First-Line Ivonescimab Improves PFS vs Pembrolizumab in PD-L1+ NSCLC in China

First-line treatment with ivonescimab (AK112; SMT112) monotherapy led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with pembrolizumab (Keytruda) monotherapy in patients with locally advanced or metastatic, PD-L1–positive non–small cell lung cancer (NSCLC), meeting the primary end point of the phase 3 HARMONi-2 trial (NCT05499390).¹

In a prespecified interim analysis of the single-region, multicenter, double-blinded trial being conducted in China, the PFS benefit was also observed in different subgroups, including patients with a PD-L1 tumor proportion score (TPS) of 1% to 49%, a PD-L1 TPS of at least 50%, squamous histology, nonsquamous histology, and other high-risk features.

“HARMONi-2 clearly demonstrates that ivonescimab is the next generation in PD-1–directed immunotherapy, and its potential to make a significant difference in the lives of patients with lung cancer and prospectively other solid tumors,” Maky Zanganeh, DDS, chief executive officer and president of Summit Therapeutics, stated in a news release. “We want to congratulate our partners at Akeso for this incredible result and their work to advance the patient-friendly standards of care today and well into the future. This result validates Team Summit’s present-time intention to execute a development plan worthy of ivonescimab’s emergent potential – including clinical trials in both NSCLC and other tumors where ivonescimab can improve upon existing standards of care.”

Ivonescimab is a novel, potential first-in-class, investigational bispecific antibody targeting PD-1 and VEGF. In May 2024, ivonescimab was approved for marketing authorization in China. It is not approved by any other regulatory agency, including the FDA and the European Commission.

HARMONi-2 enrolled patients at least 18 years of age with previously untreated, histologically or cytologically confirmed stage IIIB/C or IV NSCLC who had positive PD-L1 expression in tumor tissue.2 Patients could not harbor EGFR mutations or ALK gene translocations. Other key inclusion criteria consisted of a life expectancy of at least 3 months; an ECOG performance status of 0 or 1; measurable disease per RECIST 1.1 criteria; adequate organ function; and recovery from effects of prior radiotherapy or surgery.

Patients were excluded if they had any histologically small cell carcinoma component; received a diagnosis of immunodeficiency or received systemic steroid therapy within 2 years prior to the first dose of study treatment; underwent major surgery within 30 days of the first day of study treatment; had a known additional malignancy that was progressing or required systemic treatment, other than basal cell carcinoma of the skin or squamous cell carcinoma of the skin that had undergone potentially curative therapy, or in situ cervical cancer; had known, active central nervous system metastases; or had an active autoimmune disease that required systemic treatment in the past 2 years.

Patients were randomly assigned to receive intravenous (IV) ivonescimab at a selected dose or IV pembrolizumab at 200 mg once every 3 weeks.

Along with the primary end point of PFS per RECIST 1.1 criteria as assessed by an independent radiographic review committee (IRRC), secondary end points included overall survival; IRRC- and investigator-assessed overall response rate, duration of response, disease control rate, and time to response; investigator-assessed PFS; and safety.

The safety profile of ivonescimab was manageable and consistent with treatments intended to inhibit PD-1 and VEGF.¹

“This is an historic moment for ivonescimab, Team Summit, our partners at Akeso, and most importantly, we believe this is the beginning of a paradigm change for treatment options for patients living with cancer,” Robert W. Duggan, chairman and chief executive officer of Summit Therapeutics, added in a news release. “We are incredibly proud of our partnership with Akeso and their accomplishment with the HARMONi-2 trial.”

Ivonescimab is also being investigated in the phase 3 HARMONi (NCT06396065) and HARMONi-3 (NCT05899608) trials. HARMONi is investigating ivonescimab plus chemotherapy vs placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic nonsquamous NSCLC who experienced disease progression after treatment with a third-generation EGFR TKI. HARMONi-3 is evaluating ivonescimab plus chemotherapy compared with pembrolizumab plus chemotherapy as first-line treatment for patients with metastatic squamous NSCLC.

References

1. Ivonescimab monotherapy decisively beats pembrolizumab monotherapy head-to-head, achieves statistically significant superiority in PFS in first-line treatment of patients with PD-L1 positive NSCLC in China. News release. Summit Therapeutics. May 30, 2024. Accessed May 31, 2024. https://www.businesswire.com/news/home/20240530536730/en content/uploads/2024/05/2024_PR_0530_Ivonescimab-AK112-303-Data-_-FINAL.pdf
2. AK112 in advanced non-small cell lung cancer. ClinicalTrials.gov. Updated September 21, 2023. Accessed May 31, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05499390