Ivonescimab/Chemo After TKI Progression Improves PFS in EGFR-Mutated NSCLC

The median PFS by independent radiology review committee was 6.8 months and 4.4 months in the ivonescimab plus carboplatin/pemetrexed and the placebo plus carboplatin/pemetrexed arms, respectively.

Ivonescimab plus carboplatin/pemetrexed elicited a significant and clinically meaningful progression-free survival (PFS) advantage vs placebo plus carboplatin/pemetrexed in treating patients with EGFR-mutated non–small cell lung cancer (NSCLC) following progression after a third-generation TKI, according to data from the phase 3 HARMONi trial (NCT06396065) presented at the IASLC 2025 World Conference on Lung Cancer (WCLC).1

Data from the trial revealed that at a median follow-up of 22.3 months, the median PFS by independent radiology review committee (IRRC) was 6.8 months and 4.4 months in the ivonescimab plus carboplatin/pemetrexed (n = 172) and the placebo plus carboplatin/pemetrexed (n = 173) arms, respectively (HR, 0.52; 95% CI, 0.41-0.66; P < .0001). Specifically, at 6 and 12 months in the ivonescimab arm, the PFS rates were 54.0% 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,” Jonathan Goldman, MD, 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.2

The double-blind, multicenter trial includes patients at least 18 years of age with histologically or cytologically confirmed unresectable locally advanced or metastatic nonsquamous NSCLC with an EGFR sensitizing mutation. In accordance with eligibility criteria patients must have experienced disease progression on a third-generation EGFR TKI, have an ECOG performance status of 0 or 1, and have any PD-L1 expression level.1,3 Of note, patients are stratified based on brain metastases (yes or no).1

Patients included on the study are randomly assigned 1:1 to receive either ivonescimab plus carboplatin/pemetrexed (n = 219) or placebo plus carboplatin/pemetrexed (n = 219). Those included in the investigational arm are treated with 20 mg/kg of ivonescimab every 3 weeks plus carboplatin at area under the curve 5 every 3 weeks for 4, 21-day cycles and pemetrexed at 500 mg/m2 every 3 weeks. Patients included in the placebo arm were treated with carboplatin and pemetrexed at the same dosing levels as those in the investigational arm.

The coprimary end points were PFS and OS by IRRC per RECIST 1.1 criteria. Secondary end points included overall response rate (ORR) by IRRC, duration of response (DOR), and safety.

The median age was 62 years (range, 32-84) and 60 years (range, 36-84) in the ivonescimab and placebo arms, respectively. The majority were female (ivonescimab, 59.4%; placebo, 58.0%), had an ECOG performance status of 1 (74.0%; 71.7%), identified as Asian (69.9%; 69.9%), were never smokers (65.3%; 70.8%), had brain metastases (24.7%; 24.7%), and had exon 19 deletion (59.8%; 53.9%).

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 14.0 months in the ivonescimab and placebo arms, respectively (HR, 0.79; 95% CI, 0.62-1.01; P = .0570). Furthermore, the ORR was 45% in the ivonescimab arm compared with 34% in the placebo arm. The DCR was 84% vs 73% in the respective arms. Notably, the median DOR in the ivonescimab (n = 98) and placebo (n = 75) arms were 7.6 months (95% CI, 5.5-10.6) and 4.2 months (95% CI, 2.9-4.7), respectively.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) were observed in 95.0% and 93.1% of patients from the ivonescimab and placebo arms, respectively. In the ivonescimab arm, grade 3 or greater AEs and serious AEs occurred in 50.0% and 28.0% of patients, respectively; these occurred in 42.2% and 15.1% of patients in the placebo arm. TRAEs that led to discontinuation of ivonescimab or placebo, respectively, were observed in 7.3% and 5.0% of patients. Moreover, TRAEs that led to death were reported in 1.8% and 2.3% of patients, respectively.

In the ivonescimab arm, the most common TRAEs observed included anemia (any grade, 49.1%; grade ≥3, 10.1%), decreased white blood cell count (45.0%; 12.8%), decreased neutrophil count (42.7%; 19.3%), and decreased platelet count (32.6%; 12.4%). The most common TRAEs reported in the placebo arm included anemia (56.4%; 12.4%), decreased white blood cell count (44.0%; 11.0%), decreased neutrophil count (42.2%; 16.5%), and decreased platelet count (28.0%; 6.4%).

Of note, grade 3 or higher immune-related adverse effects (irAEs) occurred in 9.6% and 6.0% of patients in the ivonescimab and placebo arms, respectively; grade 3 or higher VEGF-related TRAEs occurred in 7.3% and 3.2% of patients. In particular, the most common irAEs occurring in at least 5 patients in the ivonescimab arm included hypothyroidism (any grade, 8.3%; grade ≥3, 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 TRAEs occurring in the ivonescimab arm included proteinuria (13.8%; 0.9%), hypertension (13.3%; 3.7%), and hemorrhage (10.6%; 0.9%).

References

1. 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.
2. 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
3. Phase III study of AK112 for NSCLC patients. ClincialTrials.gov. Updated October 8, 2024. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT06396065