Sugemalimab safe and effective as consolidation for patients with unresectable stage III NSCLC

Patients with unresectable stage III non-small cell lung cancer (NSCLC) are normally treated with concurrent or sequential chemoradiotherapy (cCRT or sCRT). Updated progression-free survival results from the phase III GEMSTONE-301 trial now confirmed that the human monoclonal antibody sugemalimab is a safe and effective consolidation therapy for patients with unresectable stage III NSCLC without disease progression after either cCRT or sCRT.

Concurrent chemoradiotherapy (cCRT) followed by immunotherapy is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, a substantial proportion of patients cannot tolerate or access cCRT, and thus sequential chemoradiotherapy (sCRT) is commonly used. Sugemalimab is a full-length, fully human IgG4 monoclonal antibody targeting PD-L1. In June 2022, sugemalimab was approved in China for the treatment of patients with unresectable stage III NSCLC whose disease had not progressed following cCRT or sCRT. In an interim progression-free survival (PFS) analysis of the GEMSTONE-301 trial, sugemalimab showed a statistically significant and clinically meaningful improvement compared with placebo (median PFS 9.0 vs. 5.8 months, p= 0.0026). During the IASLC WCLC 2022, the final PFS analysis was presented. 

Study design

GEMSTONE-301 is a randomised, double-blind, placebo-controlled, phase III trial that included patients with locally advanced, unresectable, stage III NSCLC whose disease has not progressed following cCRT or sCRT. Patients had to have an ECOG PS 0-1 and no known sensitising EGFR, ALK or ROS1 genomic alterations. Patients were randomised 2:1 to sugemalimab (1,200 mg, intravenously, Q3W) or matching placebo as consolidation therapy for up to 24 months. Stratifications factors included ECOG performance status (0 vs. 1), CRT type (cCRT vs. sCRT), and total radiotherapy dose (<60 Gy vs. ≥60 Gy). The primary endpoint was PFS by blinded independent central review (BICR) according to RECIST v1.1.

Results

In total, 381 eligible patients were randomly assigned to sugemalimab (N= 255) or placebo (N= 126). Median follow-up was 27.1 months in the sugemalimab cohort and 23.5 months in the placebo cohort. Median PFS was 10.5 vs. 6.2 months (HR[95%CI]: 0.65[0.50-0.84]; p= 0.0012). The 24- and 36-months PFS rates were 38.6% vs. 23.1% and 26.1% vs. 0%, respectively. A consistent PFS benefit was observed with sCRT (mPFS 8.1 vs. 4.1 months, HR[95%CI]: 0.57[0.38-0.87]) and cCRT (15.7 vs. 8.3 months, HR[95%CI]: 0.71[0.5-1.0]). Median OS was not reached in the sugemalimab arm, and was 25.9 months in the placebo arm (HR[95%CI]: 0.69[0.49-0.97]). The 24- and 36-months OS rates were 67.6% vs. 55.0% and 55.8% vs. 29.5%, respectively. Median OS was also not reached for the sCRT (mOS NR vs. 24.1 months, HR[95%CI]: 0.60[0.34-1.05]) nor cCRT subgroups (mOS NR vs. 32.4 months, HR[95%CI]: 0.75[0.48-1.15]), with 24- and 36-months OS rates of 70.7% vs. 53.7% for sCRT and 66.3% vs. 57.6% for cCRT and 59.0% vs. 43.7% for sCRT and 54.1% vs. 19.8% for cCRT, respectively. After two years, the objective response rates (ORR) were highly similar in de sugemalimab (24.5%) and placebo arms (25.2%).  However, duration of response (DOR) was 24.1 vs. 6.9 months in the sugemalimab and placebo arms, respectively.

Treatment-related adverse events (TRAEs) of all grades were found in 78.4% vs. 64.3% of the patients in the sugemalimab vs. placebo arms, respectively (74.4% vs. 48.8% in the sCRT patients, and 80.5% vs. 71.8% in the cCRT patients). Treatment-related AEs of grade 3-5 were found in 11.4% vs. 5.6% of the patients in the sugemalimab vs. placebo arms. Most common TRAEs of grade 1-2 were hypothyroidism, increased alanine aminotransferase and hyperthyroidism in the sugemalimab arm vs. hypothyroidism, increased alanine aminotransferase and  pneumonitis in the placebo arm. Most common ≥3 TRAEs were immune-mediated lung disease, hypothyroidism and pneumonitis in the sugemalimab  arm vs. anaemia and pneumonitis in the placebo arm.

Conclusions

Final PFS results of the GEMSTONE-301 trial showed sustained improvement in PFS with sugemalimab vs. placebo among patients with unresectable stage III NSCLC who had not progressed following cCRT or sCRT. In addition, the preliminary OS data showed a trend favouring sugemalimab. Although ORR was similar between the sugemalimab and placebo arms, DoR was longer for sugemalimab. No new safety signals were found in this analysis. Based on these findings, sugemalimab could be safely and effectively used after cCRT or sCRT in stage III inoperable NSCLC.

Reference

Wu Y-L, Zhou Q, Chen M, et al. Sugemalimab vs placebo after concurrent or sequential chemoradiotherapy in patients with unresectable stage III NSCLC (GEMSTONE-301): final progression-free survival analysis of a phase 3 study. Presented at IASLC WCLC 2022; Abstract OA02.05.