In the phase III HARMONi trial, when ivonescimab was given with carboplatin plus pemetrexed, vs the chemotherapy regimen alone, after a third-generation tyrosine kinase inhibitor, patients with EGFR-mutated non–small cell lung cancer (NSCLC) had a significant delay in disease progression.1 Ivonescimab is an investigational, humanized, tetravalent bispecific monoclonal antibody targeting both PD-1 and VEGF-A.
“Ivonescimab [plus chemotherapy] had a significant and clinically meaningful progression-free survival benefit, and the overall survival final analysis showed a favorable trend,” said Jonathan W. Goldman, MD, Professor of Medicine in the Division of Hematology/Oncology; Director of Clinical Trials in Thoracic Oncology; and Associate Director of Early Drug Development at the University of California Los Angeles (UCLA) at the International Association for the Study of Lung Cancer (IASCL) 2025 World Conference on Lung Cancer.
About the HARMONi Trial
The phase III trial included 438 patients with unresectable locally advanced or metastatic nonsquamous NSCLC with an EGFR mutation and any PD-L1 expression who had experienced disease progression on a third-generation EGFR tyrosine kinase inhibitor. They were randomly assigned to receive either ivonescimab (20 mg/kg every 3 weeks) plus standard carboplatin/pemetrexed or placebo plus carboplatin/pemetrexed. The co-primary endpoints were progression-free survival and overall survival by independent review. The median patient age was 61 years; the majority of patients were female (59%), Asian (70%), and never-smokers (68%) Brain metastases were present at baseline in 25%, and 57% had an exon 19 deletion.
Progression-Free Survival Benefit
“The trial met the progression-free survival endpoint, with a hazard ratio of 0.52 (P < .0001), and almost 20% more patients were progression-free at the 6- and 12-month landmarks,” Dr. Goldman reported. “In the Forest plot, we see that all predefined subgroups benefited from the addition of ivonescimab, with perhaps a greater benefit in those with brain metastases.” The subset with brain metastases at baseline achieved a hazard ratio (HR) of 0.34, as compared with 0.59 for patients without brain metastases.
The trial met the progression-free survival endpoint, with a hazard ratio of 0.52 (P < .0001), and almost 20% more patients were progression-free at the 6- and 12-month landmarks.— JONATHAN W. GOLDMAN, MD
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At a median follow-up of 22.3 months, the median progression-free survival by independent review was 6.8 months with ivonescimab plus carboplatin/pemetrexed and 4.4 months with placebo plus carboplatin/pemetrexed (HR = 0.52; P < .0001). The progression-free survival rate at 6 months was 54.0% with ivonescimab vs 25.4% without it, and at 12 months, the rate was 34.7% vs 8.3%, respectively, Dr. Goldman reported.
Longer-Term Follow-up and Safety Profile
The co-primary endpoint of overall survival was not met in the study at a median follow-up of 29.7 months overall, but it was 9.2 months for the 38% of the cohort from North America and Europe. There was, however, a favorable trend, with medians of 16.8 months in the ivonescimab arm vs 14.0 months in the placebo arm (HR = 0.0570).
Dr. Goldman noted that the hazard ratio did change somewhat with full accrual and further follow-up of the Western cohort (though the results are still immature). At a median follow-up of 29.7 months, the hazard ratios were 0.67 for the North American and European cohort of 165 patients (95% confidence interval [CI] = 0.45–1.00) and 0.55 for the larger Asian cohort of 273 patients (95% CI = 0.43–0.71). PD-L1 status was required for the Western cohort alone, but at this point, he explained, there was no significant difference observed. Longer follow-up of the Western cohort (after the final analysis) showed overall survival to be stable (HR = 0.78; nominal P value = .03320); the Western and Asian regions “performed similarly,” and there was consistency among the subgroups, he said.
With ivonescimab plus chemotherapy vs chemotherapy alone, the response rates were 45% and 34%, the disease control rates were 84% and 73%, and the median durations of response were 7.6 months and 4.2 months, respectively.
