Ivonescimab shows PFS benefit in NSCLC

Ivonescimab – a novel, potential first-in-class investigational bispecific antibody – demonstrates statistically significant improvement in progression-free survival (PFS) compared with pembrolizumab

Summit Therapeutics Inc. announced primary analysis data from the phase 3 HARMONi-2 trial evaluating ivonescimab monotherapy versus pembrolizumab in patients with PD-L1–positive advanced non–small-cell lung cancer (NSCLC). Ivonescimab demonstrates a statistically significant improvement in PFS by Independent Radiologic Review Committee (IRRC) compared with pembrolizumab, with a hazard ratio of 0.51 (95% CI, 0.38–0.69; p<0.0001). “This is a historic moment for ivonescimab, Team Summit, our partners at Akeso, and most importantly, we believe this is the beginning of a landscape shift for treatment options for patients living with cancer,” states Robert W. Duggan, Chairman and Chief Executive Officer of Summit.

A clinically meaningful benefit was demonstrated across clinical subgroups, including those with PD-L1 low expression (PD-L1 TPS 1–49%), PD-L1 high expression (PD-L1 TPS >50%), squamous and non-squamous histologies, as well as other high-risk patients. Both the overall response rate, measured according to RECIST v1.1 criteria, and the disease control rate were higher in patients treated with ivonescimab compared with those treated with pembrolizumab.

Ivonescimab demonstrated an acceptable and manageable safety profile, which was consistent with previous studies. There were three patients (1.5%) who discontinued ivonescimab due to treatment-related adverse events (TRAEs), compared with six patients (3.0%) who discontinued pembrolizumab. One patient in the ivonescimab arm and two patients in the pembrolizumab arm died as a result of TRAEs. The most frequent TRAEs for ivonescimab were proteinuria (grade 3+: ivonescimab, 3.0%; pembrolizumab, 0.0%), hypertension (grade 3+: ivonescimab, 5.1%; pembrolizumab, 0.5%), and various laboratory abnormalities, including aspartate aminotransferase (AST) increases, hypercholesterolemia, anemia, and bilirubin increases. Grade 3 or higher immune-related adverse events occurred in 7.1% of patients receiving ivonescimab and 8.0% of those receiving pembrolizumab. Grade 3 or higher adverse events possibly related to VEGF inhibition occurred in 10.2% of patients in the ivonescimab arm versus 1.0% in the pembrolizumab arm. Grade 3 hemorrhage events were observed in two patients in the ivonescimab arm (both with non-squamous histology) and one patient in the pembrolizumab arm.

The primary analysis data from the phase 3 HARMONi-2 trial was presented during the Presidential Symposium at the International Association for the Study of Lung Cancer’s (IASLC) 2024 World Conference on Lung Cancer (WCLC 2024) in San Diego, California, USA. The study, titled “Phase III Study of Ivonescimab (AK112) vs. Pembrolizumab as First-line Treatment for PD-L1-positive Advanced NSCLC: Primary Analysis of HARMONi-2,” evaluated ivonescimab monotherapy against pembrolizumab monotherapy in patients with locally advanced or metastatic NSCLC whose tumors have positive PD-L1 expression (PD-L1 TPS >1%).

HARMONi-2 is a single-region, multicenter, double-blinded phase 3 study conducted in China and sponsored by Akeso, Inc. (HKEX Code: 9926.HK), with data generated and analyzed by Akeso. The trial results were presented by Caicun Zhou, Chief Physician and Director of the Department of Medical Oncology at Shanghai Pulmonary Hospital, Tongji University School of Medicine, and President-Elect of IASLC.

In addition to the HARMONi-2 data, a second oral presentation featuring ivonescimab was delivered by Xiaoliang Zhao, Deputy Chief Physician, Department of Lung Cancer at Tianjin Medical University Cancer Institute & Hospital, and Visiting Scholar at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington, D.C., USA. The presentation, “A Phase II Study of Perioperative Ivonescimab Alone or Combined with Chemotherapy in Resectable Non-Small Cell Lung Cancer,” shared results from AK112-205, a single-region (China), multicenter, open-label phase 2 study in patients with stage 2 or 3 resectable NSCLC. At data cutoff, 49 patients had been enrolled in the ivonescimab plus chemotherapy arm in the neo-adjuvant setting; 39 of these patients completed surgery.

Among the 39 patients who received ivonescimab plus chemotherapy and completed surgery, 71.8% experienced a major pathological response and 43.6% experienced a pathological complete response. Median event-free survival (EFS) was not reached after 8.9 months of median follow-up; the 12-month EFS rate was 80.3% (95% CI, 59.6–91.1). The safety profile is manageable, with grade 3 or higher adverse events observed in 32.7% of patients. One patient experienced a TRAE. No TRAEs led to delayed or canceled surgery or patient death.

Additional phase 2 data featuring ivonescimab will be presented at the European Society of Medical Oncology (ESMO) Congress 2024, taking place in Barcelona, Spain, on September 13–17, 2024. These presentations will include studies sponsored by Akeso in first-line treatment for triple-negative advanced breast cancer (TNBC), advanced head and neck squamous cell carcinoma (HNSCC), and advanced colorectal cancer (CRC).

Summit has initiated clinical development of ivonescimab in NSCLC, with enrollment beginning in 2023 in two multi-regional phase 3 trials: HARMONi and HARMONi-3. HARMONi evaluates ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a third-generation EGFR tyrosine kinase inhibitor (e.g., osimertinib). HARMONi-3 evaluates ivonescimab plus chemotherapy versus pembrolizumab plus chemotherapy in patients with first-line metastatic squamous NSCLC. HARMONi-7, planned for early 2025, will compare ivonescimab monotherapy with pembrolizumab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 TPS >50%). Akeso has also reported positive readouts from two single-region phase 3 trials in NSCLC: HARMONi-A and HARMONi-2.

What is ivonescimab being evaluated for in the HARMONi-2 trial?

Ivonescimab is being evaluated as a first-line monotherapy treatment for patients with PD-L1–positive advanced NSCLC.

What is the primary endpoint result of the HARMONi-2 trial?

Ivonescimab demonstrates a statistically significant improvement in PFS compared with pembrolizumab, with a hazard ratio of 0.51 (95% CI, 0.38–0.69; p<0.0001).

How does ivonescimab perform across clinical subgroups?

A clinically meaningful benefit is demonstrated across subgroups, including PD-L1 low and high expression, squamous and non-squamous histologies, and other high-risk patients.

What is the safety profile of ivonescimab in the HARMONi-2 trial?

Ivonescimab shows an acceptable and manageable safety profile, with fewer discontinuations due to TRAEs compared with pembrolizumab.

What are the next steps following the HARMONi-2 results?

Summit plans to initiate HARMONi-7 in early 2025, a multi-regional phase 3 trial comparing ivonescimab monotherapy with pembrolizumab in patients with high PD-L1 expression.