Invikafusp Alfa Shows Promise in Checkpoint Inhibitor-Resistant Solid Tumors with High Disease Control Rates
Key Insights
Invikafusp alfa, a first-in-class bispecific dual T-cell agonist, demonstrated objective response rates of 20.5% to 33.3% across biomarker-enriched populations with TMB-H or MSI-H solid tumors resistant to immune checkpoint blockade.
The novel therapy achieved impressive disease control rates ranging from 66.7% to 79.5% in heavily pretreated patients, with tumor regression observed in target lesions in 52% of patients.
Safety profile was consistent with the drug's mechanism of action, with cytokine release syndrome being the most common treatment-related adverse event, managed effectively with supportive care including corticosteroids.
Invikafusp alfa, a first-in-class bispecific dual T-cell agonist, demonstrated clinically meaningful antitumor activity in patients with checkpoint inhibitor-resistant solid tumors, according to phase 2 data from the START-001 trial presented at the 2025 ESMO Congress. The novel immunotherapy achieved tumor regression in target lesions in 52% of patients with tumor mutational burden-high (TMB-H) or microsatellite instability-high (MSI-H) solid tumors that had previously failed immune checkpoint blockade.
Efficacy Results Across Biomarker-Enriched Populations
The study evaluated invikafusp alfa across four distinct biomarker-enriched populations, demonstrating consistent antitumor activity. In patients with TMB-H tumors (n=44), the objective response rate (ORR) was 20.5% with nine patients achieving responses, while the disease control rate reached an impressive 79.5% with 35 patients experiencing disease stabilization or better.
More encouraging results emerged in specific tumor subsets. Among patients with TMB-H gastrointestinal cancers (n=18), the ORR increased to 27.8% with five responses, and the disease control rate was 77.8% with 14 patients achieving disease control. The most promising activity was observed in TMB-H metastatic colorectal cancer (search) (mCRC), where three of nine patients (33.3%) achieved objective responses, though the disease control rate was 66.7%.
Patients with MSI-H tumors (n=10) demonstrated a 30% ORR with three responses and a 70% disease control rate with seven patients achieving disease control. The TMB-H cohort encompassed a diverse range of malignancies including colorectal, gastric, lung, breast, and other cancers.
Novel Mechanism Addresses Immunotherapy Resistance
"Invikafusp alfa, a first-in-class bispecific dual T-cell agonist, demonstrated clinically meaningful monotherapy activity in heavily pretreated immune checkpoint blockade-resistant/insensitive tumors harboring high tumor mutations," stated presenting study author Antoine Italiano, MD, PhD, professor of medicine and head of Early Phase Trials Unit at the Institut Bergonié, and head of Precision Medicine at Gustave Roussy (search) in France.
The drug was specifically designed to selectively activate and expand Vβ10 T-cell subsets (search) to overcome resistance to immune checkpoint blockade. This approach addresses a significant clinical challenge, as immunotherapy resistance limits effective treatment options for patients. Tumor-infiltrating lymphocyte therapies have shown promise in the immuno-oncology-refractory setting, with Vβ6/10 T-cell subsets representing the most common subset.
Study Design and Patient Characteristics
The START-001 trial employed a traditional dose-escalation design in phase 1, testing doses ranging from 0.01 mg/kg to 0.16 mg/kg of invikafusp alfa. Phase 2 patients received the recommended phase 2 dose of 0.08 mg/kg intravenously every 2 weeks. As of July 9, 2025, 63 patients with TMB-H/MSI-H tumors were enrolled, including 55 in phase 2 and 8 from phase 1 at the optimal biologic dose.
The patient population was heavily pretreated, with a median age of 61 years (range 53-69). Most patients were male (95.2%), White (63.5%), and had an ECOG performance status of 1 (52.8%). Notably, 65.1% of patients had received between 1 and 3 prior lines of therapy, and 67% had prior treatment with an immune checkpoint inhibitor. The majority (73.0%) had TMB-H disease.
Tumor types represented in the study included colorectal cancer (search) (25.4%), non-small cell lung cancer (search) (14.3%), head and neck squamous cell carcinoma (search) (7.9%), gastric cancer (search) (6.3%), and various other malignancies including breast, endometrial, and pancreatic cancers.
Safety Profile Consistent with Mechanism
The safety profile aligned with the drug's mechanism of action, with cytokine release syndrome being the most frequently reported treatment-related adverse event. Grade 1, 2, and 3 cytokine release syndrome occurred in 22.2%, 46.0%, and 12.7% of patients, respectively. Other common treatment-related adverse events included rash (grade 1: 11.1%, grade 2: 34.9%, grade 3: 7.9%), nausea (grade 1: 28.6%, grade 2: 20.6%, grade 3: 1.6%), and pruritus (grade 1: 22.2%, grade 2: 20.6%, grade 3: 6.3%).
"No step-up dosing and no immune checkpoint inhibitor-type immune-related adverse effects were reported. TRAEs were on target and well managed with supportive care, including corticosteroids such as tocilizumab (Actemra)," Italiano noted.
Clinical Implications and Future Directions
The results suggest that selective activation of the T-cell Vβ repertoire represents a promising therapeutic approach for patients who have exhausted conventional immunotherapy options. "Selective activation of the T-cell Vβ repertoire represents a novel class of IO bispecific therapy, with broad potential as a next generation T-cell-targeted multi-specific antibody platform for the advancement of precision immunotherapy," Italiano concluded.
The study's primary objective in phase 2 was to evaluate ORR per immune RECIST criteria, while phase 1 focused on determining the recommended phase 2 dose and evaluating safety and tolerability. The encouraging disease control rates across multiple biomarker-enriched populations suggest potential utility in various solid tumor types that have developed resistance to standard immunotherapies.