NEW YORK – Marengo Therapeutics' bispecific antibody, invikafusp alfa, showed potential as treatment for certain cancer patients who have become resistant to checkpoint inhibitors in an early-phase study.
James Gulley, the codirector of the Center for Immuno-Oncology at the US National Cancer Institute's Center for Cancer Research, presented results from the first-in-human Phase I/II clinical trial of invikafusp alfa, also called STAR0602, during the Society for Immunotherapy of Cancer's annual meeting on Saturday. "This … data validates a new class of selective TCR Vβ dual T-cell agonists," he said.
Marengo is developing the T-cell receptor (TCR) beta chain-targeting bispecific antibody for treating antigen-rich solid tumors. The antibody is designed with two arms, one that binds to the TCRs Vβ6 and Vβ10 and the other to wildtype interleukin 2 (IL2). "It has two 'go signals' for the T cell," Gulley said during his SITC presentation. In preclinical studies, invikafusp alfa reinvigorated the Vβ tumor-infiltrating lymphocytes and showed promising anti-tumor activity.
In humans, Gulley explained, between 10 percent and 12 percent of the TILs within tumors are Vβ6 or Vβ10, comprising the highest proportion of Vβ expression across thousands of TILs. "It's likely that, within those TILs, you're going to have a few that have shots on goal with a good TCR," he said.
The START-001 trial was designed to focus specifically on patients with antigen-rich tumors, such as TMB-high or virus-associated tumors. Patients were eligible to enroll in the trial if their tumors fell into either of these two categories.
In the Phase I portion of the trial, Marengo aimed to investigate invikafusp alfa's pharmacology and safety and establish a recommended Phase II dose. Investigators also tracked early signs of clinical efficacy, such as disease control rate and overall response rate.
At the meeting, Gulley shared the experience of 28 patients who received the bispecific antibody in the Phase I portion of the trial, though Marengo is already enrolling patients into the Phase II portion. Based on the Phase I results, the Phase II expansion portion will enroll three cohorts: a tissue-agnostic cohort for patients whose tumors are TMB-high; a tissue-agnostic cohort for patients whose tumors are microsatellite instability (MSI)-high; and a cohort of colorectal cancer patients with TMB-high, MSI-high, or DNA mismatch repair-positive tumors.
The 28 patients in the Phase I portion had 16 different tumor types. Half of these patients had received four or more prior lines of therapy, and the vast majority had received anti-PD-1 or anti PD-L1 immunotherapy. About half of these patients had TMB-high cancers, and half had virus-associated cancers. Two patients had MSI-high cancers.
After receiving invikafusp alfa monotherapy, Gulley noted, these patients had a dose-related expansion of peripheral Vβ6 and Vβ10 T cells. At a dose of 0.08 milligrams per kilogram, there was about a 600 percent increase in the expansion of patients' CD8-positive Vβ6 and Vβ10 T cells and about a 200 percent increase in the expansion of CD4-positive Vβ6 and Vβ10 T cells.
The disease control rate, which comprises complete and partial responses and stable disease, was 50 percent. In comparison, when patients received anti-PD-1 or -PD-L1 checkpoint inhibitors before this trial, their disease control rate with those immunotherapies had been 32 percent.
Twenty-five percent of patients experienced any tumor shrinkage, though none had a complete response. One patient remained on the bispecific antibody for more than 15 months.
The bispecific antibody's safety profile was "really consistent with the mechanism of action," Gulley noted. None of the patients experienced immune effector cell-associated neurotoxicity syndrome or grade 4 cytokine release syndrome, and none required prophylactic steroids.
Biomarker-enriched populations
Among patients with TMB-high, anti-PD-1-resistant tumors who received the optimal dose range of 0.08 mg/kg and 0.12 mg/kg, the disease control rate was 63 percent, and half of the patients experienced tumor shrinkage. The objective response rate was 25 percent.
Gulley detailed the experience of two patients who responded particularly well to invikafusp alfa. The first patient was a 46-year-old White female with metastatic colorectal cancer who had received six lines of prior therapy, including an anti-PD-1 treatment. Her cancer was classified as TMB-high, defined at a threshold of 10 mutations per megabase, microsatellite stable, and RAS wildtype.
This patient received an invikafusp alfa dose of 0.08 mg/kg as her seventh line of therapy. After nine months on the investigational agent, the target lesions in her metastatic lung cancer substantially decreased by 58 percent. "This was a rapid, deep, and durable response," Gulley said.
Another patient, a 59-year-old White female with TMB-high, microsatellite-stable metastatic colorectal cancer, had received six prior lines of therapy, none of which were anti-PD-1 or -PD-L1 checkpoint inhibitors. This patient also had a tumor with high TMB, and her tumor also had a KRAS G12D mutation. After receiving a 0.12 mg/kg dose of invikafusp alfa, her skin metastases shrunk by 39 percent and her lung metastases either shrank in size or completely disappeared.
"We have opportunities to learn from this Phase I dose-escalation" portion of the trial, Gulley said. Next, the investigators are homing in on patients who experienced initial clinical activity and enrolling them across the three biomarker-selected cohorts. Marengo's primary goal in the Phase II portion is to evaluate patients' objective response rates on invikafusp alfa.
"The single-agent activity observed in Phase I, especially in PD-1-resistant cold tumors such as colorectal cancer, is a critical milestone," Marengo CEO Zhen Su said in a statement. "We look forward to further exploring the potential of STAR0602 to become a next-generation backbone immune-oncology therapy across a range of tumor types."
Gulley also floated the possibility of moving invikafusp alfa into earlier lines of therapy, or potentially combining it with other treatments, to improve response rates going forward.
"There are many reasons why some people have responses and some don't," he said during a SITC press conference. "It's really nice to have single-agent activity, [but] I am guessing that, with combination approaches and approaches in earlier-line patients who haven't progressed despite PD-1 or PD-L1 therapy, we may see more patients responding."