Can a TKI Boost Anti-PD-L1 Activity in NSCLC?

Medscape

a day ago

Can adding a TKI that targets programmed death ligand 1 (PD-L1) to a monoclonal antibody that also targets PD-L1 improve outcomes over the monoclonal antibody alone in locally advanced, unresectable non-small cell lung cancer (NSCLC)? Researchers in China have come in with a qualified yes.
The authors of the new study found that a combination of anlotinib, an oral small-molecule TKI, and benmelstobart (TQB2450), a humanized immunoglobulin G subclass 1 (IgG1) monoclonal antibody that targets PD-L1, improved progression-free survival (PFS) compared with benmelstobart alone after concurrent/sequential chemoradiotherapy (60 Gray ± 10%).
A downside of taking the TKI was a significant increase in side effects, Ming Chen, MD, PhD, lead investigator of the R-ALPS trial, reported at American Society of Clinical Oncology (ASCO) 2025.
Study Results
'Our key finding demonstrated significant improvement in median PFS with the combination of benmelstobart plus anlotinib, with a median PFS of 15.1 months compared to 9.7 months with benmelstobart alone and 4.2 months with placebo,' said Chen, while presenting the abstract at the meeting. PFS was the primary endpoint of the study.
Ming Chen, MD, PhD
'This translated into a reduced risk of disease progression with a hazard ratio of 0.49 for the combination arm and 0.53 for benmelstobart alone,' vs placebo, said Chen, who is director of Radiation Oncology at the Sun Yat-sen University Cancer Center in Guangzhou, China. The P values for both were less than .0001.
Chen reported results of an interim analysis of the phase 3 R-ALPS study, which randomized 553 patients to one of three treatment groups after all received concurrent/sequential chemoradiotherapy: Benmelstobart alone, benmelstobart plus anlotinib, or placebo.
Twelve-month PFS rates were 54.9% in the combination group, 45.7% in the benmelstobart alone group, and 26.4% in the placebo group. The data analysis of overall survival rates has not been completed, Chen said.
Among secondary endpoints, overall response rates were 25.6% ( P = .01), 23.3 ( P = .0318), and 12.9% for the combination, benmelstobart alone, and placebo groups, respectively. The disease control rates were 84.5% ( P = .0067) and 86.1% ( P = .0023) for the combination and benmelstobart alone groups, respectively, and was 70.5% for the placebo group.
Safety Profile 'Manageable' or 'Significant'?
The combination group had consistently higher rates of adverse events than the other two groups.
Chen said the safety profile of adding anlotinib to benmelstobart was 'manageable,' while Shankar Siva, PhD, MBBS, a discussant at the oral abstracts session, characterized the toxicity profile of the study as 'significant.'
Shankar Siva, PhD, MBBS
Overall, the rates of grade 3-5 treatment-related adverse events (TRAEs) were 50% in the combination group, 32% in the benmelstobart alone group, and 21% in the placebo group. The rates of serious TRAEs were 38.3%, 33% and 26.5%, respectively.
Hematologic toxicities were not significantly different across the three groups, Chen said, but the following four biochemical measures were significantly elevated in the combination group: Antistreptokinase, creatine phosphokinase, thyroid-stimulating hormone, and amylase.
Among the grade 3-5 non-hematologic TRAEs, rates of infectious pneumonia, hypertension, and hemoptysis were significantly higher in the combination group: 8.1%, 8.6%, and 2.4%, respectively, vs 4.7%, 0.9%, and 0.5% in the benmelstobart alone group and 5.3%, 1.8%, and 0.8% in the placebo group.
Chen added that the rates of radiation pneumonitis and immune pneumonitis 'were very mild in all three arms,' with rates below 3%.
Elaborating on his different take on the combination treatment's safety profile from Chen's, Siva said the incidence of high-grade adverse events in this study was notable.
'More targeted or bispecific TKIs' might be worth exploring in a combination treatment after chemoradiotherapy for NSCLC to improve the safety profile, he said, during the session.
Knowing biomarkers of benefit and potential toxicity would also be important for using multitarget TKIs in combination therapies after chemoradiotherapy for NSCLS, noted Siva, who is a radiation oncologist at Peter MacCallum Cancer Centre in Melbourne, Australia.
One of the limitations of the study was that all patients were Chinese, Chen said.
Anlotinib was approved for advanced NSCLC in China in 2019.
Chia Tai TianQing Pharmaceutical Group funded the study. Chen reported having no relevant financial relationships. Siva reported having financial relationships with AstraZeneca, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, and Varian Medical Systems.