Merck & Co., Inc. (known as MSD outside the United States and Canada) and Eisai Co., Ltd. have announced encouraging results from the first interim analysis of the Phase 3 LEAP-012 trial evaluating the efficacy of KEYTRUDA (pembrolizumab), an anti-PD-1 therapy by Merck, combined with LENVIMA (lenvatinib), an orally available multiple receptor tyrosine kinase inhibitor (TKI) developed by Eisai. The study focuses on the combination therapy’s effectiveness with transarterial chemoembolization (TACE) compared to TACE alone for treating patients with unresectable, non-metastatic hepatocellular carcinoma (HCC). These new findings were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2024.

Significant Improvement in Progression-Free Survival

After a median follow-up of 25.6 months, the combination of KEYTRUDA and LENVIMA with TACE demonstrated a statistically significant improvement in progression-free survival (PFS) compared to TACE alone. The combination therapy reduced the risk of disease progression or death by 34%, with a hazard ratio (HR) of 0.66 (95% CI, 0.51-0.84; p=0.0002). Median PFS was 14.6 months for the KEYTRUDA plus LENVIMA-based regimen versus 10.0 months for TACE alone. Although a trend toward improved overall survival (OS) was observed, the data were not mature enough to reach statistical significance at this interim analysis (HR=0.80 [95% CI, 0.57-1.11]; p=0.0867). The trial is ongoing, with further follow-up required to assess OS fully.

Safety and Adverse Events

The safety profile of the KEYTRUDA and LENVIMA combination was consistent with previous studies. However, treatment-related adverse events (TRAEs) were more frequent in the combination group, with 98.7% of patients experiencing TRAEs compared to 84.6% in the TACE-alone group. Serious adverse events were reported in 33.3% of patients in the combination group versus 12.4% in the TACE-alone group. The combination therapy also led to higher rates of Grade 3 or 4 TRAEs (71.3% vs 31.1%) and resulted in treatment discontinuation in 8.4% of patients versus 1.2% in the TACE-alone group.

The Need for New Treatment Options in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with incidence rates expected to rise by more than 50% over the next two decades. Currently, there are limited treatment options for patients with unresectable, non-metastatic forms of the disease. Transarterial chemoembolization (TACE) has been a standard treatment but often results in disease progression within a year. The LEAP-012 study’s findings suggest that adding KEYTRUDA and LENVIMA to TACE could provide a new therapeutic option for these patients, potentially extending progression-free survival.

Expert Opinions on LEAP-012 Results

Dr. Josep Llovet, Director of the Liver Cancer Program and Professor of Medicine at the Icahn School of Medicine at Mount Sinai, highlighted the significance of these findings: “These findings from the LEAP-012 trial demonstrate the potential of pembrolizumab plus lenvatinib in combination with TACE to extend progression-free survival for patients diagnosed with unresectable, non-metastatic disease.”

Dr. Gregory Lubiniecki, Vice President of Global Clinical Development at Merck Research Laboratories, echoed this sentiment, emphasising the need for new therapies in earlier stages of the disease. “We’re encouraged by the potential for another treatment option for patients with unresectable non-metastatic hepatocellular carcinoma,” he said.

Future Prospects and Further Research

The LEAP-012 trial is a multicenter, randomized, double-blind Phase 3 study investigating the potential of the KEYTRUDA plus LENVIMA combination in various tumour types, including HCC, renal cell carcinoma (RCC), head and neck cancer, gastric cancer, and esophageal cancer across multiple clinical trials. The study is continuing, and further data will be necessary to determine the full impact of the combination therapy on overall survival and its potential as a new standard of care.

The combination of KEYTRUDA and LENVIMA with TACE presents a promising new option for patients with unresectable, non-metastatic hepatocellular carcinoma. With a significant improvement in progression-free survival, the combination therapy could mark a meaningful advance in the treatment of this challenging cancer type. However, the safety profile and adverse events associated with the combination therapy should be considered when making treatment decisions. Ongoing research will provide further clarity on the overall survival benefits and solidify the role of this combination in liver cancer treatment.

  Eisai, ESMO Congress 2024, Hepatocellular carcinoma, Keytruda, Lenvima, liver cancer treatment, Merck, Oncology