Invikafusp alfa, a selective dual T-cell agonist, has demonstrated clinically meaningful antitumor activity in patients with unresectable, locally advanced or metastatic solid tumors resistant to anti-PD(L)1 immune checkpoint inhibitor therapy, according to updated results from the phase 1/2 START-001 trial presented at the 2025 AACR Annual Meeting and ESMO Gastrointestinal Cancers Congress.
The overall disease control rate (partial response plus stable disease) with invikafusp alfa was 61% across 52 patients enrolled in the study. Among 42 patients who had received prior anti-PD(L)1 treatment, the disease control rate was 45%. Notably, 52% of patients treated with invikafusp alfa at the optimal biological dose had at least some tumor regression.
Efficacy in Colorectal Cancer and Other Tumor Types
The treatment showed particularly promising results in challenging patient populations. Among patients with tumor mutational burden-high (TMB-H) gastrointestinal tumors, the overall response rate was 23.5% with a disease control rate of 63%. In the subset of patients with TMB-H metastatic colorectal cancer, the overall response rate reached 25%.
"There were 3 responders out of 10 patients with tumor mutational burden–high, anti-PD(L)1-resistant metastatic colorectal cancer and notable CRC subtypes (RASwt, RASmut, and microsatellite instability–high)," noted Ryan J. Sullivan, MD, director of the Center for Melanoma at Massachusetts General Hospital Cancer Center, who presented the findings.
Among patients with microsatellite instability-high (MSI-H) gastrointestinal tumors, the overall response rate was 33.3%. The study highlighted several case studies, including confirmed partial responses in patients with RAS wild-type, microsatellite stable metastatic colorectal cancer and KRAS G12D-mutated colorectal cancer, achieving target lesion shrinkage of -58% and -38%, respectively.
Mechanism of Action and T-Cell Expansion
Invikafusp alfa works by promoting "potent and selective expansion of CD8+ VB6/Vβ10 T cells that acquire a novel 'memory-like effector phenotype' in both peripheral blood and tumor tissues," according to Sullivan. The treatment is designed to revitalize antitumor T-cell responses in vivo via selective activation and expansion of Vβ6 and Vβ10 memory-like effector T cells, and also features an interleukin 2R agonist.
Clinical data demonstrated significant T-cell expansion, with Vβ6 T-cell expansion in the blood increasing from 7.22% at baseline to 15.7% at day 8 of treatment. Within tumor tissue, Vβ6 T-cell expansion rose from 8.85% at baseline to 14.6% at day 8. Additional increases were observed for CD3-positive T cells (41.0% at baseline vs 50.5% at day 21), CD8-positive T cells (11.9% vs 22.1%), and CD4-positive T cells (28.3% vs 41.0%).
Safety Profile and Dosing
The safety profile at the optimal biological dose was "consistent with [the treatment's] mechanism of action, which reflects selective T cell activation and expansion in vivo," Sullivan reported. Treatment-related adverse events were mainly transient and low-grade, occurring primarily during the first and second doses of invikafusp alfa.
Cytokine release syndrome occurred at any grade in 87.0% of patients treated within the optimal biologic dose range, with grade 1 (13.0%), grade 2 (65.2%), and grade 3 (8.7%) events reported. Five patients experienced grade 3 cytokine release syndrome. Importantly, there were no cases of immune effector cell-associated neurotoxicity syndrome, grade 4 treatment-related adverse events, or treatment-related deaths.
Other common treatment-related adverse events in the optimal biologic dose range included pruritus (60.9%), nausea (47.8%), chills (43.5%), vomiting (43.5%), and rash (39.1%). Overall, treatment-related adverse events were manageable with supportive care, including corticosteroids and tocilizumab.
Study Design and Patient Population
The START-001 study enrolled patients with unresectable, locally advanced or metastatic solid tumors who had an ECOG performance status of 1 or lower. During dose escalation, patients received intravenous invikafusp alfa at increasing dose levels ranging from 0.01 mg/kg to 0.16 mg/kg every 2 weeks using a standard 3+3 design.
The optimal biological dose range was determined to be 0.08 to 0.12 mg/kg, with the recommended phase 2 dose established at 0.08 mg/kg intravenously every 2 weeks.
The study population had a median age of 59.0 years, with 48.1% female patients. Over half (53.8%) had received 4 or more prior lines of therapy, and 80.8% had prior anti-PD(L)1 treatment. Testing showed that 28.8% of patients had virally associated tumors, 59.6% had TMB-H tumors, and 9.6% had MSI-H tumors.
Phase 1 included patients with 21 different tumor types, with the most common being colorectal cancer (n = 15), head and neck squamous cell carcinoma (n = 8), cervical cancer (n = 5), non-small cell lung cancer (n = 4), and anal cancer (n = 4).
Regulatory Status and Future Development
Earlier this year, the FDA granted invikafusp alfa Fast Track designation for the treatment of patients with unresectable, locally advanced TMB-H metastatic colorectal cancer.
Phase 2 dose expansion cohorts are currently ongoing in three areas: TMB-H tumor agnostic (cohort 1, enrollment goal = 23-56), MSI-H/dMMR tissue-agnostic (cohort 2, enrollment goal = 10-29), and colorectal cancer with TMB-H and/or MSI-H (cohort 3, enrollment goal = 23-56). The primary endpoint of phase 2 is objective response rate per iRECIST criteria.
