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Combining the PD-1 inhibitor sintilimab with a bevacizumab biosimilar and chemotherapy significantly improved progression-free survival (PFS) versus chemotherapy alone in patients with EGFR-mutant nonsquamous non-small cell lung cancer (NSCLC) who progressed after a tyrosine kinase inhibitor (TKI), a phase III trial found.

At a median follow-up of 9.8 months, the regimen reduced the risk of disease progression by 53.6% compared with pemetrexed/cisplatin chemotherapy alone (HR 0.464, 95% CI 0.337-0.639, P<0.0001), reported Shun Lu, MD, PhD, of Shanghai Chest Hospital in China.

Median PFS was 6.9 months with the combination versus 4.3 months with chemotherapy alone. The survival curve for PFS separated soon after treatment initiation, "suggesting an early response," Lu said during a presentation.

The PFS benefit with the combination persisted across all subgroups, including age, sex, baseline Eastern Cooperative Oncology group performance status, brain metastases at baseline, smoking status, and prior lines of EGFR-TKI treatment.

The combination also produced a significantly higher overall response rate compared with chemotherapy alone (43.9% vs 25.2%), with a median duration of response of 8.3 months and 7.0 months, respectively.

"is the first large randomized study which demonstrated improvement of PFS with chemotherapy plus an anti-PD-1 checkpoint inhibitor plus an antiangiogenic agent compared to pemetrexed/cisplatin," said session discussant Myung-Ju Ahn, MD, of Sungkyunkwan University School of Medicine in Seoul. "Based on this data, this regimen might be a reasonable option in patients with EGFR-mutant NSCLC who progressed on EGFR TKI."

The study enrolled 444 patients (median age 57, 36% with brain metastases) with unresectable, advanced, or metastatic EGFR-mutant nonsquamous NSCLC who had received no prior systemic chemotherapy.

The patients were randomized into three arms:

• Arm A (148 patients): sintilimab + IBI305 (a bevacizumab biosimilar) + chemotherapy
• Arm B (145 patients): sintilimab + placebo 1 + chemotherapy
• Arm C (151 patients): placebo 1 + placebo 2 + chemotherapy

For patients in arm C, crossover to sintilimab monotherapy was allowed after disease progression.

The prespecified futility analysis comparing arm A with arm B did not cross the futility boundary (HR 0.726, 95% CI 0.528-0.998). Arm B demonstrated a trend toward a PFS benefit compared with arm C (HR 0.750, 95% CI 0.555-1.013, P=0.0584), although the PFS data were not yet mature at the time of this analysis.

As for safety, the incidence rates of grade 3 or higher treatment-emergent adverse events (TEAEs) in arms A, B, and C were 54.7%, 39.3%, and 51.0%, respectively. Serious TEAEs occurred in 27.7%, 15.9%, and 24.5%, respectively.

"The safety profile was acceptable, without any new unexpected safety signals," Lu noted.

Ahn pointed out that a PFS benefit was observed regardless of brain metastasis, "which is quite promising." However, further analysis -- such as the evaluation of intracranial PFS -- would be useful, she suggested.

Development of biomarkers will be needed to determine which patients are most likely to benefit from the four-drug combination, Ahn concluded.

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