Early results of the first clinical trial (link is external) to evaluate the drug invikafusp alfa (invika) in humans indicate that the pioneering treatment may be capable of managing cancers that have rebuffed most other interventions, including standard immunotherapy. A study led by researchers at the National Institutes of Health (NIH), Mass General Brigham and Memorial Sloan Kettering found that, at optimal doses, invika was well tolerated and, in patients whose solid tumors had resisted standard immunotherapy, halted disease progression in most and shrank tumors in some.
"Patients whose tumors are advanced - particularly tumors that don't respond well to immunotherapy - often have their backs against a wall. Few options remain once you reach that point, but these results highlight a more precise means of stimulating anti-tumor immunity that could provide another solution," said co-corresponding author James Gulley, M.D., Ph.D., clinical director at the Center for Cancer Research (CCR), part of NIH's National Cancer Institute (NCI).
While immunotherapies have already transformed treatment for several cancers, many patients benefit from them for only a short time, or not at all. Tumors frequently adapt to immune checkpoint blockade (ICB) therapies, such as pembrolizumab, limiting long-term benefits. Other strategies aim to rally T cells, the frontline soldiers of adaptive immunity, but usually do so indiscriminately, commonly leading to severe side effects.
Scientists designed the protein invika to engage a small subset of T cells, two groups of tumor-infiltrating lymphocytes specifically. By activating only this narrow population rather than T cells broadly, invika is designed to drive anti-tumor activity while avoiding the severe side effects that less selective approaches can cause. Preclinical studies also conducted at CCR indicate that the drug hits its intended marks and stimulates anti-tumor activity in animal models (link is external). This new study describes the next step for invika, detailing the results of phase 1 and initial phase 2 experiments in humans.
The researchers leading the trial recruited patients with a wide variety of cancers, the majority of which had not responded well to ICB. In phase 1, they treated study participants with varying dosages of invika every two weeks to evaluate the drug's safety and determine the optimal dose. While several participants experienced flu-like side effects, these were expected and generally manageable with additional medication and supportive care. After identifying the lowest dose at which desired effects peaked, the researchers advanced to phase 2, treating participants at this optimal dose.
Of the 27 participants treated with the optimal dose across both phases, disease did not progress in 16 (59.3%) of them. Four (14.8%) participants experienced greater than 30% decreases in the size of targeted tumors, two of whom had metastatic colorectal cancer with tumors of a notoriously treatment-resistant type and were receiving invika as their seventh-line therapy. Another responsive participant had stage 4 non-small cell lung cancer, again with tumors that had repelled multiple therapies including ICB. In participants receiving non-optimal levels, invika did not appear to have significant benefit.
In these patients, the study authors found that the drug fostered growth in the target T-cell populations without affecting any other T cells. They linked the four instances of tumor reduction to the largest shifts in target populations, though, as the authors expected at this early stage, immune activity alone did not always produce a measurable clinical response.
"These results are early, and although signs of immune activity don't always translate into benefit to patients at this stage, it is new and exciting to see activity in patients whose cancers had stopped responding to immunotherapy - a group of people with very few options left," said co-first author Nicholas Tschernia, M.D., a physician-scientist early investigator in the CCR at NCI. "These findings give us a reason to keep studying this new type of immunotherapy, particularly by combining it with other cancer treatments to continue to seek improved results."
The treatment sponsor, Marengo Therapeutics, previously announced (link is external) that the U.S. Food and Drug Administration (FDA) granted a Fast Track designation to invika to accelerate its evaluation as a treatment for antigen-rich, metastatic colorectal cancer. More recently, FDA has granted the same designation to invika for similar solid tumors, regardless of tissue type, following prior therapy including checkpoint inhibitors.
