Add-on ivonescimab nearly halves risk of progression, death in EGFR+ NSCLC

Results from the phase III HARMONi trial presented at WCLC 2025 show that adding ivonescimab to chemotherapy prolongs progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) harbouring EGFR mutations whose disease progressed on third-generation EGFR tyrosine kinase inhibitors (TKIs).

“Ivonescimab plus chemo provided a clinically meaningful and statistically significant PFS benefit, while maintaining a favourable safety profile in this difficult-to-treat patient population,” said Dr Jonathan Goldman from UCLA Health, Santa Monica, California, US. “The benefits were seen regardless of brain metastases (BM) status or geographic region and were supported by a positive overall survival (OS) trend.”

Survival outcomes

At a median follow-up of 22.3 months, PFS by independent radiology review committee (IRRC) was significantly improved when ivonescimab was added to chemo as opposed to chemo only (median 6.8 vs 4.4 months). The risk of disease progression or death was nearly halved with the active regimen (hazard ratio [HR], 0.52; p<0.0001), and this trend favouring the active regimen was consistent in the investigator-assessed PFS (HR, 0.58).

The experimental arm had higher PFS rates than the control arm, both at 6 (54 percent vs 34.7 percent) and 12 months (25.4 percent vs 8.3 percent). [WCLC 2025, abstract PL02.12]

The PFS benefit was consistent across all predefined subgroups, with the most profound effects observed among patients from North America and Europe (HR, 0.30) and those with BM (HR, 0.34) and T790M mutation at baseline (HR, 0.35).

The PFS benefit with the combination regimen was consistent irrespective of the presence or absence of BM (HRs, 0.34 vs 0.59) and in both the primary analysis and long-term follow-up (HRs, 0.52 and 0.57). PFS was also comparable between PD-L1 ≥1 and <1 percent (HRs, 0.55 and 0.62).

Although the follow-up in North America and Europe was immature at the time of analysis, a favourable OS trend was observed with the combo regimen vs chemo alone (median 16.8 vs 14 months; HR, 0.79; p=0.0570) after a median follow-up of 29.7 months.

In the longer-term follow-up of the Western cohort, OS was stable (median 16.8 vs 14 months; HR, 0.78; p=0.032), and OS subgroup analysis results consistently favoured the combo regimen over chemo alone (HRs ranging between 0.55 and 0.91).

Responses, safety

The combo regimen trumped chemo alone in terms of overall response rate (45 percent vs 34 percent), disease control rate (84 percent vs 73 percent), and duration of response (7.6 vs 4.2 months) by IRRC.

Compared with chemo, ivonescimab + chemo was associated with higher rates of treatment-related adverse events (TRAEs), such as grade ≥3 (50 percent vs 42.2 percent), serious (28 percent vs 15.1 percent), grade ≥3 immune-related (9.6 percent vs 6 percent), grade ≥3 VEGF-related (7.3 percent vs 3.2 percent), and those that led to discontinuation of ivonescimab or placebo (7.3 percent vs 5 percent). Conversely, deaths from TRAEs were fewer with the combo vs chemo alone (1.8 percent vs 2.3 percent).

The most frequently reported grade ≥3 TRAEs with the combo regimen were decreased neutrophil (19.3 percent) and white blood cell counts (12.8 percent). Immune-related and VEGF-related TRAEs were mostly low grade.

Acquired resistance an issue

There is a clinical unmet need in patients with advanced NSCLC harbouring EGFR mutations in the relapsed/refractory setting, Goldman and colleagues noted.

“Unfortunately, acquired resistance invariably happens and we have very limited options for these patients besides platinum-based chemo, which has remained the cornerstone [of treatment],” noted discussant Dr Suresh Ramalingam from Winship Cancer Institute of Emory University, Atlanta, Georgia, US.

As such, the team sought to evaluate the efficacy and safety of adding the first-in-class bispecific antibody ivonescimab to chemo in patients with locally advanced or metastatic EGFR+ NSCLC whose disease had progressed on third-generation EGFR TKI. They randomized 438 participants (median age 61 years, 58.7 percent women) 1:1 to ivonescimab 20 mg/kg or placebo plus pemetrexed 500 mg/m² and carboplatin AUC 5 Q3W for four cycles, followed by maintenance pemetrexed plus ivonescimab or placebo Q3W.

Sixty-two percent of participants were from Asia, while the rest were from North America and Europe. Approximately 25 percent of patients had BM at study entry. A majority of participants were Asian (69.9 percent), never smokers (68 percent), and had stage IV disease (98 percent). The most prevalent EGFR mutation was 19del (57 percent).

The current findings support the positive outcomes reported in the Asia study (HARMONi-A). [JAMA 2024;332:561-570] “The level of PFS benefit observed in HARMONi is comparable to studies that have evaluated VEGF inhibitors in NSCLC,” Ramalingam said.