Ivonescimab Plus Chemotherapy in EGFR+ NSCLC After TKI Therapy

Ali Al Sbihi, MD Sylvester Comprehensive Cancer Center | Chinmay Jani, MD University of Miami Health System

EGFR tyrosine kinase inhibitors (TKIs) have transformed the frontline treatment paradigm for patients with EGFR-mutated non-small cell lung cancer (NSCLC). By selectively inhibiting oncogenic driver mutations, these agents have significantly improved survival outcomes and offer better tolerability than traditional chemotherapy. 

Despite these advances, prognosis after progression on first-line EGFR TKI therapy remains challenging. The median overall survival is approximately 9 months in multiple studies, particularly when patients receive chemotherapy alone.^1,2  These findings underscore the urgent need to explore additional therapeutic strategies and incorporate agents targeting alternative or complementary pathways.

Dual PD-1/VEGF Blockade With Ivonescimab

Ivonescimab (SMT112 or AK112) is an emerging bispecific antibody designed to simultaneously inhibit PD-1 and VEGF. Through this dual mechanism, ivonescimab aims to enhance antitumor immune activity while disrupting pro-angiogenic signaling. The agent is currently approved in China for patients with locally advanced or metastatic EGFR-mutant non-squamous NSCLC following TKI progression, as well as for first-line monotherapy in NSCLC with PD-L1 CPS of at least 1%. It is not approved in the United States, Europe, or Japan. Global data, particularly from the phase 3 HARMONi-A trial, are expected to influence future submissions and regulatory decisions.

Overview of the HARMONi-A Trial

HARMONi-A (AK112-301) is a randomized, double-blind, multicenter study initiated in 2023. It evaluated ivonescimab plus chemotherapy compared with placebo plus chemotherapy in patients with stage IIIB or IIIC NSCLC who were ineligible for surgery or local therapy, as well as patients with stage IV EGFR-mutant non-squamous NSCLC after progression on a first-line EGFR TKI. Importantly, the trial included patients irrespective of PD-L1 expression. Treatment was administered for up to 24 months.³ 

In the trial, 322 patients were randomized in a 1:1 ratio to receive ivonescimab 20 mg/kg or placebo, each combined with pemetrexed and carboplatin every 3 weeks for 4 cycles. The primary endpoint was median progression-free survival (mPFS). Interim results demonstrated an mPFS of 7.1 months in the ivonescimab plus chemotherapy arm compared with 4.8 months in the chemotherapy alone arm. The hazard ratio (HR) for progression or death was 0.46 (95% CI: 0.34–0.62), corresponding to an approximately 54% reduction in risk.⁴  

The key secondary endpoint was median overall survival (mOS). With a median follow-up of 32.5 months, results showed an mOS of 16.8 months in the ivonescimab combination arm versus 14.1 months in the chemotherapy alone arm, with an HR of 0.76 (95% CI: 0.58–0.95).⁵ Additional OS landmarks presented at SITC 2025 showed 12-, 24-, and 30-month survival rates of 65% versus 60%, 35.3% versus 28.8%, and 29.1% versus 18.4% for ivonescimab plus chemotherapy versus chemotherapy alone, respectively.⁶

OS improvement was observed across key clinical subgroups. Among patients with brain metastases, the HR for OS was 0.61 (95% CI: 0.37–1.03), whereas the HR for those without brain involvement was 0.77 (95% CI: 0.58–1.03). These findings suggest a consistent OS signal independent of brain metastasis status. However, careful interpretation is needed because differences in baseline characteristics, such as the number of brain lesions or performance status, may influence outcomes. The proportion of patients with brain metastases was comparable at 21.7% in the ivonescimab arm and 23% in the placebo arm.

When stratified by EGFR mutation subtype, OS benefit was seen in both L858R and exon 19 deletion (19del) groups. The HRs were 0.60 (95% CI: 0.41–0.89) for L858R and 0.83 (95% CI: 0.58–1.17) for 19del. This corresponds to an approximate 40% reduction in risk of death for L858R-mutant disease and a more modest 17% reduction for 19del, suggesting that both subgroups may benefit from the addition of ivonescimab. Although, the signal appears numerically stronger in L858R disease. 

