Benefit of ivonescimab over pembrolizumab in patients with PD-L1-positive advanced NSCLC

The phase III HARMONi-2 study compared the efficacy of ivonescimab vs. pembrolizumab as first-line treatment in patients with PD-L1-positive advanced non-small cell lung cancer (NSCLC) and reported a significant benefit of ivonescimab over pembrolizumab in terms of progression-free survival (PFS), with no new safety signals being identified. The findings of this study support the use of ivonescimab in the first-line treatment of PD-L1-positive advanced NSCLC.

Current standard of care for first-line treatment of PD-L1-positive NSCLC comprises of anti-PD-1/L1 monotherapy or in combination with chemotherapy. Treatment with an immune checkpoint inhibitor as monotherapy delivers limited clinical benefits for these patients, highlighting the need for more effective treatment strategies. The use of ivonescimab, a novel anti-PD-1 and -VEGF bispecific antibody has yielded promising safety and efficacy results in the phase II AK112-202 study. At WCLC 2024, the interim analysis of the randomised, double-blind phase III HARMONi-2 trial was presented.

Study design

HARMONi-2 enrolled 398 patients with stage IIIB-IV advanced NSCLC with no prior systemic therapy and PD-L1 tumour proportion score (TPS) ≥1%. Further eligibility criteria included the absence of EGFR mutations or ALK rearrangements and an ECOG PS of 0 or 1. These patients were randomised 1:1 to receive either ivonescimab (20mg/kg Q3W; n=198) or pembrolizumab (200mg Q3W; n=200). Treatment was continued until no clinical benefit was noted, unacceptable toxicity, or 24 months had elapsed. The primary endpoint was PFS by blind IRRC per RECIST v1.1. Key secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response, and safety.

Results

At this interim analysis with a median follow-up of 8.67 months, ivonescimab demonstrated a significant improvement in PFS vs. pembrolizumab (median PFS 11.14 vs. 5.82 months, respectively; HR[95% CI]: 0.51[0.38-0.69], p< 0.0001). This benefit was also apparent across various subgroups including squamous and non-squamous NSCLC (HR[95% CI]: 0.48[0.31-0.74] and 0.54[0.36-0.82], respectively), and in patients with both low (TPS 1-49%) and high (TPS ≥50%) PD-L1 expression (0.54[0.37-0.79] and 0.46[0.28-0.75], respectively). In addition, the overall response rate was higher in the ivonescimab group (50% vs. 38.5%). In terms of safety, 29.4% of patients receiving ivonescimab experienced a grade ≥3 treatment-related adverse event (TRAE) vs. 15.6% in the pembrolizumab arm. Furthermore, 1.5% of patients discontinued due to TRAEs from ivonescimab compared to 3% with pembrolizumab. In patients with squamous cell carcinoma, 22.2% of patients who received ivonescimab experienced a grade ≥3 TRAE vs. 18.7% of patients in the pembrolizumab arm. Finally, the incidence of immune-related adverse events was similar between patients receiving ivonescimab and pembrolizumab (grade ≥3: 7.1% vs. 8%, respectively).

Conclusion

Ivonescimab used in the first-line treatment of advanced PD-L1-positive NSCLC resulted in a significant improvement in PFS, which was also seen across major clinical subgroups. A higher ORR was reported in this group. The safety profile of ivonescimab was consistent with prior reports and was well-tolerated. These results support the potential use of ivonescimab in the first-line treatment of advanced PD-L1-positive NSCLC.

Reference

Zhou C, et al. Phase 3 Study of Ivonescimab (AK112) vs. Pembrolizumab as First-line Treatment for PD-L1-positive Advanced NSCLC: HARMONi-2. Presented at WCLC 2024; Abstract 2700.