Among patients with EGFR-mutated non-small cell lung cancer (NSCLC) who experienced disease progression following a third-generation tyrosine kinase inhibitor, treatment with ivonescimab plus carboplatin/pemetrexed was associated with significant and clinically meaningful progression-free survival (PFS) versus placebo plus carboplatin/pemetrexed, study results have shown.
Data from the phase 3 HARMONi trial were presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer, and the findings revealed that at a median follow-up of 22.3 months, the median PFS was 6.8 months and 4.4 months in the ivonescimab plus carboplatin/pemetrexed (172 patients) and the placebo plus carboplatin/pemetrexed (173 patients) arms, respectively. Specifically, at six and 12 months in the ivonescimab arm, the PFS rates were 54.% and 25.4%, respectively; these rates were 34.7% and 8.3% in the placebo arm.
“The efficacy of [ivonescimab] was consistent across subgroups, with perhaps more benefit [in patients] with brain metastases,” Dr. Jonathan Goldman, a professor of medicine in the Division of Hematology/Oncology, the director of Clinical Trials in Thoracic Oncology, and the associate director of Early Drug Development at the University of California Los Angeles, said in a presentation of the data.
What Was the Background and Design of the HARMONi Study?
Topline results from the HARMONi trial revealed that the study met the PFS primary end point and showed a positive trend in the other primary end point of overall survival (OS) with ivonescimab plus carboplatin/pemetrexed compared with placebo plus carboplatin/pemetrexed in patients with EGFR-mutated NSCLC who experienced disease progression after treatment with a third-generation TKI.
The double-blind, multicenter trial includes patients at least 18 years of age with histologically or cytologically confirmed unresectable locally advanced or metastatic non-squamous NSCLC with an EGFR-sensitizing mutation.
Patients included on the study are randomly evenly assigned to receive either ivonescimab plus carboplatin/pemetrexed (219 patients) or placebo plus carboplatin/pemetrexed (219 patients). Those included in the investigational arm are treated with 20 mg/kg of ivonescimab every three weeks plus carboplatin at area under the curve 5 every three weeks for four 21-day cycles and pemetrexed at 500 mg/m2 every three weeks. Patients included in the placebo arm were treated with carboplatin and pemetrexed at the same dosing levels as those in the investigational arm.
What Were the Additional Efficacy and Safety Findings From the HARMONi Study?
At an overall median follow-up of 29.7 months, the median OS was 16.8 months and 14 months in the ivonescimab and placebo arms, respectively. Furthermore, the objective response rate (ORR) was 45% in the ivonescimab arm compared with 34% in the placebo arm. The disease control rate (DCR) was 84% vs 73% in the respective arms. Notably, the median duration of response (DOR) in the ivonescimab (98 patients) and placebo (75 patients) arms were 7.6 months and 4.2 months, respectively.
Regarding safety, any-grade treatment-related side effects were observed in 95% and 93.1% of patients from the ivonescimab and placebo arms, respectively. In the ivonescimab arm, grade 3 (severe) or greater side effects and serious side effects occurred in 50% and 28% of patients, respectively; these occurred in 42.2% and 15.1% of patients in the placebo arm. Treatment-related side effects that led to discontinuation of ivonescimab or placebo, respectively, were observed in 7.3% and 5% of patients. Moreover, treatment-related side effects that led to death were reported in 1.8% and 2.3% of patients, respectively.
In the ivonescimab arm, the most common treatment-related side effects observed included anemia (any grade, 49.1%; grade 3 or higher, 10.1%), decreased white blood cell count (45%; 12.8%), decreased neutrophil count (42.7%; 19.3%) and decreased platelet count (32.6%; 12.4%). The most common treatment-related side effects reported in the placebo arm included anemia (56.4%; 12.4%), decreased white blood cell count (44%; 11%), decreased neutrophil count (42.2%; 16.5%) and decreased platelet count (28.0%; 6.4%).
Of note, grade 3 or higher immune-related side effects occurred in 9.6% and 6% of patients in the ivonescimab and placebo arms, respectively; grade 3 or higher VEGF-related treatment-related side effects occurred in 7.3% and 3.2% of patients. In particular, the most common irAEs occurring in at least five patients in the ivonescimab arm included hypothyroidism (any grade, 8.3%; grade 3 or higher, 0.5%), hyperthyroidism (any grade, 4.1%), increased alanine aminotransferase levels (2.8; 0.9%), and increased aspartate aminotransferase levels (any grade, 3.2%). Additionally, the most common VEGF-related treatment-related side effects occurring in the ivonescimab arm included proteinuria (13.8%; 0.9%), hypertension (13.3%; 3.7%) and hemorrhage (10.6%; 0.9%).
References
- Goldman JW, Passaro A, Laskin J, et al. Ivonescimab vs placebo plus chemo, phase 3 in patients with EGFR+ NSCLC progressed with 3rd gen EGFR-TKI treatment: HARMONi. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 4808.
- Ivonescimab plus chemotherapy demonstrates statistically significant and clinically meaningful improvement in progression-free survival in patients with EGFR-mutant non-small cell lung cancer after EGFR TKI therapy in global study. News release. Summit Therapeutics. May 30, 2025. Accessed September 7, 2025. https://www.smmttx.com/wp-content/uploads/2025/05/2025_PR_0530-_-HARMONi-Data-_-FINAL.docx.pdf
- Phase III study of AK112 for NSCLC patients. ClincialTrials.gov. Updated October 8, 2024. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT06396065
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