Invikafusp Alfa Earns Expanded Fast Track Designation in TMB-H Solid Tumors

The FDA has granted fast track designation to invikafusp alfa (STAR0602) for patients with unresectable, locally advanced, or metastatic tumor mutational burden–high (TMB-H) solid tumors who have no satisfactory treatment alternatives after disease progression on prior therapy, including an immune checkpoint inhibitor.¹ The bispecific dual T-cell agonist previously received fast track designation in TMB-H colorectal cancer (CRC) in January 2025, and the new grant extends its fast track status to a tissue-agnostic indication.²

Results from the phase 1/2 START-001 trial (NCT05592626) supported the designation.^1,3 These responses spanned several tumor types, including colorectal, gastric, breast, urothelial, endometrial, gastroesophageal, head and neck, and lung cancers.

In initial phase 2 data presented at the 2025 ESMO Congress, invikafusp alfa produced an objective response rate (ORR) of 20.5% and a disease control rate (DCR) of 79.5% in patients with TMB-H tumors (n = 44).³ Among patients with TMB-H gastrointestinal cancers (n = 18), the ORR and DCR were 27.8% and 77.8%, respectively. Among those with TMB-H metastatic CRC (n = 9), the ORR and DCR were 33.3% and 66.7%, respectively. Overall, target-lesion shrinkage was observed in 52% of patients with TMB-H or microsatellite instability–high (MSI-H) tumors.

“A second fast track designation, now in a pan-tumor setting, reinforces our conviction that invikafusp alfa can become a next-generation, tissue-agnostic immuno-oncology backbone," Ke Liu, MD, PhD, chief development officer of Marengo Therapeutics, said in a news release.¹

Invikafusp alfa’s initial fast track designation, granted in January 2025, covered unresectable, locally advanced, or metastatic TMB-H CRC.² Marengo indicated that it believes invikafusp alfa is the first immuno-oncology T-cell agonist granted fast track designation for a tissue-agnostic population selected by biomarker.¹

How was the phase 1/2 START-001 trial designed?

START-001 is a first-in-human, open-label, multicenter study of with planned enrollment of 366 patients who have histologically confirmed unresectable, locally advanced or metastatic tumors for which curative therapies are ineffective or do not exist.⁴ Patients also need to have no concurrent treatment for central nervous system disease, any checkpoint inhibitor immune-related toxicities resolved to grade 1 or less, and an ECOG performance status of 1 or less.^3,4

Phase 1 is specifically enrolling patients with TMB-H, MSI-H/mismatch repair–deficient (dMMR), or virally associated tumors. Additionally, phase 2 is restricted to TMB-H or MSI-H/dMMR disease, including CRC that is TMB-H, MSI-H, or both. Patients needed an ECOG performance status of 0 or 1 and could have received a PD-(L)1 inhibitor previously.

The phase 1 dose escalation tested 6 dose levels, 0.01 mg/kg 0.02 mg/kg, 0.04 mg/kg, 0.08 mg/kg, 0.12 mg/kg, or 0.16 mg/kg of invikafusp alfa.² All patients in phase 2 receive invikafusp alfa at the recommended phase 2 dose (RP2D) of 0.08 mg/kg intravenously every 2 weeks.

Phase 1 aimed to establish the RP2D and to characterize safety and tolerability. The primary end point of phase 2 is ORR by immune RECIST. Secondary end points are duration of response, DCR, progression-free survival, overall survival, and pharmacokinetics.

What safety data were reported for invikafusp alfa?

Cytokine release syndrome was the most frequently reported treatment-related adverse effect (TRAE), occurring at grade 1, 2, and 3 in 22.2%, 46.0%, and 12.7% of patients, respectively. Other common TRAEs, given as grade 1, 2, and 3 rates, included rash (11.1%, 34.9%, and 7.9%), nausea (28.6%, 20.6%, and 1.6%), pruritus (22.2%, 20.6%, and 6.3%), increased alanine aminotransferase (22.2%, 4.8%, and 9.5%), decreased platelet count (11.1%, 12.7%, and 12.7%), diarrhea (19.0%, 6.3%, and 1.6%), and increased blood bilirubin (7.9%, 4.8%, and 3.2%).

"Across multiple clinical data sets, invikafusp alfa has shown encouraging monotherapy activity in heavily pretreated patients across tumor types that were either insensitive to checkpoint inhibitors or progressed after PD-1–directed therapy. In parallel, we are evaluating invikafusp alfa in combination with standard-of-care therapies, including an antibody-drug conjugate, to support its potential in earlier lines of therapy. We look forward to presenting Phase 2 STARt-001 data at ESMO later this month,” Liu added.¹

References

1. Marengo Therapeutics receives second U.S. FDA fast track designation for invikafusp alfa, expanding to a tissue-agnostic indication across tumor mutational burden-high solid tumors that progress after prior therapy, including checkpoint inhibition. News release. Marengo Therapeutics. October 15, 2026. Accessed October 15, 2026. https://www.prnewswire.com/news-releases/marengo-therapeutics-receives-second-us-fda-fast-track-designation-for-invikafusp-alfa-expanding-to-a-tissue-agnostic-indication-across-tumor-mutational-burden-high-solid-tumors-that-progress-after-prior-therapy-including-chec-302907721.html
2. Marengo's first-in-class invikafusp alfa (STAR0602) receives U.S. FDA fast track designation for treatment of unresectable, locally advanced, or metastatic colorectal cancers with high tumor mutational burden (TMB-H). News release. Marengo Therapeutics, Inc. January 8, 2025. Accessed October 15, 2026. https://www.prnewswire.com/news-releases/marengos-first-in-class-invikafusp-alfa-star0602-receives-us-fda-fast-track-designation-for-treatment-of-unresectable-locally-advanced-or-metastatic-colorectal-cancers-with-high-tumor-mutational-burden-tmb-h-302344827.html
3. Garralda E, Italiano A, Marabelle A, et al. START-001: initial phase 2 clinical activity of invikafusp alfa, a first-in-class T cell receptor (TCR) β-chain-targeted bispecific antibody as monotherapy in patients with antigen-rich solid tumors resistant to immune checkpoint blockade (ICB). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA55.
4. A study of a selective T cell receptor (TCR) targeting, bifunctional antibody-fusion molecule STAR0602 in participants with advanced solid tumors. ClinicalTrials.gov. Accessed October 15, 2026. https://clinicaltrials.gov/study/NCT05592626