Benmelstobart With/Without Anlotinib Is Effective Consolidation Therapy in NSCLC

Benmelstobart-based regimens provide clinically meaningful PFS benefits as consolidation therapy for unresectable stage III non–small cell lung cancer.

Benmelstobart (TQB2450), both alone and in combination with anlotinib, demonstrated significant progression-free survival (PFS) benefits as consolidation therapy vs placebo for patients with unresectable stage III non–small cell lung cancer (NSCLC) who did not progress following chemoradiotherapy, while maintaining a manageable safety profile, according to results from the phase 3 R-ALPS trial (NCT04325763) shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

In this multicenter, double-blind study, 553 patients were randomly assigned following concurrent or sequential chemoradiotherapy to receive benmelstobart plus anlotinib, benmelstobart alone, or placebo. At the November 2023 data cutoff, the median PFS assessed by independent review was 15.1 months for the combination therapy (95% CI, 9.4-21.7), compared with 9.7 months with benmelstobart alone (95% CI, 6.0-34.4) and 4.2 months with placebo (95% CI, 3.2-6.8). Both active treatment arms demonstrated highly significant improvements vs placebo (HR 0.49 and 0.53, respectively; P <.0001).

By July 2024, updated data showed continued benefit, with a median PFS of 17.4 months for the combination (95% CI, 12.5-24.8) vs 11.2 months for monotherapy (95% CI, 7.0-20.7), though the between-arm comparison did not reach statistical significance (HR 0.82, P =.1218). Twelve-month PFS rates echoed these findings, with 54.9% for the combination, 45.7% for monotherapy, and 26.4% for placebo.

"The R-ALPS study demonstrates that benmelstobart, with or without anlotinib, provides significant progression-free survival benefits as consolidation therapy for unresectable stage III non–small cell lung cancer, with a manageable safety profile,” said Ming Chen, MD, PhD, professor and the chair of the Department of Radiation Oncology of Sun Yat-sen University Cancer Center, during the presentation.

About Benmelstobart and the R-ALPS Trial

Benmelstobart was developed in China, where PD-L1 inhibitors only became clinically available after 2019. The rationale for combining it with anlotinib stems from the latter’s ability to normalize tumor vasculature, potentially enhancing immune infiltration and synergy with immune checkpoint blockade.

This study, which enrolled patients without EGFR or ALK genomic alterations and with good performance status, is the first phase 3 trial to evaluate PD-L1 inhibition with or without antiangiogenic therapy as consolidation in this setting.

R-ALPS, a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial, enrolled patients with unresectable stage III NSCLC who had an ECOG performance score of 0 or 1. In the first arm, patients were given benmelstobart 1200 mg intravenously (IV) every 3 weeks with oral anlotinib 8 mg daily on days 1 through 4 for 3 weeks. In the benmelstobart without anlotinib arm, patients received just IV benmelstobart 1200 mg every 3 weeks. In the third arm, patients were given placebo only.

In addition to the primary end point of PFS, secondary end points consisted of overall survival, objective response rates (ORR), disease control rate (DCR), and safety.

This study followed a 2-phase design. In the first phase, it was hypothesized that benmelstobart would improve PFS from 6 to 9 months compared with placebo, with patients randomized in a 1:1:1 ratio across 3 arms. In the second phase, direct comparisons between the 2 experimental arms were introduced, with the hypothesis that the combination of benmelstobart and anlotinib would achieve a PFS of 12.5 months. A total sample size of 534 was estimated, with a 2-sided alpha of 0.05. Interim analysis was planned upon reaching 17% of the 286 targeted PFS events.

Out of 808 patients screened, 553 were ultimately enrolled and received treatment per protocol. Baseline characteristics were well balanced across groups, with 209 patients in the combination arm, 212 in the benmelstobart monotherapy arm, and 132 in the placebo arm. Most patients were male (90%, 88.7%, and 90.2%), had squamous cell carcinoma (73.2%, 70.3%, and 67.4%), and presented with stage IIIB (46.9%, 50.9%, and 58.3%) or IIIC (24.4%, 21.2%, and 18.2%) disease. Approximately 80% of patients across arms received concurrent chemoradiation with a radiation dose between 60 and 66 Gy in conventional fractions. PFS was evaluated by an independent review committee.

Safety and Efficacy Data

Secondary end points also favored active treatment, with an ORR of 25.6% with the combination (P =.0100), 23.3% with monotherapy (P =.0318), and 12.9% with placebo. The complete response (CR) rate was 4.7% in the combination arm, 3.1% with benmelstobart alone, and 3.0% with placebo. Partial responses (PR) occurred in 20.9% of patients receiving the combination, 20.2% with benmelstobart, and 9.9% with placebo.

DCRs, which include CR, PR, and stable disease, were also higher in the active treatment arms: 84.5% with the combination (P =.0067), 86.1% with monotherapy (P =.0023), and 70.5% with placebo.

Importantly, safety remained manageable. Grade ≥3 treatment-emergent adverse events (AEs) occurred in 49.8% of combination-treated patients, 31.8% with monotherapy, and 21.2% with placebo. Grade 3 to 5 events, including serious AEs (SAEs) and immune-related AEs (irAEs), were consistently elevated in the benmelstobart (99.5%) and benmelstobart with anlotinib arms (97.6%) relative to placebo (91.7%).

For SAEs, the rates were 40.7%, 35.5%, and 28.8% across arms, with treatment-related SAEs at 38.3%, 33.2%, and 26.5%. Furthermore, irAEs occurred in 41.6%, 42.7%, and 22.7%, with grade 3 to 5 irAEs at 7.2%, 4.7%, and 3.8%.

Potential Limitations and Future Directions

While the results are promising, limitations include a study population limited to Chinese patients and the absence of planned PD-L1 biomarker analysis. Overall survival data are not yet mature, and longer follow-up is underway.

“Overall survival data are still immature, and long-term follow-up is ongoing," Chen added.

This trial supports the use of benmelstobart, alone or with anlotinib, as effective maintenance therapy after chemoradiation in unresectable stage III NSCLC. These regimens offer clinically meaningful PFS improvements with acceptable safety profiles.

Reference

Chen M, Ji Y, Chen L, et al. R-ALPS: A randomized, double-blind, placebo-controlled, multicenter phase III clinical trial of TQB2450 with or without anlotinib as maintenance treatment in patients with locally advanced and unresectable (stage III) NSCLC without progression following concurrent or sequential chemoradiotherapy. J Clin Oncol. 2025;43(suppl 17):LBA8004. doi:10.1200/JCO.2025.43.17_suppl.LBA8004