Summit Therapeutics' experimental drug, ivonescimab, has demonstrated a significant advantage over Merck's Keytruda in a Phase 3 clinical trial for advanced non-small cell lung cancer (NSCLC). The study, known as HARMONi-2, revealed that ivonescimab reduced the risk of cancer progression or death by 49% compared to Keytruda, marking a potential shift in the treatment landscape for this disease.
The data, presented at the World Conference on Lung Cancer in San Diego, showed that patients treated with ivonescimab experienced a median progression-free survival (PFS) of 11.1 months, compared to 5.8 months for those receiving Keytruda. This 5.3-month difference in PFS was statistically significant (p<0.0001), indicating a substantial benefit for patients treated with Summit's drug.
Mechanism of Action and Clinical Significance
Ivonescimab, discovered by Akeso, is a bispecific antibody that simultaneously targets PD-1 and VEGF, two key pathways implicated in tumor growth and immune evasion. Keytruda, on the other hand, is a PD-1 inhibitor that blocks the interaction between PD-1 and PD-L1, thereby enhancing the immune system's ability to attack cancer cells. The dual-targeting mechanism of ivonescimab may offer a more comprehensive approach to cancer treatment, potentially leading to improved outcomes.
"It's not always that we see a drug improving median progression-free survival by almost six months," said Gilberto Lopes, chief of medical oncology at the University of Miami's Sylvester Comprehensive Cancer Center. "I have no doubt that this is a positive study."
Trial Design and Patient Population
The HARMONi-2 trial enrolled 398 patients in China with previously untreated, advanced NSCLC whose tumors expressed PD-L1 in at least 1% of malignant cells. Participants were randomized to receive either ivonescimab or Keytruda every three weeks until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS, with overall survival (OS) as a secondary endpoint.
Efficacy Across Subgroups
In addition to the primary finding, investigators observed a roughly 50% risk reduction in participants with both low and high levels of PD-L1. The benefit of ivonescimab was also consistent across squamous and non-squamous forms of lung cancer. Furthermore, treatment with ivonescimab resulted in a greater percentage of patients experiencing tumor shrinkage compared to Keytruda.
Safety Profile and Considerations
While ivonescimab demonstrated superior efficacy, it was associated with a higher rate of treatment-related adverse events (TRAEs). Approximately 29.4% of patients receiving ivonescimab experienced Grade 3 or higher TRAEs, compared to 15.6% of patients receiving Keytruda. Common side effects included high blood pressure and proteinuria, which are known to be associated with VEGF inhibitors. Despite the higher rate of TRAEs, only 1.5% of ivonescimab patients discontinued treatment due to adverse events, compared to 3% in the Keytruda arm.
Future Directions and Ongoing Studies
Summit has initiated a global Phase 3 trial, HARMONi-7, comparing ivonescimab monotherapy to Keytruda monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression. This study aims to address some of the limitations of the HARMONi-2 trial, including the lack of a comparison to Keytruda plus chemotherapy, which is the current standard of care for many patients. Results from the HARMONi-7 trial are expected in 2027.
Implications for the Treatment Landscape
The results of the HARMONi-2 trial suggest that ivonescimab has the potential to become a new standard of care for first-line treatment of PD-L1-positive NSCLC. However, further studies are needed to confirm these findings in more diverse populations and to determine the impact of ivonescimab on overall survival. Additionally, it will be important to compare ivonescimab to Keytruda plus chemotherapy to fully understand its place in the treatment algorithm.
"I would want to see overall survival data and the magnitude of that difference, to see if it were something that would be meaningfully important to put into practice," said Richard Hall, a medical oncologist at the University of Virginia.
