Invikafusp Alfa Generates Clinical Activity in Checkpoint Inhibitor–Resistant Solid Tumors

Invikafusp Alfa in Solid Tumors
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Updated findings from the phase 1/2 START-001 trial (NCT05592626) demonstrated that the select dual T cell agonist invikafusp alfa yielded clinically meaningful antitumor activity with a manageable safety profile in patients with unresectable, locally advanced or metastatic solid tumors that were resistant to anti–PD-(L)1 immune checkpoint inhibitors.1

Findings presented during the 2025 AACR Annual Meeting showed that the overall disease control rate (partial response plus stable disease) with invikafusp alfa was 61% (32 of 52 patients). Among 42 patients who had received prior anti-PD(L)1 treatment, the disease control rate was 45% (n = 19). Further, 52% (20/38) of patients treated with invikafusp alfa at the optimal biological dose (OBD) had at least some tumor regression.

Of note, there were 3 responders out of 10 patients with tumor mutational burden–high (TMB-H), anti-PD(L)1-resistant metastatic colorectal cancer (CRC) and notable CRC subtypes (RASwt, RASmut, and microsatellite instability–high [MSI-H]).

The safety profile at the OBD was, “consistent with [the treatment’s] mechanism of action, which reflects selective T cell activation and expansion in vivo,” said presenting author Ryan J. Sullivan, MD, director, Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, MA. “Treatment-related adverse events [TRAEs] were mainly transient and low-grade and occurred in the first and second dose of invikafusp alfa.”

Overall, TRAEs were manageable with supportive care, including corticosteroids and tocilizumab (Actemra). Five patients had grade 3 cytokine release syndrome. There were no cases of immune effector cell–associated neurotoxicity syndrome, grade 4 TRAEs, or treatment-related deaths.

“Invikafusp promotes potent and selective expansion of CD8+ VB6/Vß10 T cells that acquire a novel ‘memory-like effector phenotype’ in both peripheral blood and tumor tissues,” said Sullivan, adding, “Phase 2 dose expansion cohorts are ongoing in TMB-H or MSI-H/mismatch repair–deficient (dMMR) tumors to confirm the efficacy signal from phase 1.”

Study Design and Patient Characteristics

The study enrolled patients with unresectable, locally advanced or metastatic solid tumors who had an ECOG performance status of 1 or lower. Prior anti-PD(L)1 therapy was permitted. Phase I specifically accrued patients with TMB-H or MSI-H/dMMR or virally associated tumors.

In the dose-escalation phase of the study, a standard 3+3 design was used, with patients receiving intravenous invikafusp alfa at increasing dose levels of 0.01 mg/kg, 0.02 mg/kg, 0.04 mg/kg, 0.08 mg/kg, 0.12 mg/kg, and 0.16 mg/kg every 2 weeks.

The OBD range was determined to be range of 0.08-0.12 mg/kg. The recommended phase 2 dose determined through the dose-escalation phase was 0.08mg/kg intravenously every 2 weeks.

Across all patients the median age was 59.0 years (range, 50.5-65.5) and 48.1% of patients were female. Regarding race, 3.8% were Asian, 5.8% were Black/African American, 71.2% were White, and 19.2% were other races. ECOG performance status was 0 (32.7%) or 1 (67.3%). Over half (53.8%) of patients had received 4 or more prior lines of therapy and 46.2% had received 1 to 3 prior lines. A large majority (80.8%) of patients had prior anti-PD(L)1 treatment and about one-fifth (19.2%) of patients were anti-PD(L)1 naive. Testing showed that 28.8% of patients had virally associated tumors, 59.6% had TMB-H tumors, and 9.6% had MSI-H tumors. Only 1 patient had an immunogenic tumor.

These patient characteristics were nearly identical in the subgroup of 38 patients who were treated with the OBD.

Phase 1 of the study included patients with 21 different tumor types. The most common tumor types were CRC (n = 15), head and neck squamous cell carcinoma (n = 8), cervical (n = 5), non–small cell lung cancer (n = 4), anal (n = 4), melanoma (n = 2), and Merkel cell carcinoma (n = 2). There was 1 patient each with the following cancers: gastric, adrenocortical carcinoma, ampullary, bladder, breast, choroidal melanoma, duodenal adenocarcinoma, esophageal, gastroesophageal junction, ovarian, pancreatic, skin, vagina-cervix, and vulvar.

Ongoing cohorts in phase 2 include TMB-H tumor agnostic (cohort 1, enrollment goal = 23-56), MSI-H/dMMR tissue-agnostic (cohort 2, enrollment goal = 10-29), and CRC with TMB-H and/or MSI-H (cohort 3, enrollment goal = 23-56). The primary end point of phase 2 is object response rate per iRECIST criteria.

Earlier this year, the FDA granted invikafusp alfa Fast Track designation for the treatment of patients with unresectable, locally advanced TMB-H metastatic CRC.2

References

1. Sullivan RJ, Friedman CF, Tschernia N et al. Updated clinical results, recommended phase 2 dose (RP2D) determination and translational study results for START-001: A phase 1/2 trial of invikafusp alfa, a first-in-class TCR b chain-targeted bispecific antibody in patients with anti-PD(L)1-resistant, antigen-rich solid tumors. Cancer Res (2025) 85 (8_Supplement_2): CT205. doi:10.1158/1538-7445.AM2025-CT205
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. April 29, 2025. https://tinyurl.com/zbcerb9k