Sintilimab Plus Chemo With or Without IBI305 Provides PFS Benefit in EGFR TKI–Pretreated EGFR+ NSCLC

The combination of sintilimab and chemotherapy with or without the bevacizumab biosimilar IBI305 (Byvasda) produced 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 treatment with an EGFR TKI, according to data from the second prespecified interim analysis of the phase 3 ORIENT-31 trial (NCT03802240).^1,2

Findings published in Lancet Respiratory Medicine showed that at a median follow-up of 12.9 months, 15.1 months, and 14.4 months for patients treated with sintilimab plus chemotherapy and IBI305 (arm A), sintilimab plus chemotherapy (arm B), and chemotherapy alone (arm C), respectively, those in arm A experienced a median PFS of 7.2 months (95% CI, 6.6-9.3) per independent radiographic review committee (IRRC) assessment, compared with 4.3 months (95% CI, 4.1-5.3) in arm C (HR, 0.51; 95% CI, 0.39-0.67; P < .0001).

Patients in arm B achieved a median PFS of 5.5 months (95% CI, 4.5-6.1), which reached the prespecified superiority boundary value vs arm C (HR, 0.72; 95% CI, 0.55-0.94; P = .016).

Additionally, results from the first survival analysis showed that at the data cutoff date of July 4th, 2022, a trend in overall survival (OS) benefit was observed in arm A; however, the median OS for arm C was prolonged due to crossover after disease progression.

Patients in arm A experienced a median OS of 21.1 months (95% CI, 17.5-23.9) vs 19.2 months (95% CI, 15.8-22.4) for arm C (HR, 0.98; 95% CI, 0.72-1.34). The median OS was 20.5 months (95% CI, 15.8-25.3) for patients in arm B (HR vs arm C, 0.97; 95% CI, 0.71-1.32).

After adjusting for crossover, the HR for sintilimab plus IBI305 and chemotherapy vs chemotherapy alone ranged from 0.79 (95% CI, 0.57-1.09) to 0.84 (95% CI, 0.61-1.15). The HR for sintilimab plus chemotherapy vs chemotherapy alone ranged from 0.78 (95% CI, 0.57-1.08) to 0.84 (95% CI, 0.61-1.16).

“ORIENT-31 is globally the first prospective, randomized, double-blind phase 3 study that demonstrated significant PFS benefit of combination therapy of [an] anti–PD-1 antibody and chemotherapy with or without the bevacizumab [biosimilar] in patients with EGFR-mutated nonsquamous NSCLC that progressed on prior EGFR TKI therapy, which was revolutionary in immunotherapy,” Shun Lu, PhD, a professor in the Oncology Department of Shanghai Chest Hospital, in Shanghai, China, and principal investigator of ORIENT-31, stated in a news release.

“I am pleased to witness the first and second interim analysis results of the ORIENT-31 study were published in international authoritative and influential journals,” Lu added. “I hope that the [potential] approval of sintilimab in combination with the bevacizumab [biosimilar] and chemotherapy in treatment of patients with EGFR-mutated nonsquamous NSCLC that progressed on prior EGFR TKI therapy can bring a new treatment option benefiting more cancer patients.”

China’s National Medical Products Administration is currently reviewing a regulatory submission for sintilimab in combination with a bevacizumab biosimilar and chemotherapy for the treatment of patients with EGFR-mutated nonsquamous NSCLC who progressed after a prior EGFR TKI.

Previous findings from the first interim analysis showed that at a median follow-up of 9.8 months (interquartile range, 4.4-13.3), sintilimab plus IBI305 and chemotherapy resulted in a median PFS of 6.9 months (95% CI, 6.0-9.3) compared with 4.3 months (95% CI, 4.1-5.4) with chemotherapy alone (HR, 0.46; 95% CI, 0.34-0.64; P < .0001).³

The double-blind, randomized, placebo-controlled ORIENT-31 study enrolled patients between the ages of 18 and 75 with locally advanced or metastatic EGFR-mutated nonsquamous NSCLC who experienced disease progression after treatment with an EGFR TKI. Patients are also required to have at least one measurable lesion per to RECIST v1.1 criteria.²

Patients were randomly assigned 1:1:1 to receive 200 mg of sintilimab plus 15 mg/kg of IBI305, 500 mg/m² of pemetrexed, and 75 mg/m² of cisplatin; 200 mg of sintilimab plus 500 mg/m² of pemetrexed and 75 mg/m² of cisplatin; or 500 mg/m² of pemetrexed plus 75 mg/m² of cisplatin on day 1 of each 3-week cycle for 4 cycles. Maintenance therapy consisted of sintilimab, IBI305, and pemetrexed.

IRRC-assessed PFS in the intent-to-treat population served as the primary end point. Key secondary end points included OS, investigator-assessed PFS, overall response rate, and safety.

Regarding safety, findings were generally consistent with data reported from the first interim analysis. Grade 3 or higher treatment-related adverse effects occurred in 56% of patients who received sintilimab plus IBI305 and chemotherapy, 41% of patients in the sintilimab plus chemotherapy group, and 49% of patients given chemotherapy alone.

“The ORIENT-31 study is the first phase 3 study that met primary end points in the world evaluating efficacy of PD-1 inhibitor and chemotherapy with or without [a] bevacizumab [biosimilar] in patients with EGFR-mutated nonsquamous NSCLC that progressed on prior EGFR-TKI therapy. The results of first and second interim analysis were published in the Lancet Oncology and the Lancet Respiratory Medicine, respectively,” Hui Zhou, MD, senior vice president of Innovent, stated in a news release.¹

“That represents the international academia’s recognition of high quality, innovative clinical trial conducted by investigators in China, and is also a milestone marking Innovent’s solid and outstanding capabilities in new drug development,” Zhou added. “Meanwhile, we look forward to the approval of sintilimab in combination with bevacizumab and chemotherapy based on the results of the ORIENT-31 study [that] can bring new hope to patients with EGFR-mutated nonsquamous NSCLC that progressed on prior EGFR TKI therapy. Innovent endeavors to advance innovative drug development targeting unmet medical needs, to bring more effective and affordable treatment options to patients in China and the world.”

References

1. Innovent updates the results from the ORIENT-31 study of sintilimab plus chemotherapy with or without bevacizumab in patients with EGFR-TKI failed EGFR-mutated non-squamous non-small cell lung cancer in the Lancet Respiratory Medicine. News release. Innovent. May 6, 2023. Accessed May 8, 2023. https://www.innoventbio.com/InvestorsAndMedia/PressReleaseDetail
2. Lu, S, Wu L, Jian H, et al. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. Published online May 5, 2023. doi:10.1016/S2213-2600(23)00135-2
3. 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