Marengo Therapeutics has successfully completed the Phase 1b safety run-in portion of its STARt-002 clinical trial and determined the recommended Phase 2 dose for invikafusp alfa in combination with TRODELVY® (sacituzumab govitecan-hziy), Gilead's approved TROP2-directed antibody-drug conjugate. The study is now advancing into two expansion cohorts evaluating the combination in hormone receptor-positive, HER2-negative (HR+/HER2−) and triple-negative metastatic breast cancer patients.
Novel Combination Approach Shows Early Promise
The STARt-002 trial represents a strategic approach to addressing treatment challenges in advanced breast cancer by combining Marengo's dual T-cell agonist with an established ADC therapy. Early data from the study has revealed signs of anti-tumor activity, including confirmed partial responses and tumor regressions in patients treated with this first-in-class T-cell agonist combined with the TROP2-directed ADC.
"Breast cancer remains an area of tremendous unmet need, particularly for patients with advanced HR+/HER2− and triple-negative disease," said Erika Hamilton, M.D. FASCO, Director of Breast Cancer Research at Sarah Cannon Research Institute. "The ability to combine a novel T cell agonist like invikafusp with a proven ADC such as sacituzumab govitecan represents an exciting step toward potentially broadening the benefit of immunotherapy-based combination regimens for patients with historically limited treatment options."
Invikafusp Alfa's Mechanism and Previous Results
Invikafusp alfa (STAR0602) is designed to selectively activate a common Vβ T cell subset found in all cancers by combining a non-clonal mode of TCR activation with a T cell co-stimulatory signal in a single molecule. This approach promotes the expansion of clonally diverse, effector memory Vβ T cells, enhancing anti-tumor immunity and enabling durable tumor clearance.
Previous monotherapy data for invikafusp alfa in PD-1-resistant tumors, including colorectal and gastrointestinal cancers, demonstrated a 63% disease control rate and 50% tumor shrinkage in TMB-H patients. The FDA has granted Fast Track designation to invikafusp alfa for advanced colorectal cancer, underscoring regulatory interest in its novel mechanism of action.
Strategic Market Positioning
The combination therapy positions Marengo strategically within the rapidly expanding TROP2-targeted oncology market. Trodelvy, the first and only approved TROP2-directed ADC, achieved 2024 sales surpassing $600 million, driven by its role in second-line metastatic TNBC and HR+/HER2- breast cancer. The global TROP2 therapy market is projected to exceed $4 billion by 2030, with a compound annual growth rate of 18% through 2033.
"As highlighted at recent oral presentations at major scientific conferences, invikafusp has already demonstrated promising single-agent activity in PD-1 resistant tumors including breast cancer," said Kevin Chin, M.D., Chief Medical Officer of Marengo Therapeutics. "Advancing STARt-002 into Phase 2 expansion cohorts reinforces invikafusp's potential as an immunotherapy backbone, particularly in combination with ADCs for immunologically cold tumors such as breast cancer."
Trial Design and Enrollment
The STARt-002 study (NCT06827613) is a Phase 1b/2, open-label, multicenter study investigating the combination in patients with unresectable, locally advanced, or metastatic breast cancer. The trial consists of the completed safety lead-in phase followed by two dose-expansion cohorts: one in triple-negative breast cancer and one in HR+/HER2− metastatic breast cancer.
The study is currently enrolling patients across leading North American cancer centers including Massachusetts General Hospital, Sarah Cannon Research Institute, Princess Margaret Cancer Centre, University of Southern California, University of California Los Angeles, University of Texas at San Antonio, and Ohio State University, with additional sites planned in the near term.
Competitive Landscape and Future Outlook
Marengo's approach diverges from competitors by addressing two critical challenges: the limited efficacy of ADCs in PD-1-resistant tumors and the need to enhance immune response in immunologically "cold" tumors. While over 40 other TROP2-targeted therapies are in clinical trials, including Datopotamab deruxtecan from Daiichi Sankyo/AstraZeneca, Marengo's combination strategy with its proprietary STAR™ platform technology offers a differentiated mechanism of action.
The company's collaboration with Gilead adds credibility to its platform, while the Fast Track designation for invikafusp alfa in colorectal cancer suggests potential for expedited regulatory pathways if the combination demonstrates robust clinical outcomes in breast cancer indications.
