Ivonescimab Combo Improves Progression-Free Survival in Advanced NSCLC

Ivonescimab combined with chemotherapy significantly improved progression-free survival (PFS) compared with Tevimbra (tislelizumab-jsgr) plus chemotherapy in patients with advanced squamous non–small cell lung cancer (NSCLC), according to results from the phase 3 HARMONi-6 study presented at the 2025 ESMO Congress.

The median PFS was 11.14 months with ivonescimab plus chemotherapy (266 patients) versus 6.9 months with versusTevimbra plus chemotherapy (266 patients), representing a 40% reduction in the risk of disease progression or death. The PFS benefit favored ivonescimab plus chemotherapy across all key subgroups.

“Ivonescimab plus chemotherapy showed meaningful efficacy with a manageable safety profile and may represent a new standard of care for advanced squamous NSCLC,” Dr. Shun Lu, of Shanghai Chest Hospital, said during a presidential symposium.
The multicenter, double-blind, parallel-controlled study enrolled patients with pathologically confirmed stage 3 or 4 squamou
s NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had no prior systemic therapy and no EGFR mutations or ALK rearrangements.

Participants (532 patients) were randomly assigned 1:1 to receive ivonescimab 20 mg/kg every 3 weeks or versusTevimbra 200 mg every 3 weeks plus carboplatin at area under the curve 5 and paclitaxel 175 mg/m2 every 3 weeks for up to 4 cycles, followed by ivonescimab or versusTevimbra every 3 weeks for up to 24 months or until intolerable toxicity.
The primary end point was PFS by independent radiology review committee assessment using RECIST 1.1 criteria. Secondary end points included overall survival, investigator-assessed PFS, objective response rate, disease control rate, duration of response, time to response, and safety.

Baseline characteristics were balanced between arms. Most patients were male, current or former smokers, and had stage 4 disease. PD-L1 tumor proportion scores varied across arms, and a subset had three or more metastatic sites, liver metastases, or brain metastases.

Ivonescimab demonstrated PFS benefit across all PD-L1 subgroups. In all patients, the objective response rate by independent review was 75.9% with ivonescimab versus 66.5% with versusTevimbra. Median duration of response was 11.2 months versus 8.38 months.

Treatment-related side effects occurred in 99.2% of patients receiving ivonescimab versus 98.5% with versusTevimbra. Grade 3 or higher side effects occurred in 63.9% versus 54.3%. Serious side effects occurred in 32.3% versus 30.2%. Most common side effects included alopecia, anemia, decreased neutrophil count, decreased white blood cell count, hypoesthesia, proteinuria, nausea, and fatigue. Immune-related side effects were reported in 27.4% versus 25.3% of patients.

Ivonescimab-related side effects potentially linked to vascular endothelial growth factor inhibition occurred more frequently and were mostly grade 1 or 2, including proteinuria, hemorrhage, hypertension, arterial thromboembolism, venous thromboembolism, and fistula.

“Dr. Myung-Ju Ahn, noted that ivonescimab plus chemotherapy demonstrates clinically meaningful PFS and objective response rate across PD-L1 subgroups, with a low rate of hemorrhage in a high-risk population,” she said. Key unanswered questions include real-world application, translation of PFS benefit to overall survival, need for mature overall survival and quality-of-life data, angiogenic and immune biomarker evaluation, and global validation across diverse populations.

In summary, the findings from the phase 3 HARMONi-6 study highlight the potential of ivonescimab combined with chemotherapy as a highly effective first-line treatment option for patients with advanced squamous NSCLC. The combination demonstrated a substantial improvement in PFS compared with Tevimbra plus chemotherapy, showing consistent benefits across PD-L1 subgroups and supporting its activity in a high-risk population.

While the safety profile was manageable and largely consistent with expectations for chemotherapy and immunotherapy, some side effects were observed more frequently with ivonescimab, though most were low grade.

References

1. "Phase III study of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small cell lung cancer (HARMONi-6)," Dr. Shun Lu, et al. Presented at: 2025 ESMO Congress; October 17-25, 2025; Berlin, Germany. Abstract LBA4.
2. Ivonescimab in combination with chemotherapy demonstrates statistically significant and strongly positive results in first-line treatment of squamous non-small cell lung cancer (sq-NSCLC) vs. tislelizumab in combination with chemotherapy. News Release. Akeso. April 23, 2025. Accessed October 19, 2025. https://www.akesobio.com/en/media/akeso-news/250423/
3. AK112 in combination with chemotherapy in advanced squamous non-small cell lung cancer. ClinicalTrials.gov. May 2, 2025. Accessed October 19, 2025. https://clinicaltrials.gov/study/NCT05840016

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