Safety Considerations

Unique adverse events (AEs) associated with ivonescimab were primarily related to VEGF pathway inhibition, including hypoalbuminemia and proteinuria. Treatment discontinuation due to AEs occurred in 5.6% of patients receiving ivonescimab, compared with 2.5% in the placebo arm. Importantly, all reported deaths were attributed to disease progression rather than treatment-related toxicity, and no new safety signals were identified.⁷ 

The limitations of HARMONI-A trial mainly include geographic and ethnic homogeneity (Chinese population), the comparator arm being chemotherapy, and relatively small subgroup sizes.

Future Directions and Clinical Implications

The HARMONi-A trial introduces ivonescimab as a potentially practice-changing option for patients with EGFR-mutant NSCLC following progression on an EGFR TKI, demonstrating clinically meaningful improvements in both mPFS and mOS when added to platinum-pemetrexed chemotherapy. These results establish a new benchmark for post-TKI outcomes in this molecular subset.

Although direct comparisons with other emerging strategies, such as chemotherapy combined with immune checkpoint inhibitors or anti-angiogenic combinations, are not yet available, the early data position ivonescimab as a promising addition to the continuum of care. If approved in the US, ivonescimab could offer an important therapeutic alternative in the second-line setting after osimertinib alone, or after amivantamab-lazertinib-based approaches. It may also serve as a potential third-line option in sequencing pathways such as osimertinib followed by amivantamab combinations and then ivonescimab.

As the field moves toward individualized therapy, integrating bispecific immuno-angiogenic agents into resistance-driven treatment algorithms represents a meaningful advancement. 

Future randomized studies, real-world evidence, and biomarker-guided analyses will be crucial to refining the placement of ivonescimab within the therapeutic sequence, especially in the context of differing toxicity profiles, central nervous system penetration, and mechanisms of acquired resistance. Ultimately, adaptive and biology-driven strategies will be essential to improving long-term outcomes in EGFR-mutant NSCLC.

References

1. Peled N, Tufman A, Sequist LV, et al. COMPEL: osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC and progression on first-line osimertinib. ESMO Open. 2025;10(10):105807. doi:10.1016/j.esmoop.2025.105807 
2. Kogure Y, Saka H, Oki M, et al. Post-progression survival after EGFR-TKI for advanced non-small cell lung cancer harboring EGFR mutations. PLoS One. 2015;10(8):e0135393. doi:10.1371/journal.pone.0135393
3. Zhang L, Fang W, Zhao Y, et al. Ivonescimab combined with chemotherapy in patients with EGFR-mutant non-squamous non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor treatment (HARMONi-A): A randomized, double-blind, multi-center, phase 3 trial. J Clin Oncol. 2024;42, 8508-8508. doi:10.1200/jco.2024.42.16_suppl.850 
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5. Akeso, Inc. Ivonescimab HARMONi-A study final OS analysis results presented at SITC 2025 with OS HR=0.74 [press release]. November 7, 2025. Accessed [TBD]. www.prnewswire.com/news-releases/ivonescimab-harmoni-a-study-final-os-analysis-results-presented-at-sitc-2025-with-os-hr0-74–302608764.html 
6. Zhang L, Fang W, Zhao Y, et al. 1348 Final overall survival analysis of HARMONi-A study comparing ivonescimab plus chemotherapy to chemotherapy alone in patients with EGFR+ NSCLC progressed on EGFR-TKI treatment. J Immunother Cancer. 13(Suppl 3):A1592-A1592. doi:10.1136/jitc-2025-SITC2025.1348
7. HARMONi-A Study Investigators. Ivonescimab plus chemotherapy in non–small cell lung cancer with EGFR variant: a randomized clinical trial. JAMA. 2024;332(7):561–570. doi:10.1001/jama.2024.10613