KEY TAKEAWAYS
- The phase 3 trial aimed to evaluate ivonescimab plus chemotherapy versus chemotherapy alone in patients with EGFR-TKI failure.
- The primary endpoint was PFS.
- Ivonescimab plus chemotherapy improved PFS and maintained safety in patients who experienced EGFR-TKI treatment failure.
Ivonescimab (AK112/SMT112) is an experimental anti-PD-1/VEGF bispecific monoclonal antibody blocking the interaction of both PD-1 and VEGFR2. Phase I/II trials observed that it might help non-small cell lung cancer (NSCLC) and EGFR mutations and who failed EGFR-TKI treatment.
Li Zhang and the team conducted a study that aimed to evaluate and confirm the efficacy and safety of ivonescimab combined with chemotherapy versus chemotherapy alone in people with EGFR-TKI treatment failure.
Participants were randomized 1:1 to receive the Ioveschemab arm (20 mg/kg with a combination of pemetrexed 500 mg/m² and carboplatin, AUC 5) or placebo and chemotherapy arm every 3 weeks for 4 cycles with regard to third-generation EGFR-TKI (received vs. not received) and presence or absence of brain metastases. The maintenance therapy entailed ivonescimab and pemetrexed or placebo and pemetrexed.
The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population, assessed by an independent radiographic review committee (IRRC) per RECIST v1.1.
About 322 participants were randomized (161 to the ivonescimab plus chemotherapy arm, 161 to the placebo plus chemotherapy arm). Among them, 86.3% versus 85.1% had received third-generation EGFR-TKI treatment, and 21.7% versus 23.0% had brain metastases.
As of March 10, 2023, the median follow-up time was 7.89 months. PFS was significantly improved in the ivonescimab plus chemotherapy arm (HR 0.46 [0.34, 0.62], P < 0.0001). Median PFS (95% CI) by IRRC was 7.06 months (5.85, 8.74) in the ivonescimab arm versus 4.80 months (4.21, 5.55) in the chemotherapy arm.
The prespecified subgroup analysis showed PFS benefit favoring those receiving ivonescimab over placebo across almost all subgroups, including individuals who progressed on third-generation EGFR-TKI therapy (HR 0.48, 95% CI 0.35-0.66), those with brain metastases (HR 0.40, 0.22-0.73), those with EGFR mutation of deletion 19 (HR 0.48, 0.32-0.73), and individuals with T790M mutation-positive (HR 0.22, 0.09-0.54). The overall response rates (ORR) were 50.6% and 35.4%, respectively.
Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 99 (61.5%) participants versus 79 (49.1%) participants, with the most common grade ≥3 TEAEs being chemotherapy-related adverse events. Grade ≥3 immune-related adverse events occurred in 10 (6.2%) participants versus 4 (2.5%). Grade ≥3 VEGF blocking-related adverse events occurred in 5 participants (3.1%) versus 4 participants (2.5%).
The study concluded that ivonescimab plus chemotherapy effectively enhanced PFS and maintained a manageable safety profile among individuals who had previously undergone EGFR-TKI treatments.
Source: https://meetings.asco.org/abstracts-presentations/232409
Clinical Trial: https://clinicaltrials.gov/study/NCT05184712
The trial is sponsored by Summit Therapeutics.
Zhang L, Fang W, Zhao Y, et al. (2024). “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 42, 2024 (suppl 16; abstr 8508), 10.1200/JCO.2024.42.16_suppl.8508 (8508)
