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Ivonescimab Plus Chemotherapy Significantly Improves PFS in Patients with NSCLC Previously Treated with EGFR TKI

Findings from the HARMONi-A study
19 Jun 2024
Non-Small Cell Lung Cancer

HARMONi-A is the first phase III study to show a notable clinical benefit of ivonescimab plus chemotherapy in patients whose disease progressed while receiving treatment with EGFR tyrosine kinase inhibitors (TKIs). Ivonescimab plus chemotherapy led to a significant longer progression-free survival (PFS) duration than chemotherapy alone with tolerable safety profile.

Ivonescimab has been developed as a first-in-class humanised tetravalent bispecific antibody. The in vitro studies have shown that ivonescimab possesses great binding affinity to PD1 and VEGF. Several phase III studies with ivonescimab monotherapy and combination therapy in NSCLC are ongoing. The findings are presented at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Li Zhang of the Sun Yat-sen University Cancer Center in Guangzhou, China and colleagues on 31 May 2024 in the JAMA.

For patients whose NSCLC harbouring the EGFR variant has progressed while receiving EGFR TKIs therapy, especially with third-generation TKIs, optimal treatment options remain limited. Although immune checkpoint inhibitors (ICIs) combined with chemotherapy are the standard treatment for patients with wild-type NSCLC, anti–PD1 combined with chemotherapy has shown limited efficacy in patients with EGFR-variant NSCLC whose disease progressed while receiving EGFR TKI. The authors wrote in the background that preclinical studies have demonstrated the synergistic effects of VEGF inhibitors and ICIs, and studies evaluating immunotherapy in combination with antiangiogenic agents and chemotherapy have shown promising results.

The first in human study with ivonescimab demonstrated favourable safety and antitumour activity in solid tumours. A phase II study in patients with NSCLC demonstrated the promising efficacy of ivonescimab plus chemotherapy in those whose disease progressed while receiving EGFR TKI with an objective response rate (ORR) of 49.8% and median PFS of 12 months, and the safety profile was shown to be tolerable and manageable.

The HARMONi-A (AK112-301) study is the first double-blind, placebo-controlled, randomised phase III study to compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with advanced or metastatic EGFR-variant NSCLC who showed disease progression after EGFR TKI. The results of the first preplanned interim analysis are reported in the article published in JAMA. The study was conducted at 55 sites in China and enrolled participants from January 2022 to November 2022.

A total of 322 eligible patients were enrolled of whom 161 received ivonescimab and 161 received placebo plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance treatment of ivonescimab plus pemetrexed or placebo plus pemetrexed. The primary endpoint was PFS in the intention-to-treat (ITT) population assessed by an independent radiographic review committee per RECIST v1.1.

Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 versus 59.4 years and 52.2% versus 50.9% of patients were female. As of 10 March 2023, median follow-up time was 7.89 months. Median PFS was 7.1 months (95% confidence interval [CI] 5.9-8.7) in the ivonescimab group versus 4.8 months (95% CI 4.2-5.6) for placebo (difference 2.3 months; hazard ratio [HR] 0.46, 95% CI 0.34-0.62; p < 0.001).

The prespecified subgroup analysis showed PFS benefit favouring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR TKI (HR 0.48, 95% CI 0.35-0.66) and those with brain metastases (HR 0.40, 95% CI 0.22-0.73). The rate of ORR was 50.6% (95% CI 42.6%-58.6%) with ivonescimab and 35.4% (95% CI 28.0%-43.3%) with placebo (difference 15.6%, 95% CI 5.3%-26.0%; p = 0.006). The median overall survival data were not mature; at data cut-off, 69 patients (21.4%) had died.

Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group versus 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group versus 4 (2.5%) in the placebo group. Grade 3 or higher VEGF–related adverse events occurred in 5 patients (3.1%) in the ivonescimab group versus 4 (2.5%) in the placebo group.

In the current study in which 86% of patients received the third-generation EGFR TKI, ivonescimab plus chemotherapy significantly improved PFS in the ITT population. The subgroup analysis showed consistent results that ivonescimab plus chemotherapy significantly improved PFS in patients who had received third-generation TKI treatment, regardless of whether the third-generation TKI was used as first- or second-line treatment. The benefit of ivonescimab in terms of PFS was consistent across all prespecified subgroups. However, the authors underlined that the sample size in the subgroups were relatively small, so the current findings should be interpreted with caution. Biomarker analyses, including the correlation between PD-L1 expression and efficacy, requires further exploration.

The study was supported by Akeso Biopharma, Inc, Zhongshan, China. This work was partly supported by the Chinese National Natural Science Foundation Projects.  


HARMONi-A Study Investigators. Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant A Randomized Clinical Trial. JAMA; Published online 31 May 2024. doi:10.1001/jama.2024.10613

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