Sintilimab-IBI305-chemo improves PFS in EGFRm non-squamous NSCLC

The combination of the anti-PD-1 monoclonal antibody sintilimab with the bevacizumab biosimilar IBI305 and pemetrexed and cisplatin chemotherapy improved progression-free survival (PFS) in patients with EGFR*-mutated (EGFRm) non-squamous non-small-cell lung cancer (NSCLC), according to interim analysis results of the phase III ORIENT-31 trial from China.

“This is the first randomized, placebo-controlled study that indicates significant PFS benefit with platinum-based doublet chemotherapy + anti-PD-1 antibody and VEGF-inhibitor vs chemotherapy alone,” presented Dr Shun Lu from the Shanghai Chest Hospital, Shanghai, China, at the ESMO Asia Virtual Oncology Week 2021.

Participants in this double-blind study were 444 patients aged 18–75 years (median age 57 years, ~41 percent male) with unresectable advanced or metastatic EGFRm non-squamous NSCLC who were systemic chemotherapy naïve and experienced disease progression following EGFR-TKI** therapy. They were randomized 1:1:1 to receive four cycles of intravenous sintilimab (200 mg) + IBI305 (15 mg/kg) + chemotherapy (pemetrexed 500 mg/m² + cisplatin 75 mg/m²; arm A) Q3W, four cycles of sintilimab + chemotherapy + placebo Q3W (arm B), or four cycles of chemotherapy + placebos 1 and 2 Q3W (arm C). This was followed by maintenance sintilimab + IBI305 + pemetrexed (arm A), sintilimab + placebo 2 + pemetrexed (arm B), and placebos 1 and 2 + pemetrexed (arm C) Q3W.

Patients in arms A and B were treated for ≤24 months or until disease progression, while those in arm C were allowed to cross over (conditionally) to receive sintilimab Q3W monotherapy upon progression. Thirty-six percent of patients had brain metastases.

Patients were followed up for a median 9.8 months. Median PFS, as per independent radiological review committee, was 6.9, 5.6, and 4.3 months in arms A, B, and C, respectively. [ESMO Asia 2021, presentation VP9-2021]

Compared with patients on chemotherapy alone (arm C), patients on sintilimab + IBI305 + chemotherapy (arm A) demonstrated a significant improvement in PFS (hazard ratio [HR], 0.464, 95 percent confidence interval [CI], 0.337–0.639; p<0.0001), with 74 and 101 events occurring in arms A and C, respectively.

The PFS benefit was consistent across multiple subgroups including presence or absence of brain metastases at baseline.

A futility analysis showed that the comparison between arms A and B did not cross the futility boundary (HR, 0.726, 95 percent CI, 0.528–0.998).

Confirmed objective response rate (ORR) was also improved in arm A vs C (43.9 percent vs 25.2 percent), with a median duration of response (DoR) of 8.3 vs 7.0 months.

There was also a non-significant trend toward improved PFS with sintilimab + chemotherapy (arm B) vs chemotherapy alone (HR, 0.750, 95 percent CI, 0.555–1.013; p=0.0584), though these results are immature.

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.7, 39.3, and 51.0 percent of patients in arms A, B, and C, respectively, with 51.4, 35.9, and 45.0 percent, respectively, deemed treatment related. Treatment-related serious AEs occurred in 27.7, 15.9, and 24.5 percent, respectively. TEAEs led to treatment discontinuation in 16.9, 8.3, and 6.6 percent, respectively. Immune-related AEs occurred in 35.1, 23.4, and 15.2 percent, respectively. Eight patients in arm A and four in arm C experienced TEAEs that led to death.

“The safety profile was acceptable without new unexpected safety signals,” noted Lu.

A new find?

“Currently, the standard treatment for patients with EGFRm NSCLC who progress with EGFR-TKIs is platinum-based chemotherapy and there is a significant need for new therapeutic options,” commented Dr Antonio Passaro from the European Institute of Oncology, IRCCS, Milan, Italy, who was not involved in the study.

“Sintilimab + IBI305 + pemetrexed + cisplatin might be a reasonable option in patients with EGFRm NSCLC who progressed on EGFR-TKI,” said Dr Myung-Ju Ahn from the Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, who commented on the findings.

“The results from the ORIENT-31 trial are clearly positive in favour of sintilimab + bevacizumab and chemotherapy but it is difficult to consider the small PFS improvement of less than 3 months as clinically significant. Mature results are eagerly awaited,” said Passaro.