Invikafusp Alfa Shows Potential in PD-1 Refractory Solid Tumors

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Invikafusp alfa (STAR0602) given as a monotherapy led to clinical activity in cancers with high tumor mutation burden (TMB-H) including confirmed responses in microsatellite stable colorectal cancer, according to findings from the ongoing phase 1/2 START-001 trial (NCT05592626).^1,2

According to findings presented during a late-breaking oral presentation at the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting, in biomarker-enriched, heavily pretreated patients with advanced anti-PD-1 resistant, or refractory solid tumors, early antitumor activity was observed with invikafusp alfa. Sustained and selective in vivo expansion of TCRVβ6/Vβ10 T cells was observed across all 6 dose levels, with up to a ~500% peak increase seen following treatment.

Among 28 patients across all dose-escalation cohorts, the disease control rate (DCR), defined as the combination of partial responses and stable disease, was 50%. Additionally, 32% of patients experienced tumor shrinkage across 6 different tumor types.

Notably, in the optimal biological dose range of 0.08 mg/kg to 0.12 mg/kg, invikafusp alfa exhibited single-agent clinical activity, achieving a 63% DCR. A total of 50% of patients saw tumor shrinkage, and a 25% objective response rate (ORR) was reported in patients with TMB-H and those resistant to anti–PD-1 therapies.

"Having completed phase 1 and commenced the phase 2 dose-expansion cohorts of START-001, Marengo is thrilled to share initial clinical findings that validate our novel selective dual T-cell agonist platform," said Zhen Su, MD, MBA, chief executive officer of Marengo Therapeutics, in a press release.¹ "The single-agent activity observed in phase 1, especially in PD-1 resistant cold tumors such as colorectal cancer is a critical milestone, and we look forward to further exploring the potential of STAR0602 to become a next-generation backbone [immunotherapy] across a range of tumor types."

Invikafusp alfa also had a manageable safety, which was consistent with its mechanism of action. This involves T-cell activation and expansion, and did not require pre-treatment with corticosteroids or tocilizumab (Actemra).

The most common treatment-related adverse events (TRAEs) seen in the trial were primarily transient grade 1 and 2 cytokine release syndrome observed after the first and second infusions. No grade 4 AEs or immune effector cell–associated neurotoxicity syndrome were reported.

Based on safety data, pharmacokinetic (PK) and pharmacodynamic findings, and the preliminary antitumor activity, the recommended phase 2 dose of 0.08 mg/kg was selected for further evaluation in phase 2 dose expansion studies.

"The first-in-human data suggest that this novel approach to selectively activate and expand Vβ T-cell subsets may hold promise for treating patients with advanced solid tumors," said James L. Gulley, MD, PhD, co-director of the Center for Immuno-Oncology and clinical director of the National Cancer Institute, in a press release. "The observed unique Vβ T cell biology in humans and selective expansion of Vβ6/Vβ10 across a range of solid tumors, combined with the initial anti-tumor activity, particularly in heavily pretreated anti–PD-1 resistant cancer patients with TMB-H colorectal cancer, are encouraging signs. The differentiated clinical profile supports further investigation of this unique mechanism of action in the next phase of clinical trials for high unmet medical needs in anti–PD-1 resistant tumors."

About STAR0602 and the Phase 1/2 Study

STAR0602 is the first T-cell activator made as part of the STAR platform, currently in development through Marengo Therapeutics, Inc. STAR0602 selectively targets a common subset of T cells that are present in all cancers and activates the TCR with a T-cell co-stimulator, allowing for the expansion of clonally enriched effector memory Vβ T cells that boost tumor immune responses to target tumors.³

In the open-label, multicenter, phase 1/2 START-001 trial, the safety, tolerability, and preliminary clinical activity of STAR0602 monotherapy is being evaluated for the treatment of patients with advanced solid tumors, including those that are PD-1 refractory.

Enrollment for part 1 of the study was open to patients with a histologically confirmed solid tumor(s) that is unresectable, locally advanced, or metastatic. Standard curative therapies must not exist or no longer be effective, symptomatic central nervous system metastases must have been treated, and patients must be asymptomatic for at least 14 days.

The primary end points are to assess patients with dose-limiting toxicities in phase 1, number of patients with AEs in parts 1 and 2, and overall response rate (ORR) in part 2. Secondary end points include ORR in part 1, duration of response, progression-free survival, overall survival, and PK.

REFERENCES

1. Marengo presents promising first-in-human safety, tolerability and clinical activity data for its lead program, invikafusp alfa (STAR0602), at the 2024 SITC annual meeting. News release. Marengo Therapeutics, Inc. November 9, 2024. Accessed November 18, 2024. https://tinyurl.com/5n9yj8n7

2. Gulley JL. A phase 1/2 study of invikafusp alfa (STAR0602), a first-in-class TCR β chain-targeted bispecific antibody, as monotherapy in patients with antigen-rich solid tumors resistant to anti-PD(L)1. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract LBA-1470.

3. Marengo Therapeutics announces first patient dosed in phase 1/2 clinical trial of its novel TCR Vβ directed antibody-fusion molecule STAR0602, in cancer patients refractory to anti-PD1 therapy. News release. Marengo Therapeutics, Inc. January 27, 2023. Accessed November 18, 2024. https://prn.to/3HjmHdg