PD-L1, treatment intensity, and outcomes in squamous NSCLC - Authors' reply.

# PD-L1, treatment intensity, and outcomes in squamous NSCLC – Authors' reply *The Lancet 2026* Correspondence could have contributed to the lower HR 0·55 (0·37–0·82) for PD-L1 tumour (82 [68%] of 120),4 which might explain median progression-free survival proportion score (TPS) under 1%, the shorter PFS and fewer treatment observed in the control group of this 0·66 (0·46–0·95) for TPS 1% or higher, cycles in HARMONi-6. study compared with RATIONALE-307. 0·63 (0·41–0·98) for TPS 1–49%, Finally, HARMONi-6 was conducted and 0·71 (0·37–1·33) for TPS 50% or in China with demographics repre- This Correspondence was supported by grants awarded to XX from the Zhejiang Provincial Natural higher. These findings reinforced the sentative of east Asian populations. Science Foundation of China (grant numbers robustness of the primary analysis Generalisability to global cohorts LTGY23H160011 and LTGY24H010003), Program of results. Given the exploratory nature is being evaluated in multinational Province TCM Sci-Tech Plan (2024ZL298), and Shanghai Natural Science Foundation of subgroup analysis, a well designed trials, including HARMONi-3 (25ZR1402449). All other authors declare no phase 3 trial is warranted to evaluate (NCT05899608) and HARMONi-7 competing interests. ivonescimab plus chemotherapy in (NCT06767514). Xiaoling Xu, Wenjing Wang, Huihui Li, patients with PD-L1 TPS 50% or higher. SL has received research support from AstraZeneca, *Xuefei Hu We concur on the value of deeper Hutchison, Bristol Myers Squibb, Heng Rui, Beigene, 024331huxuefei@tongji.edu.cn biomarker exploration. The exploratory Akeso Biopharma, and Hansoh; received speaker fees from Astra Zeneca, Roche, Hansoh, and Hengrui Shanghai Pulmonary Hospital, Tongji University evaluations of immune-vascular Therapeutics; is an advisor and consultant for School of Medicine, Shanghai, China (XX); signatures (eg, VEGF-related markers AstraZeneca, Pfizer, Hutchison MediPharma, ZaiLab, Postgraduate Training Base Alliance, Wenzhou and T-cell infiltration) are under way. Yuhan Corporation, Menarini, InventisBio, Shanghai Medical University, Wenzhou, Zhejiang, China (WW); Fosun Pharmaceutical (Group), and Simcere Zaiming Department of Gastroenterology, Sanmen People’s Regarding treatment discon- Pharmaceutical; and is an independent Director and Hospital of Zhejiang Province, Taizhou, Zhejiang, tinuations due to death, in board member of Innovent Biologics. ZC declares no China (HL); Department of Thoracic Surgery, HARMONi-6, the end-of-treatment competing interests. Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200443, China (XH) reasons were classified strictly according Zhiwei Chen, *Shun Lu 1 Chen Z, Yang F, Jiang Z, et al. Ivonescimab plus to protocol-defined criteria. If a patient shunlu@sjtu.edu.cn chemotherapy versus tislelizumab plus died without evidence of radiographic chemotherapy as first-line treatment for Shanghai Chest Hospital, School of Medicine, advanced squamous non-small-cell lung cancer disease progression or without an Shanghai Jiao Tong University, Shanghai, China (ZC, (HARMONi-6): a randomised, double-blind, adverse event leading to permanent SL) phase 3 trial. Lancet 2025; 406: 2078–88. treatment discontinuation, end of 1 Chen Z, Yang F, Jiang Z, et al. Ivonescimab plus 2 Osarogiagbon RU. Tislelizumab-a promising chemotherapy versus tislelizumab plus treatment was attributed to death. It new option for enhancing chemotherapy chemotherapy as first-line treatment for benefit in treatment for advanced squamous is possible that differences in protocol advanced squamous non-small-cell lung cell lung cancer. JAMA Oncol 2021; 7: 717–19. definitions and reporting conventions cancer (HARMONi-6): a randomised, double- 3 Paz-Ares L, Luft A, Vicente D, et al, and the blind, phase 3 trial. Lancet 2025; KEYNOTE-407 Investigators. Pembrolizumab across trials contributed to the observed 406: 2078–88. plus chemotherapy for squamous non-small-cell differences of HARMONi-6 versus the 2 Wu YL, Wang Z, Cheng Y, et al. 1255MO A phase lung cancer. N Engl J Med 2018; 379: 2040–51. II safety and efficacy study of PM8002/BNT327 RATIONALE-307 and KEYNOTE-407 in combination with chemotherapy in patients trials. Importantly, end of treatment with EGFR-mutated non-small cell lung cancer Authors’ reply due to death was balanced between the (NSCLC). Ann Oncol 2024; 35: S804. 3 Zhou C, Wang L, Bai J, et al. 1860P Preliminary We appreciate Shujie Huang and ivonescimab and tislelizumab groups results of phase II study on HB0025 (a PD-L1/ colleagues and Xiaoling Xu and (16 patients in each). HARMONi-6 was VEGF trap antibody fusion) with chemotherapy as first-line treatment for colleagues highlighting valuable a double-blind, randomised trial, which advanced non-small cell lung cancer (NSCLC). considerations from the HARMONi-6 effectively minimised bias in treatment Ann Oncol 2025; 36: S1072. trial.1 administration, continuation, and 4 Osarogiagbon RU. Tislelizumab–a promising new option for enhancing chemotherapy Regarding PD-L1-stratified outcomes, discontinuation decisions. In the benefit in treatment for advanced squamous we agree that VEGF inhibition might control group of HARMONI-6, the cell lung cancer. JAMA Oncol 2021; 7: 717–19. enhance immunotherapy in so-called median number of tislelizumab doses cold tumours, which is suggested in administered was eight, which aligned studies of both ivonescimab and other with the median PFS of 6·9 months in bispecific antibodies targeting PD-1– this group. Earlier disease progression VEGF.2,3 In HARMONi-6, ivonescimab in patients led to fewer treatment plus chemotherapy showed superior cycles being completed. The study’s progression-free survival (PFS; hazard double-blind design supported that ratio [HR] 0·60, 95% CI 0·46–0·78; treatment decisions were driven by p<0·0001) compared with tislelizumab clinical events rather than investigator plus chemotherapy in patients with bias. Additionally, HARMONi-6 enrolled advanced squamous non-small- a higher proportion of stage IV patients cell lung cancer. The benefit was in the tislelizumab group (246 [92%] consistent across PD-L1 strata, with of 266) than RATIONALE-307 group A 1146 --- [PDF原文](https://sci-net.xyz/storage/7932541/a491b630e61901d36fdd49e44f7f511e39efb2ce4342aaec9a9c47f925540a78/PD-L1-treatment-intensity-and-outcomes-in-squamous-NSCLC-Authors-reply.pdf) DOI: 10.1016/S0140-6736(26)00295-3