Summit Therapeutics (SMMT) Study Update summary

Study design and patient population

• HARMONi-2 is a randomized, double-blind phase III trial comparing ivonescimab to pembrolizumab in advanced or metastatic PD-L1-positive NSCLC, enrolling 398 patients stratified by stage, histology, and PD-L1 expression.

• Patients had stage IIIB-IV NSCLC, no prior systemic therapy, ECOG PS 0 or 1, and no EGFR/ALK alterations.

• Median age was ~65, with most patients having stage IV disease; 42% had high PD-L1 expression, and 13% had liver metastases.

• Baseline characteristics were balanced between arms, with similar distributions in age, sex, smoking status, stage, histology, and PD-L1 expression.

• Patients with central tumors, cavitation, or tumors encasing large vessels were eligible, with higher baseline risk in the ivonescimab arm.

Efficacy and subgroup results

• Ivonescimab demonstrated a median PFS of 11.14 months versus 5.82 months for pembrolizumab (HR=0.51, p<0.0001), reducing risk of progression or death by 49%.

• PFS benefit was consistent across subgroups, including age, sex, ECOG status, liver/brain metastases, stage, histology, and both low (TPS 1-49%) and high (TPS ≥50%) PD-L1 expression.

• Ivonescimab achieved higher ORR (50.0% vs. 38.5%) and DCR (89.9% vs. 70.5%) compared to pembrolizumab.

• Duration of response was not reached in either arm.

• Serious treatment-related adverse events and discontinuation rates were comparable between arms.

Safety and tolerability

• Treatment-related adverse events (TRAEs) of any grade occurred in 89.8% of ivonescimab patients and 81.9% of pembrolizumab patients; grade ≥3 TRAEs were higher with ivonescimab (29.4% vs. 15.6%).

• Most common TRAEs for ivonescimab included proteinuria, hypertension, and laboratory abnormalities; safety profile was manageable and consistent with prior studies.

• Immune-related AEs were similar between arms (29.9% vs. 28.1% all grades); serious irAEs were less frequent with ivonescimab (5.6% vs. 11.1%).

• VEGF-related AEs were more common with ivonescimab but were mostly grade 1-3; no grade 4/5 VEGF-related AEs or life-threatening bleeding observed.

• No TRAEs led to delayed or cancelled surgery or death in perioperative studies.