Ivonescimab Plus Chemo Meets PFS End Point in EGFR+ NSCLC After an EGFR TKI

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Ivonescimab in combination with platinum-doublet chemotherapy met the coprimary end point of the phase 3 HARMONi trial (NCT06396065), demonstrating a significant improvement in progression-free survival (PFS) compared with placebo plus platinum-doublet chemotherapy in patients with locally advanced or metastatic, nonsquamous, EGFR-mutated non–small cell lung cancer (NSCLC) who experienced disease progression following treatment with a third-generation EGFR TKI.1

At the prespecified primary data analysis, treatment with the ivonescimab combination reduced the risk of disease progression or death by 48% vs placebo plus chemotherapy (HR, 0.52; 95% CI, 0.41-0.66; P < .00001). Notably, a clinically meaningful HR was reported in the Asian and ex-Asian subgroups; approximately 38% of patients who were randomly assigned in the study were from outside of Asia.

Ivonescimab plus chemotherapy also demonstrated a positive trend in overall survival (OS), the other primary end point of HARMONi (HR, 0.79; 95% CI, 0.62-1.01; P = .057).

“The evidence of a consistent benefit in PFS for both Asian and Western patients, as well as the consistent OS results between the single-region [phase 3] HARMONi-A [NCT05184712] study and our global HARMONi study, demonstrates the potential benefit ivonescimab has to bring to patients around the world, including the United Stated,” Robert W. Duggan, chairman and co-chief executive officer of Summit Therapeutics, stated in a news release.

HARMONi was a double-blind, multicenter study that enrolled patients with EGFR-mutated locally advanced or metastatic nonsquamous NSCLC who experienced disease progression on or following treatment with an EGFR TKI.2 Patients were required to be between 18 and 75 years of age, have an ECOG performance status of 0 or 1, have an expected survival of at least 3 months, have at least 1 measurable lesion per RECIST 1.1 criteria, and have adequate organ function. Those who received prior immune checkpoint inhibitor therapy, prior systemic chemotherapy, anti-angiogenic therapy, or more than 1 prior line of antitumor therapy (other than EGFR inhibitors) in the advanced NSCLC setting were excluded from the study.

Patients were randomly assigned 1:1 to receive intravenous (IV) ivonescimab or placebo, both in combination with IV pemetrexed and carboplatin every 3 weeks for up to 4 cycles. Then, patients received maintenance ivonescimab or placebo plus pemetrexed on day 1 of each cycle for up to 2 years.

Beyond the primary end points, secondary end points included overall response rate, duration of response, safety, and pharmacokinetic measures.

In terms of safety, grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 56.9% of patients in the ivonescimab plus chemotherapy arm compared with 50.0% in the placebo plus chemotherapy arm.1 TEAEs leading to death occurred at rates of 1.8% and 2.8%, respectively. No new safety signals were reported; investigators concluded that the safety profile of ivonescimab plus chemotherapy was acceptable and manageable in light of the clinical benefit of the combination.

Summit Therapeutics intends to file a biologics license application (BLA) to the FDA seeking the approval of ivonescimab plus chemotherapy for the treatment of patients with locally advanced or metastatic, nonsquamous, EGFR-mutated NSCLC who experienced disease progression after treatment with a third-generation EGFR TKI. The BLA will be supported by data from HARMONi. The company is planning to share more complete data from the trial at a future medical meeting.

“Our conviction in the promise that this therapy holds for patients continues to be validated: we believe that ivonescimab has the potential to make a meaningful difference for the betterment of patients’ lives,” Maky Zanganeh, DDS, MBA, president and co-chief executive officer of Summit Therapeutics, added in the news release.

References

1. 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 May 30, 2025. https://www.smmttx.com/wp-content/uploads/2025/05/2025_PR_0530-_-HARMONi-Data-_-FINAL.docx.pdf
2. Phase III study of AK112 for NSCLC patients. ClinicalTrials.gov. Updated October 10, 2024. Accessed May 30, 2025. https://clinicaltrials.gov/study/NCT06396065