Invikafusp Alfa Plus Sacituzumab Govitecan Generates Responses in Metastatic TNBC and HR+/HER2– Breast Cancer

Treatment with the combination of the first-in-class dual T-cell agonist invikafusp alfa (STAR0602) and sacituzumab govitecan-hziy (Trodelvy) led to preliminary antitumor activity with no new safety signals in patients with pretreated metastatic triple-negative breast cancer (TNBC) or hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, according to interim data from the phase 1b/2 STARt-002 trial (NCT06827613) presented at the 2026 SITC Annual Meeting.¹

Findings showed that as of an October 16, 2026, data cutoff, the objective response rate (ORR), which included unconfirmed responses, was 28% in the TNBC cohort (n = 18) and 25% in the HR-positive/HER2-negative cohort (n = 20), with respective disease control rates (DCRs) of 67% and 80%. Among patients without prior exposure to a topoisomerase I inhibitor–based antibody-drug conjugate (ADC), the ORR was 36% in the TNBC group (n = 14) and 27% in the HR-positive/HER2-negative group (n = 15), with respective DCRs of 79% and 87%. Across both cohorts (n = 38), the DCR was 74%, and 71% of patients had any reduction in target lesions.

"This [trial] was not designed to look at the detailed efficacy in terms of objective response rate as a single-arm study. It was really just to get a sense of the preliminary activity, and indeed we saw responses [in] 25% to 28% [of patients] in both cohorts, demonstrating that the combination, as expected, showed some activity," lead study author Steven Isakoff, MD, PhD, MMSc, said in an exclusive interview with OncLive^®. Isakoff is a breast oncologist at Mass General Brigham Cancer Institute and an associate member of the Termeer Center for Targeted Therapies in Boston, Massachusetts.

What is the rationale for the combination?

Sacituzumab govitecan holds FDA-approved indications in both TNBC and HR-positive, HER2-negative breast cancer, including:²

• as a single agent for the first-line treatment of adult patients with unresectable locally advanced or metastatic TNBC who are not candidates for PD-1 or PD-L1 inhibitor-based therapy.
• in combination with pembrolizumab (Keytruda) for the first-line treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (combined positive score [CPS] ≥10), as determined by an FDA-authorized test.
• as a single agent for adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.
• as a single agent for the treatment of adult patients with unresectable locally advanced or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

Invikafusp alfa binds the Vβ6 subset of T-cell receptors and delivers an interleukin-2 molecule to those cells, selectively activating the T cells most involved in fighting tumors, Isakoff explained. Pairing the cytotoxic and potentially immunogenic cell death induced by sacituzumab govitecan, a TROP2-directed ADC, with a T-cell activator could stimulate a deeper immune response in tumors that historically derive little benefit from immunotherapy, he said.

How was STARt-002 designed?

Eligible patients had an ECOG performance status of 0 or 1, measurable disease per RECIST 1.1 criteria, and a life expectancy of at least 12 weeks.^{1 T}reated, asymptomatic central nervous system metastases were allowed. Patients with TNBC were required to have received at least 2 prior systemic therapies, including at least 1 for metastatic disease. Those with HR-positive/HER2-negative disease were required to have received prior endocrine-based therapy and at least 1 additional systemic therapy in the metastatic setting.

In the phase 1b safety run-in, patients received invikafusp alfa at 0.04 mg/kg or 0.08 mg/kg plus sacituzumab govitecan at 10 mg/kg in 21-day cycles, and 0.08 mg/kg was selected as the recommended phase 2 dose. The phase 2a portion used a Simon 2-stage design with 20 patients per cohort; both cohorts advanced to stage 2.

Primary end points were feasibility, safety, tolerability, and ORR per RECIST 1.1 and iRECIST criteria.

Of 48 enrolled patients (TNBC, n = 21; HR-positive/HER2-negative, n = 27), 86% of those with TNBC had received a prior immune checkpoint inhibitor, and 48% of those with HR-positive/HER2-negative disease had received at least 4 prior lines of metastatic therapy. Median follow-up was 3.5 months and 6.7 months, respectively.

What additional efficacy findings were reported?

In the TNBC cohort, responses among ADC-naive patients included 3 confirmed responses, comprising a complete response (CR) ongoing on treatment beyond 12 months and 2 partial responses (PRs), plus 2 unconfirmed PRs. Activity was concentrated in PD-L1–negative disease (CPS <10), where the ORR was 67% and the DCR was 83% (n = 6). Among patients with prior immunotherapy who were ADC naive, the ORR was 36% and the DCR was 91% (n = 11). No responses occurred in patients with TNBC who had received a prior topoisomerase I inhibitor–based ADC (n = 4).

In the HR-positive/HER2-negative cohort, there were 4 confirmed responses (1 CR and 3 PRs) and 1 unconfirmed PR, with responses observed in patients who were chemotherapy naive, chemotherapy pretreated, or previously treated with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), including a CR after prior T-DXd.

Translational analyses showed Vβ6-positive T-cell expansion in all 8 patients examined in cycle 1, mirroring results with invikafusp alfa monotherapy in the phase 1/2 STARt-001 trial (NCT05592626).

"We saw identical results from the pharmacodynamic studies that we saw in the monotherapy. So that was really important," Isakoff said.

What did the safety analysis show?

Because the 2 agents were not expected to have overlapping toxicities, the safety profile of the combination aligned with the known profile of each drug, with no new or unexpected toxicities and no treatment-related deaths, Isakoff noted. Among all patients (n = 48), the most common treatment-related adverse effects (TRAEs) were cytokine release syndrome (CRS; 85.4%), decreased neutrophil count (68.8%), fatigue (64.6%), and diarrhea (62.5%).

CRS was mostly grade 1 or 2 (68.8%); grade 3 CRS occurred in 16.7% of patients, with no grade 4/5 CRS. Grade 3/4 decreased neutrophil count occurred in 58.3% of patients and grade 3 diarrhea in 20.8%, which were consistent with the known sacituzumab govitecan profile. These were managed with standard supportive medications, Isakoff said. TRAEs led to discontinuation in 8.3% of patients and dose reductions in 50.0%.

What are the next steps for invikafusp alfa?

Because STARt-002 is a single-arm study, it cannot define the added benefit of invikafusp alfa over sacituzumab govitecan alone, so studies comparing the combination with standard of care are being designed, Isakoff explained.

"The ideal setting would be to identify tumor types with unmet need where immunotherapy has not been proven to be helpful, but where antibody-drug conjugates have some activity, and potentially see if this might be a way to bring immunotherapy to not just breast cancer but also other tumor types," Isakoff said.

References

1. Isakoff SJ. Initial clinical results from STARt-002: a phase 1b/2 study of invikafusp alfa, a first-in-class dual T-cell agonist, in combination with sacituzumab govitecan in triple-negative or HR+/HER2- mBC. Presented at: 2026 Society for Immunotherapy of Cancer Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract 514.
2. Trodelvy. Prescribing information.