Innovative Combination Therapy to Overcome Hypoxia in Pancreatic Cancer

The University of Texas MD Anderson Cancer Center has initiated a Phase 1/2 clinical trial (NCT07377526) evaluating the combination of a TROP2-targeting CAR-NK cell therapy and Welireg (belzutifan), a HIF-2α inhibitor from Merck & Co. (MRK). Pancreatic cancer has a dismal 5-year survival rate of less than 10% and is often resistant to standard chemotherapy regimens like FOLFIRINOX or GnP. This trial represents a significant step forward, combining a small molecule agent to control the hypoxic microenvironment within tumors with an immunotherapy approach, aiming to overcome the limitations of existing cancer treatments. The trial aims to provide new treatment options for pancreatic cancer patients, garnering significant attention within the industry.

Unique Design of Genetically Engineered TROP2 CAR-NK

The CAR-NK therapy used in the trial is characterized by genetically engineered NK cells derived from cord blood, designed to maximize their ability to penetrate and survive within solid tumors. These cells target the TROP2 protein, which is highly expressed on cancer cells. To enhance the long-term activity of the immune cells, the interleukin-15 (IL-15) gene is incorporated into the cells. Furthermore, CRISPR/Cas9 technology is employed to eliminate TGFBR2, a potent immunosuppressive gene within the tumor microenvironment, thereby preventing the reduction of anti-tumor efficacy. This triple-design enhances the ability of CAR-NK cells to attack cancer cells.

Synergistic Effect of Welireg in Controlling Hypoxic Microenvironment

Welireg, the combination drug, is a small molecule inhibitor that initially received FDA approval in August 2021 for tumors associated with von Hippel-Lindau (VHL) disease and subsequently expanded its approval to include treatment for advanced renal cell carcinoma (RCC) in December 2023. Pancreatic cancer cells induce severe hypoxia, creating a significant physical barrier that hinders immune cell infiltration. By inhibiting the HIF-2α protein, Welireg disrupts tumor angiogenesis and abnormal metabolism, improving the microenvironment. This allows the TROP2 CAR-NK cells to penetrate the weakened tumor barrier and effectively destroy cancer cells, creating a powerful synergistic effect.

Diversified Clinical Endpoints and Administration Routes

The Phase 1/2 trial will enroll 37 patients with pancreatic adenocarcinoma (PDAC) who have previously received standard therapy and experienced recurrence or progression. Uniquely, the CAR-NK cells will be administered via both intraperitoneal and intravenous routes, with patients receiving 120mg of Welireg daily via oral administration. The primary endpoint focuses on assessing the incidence of adverse events and toxicity to determine the recommended Phase 2 dose (RP2D). The secondary endpoint, including the objective response rate (ORR) at 12 weeks and progression-free survival (PFS), will serve as a key milestone in demonstrating the local and systemic therapeutic efficacy of the dual administration route in pancreatic cancer with peritoneal metastasis.

Merck's Product Diversification and Prospects for the Immune Cell Market

The global pancreatic cancer treatment market is projected to grow significantly from approximately $2.7 to $3.8 billion in 2025 to $5.8 billion in 2030. Merck & Co. (MRK) is actively seeking to expand the indications of Welireg to include difficult-to-treat solid tumors, in response to the upcoming patent expiration of its leading immune checkpoint inhibitor, Keytruda. Welireg recorded sales of $199 million in the first quarter of 2026, a 43% increase year-over-year. This trial will be a critical test to demonstrate the clinical utility and cost-effectiveness of the 'off-the-shelf' NK cell platform in the solid tumor market, differentiating it from existing TROP2-targeted antibody-drug conjugates (ADCs) such as sacituzumab govitecan (Trodelvy) from Gilead. It is expected to provide key data for investment and portfolio strategy development in the field of cellular therapy for solid tumors.