3 weeks for up to 24 months plus pemetrexed at the 500 mg/m2 every 3 weeks. Thereafter, patients on the control arm were allowed to crossover to receive sintilimab at 200 mg every 3 weeks for up to 24 months.
The primary end point of the trial was PFS per IRRC. Key secondary end points comprised OS, response rate, duration of response (DOR), time to response, and safety.
Additional data showed that PFS benefit correlated with PD-L1 expression level. The median PFS in patients with a TPS of less than 1% was 7.3 months (95% CI, 6.2–not reached [NR]) vs 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 subset of patients with a TPS of 1% to 49%, the median PFS 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 with a 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).
The addition of sintilimab was also found to result in an approximate 40% reduction in the risk of death vs chemotherapy alone, and this was noted to be nominally significant (HR, 0.609; 95% CI, 0.400-0.926; P = .01921). Moreover, the OS rates at 6 months in the investigative and control arms were 89.6% and 80.4%, respectively.
The sintilimab combination also elicited a higher ORR of 51.9% compared with 29.8% with chemotherapy alone. The disease control rates were 86.8% and 75.6%, respectively. Time to response was found to be shorter in the investigative arm vs the control arm, at 1.5 months and 2.6 months, respectively.
The most common adverse effects reported 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.