There were no new safety signals with ivonescimab. The rates of treatment-related discontinuation of therapy and deaths were comparable between the arms, according to Dr. Goldman. Grade ≥ 3 adverse events and serious adverse events occurred in 50.0% and 28.0% of the ivonescimab arm and in 42.2% and 15.1% of the placebo arm, respectively; those leading to treatment discontinuation were observed in 7.3% and 5.0%, respectively, and treatment-related deaths were seen in 1.8% and 2.3% of patients, respectively. Grade ≥ 3 immune-related adverse effects occurred in 9.6% and 6.0% of patients in the ivonescimab and placebo arms, respectively; grade ≥ 3 VEGF-related events occurred in 7.3% and 3.2% of patients, respectively.
DISCLOSURE: Dr. Goldman has served as a consultant or advisor to Summit, Amgen, Genentech, Eli Lilly, Janssen, and AbbVie; and has received research grants from Summit, Amgen, AstraZeneca, Genentech, Eli Lilly, Janssen, Bristol Myers Squibb, and AbbVie.
REFERENCE
1. Goldman JW, et al: 2025 World Conference on Lung Cancer. Abstract PL02.12. Presented September 7, 2025.
EXPERT POINT OF VIEW
Despite many advances in EGFR-mutant non–small cell lung cancer (NSCLC), acquired resistance invariably occurs and results in limited treatment options beyond platinum-based chemotherapy. In this “widely heterogeneous” population, immune checkpoint inhibitors have not been effective, although the investigational agent ivonescimab works differently through a dual mechanism of action, as pointed out by the invited discussant of the HARMONi trial, Suresh S. Ramalingam, MD, FACP, FASCO, Professor of Hematology and Medical Oncology and Executive Director of the Winship Cancer Institute of Emory University, Atlanta.
Suresh S. Ramalingam, MD, FACP, FASCO
As a result, ivonescimab has the potential to reverse T-cell exhaustion, enhance T-cell trafficking and function, counteract suppression of the immune tumor microenvironment, overcome suppression of dendritic cell differentiation, and inhibit the recruitment of regulatory T and myeloid-derived suppressor cells. However, Dr. Ramalingam questioned whether this comprehensive attack was responsible for the improvements seen over chemotherapy alone in the trial.
Although the HARMONi trial documented a significant progression-free survival benefit with the addition of ivonescimab, a lack of significant overall survival benefit was reported “despite the favorable trend,” he noted. Dr. Ramalingam did not attach particular importance to the additional nominal P value that was also reported, as that analysis did not adjust for multiple comparisons and variations from the protocol-specified analysis.
Does Dual Blockade Offer an Advantage?
Dr. Ramalingam posed the following questions: Since other PD-1 inhibitors have not been effective in EGFR-mutant NSCLC, is ivonescimab different? Were the positive benefits in the HARMONi trial attributable to PD-1 blockade? In his opinion, probably not. Outcomes did not differ based on the PD-L1 expression level, there was no robust “tail” on the survival curve, and the median duration of response was a modest 7.6 months, he noted. According to Dr. Ramalingam, it is more likely that the drug’s blockade of VEGF had the positive effect, based on efficacy shown in other studies, especially in Asian patients.
“Taken together, the level of progression-free survival benefit observed in HARMONi is comparable to studies that have evaluated VEGF inhibitors in NSCLC,” said Dr. Ramalingam. “In my view, there is no clear evidence of PD-1 blockade as a contributor to the efficacy; however, the adverse events associated with ivonescimab are related to both VEGF and PD-1 blockade. So, although ivonescimab may be effective in other types of NSCLC, in EGFR-mutated disease, its mechanism of action of dual blockade does not appear to offer an advantage.” Dr. Ramalingam said that additional follow-up of all 438 patients will determine whether ivonescimab plus chemotherapy will represent a new standard of care.
Dr. Ramalingam added that despite having numerous strategies for treating EGFR-resistant disease, progression-free survival remains relatively modest. “It’s humbling that no regimen has surpassed chemotherapy in extending overall survival so far,” he remarked. “The relative merits of incremental efficacy vs toxicity should be contextualized to individual patients.”
DISCLOSURE: Dr. Ramalingam has received institutional research funding from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Merck, Pfizer, and Takeda; has received reimbursement for travel, accommodations, or other expenses from AbbVie; and has reported a relationship with the American Cancer Society.
