Invikafusp Alfa Generates Antitumor Activity in PD-(L)1–Resistant and –Naive, Antigen-Rich GI Tumors

The selective, dual T-cell agonist invikafusp alfa (STAR0602) showcased antitumor activity when given as monotherapy in patients with advanced, antigen-rich gastrointestinal (GI) tumors, including those naive and resistant to anti–PD-(L)1 therapy, with a safety profile consistent with selective T-cell activation, according to data from the phase 1/2 STARt-001 trial (NCT05592626).¹

Data presented at the 2025 ESMO Gastrointestinal Cancers Congress demonstrated that patients with tumor mutational burden–high (TMB-H) GI tumors (n = 17) achieved an overall response rate (ORR) of 23.5% and a disease control rate of 63%. In patients with TMB-H metastatic colorectal cancer (mCRC; n = 12), the ORR was 25%. Among those with microsatellite instability–high (MSI-H) GI tumors (n = 6), the ORR was 33.3%.

Regarding safety, most treatment-related adverse effects (TRAEs) were transient, low grade, and occurred during the first 2 doses of invikafusp alfa. No instances of immune effector cell–associated neurotoxicity syndrome, grade 4 TRAEs, or treatment-related deaths were reported. Cytokine release syndrome (CRS) occurred at any grade in 87.0% of patients treated within the optimal biologic dose range (n = 23). CRS was reported at grade 1 (13.0%), grade 2 (65.2%), and grade 3 (8.7%). Notably, the study did not utilize primary prophylaxis with corticosteroids or tocilizumab (Actemra), and step-up dosing was not used.

“The US FDA [previously] granted fast track designation for invikafusp alfa in TMB-H mCRC,” lead study author Elena Elez, MD, PhD, said in a presentation of the data. “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.” Elez is an attending physician in the Gastrointestinal Tumors Service of the Medical Oncology Service of the Vall d’Hebron University Hospital in Barcelona, Spain.

Invikafusp Alfa and STARt-001 Background

The T-cell agonist is intended to revitalize antitumor T-cell responses in vivo via the selective activation and expansion of Vβ6 and Vβ10 memory-like effector T cells. The agent also features an interleukin 2R agonist.

STARt-001 is a dose-escalation and -expansion study evaluating invikafusp alfa monotherapy in patients with unresectable locally advanced or metastatic solid tumors. In phase 1, patients needed to have TMB-H, MSI-H/dMMR, or virally associated tumors. Phase 2 also included a cohort for patients with TMB-H and/or MSI-H/dMMR mCRC. All patients needed to have an ECOG performance status of 0 or 1, and they could not have liver metastases unless they were adequately treated and stable. Prior anti–PD-(L)1 therapy was allowed but not required.

During dose escalation, invikafusp alfa was given at 1 of 6 dose levels ranging from 0.01 mg/kg to 0.16 mg/kg once every 2 weeks. The 0.08-mg/kg and 0.12-mg/kg doses were determined to fall within the optimal biological dose range; the 0.08-mg/kg dose given once every 2 weeks was established as the recommended phase 2 dose.

The incidence of dose-limiting toxicities served as a primary end point in phase 1; ORR was the primary end point in phase 2.² Safety is a primary end point in both phases.

Select Case Studies

During the presentation, Elez highlighted 4 patients treated with invikafusp alfa during the study who achieved a confirmed or unconfirmed partial response (PR). The 2 confirmed PRs spotlighted included a patient with RAS wild-type, microsatellite stable (MSS) mCRC who had a TMB of 10 mut/mb, primary anti–PD-(L)1 resistance, and liver metastases; and a patient with KRAS G12D–mutated, MSS CRC with a TMB of 10 mut/mb and disease that was naive to PD-(L)1 inhibition. These 2 patients achieved target lesion shrinkage of –58% and –38%, respectively.

Among the 2 unconfirmed PRs highlighted by Elez, 1 patient had MSI-H mCRC with a TMB of 16 mut/mb and secondary anti–PD-(L)1 resistance, and the other had MSI-H gastroesophageal junction cancer with a TMB of 14 mut/mb and primary PD-(L)1 resistance. Both of these patients experienced target lesion reductions of –31% at their first tumor assessment.

Data on T-Cell Expansion

Vβ6 T-cell expansion in the blood increased from 7.22% at baseline to 15.7% at day 8 of treatment; Vβ6 T-cell expansion within the tumor rose from 8.85% at baseline to 14.6% at day 8. Notably, increases between baseline and day 21 were also 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%).

Expanded Safety Findings

Outside of CRS, the most common any-grade TRAEs reported in patients treated in the optimal biologic dose range included pruritus (60.9%), nausea (47.8%), chills (43.5%), vomiting (43.5%), rash (39.1%), infusion-related reaction (21.7%), arthralgia (17.4%), pyrexia (13.0%), and hypotension (8.7%). Grade 3 TRAEs outside of CRS comprised pruritus (13.0%), rash (8.7%), and arthralgia (8.7%).

Disclosures: Elez reported receiving honoraria, serving in consulting or advisory role, and being part of a speakers’ bureau for Agenus, Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cure Teq AG, GlaxoSmithKline, Hoffman La – Roche, Janssen, Johnson&Johnson, Lilly, Medscape, Merck Serono, MSD, Nordic Group BV, Novartis, Organon, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Rottapharm Biotech, Sanofi, Seagen International GmbH, Servier, and Takeda; and receiving research funding from Abbvie Deutschland Gmbh & Co KG, Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer Pharma, BeiGene, Bioncotech Therapeutics, S.L., Biontech Rna Pharmacuticals GMBH, Biontech Small Molecules GMBH, Boehringer Ingelheim, Boehringer Ingelheim de España SA, Bristol Myers Squibb International Corporation, Celgene International SARL, Dalichi Sankyo, Debiopharm International SA, Enterome BioScience SA, Exelixis, Genentech, Gercor, GSK, HalioDX SAS, Hoffmann-La Roche Ltd, Hutchinson Medipharma Limited, Hutchison MediPharma, International, lovance Biotherapeutics, Janssen Research & Development, Janssen-Cilag SA, MedImmune, Menarini, Menarini Ricerche SPA, Merck Health KGAA, Merck Sharp & Dohme de España SA, Merus NV, Mirati, Nouscom SRL, Novartis Farmacéutica SA, NuCana, Pfizer, PharmaMar SA, Pledpharma AB, Redx Pharma, Sanofi Aventis Recherche & Développement, Scandion Oncology, Seattle Genetics, Servier, Sotio A.S., Taiho Pharma USA, and Wntresearch AB.

References

1. Elez E, Garralda E, Parikh A, et al. Phase I/II clinical investigation of invikafusp alfa, a first-in-class TCR-beta chain-targeted bispecific antibody, as monotherapy in patients with anti-PD(L)1-resistant, antigen-rich gastrointestinal (GI) cancers. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 479MO.
2. A study of a selective T cell receptor (TCR) targeting, bifunctional antibody-fusion molecule STAR0602 in participants with advanced solid tumors (START-001). ClinicalTrials.gov. Updated January 30, 2025. Accessed July 2, 2025. https://clinicaltrials.gov/study/NCT05592626