Invikafusp alfa, a first-in-class dual T cell agonist, showed an objective response in various types of cancer, particularly among patients who did not respond to previous checkpoint inhibitor therapy.
Phase 2 results for Marengo Therapeutics’ first-in-class cancer-targeted bispecific antibody invikafusp alfa showed objective responses across eight tumor types, particularly among patients who had been unresponsive to other immunotherapies.
The results, which stem from a first-in-human Phase 1/2 study called Start-001 were announced Friday at the European Society for Medical Oncology conference in Madrid, showing tumor shrinkage in 56% of patients with various tumor types. These included breast, colorectal, endometrial, gastrosophageal junction, gastric, head and neck, non-small cell lung and bladder cancers, according to a company release. The study showed an 18% objective response rate and a 60% disease control rate across all patients.
Invikafusp alfa, a selective T cell agonist, activates and expands a naturally occurring group of T cells called Vβ, increasing the immune capacity for an antitumor response, Marengo CEO Zhen Su told BioSpace in an email.
“We are pioneering this biology to extend the reach of immunotherapy beyond immune checkpoint blockade, including for patients whose cancers have progressed despite these transformative treatments,” Su said, noting the “remarkable success of Keytruda” as well as the mega-blockbuster’s shortcomings, with certain patients forming a resistance to Merck’s drug over time.
The 62 patients in the study came in with heavily pretreated tumors that showed a high mutational burden. Patients who had previously received an immune checkpoint blockade drug fared better than those who had never been treated with immunotherapy, showing a 20% objective response rate versus 14%, as well as a 68% disease control rate versus 43%.
In terms of safety, the drug demonstrated manageable tolerability typically seen alongside T cell activation, with some low-grade cytokine release and no neurotoxicity.
The study was a proof of concept that activation of Vβ T cells can expand the immune response beyond what PD-1 checkpoint inhibitors like Keytruda can accomplish.
“We believe the key is the different mechanism,” Su said. “Immune checkpoint blockade releases the brakes on existing T cells, but that may not be enough when responsive T cells are too few or dysfunctional.”
Studies have shown that only 20% to 30% of cancers respond to immune checkpoint blockade drugs, with some types even more resistant than others. Marengo has shown that invikafusp alfa’s bispecific approach is effective across tumor types, including both “cold” cancers like colorectal and “hot” ones like non-small cell lung cancer, Su said.
The tissue-agnostic behavior of invikafusp alfa comes from shared immune biology of Vβ-defined T cells that are “part of the normal human immune repertoire,” Su said. He added that “Keytruda’s recent full FDA approval in TMB-high solid tumors reinforces the principle of treating cancers according to shared biology rather than organ of origin.”
Targeting cancer this way fuels what could be the next wave of innovation in oncology, Su said.
“We see the next wave as precision immunology, enabled by next-generation multispecific technologies that select which immune cell subsets to activate and coordinate the signals they receive,” Su said.
Marengo has two FDA fast track designations for invikafusp alfa and plans to take the candidate into late-stage development in 2027, Su said. Meanwhile, the Start-001 trial carries on, with a monotherapy cohort expected to read out in the second half of next year.
The company has also combined invikafusp alfa with Gilead Sciences’ breast cancer antibody-drug conjugate (ADC) Trodelvy in patients with metastatic triple-negative and HR-positive, HER2-negative forms of the disease. Early results from a Phase 2 study called Start-002 showed complete responses in heavily pretreated patients, Su said.
“Our vision is to establish invikafusp alfa as a precision immunotherapy backbone, bringing fresh T-cell responses together with the tumor-killing activity of standard treatments,” Su said. “These findings support a new dimension in immunotherapy that activates and expands fresh, diverse T-cell responses against cancer.”
