FDA Receives BLA for Ivonescimab Plus Chemo in Second-Line or Later EGFR-Mutant NSCLC

A biologics license application (BLA) seeking the approval of ivonescimab in combination with chemotherapy in the second-line or later for patients with EGFR-mutated locally advanced or metastatic non-squamous non–small cell lung cancer (NSCLC) has been submitted to the FDA.¹

The BLA, which was submitted in the fourth quarter of 2025, is supported by overall data from the phase 3 HARMONi trial (NCT06396065). ^1,2 Topline findings from HARMONi showed a progression-free survival (PFS) benefit 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, meeting the study’s primary end point.² A positive trend toward the other primary end point of overall survival (OS) was also observed with the ivonescimab regimen.

“This BLA submission, the first for ivonescimab, marks a critical milestone for Summit, our global clinical development plan, and the many patients with [EGFR-mutant] NSCLC in need of better therapeutics options,” Robert W. Duggan and Maky Zanganeh, DDS, MBA, co-chief executive officers of Summit Therapeutics, stated in a news release.¹ “As we continue to support and expand ivonescimab’s rapid development via our growing set of global phase 3 trials and clinical collaborations, we look forward to the potential first [United States] approval for ivonescimab in this difficult to treat setting.”

If accepted, Summit Therapeutics anticipates a decision from the FDA by the fourth quarter of 2026, according to standard review timelines.¹

What is the design of the HARMONi trial?

The HARMONi study enrolled patients aged at least 18 years with histologically or cytologically confirmed unresectable locally advanced or metastatic non-squamous NSCLC harboring an EGFR-sensitizing mutation.³ Eligible patients were required to have experienced disease progression on a third-generation EGFR TKI, have an ECOG performance status of 0 or 1, and could have any level of PD-L1 expression. Patients were stratified according to the presence or absence of brain metastases.

Eligible patients were randomly assigned 1:1 to receive ivonescimab plus carboplatin/pemetrexed (n = 219) or placebo plus carboplatin/pemetrexed (n = 219). Ivonescimab was administered at 20 mg/kg every 3 weeks in combination with carboplatin at an area under the curve of 5 every 3 weeks for 4 21-day cycles and pemetrexed at 500 mg/m² every 3 weeks. Patients in the control arm received carboplatin and pemetrexed at identical dosing schedules.

The study’s coprimary end points were PFS and OS as assessed by an independent radiology review committee (IRRC) per RECIST 1.1 criteria. Secondary end points included overall response rate (ORR), duration of response (DOR), and safety.

What were the most recent efficacy and safety findings to read out from HARMONi?

Updated results presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer, showed that, at a median follow-up of 22.3 months, the median PFS was 6.8 months in the ivonescimab plus carboplatin/pemetrexed arm (n = 172) compared with 4.4 months in the placebo plus carboplatin/pemetrexed arm (n = 173; HR, 0.52; 95% CI, 0.41-0.66; P < .0001). The PFS rates at 6 and 12 months were 54.0% and 25.4%, respectively, with ivonescimab; corresponding rates were 34.7% and 8.3% in the placebo arm.

At a median follow-up of 29.7 months, the median OS was 16.8 months with ivonescimab and 14.0 months with placebo (HR, 0.79; 95% CI, 0.62-1.01; P = .0570). The ORR was 45% in the ivonescimab arm vs 34% in the placebo arm, and disease control rates were 84% and 73%, respectively. The median DOR was 7.6 months (95% CI, 5.5-10.6) in the ivonescimab arm (n = 98) and 4.2 months (95% CI, 2.9-4.7) in the placebo arm (n = 75).

Regarding safety, treatment-related adverse effects (TRAEs) of any grade occurred in 95.0% of patients receiving ivonescimab and 93.1% of those receiving placebo. Grade 3 or higher AEs were reported in 50.0% and 42.2% of patients in these respective arms. Serious AEs occurred in 28.0% and 15.1% of patients, respectively. TRAEs leading to treatment discontinuation were observed in 7.3% of patients receiving ivonescimab and 5.0% receiving placebo, and TRAEs resulting in death were reported in 1.8% and 2.3% of patients, respectively.

The most common TRAEs in the ivonescimab arm 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%).

What are the next steps for ivonescimab development in NSCLC?

In addition to the HARMONi trial, Ivonescimab is currently being evaluated in multiple phase 3 trials both globally and in commercial settings in China, including¹:

• The HARMONi-3 trial (NCT05899608) evaluating ivonescimab combined with chemotherapy vs pembrolizumab (Keytruda) plus chemotherapy in patients with first-line metastatic NSCLC, irrespective of PD-L1 expression.
• The HARMONi-7 trial (NCT06767514) evaluating ivonescimab vs pembrolizumab monotherapy in patients with first-line metastatic NSCLC and high PD-L1 expression.
• The HARMONi-GI3 trial (NCT06767514) evaluating ivonescimab plus chemotherapy compared with bevacizumab (Avastin) plus chemotherapy in patients with first-line unresectable metastatic colorectal cancer.

Positive data from 3 randomized phase 3 clinical trials evaluating ivonescimab in NSCLC in China— HARMONi-A (NCT05184712), HARMONi-2 (NCT05499390), and HARMONi-6 (NCT05840016)— have also been reported.

References

1. Summit Therapeutics announces submission of biologics license application (BLA) to U.S. FDA seeking approval for ivonescimab in combination with chemotherapy in 2L+ treatment of patients with EGFRm NSCLC.News release. Summit Therapeutics. January 12, 2026 Accessed January 12, 2026. https://smmttx.com/news/press-releases/news-details/2026/Summit-Therapeutics-Announces-Submission-of-Biologics-License-Application-BLA-to-U-S--FDA-Seeking-Approval-for-Ivonescimab-in-Combination-with-Chemotherapy-in-2L-Treatment-of-Patients-with-EGFRm-NSCLC/default.aspx
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 January 12, 2026. https://www.smmttx.com/wp-content/uploads/2025/05/2025_PR_0530-_-HARMONi-Data-_-FINAL.docx.pdf
3. 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. https://s206.q4cdn.com/652410165/files/doc_downloads/publications/2025/FINAL-HARMONi-WCLC-2025-Presidential-Presentation-UNBRANDED_05Sep2025-1.pdf