EGFR‐TKIs have revolutionized frontline treatment for advanced EGFR‐mutated non-small cell lung cancer (NSCLC). However, managing acquired resistance to third-generation EGFR-TKIs remains a critical unmet need in NSCLC care.
The phase III HARMONi study compared the safety and efficacy of ivonescimab combined with chemotherapy to chemotherapy alone in patients with advanced EGRF-mutated NSCLC who had previously received third-generation EGFR-TKIs.
Jonathan W. Goldman, MD, Professor of Medicine at UCLA, shared key findings from the HARMONi trial. “Ivonescimab had a significant and clinically meaningful progression-free survival (PFS) benefit in EGFR-mutated NSCLC patients after a third-generation TKI,” Dr. Goldman said. “The hazard ratio [HR] was 0.52 and the benefit was consistent across the subgroups, with perhaps greater benefit among those with brain metastases.”
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Suresh S. Ramalingam, MD, Executive Director of the Winship Cancer Institute of Emory University, who contextualized the study as the discussant, noted, “We have very limited options for these patients aside from platinum-based chemotherapy, which has remained the cornerstone. There is wide molecular heterogeneity in this population when it comes to resistance mechanisms. And, we have seen that immune checkpoint inhibitors have not shown effectiveness in the acquired resistance setting.”
In this context, the novel mechanism of action of ivonescimab—a bispecific antibody that targets both PD-L1 and VEGF— a bispecific antibody that targets both PD-L1 and VEGF, may offer advantages.
HARMONi, in which 438 patients were randomized 1:1 to receive either ivonescimab with chemotherapy (carboplatin and pemetrexed) or chemotherapy alone, began enrollment first in China (Asian cohort, 68%), and was subsequently expanded to include patients in Europe and North America (Western cohort, 32%). The primary endpoints were PFS, as assessed by an independent radiologic review committee, and overall survival (OS).
Positive outcomes were previously reported from the phase III HARMONi-A study, which evaluated the ivonescimab-chemotherapy combination in Chinese patients. This single-region study showed a PFS benefit with the addition of ivonescimab to chemotherapy within that respective cohort.
The median PFS (median follow-up, 22.3 months) was longer with the ivonescimab-chemotherapy combination in HARMONi (6.8 months vs. 4.4 months), translating to a 48% reduction in risk of death or disease progression. The PFS benefit was seen in all prespecified subgroups, including the 25% of patients with brain metastases in Western patients. There were no significant differences in outcomes by PD-L1 status, which was only required for enrollment of Western patients.
At a median follow-up of 29.7 months, the median OS was 16.8 months with the ivonescimab-chemotherapy combination, compared with 14 months with chemotherapy alone (HR 0.79; p = 0.0570). The overall response rate was higher in the ivonescimab group (44.7% vs. 34.2%).
The frequency of grade ≥ 3 treatment-related adverse events was comparable in the two study arms (50% in the ivonescimab-chemotherapy arm and 42.2% in the chemotherapy arm). Although immune-related and VEGF-related adverse events were more frequent with ivonescimab, they were mainly low grade and generally manageable, Dr. Goldman said.
Dr. Goldman also noted that the low toxicity with the addition of ivonescimab stood out to him as a notable finding, as well as the PFS benefit, which was clear across subgroups.
Despite the favorable OS trend associated with the addition of ivonescimab, Dr. Ramalingam pointed out that the lack of clear OS benefit in HARMONi reflects the unmet needs in the setting of acquired resistance to EGFR-TKIs. He illustrated this by weighing HARMONi findings against those of MARIPOSA-2 and HERTHENA-Lung02 and those of other large immune checkpoint inhibitor trials in this setting.
Dr. Ramalingam also pointed out the complexity of interpreting findings for the entire HARMONi cohort, as the median follow-up duration was significantly longer for Asian (33 months) than for Western (9.2 months) patients.
“Regardless of the strategy, the PFS is relatively modest. And it is rather humbling that no regimen has surpassed chemotherapy in extending OS in this setting so far.”
Suresh S. Ramalingam, MD
He summarized the two main approaches to treating acquired resistance to EGFR-TKIs: mechanism-based strategies, exemplified by MET-targeted therapies, and mechanism-agnostic approaches, which include chemotherapy and chemotherapy combinations with amivantamab, antibody-drug conjugates, and ivonescimab.
“Regardless of the strategy, the PFS is relatively modest. And it is rather humbling that no regimen has surpassed chemotherapy in extending OS in this setting so far,” Dr. Ramalingam said.
It was concluded that ivonescimab “may be” one new standard of care for EGFR-mutated advanced NSCLC post-EGFR-TKI, pending final PFS data for the entire intent-to-treat population in HARMONi.
