The combination of sintilimab, a bevacizumab biosimilar injection, and chemotherapy resulted in a significant improvement in progression-free survival in patients with EGFR-mutated, nonsquamous, non–small cell lung cancer that as progressed following treatment with an EGFR TKI, meeting the primary end point of the phase 3 ORIENT-31 trial.
The combination of sintilimab (Tyvyt), a bevacizumab biosimilar injection (Byvasda), and chemotherapy resulted in a significant improvement in progression-free survival (PFS) in patients with EGFR-mutated, nonsquamous, non–small cell lung cancer (NSCLC) that as progressed following treatment with an EGFR TKI, meeting the primary end point of the phase 3 ORIENT-31 trial (NCT03802240).1
Data from the first interim analysis, which were reviewed by the independent data monitoring committee and were based on an assessment by the blinded independent radiographic review committee (BIRRC), showed a statistically significant and clinically meaningful PFS improvement with the combination vs pemetrexed/cisplatin alone in the intent-to-treat (ITT) population.
Moreover, sintilimab in combination with chemotherapy also demonstrated a trend toward a PFS benefit vs chemotherapy alone, although the data are not yet mature.
Additionally, the prespecified PFS futility analysis comparing sintilimab plus bevacizumab biosimilar injection and chemotherapy with sintilimab plus chemotherapy was not found to cross the futility stopping boundary. The addition of the biosimilar to sintilimab and chemotherapy has a numerical benefit.
No additional safety signals were reported with sintilimab and bevacizumab biosimilar injection.
Detailed findings from the trial will be shared at an upcoming medical conference.
“ORIENT-31 is the first prospective, double-blind, phase 3 study worldwide to demonstrate significant PFS benefit with an anti–PD-1 antibody combination therapy in this patient population,” Professor Shun Lu, Oncology Department of Shanghai Chest Hospital, and principal investigator of ORIENT-31, stated in a press release. “It has shown the clinical value of adding sintilimab plus bevacizumab biosimilar injection to platinum chemotherapy. This quadruple regimen has the potential to bring forth a new and more effective treatment option to patients with EGFR-mutated nonsquamous NSCLC following treatment with an EGFR TKI.”
ORIENT-31 enrolled patients with disease progression following a first- or second-generation EGFR TKI who had either confirmed T790M negativity or had T790M-positive disease but progression on a third-generation EGFR TKI treatment. The trial also enrolled those who experienced progressive disease after first-line treatment with a third-generation EGFR TKI.
Study participants were randomized 1:1:1 to receive intravenous (IV) sintilimab at 200 mg every 3 weeks plus bevacizumab biosimilar injection at 15 mg/kg every 3 weeks and pemetrexed at 500 mg/m2 every 3 weeks and cisplatin at 75 mg/m2 every 3 weeks or sintilimab plus placebo 2 combined with pemetrexed/cisplatin or placebo 1 plus placebo 2 plus pemetrexed/cisplatin.2
Following a total of 4 cycles of combination therapy, participants will go on to receive maintenance treatment with sintilimab plus bevacizumab biosimilar injection and pemetrexed, sintilimab plus placebo 2 and pemetrexed, or placebo 1 plus placebo 2 and pemetrexed. Maintenance treatment will continue until radiographic disease progression, intolerable toxicity, or any other conditions that necessitate treatment discontinuation.
The trial seeks to enroll 480 participants, and the primary end point is PFS per BIRRC and based on RECIST v1.1 criteria. Key secondary end points comprise overall survival (OS), investigator-assessed PFS, objective response rate, and safety.
Previously, 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 findings from the phase 3 ORIENT-11 trial (NCT03607539), which indicated that the combination resulted in a significant improvement in PFS compared with chemotherapy alone in this patient 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.
Patients had to have stage IIIB/C or IV disease and not be eligible to undergo surgery or receive local therapy. They also needed to have an ECOG performance status of 0 or 1 and have a tumor sample available for PD-L1 assessment. Patients were stratified by gender, type of platinum therapy (cisplatin vs carboplatin) and PD-L1 expression level (tumor proportion score [TPS] less than 1% vs 1% or higher).
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 at area under the curve (AUC) 5, every 3 weeks for 4 cycles.
Patients in the investigative arm received sintilimab at 200 mg every 3 weeks for up to 2 years; plus pemetrexed at 500 mg/m2 every 3 weeks; those in the control arm received placebo every 3 weeks for up to 24 months plus pemetrexed at the 500 mg/m2 every-3-week dosing schedule. Thereafter, patients on the control arm were permitted 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. Secondary end points included OS, response rate, duration of response (DOR), time to response, and safety. Efficacy was examined in the ITT population and safety data included all patients who received at least 1 dose of study treatment.
Additional data from the trial 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 those 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 those 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).
The addition of sintilimab was also found to result in an approximate 40% reduction in the risk of death vs chemotherapy alone, which was determined to be nominally significant (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.
Moreover, the sintilimab combination induced 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. Time to response was shorter in the sintilimab arm vs the chemotherapy-alone arm, at 1.5 months and 2.6 months, respectively.
The most common 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.