Background Invikafusp alfa, a dual T cell agonist, promotes the selective activation and expansion of Vβ6/Vβ10 TCR-expressing CD8+ and CD4+ effector memory T cells, which in nonclinical studies promote potent anti-tumor activity in anti-PD(L)1-resistant solid tumors.^{1 2}

Methods START001 is a first-in-human, multicenter Phase 1/2 study evaluating invikafusp as monotherapy in patients with anti-PD(L)1-resistant, antigen-rich solid tumors (TMB-H, MSI-H/dMMR, or virally associated). Reported here are the initial results of the completed dose escalation of intravenous (IV) invikafusp Q2W per 3+3 design with additional enrollment to DLT-cleared dose levels.

Results As of 9 July 2024, 35 patients with a median of 4 prior lines of therapies across 16 different types of antigen-rich tumors were enrolled.

Overall, TEAEs were consistent with selective T cell activation mechanism of invikafusp. All patients experienced grade 1 fever and 60% had grade 2 CRS without premedication with corticosteroids or tocilizumab. Other common TEAEs (mostly grades 1 and 2) included rash (51.4%) and thrombocytopenia (34.3%). One DLT (grade 3 CRS) at 0.08mg/kg and another DLT (grade 3 elevated bilirubin) at 0.16mg/kg were reported. No grade 4 non-lab TEAEs or treatment-related deaths were observed.

Consistent with the model predictions based on the preclinical study results, dose-dependent increases in invikafusp serum concentrations (AUC and Cmax) were observed. Notably, sustained and selective expansion of predominantly Vβ6/Vβ10 T cells was observed with >400% peak increase in peripheral CD8⁺ Vβ6/Vβ10 T cells. Stable disease was reported in 56% of patients with 8 patients across 6 tumor types experiencing tumor shrinkage including 2 confirmed partial response (PR) among 4 patients with MSS metastatic colorectal cancer (mCRC). At 0.08mg/kg, a confirmed PR per RECIST 1.1 was reported with rapid onset (at week 6) and ongoing (230+ days) in a patient with TMB-H (10mut/Mb), MSS mCRC who had 6 lines of prior therapies including anti-PD-1 agents. A second confirmed, ongoing PR occurred at 0.12mg/kg in a patient with TMB-H (10.3mut/Mb), MSS mCRC. Both doses led to similar peak increases in selective Vβ6/Vβ10 T cell expansion, and are considered as optimal biological doses, based on safety, PK/PD data and preliminary anti-tumor activity. The 0.08 mg/kg was selected as recommended Phase 2 dose.

Conclusions Invikafusp, a selective dual T cell agonist, showed potent activation and expansion of target Vβ T cells, a manageable safety profile and promising early clinical activity as single-agent in heavily pre-treated patients across multiple tumor types with antigen-rich, anti-PD(L)-1-resistant solid tumors. Phase 2 dose expansion is ongoing.

Acknowledgements We thank all the participants and their families and caregivers; all site personnel; our CRO; vendors; and consultants for their contribution.

Trial Registration STUDY START-001 trial is registered on ClinicalTrials.gov - ID NCT05592626: A Study of a Selective T Cell Receptor (TCR) Targeting, Bifunctional Antibody-fusion Molecule STAR0602 in Participants With Advanced Solid Tumors.

References

1. Hsu J, Donahue RN, Katragadda M, et al. A T cell receptor β chain–directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity. Sci. Transl. Med. 29 November 2023;15:eadi0258.

2. Vantourou P, Eum J, Poole MC, et al. Innate TCRβ-chain engagement drives human T cells toward distinct memory-like effector phenotypes with immunotherapeutic potentials. Sci. Adv. 6 December 2023;9:eadj6174.

Ethics Approval Study START-001 has been approved by the following ethics committee or institutional review boards. All participants gave informed consent before taking part in this study. 1. National Cancer Institute, NIH, IRB. ID of the approval: 0010099 2. Massachusetts General Hospital IRB. ID of the approval:22-577 3. Memorial Sloan Kettering Cancer Center IRB. ID of the approval: 23-239 4. Princess Margaret Cancer Center IEB. ID of the approval:23-5345 5. Advent Health (Central Florida) IRB. ID of the approval:2052490-3.