Addition of Sintilimab to Bevacizumab Biosimilar IBI305 and Chemo Boosts PFS vs Chemo in Advanced EGFR-Mutant NSCLC


Patients with locally advanced or metastatic EGFR-mutant nonsquamous non–small cell lung cancer who progressed on an EGFR inhibitor may benefit from treatment with sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy vs chemotherapy alone.

Treatment with sintilimab (Tyvyt) and bevacizumab biosimilar IBI305 plus pemetrexed and cisplatin resulted in superior progression-free survival (PFS) in patients with locally advanced or metastatic EGFR-mutant nonsquamous non-small cell lung cancer (NSCLC) who progressed following therapy with EGFR tyrosine kinase inhibitors, according to interim results from the phase 3 ORIENT-31 study (NCT03802240) that were published in Lancet Oncology.

The results from the study showed that after a median follow-up of 9.8 months, patients receiving sintilimab plus IBI305 and chemotherapy had superior PFS compared with those receiving chemotherapy alone, with medians of 6.9 months (95% CI, 6.0-9.3) vs 4.3 months (95% CI 4.1-5.4 months), respectively (Hazard ratio [HR], 0.46 [0.34-0.64]; P <.0001). Survival benefit in the sintilimab, IBI3-5, and chemotherapy group was present across multiple subgroups, including patients with brain metastases, which notably account for about half of patients with advanced NSCLC.

“To our knowledge, this study is the first prospective, double-blind, placebo-controlled, phase 3 trial of combined therapy with a PD-1 inhibitor, anti-VEGF therapy, and chemotherapy to show a significant improvement in [PFS vs] chemotherapy alone in this patient population,” the authors wrote.

EGFR-targeted therapy is considered the standard of care, first-line therapy for patients with advanced EGFR-mutated nonsquamous NSCLC, although existing evidence shows most patients will eventually develop resistance. Once disease progression occurs, platinum-containing doublet chemotherapy with or without bevacizumab (Avastin) is often the next step, although the regimen provides little survival benefit to patients. This has resulted in a need for novel treatment strategies for this patient population.

In ORIENT-31, 444 adults with locally advanced or metastatic EGFR-mutant disease were randomized into 1 of 3 treatment cohorts. The first group received sintilimab at 200 mg and IBI305 at 15 mg/kg plus pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 (n = 148), the second cohort received the same regimen without IBI305 (n = 145), and the final cohort received chemotherapy alone (n = 151). All agents were administered every 3 weeks. Most of the agents, with the exception of cisplatin, were administered for 24 months or until disease progression, intolerable adverse effects (Aes), withdrawal, or death; cisplatin was only given in the first 4 cycles.

To enroll on the trial, patients were required to have an ECOG performance status of 0 or 1, had at least 1 measurable lesion, and a life expectancy of at least 3 months.

The investigators noted that it was not yet possible to compare survival outcomes between the sintilimab plus chemotherapy cohort and the chemotherapy-only cohort, as the data were not sufficiently mature and require a longer follow-up period.

The most common grade 3 or 4 treatment-related AEs in the quadruplet, triplet, and doublet arms, respectively, were decreased neutrophil count (20% vs 18% vs 18%), decreased white blood cell count (11% vs 8% vs 9%), and anemia (12% vs 7% vs 10%). Six deaths were noted in the quadruplet group and 1 death in the chemotherapy-alone group that were considered to be potentially related to treatment.

Results from the study were limited by the fact that third-generation EGFR tyrosine kinase inhibitors were not yet available in China at the time of the study’s initiation in 2019. As such, most patients had received only first- or second-generation EGFR-targeted drugs. Additionally, a biomarker analysis of the data was not yet complete, which could help better explain the mechanism of action behind the combination of immunotherapy with an anti-VEGF inhibitor.

“Despite these potential limitations, our results provide strong evidence for this promising treatment strategy and can potentially change the standard of care for a difficult-to-treat patient population,” they concluded.


Lu S, Wu L, Jian H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022;23(9):1167-1179. doi:10.1016/S1470-2045(22)00382-5

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