Akeso reports 70.1% major pathological response with perioperative ivonescimab plus chemotherapy in resectable NSCLC, with notable results in squamous disease.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
Akeso’s PD-1/VEGF bispecific antibody ivonescimab demonstrated encouraging pathological responses when administered with platinum-based chemotherapy before surgery in patients with resectable non-small cell lung cancer (NSCLC). In a Phase II study published in Nature Medicine, the combination achieved a major pathological response (MPR) rate of 70.1% and a pathological complete response (pCR) rate of 50.7% among patients who underwent surgery.
The findings extend ivonescimab’s clinical development into the perioperative setting, with particularly high response rates observed in squamous NSCLC. However, the nonrandomised study design and immature survival data limit conclusions about its potential advantage over established perioperative immunotherapy regimens.
Study Design: Perioperative Ivonescimab with or Without Chemotherapy
The multicentre, open-label Phase II study (NCT05247684; AK112-205) enrolled 90 patients with resectable stage II–IIIB NSCLC without sensitising EGFR mutations or ALK rearrangements. Eleven patients received ivonescimab monotherapy, while 79 received ivonescimab combined with platinum-paclitaxel chemotherapy.
Both cohorts received three or four neoadjuvant treatment cycles, followed by surgery and adjuvant ivonescimab. The original study design underwent protocol modifications, including discontinuation of monotherapy enrolment and expansion of the combination cohort. Consequently, the final analysis was nonrandomised and noncomparative, preventing a reliable assessment of the incremental contribution of chemotherapy.
The primary efficacy endpoint was MPR, defined as 10% or less residual viable tumour in the resected primary tumour and lymph nodes.
Combination Therapy Achieves 70.1% MPR
Among 67 patients in the combination cohort who underwent surgery, 47 achieved MPR (70.1%; 95% CI 57.7–80.7). The result exceeded the prespecified historical benchmark of 41%, meeting the study’s primary efficacy criterion.
In the monotherapy cohort, six of ten operated patients achieved MPR (60.0%). When all treated patients were considered, MPR rates were 59.5% with combination therapy and 54.5% with monotherapy, illustrating the importance of accounting for patients who did not proceed to surgery.
The combination also achieved a pCR rate of 50.7% (34/67), compared with 30.0% (3/10) with monotherapy. Residual viable tumour of 5% or less was observed in 68.7% of operated combination patients.
Squamous NSCLC Shows Particularly High Response Rates
One of the most notable findings emerged from the exploratory histological subgroup analysis. In the combination cohort, squamous NSCLC demonstrated an MPR rate of 81.5% (44/54) and a pCR rate of 61.1% (33/54).
By comparison, nonsquamous tumours achieved MPR and pCR rates of 23.1% (3/13) and 7.7% (1/13), respectively.
These numerical differences are noteworthy given historical safety concerns surrounding VEGF inhibition in squamous lung cancer, particularly haemorrhagic complications. No grade 3 or higher haemorrhage was reported in the study. Nevertheless, the small nonsquamous subgroup and exploratory nature of the analysis prevent conclusions about a histology-specific treatment advantage.
The findings provide a rationale for further investigation of dual PD-1/VEGF inhibition in squamous NSCLC, rather than establishing a differential benefit.
PD-L1 and ctDNA Findings Provide Additional Insights
The combination cohort also demonstrated an MPR rate of 69.2% in PD-L1-negative tumours, comparable to PD-L1-positive disease. However, pCR rates differed, at 30.8% and 55.8%, respectively. This suggests that substantial pathological tumour reduction may occur irrespective of PD-L1 expression, although the findings do not establish PD-L1 as a predictive biomarker.
Exploratory circulating tumour DNA (ctDNA) analysis provided another potential response-monitoring signal. Baseline ctDNA was detectable in 52 of 69 tested patients (75.4%), while 28 of 43 evaluable patients cleared detectable ctDNA before surgery (65.1%). Preoperative pCR was 57.5% among ctDNA-negative patients compared with 33.3% among those with detectable ctDNA. Patients maintaining sustained ctDNA negativity had a pCR rate of 69.2%.
These observations suggest a potential relationship between molecular response and pathological outcomes, but ctDNA monitoring remains exploratory and requires prospective validation.
Surgical Feasibility and Safety
Seventy-seven of the 90 enrolled patients underwent surgery, and all achieved R0 resection. No surgery was cancelled because of treatment-related toxicity, although one patient experienced a treatment-related surgical delay.
Grade 3 or higher treatment-related adverse events occurred in 30.4% of combination patients and 36.4% of monotherapy patients. Neutrophil and white blood cell count reductions were among the most frequent severe events with combination treatment. Although no grade 3 or higher haemorrhage occurred, lower-grade bleeding and other VEGF-related adverse events, including proteinuria and hypertension, warrant continued monitoring.
The 100% R0 resection rate applies exclusively to patients who underwent surgery, not the entire enrolled population.
Survival Evidence Remains Immature
At the August 2025 data cutoff, estimated 12-month event-free survival (EFS) was 83.3% with combination therapy and 81.8% with monotherapy. Median EFS had not been reached, and overall survival was not reported.
These findings are encouraging but cannot establish durable disease control or superiority over established perioperative regimens. Pembrolizumab (KEYNOTE-671), nivolumab (CheckMate 77T) and durvalumab (AEGEAN) have demonstrated EFS benefits in randomised Phase III studies. Comparisons across these trials remain inappropriate because of differences in design, populations and treatment regimens.
Ivonescimab’s Phase III HARMONI-2 results against pembrolizumab in advanced PD-L1-positive NSCLC provide relevant development context, but do not demonstrate superiority in resectable disease.
Clinical Interpretation
The Phase II findings position perioperative ivonescimab, particularly with platinum-based chemotherapy, as a promising investigational approach in resectable NSCLC. The 70.1% MPR and 50.7% pCR rates, together with the 81.5% MPR in squamous disease, provide a strong rationale for further clinical evaluation.
However, the nonrandomised design, small subgroup populations and immature survival outcomes remain important limitations. The next development priority is randomized evaluation against contemporary perioperative standards, with event-free and overall survival as key endpoints.
For now, the study establishes encouraging pathological activity and preliminary surgical feasibility, but not a new perioperative treatment standard.
References
Phase II Study of Ivonescimab in the Perioperative Setting for Resectable NSCLC Published in Nature Medicine, Akesobio, 05 November 2026
Zhao, X., Zhang, B., Li, C. et al. Perioperative ivonescimab with or without chemotherapy in resectable non-small cell lung cancer: a phase 2 trial. Nat Med (2026). https://doi.org/10.1038/s41591-026-04745-4
AK112 Neoadjuvant/Adjuvant Treatment for Resectable NSCLC, ClinicalTrials.gov ID NCT05247684
About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.