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FDA Approves Nivolumab for Some Metastatic Colorectal Cancers

, by NCI Staff

FDA has approved nivolumab for some patients with metastatic colorectal cancer whose tumors have genetic alterations that impair their ability to repair mistakes in DNA replication.

Credit: National Institutes of Health

On July 31, the Food and Drug Administration (FDA) granted accelerated approval to the immunotherapy drug nivolumab (Opdivo®)® for patients with metastatic colorectal cancer that has one of two specific genetic features and whose disease has progressed after chemotherapy.

These genetic features are called high microsatellite instability (MSI-H) and DNA mismatch repair deficiency (dMMR). Because tumor cells with these features tend to have more genetic mutations than tumor cells without them, they are more likely to be recognized by the immune system. This makes tumors with these features promising targets for immunotherapies like nivolumab, which encourage the immune system to attack cancer cells.

In the phase II clinical trial that led to the accelerated approval, 28% of patients treated with nivolumab experienced an objective response to treatment: their tumors shrank, as measured by regular imaging scans. One of the trial participants had a complete response.

Although fewer than one-third of the 74 participants in the trial responded to treatment, Zev Wainberg, M.D., co-director of the Gastrointestinal Oncology Program at the University of California, Los Angeles, who was not involved in the trial, said the results are encouraging because the responses seen “were durable, and with fewer side effects than seen with conventional treatments.”

Lasting Treatment Responses with Nivolumab

The trial, called CheckMate 142, is still ongoing, and is testing nivolumab alone or in combination with other drugs. The 74 patients who received nivolumab alone had previously undergone at least one standard treatment regimen. During the trial they received nivolumab as an infusion every 2 weeks until their tumors progressed or until they experienced unacceptable side effects or died.

At a median of 12 months of follow-up, all participants who had responded to nivolumab remained alive. Of the responders, 86% had treatment responses that lasted a year or longer.

Twenty percent of patients treated with nivolumab experienced serious side effects, most commonly increases in enzyme levels that indicate possible damage to the pancreas. Five participants discontinued treatment because of side effects.

Common low-grade side effects included fatigue, rash, musculoskeletal pain, and gastrointestinal side effects. Some worsening of cognitive functioning was seen in patients who received the drug for more than a year.

Coaxing a Broader Immune Response

Although the results were encouraging, in general “a single agent won’t be sufficient to get most [colorectal] tumors to respond,” said Dr. Wainberg.

More and more, immunotherapy drugs are being studied in combination, he explained. In some studies, they are being combined with other immune-based treatments, including therapeutic vaccines and CAR T-cells, with the aim of manipulating the immune system in two different ways at once to improve the response rate.

Patients currently being enrolled onto the CheckMate 142 trial, for example, may receive nivolumab in combination with one or more other drugs, including ipilimumab (Yervoy®) and daratumumab (Darzalex®)®.

Using immunotherapy drugs in combination might also have the potential to increase the number of different colorectal cancer subtypes that respond to treatment, Dr. Wainberg added.

MSI-H/dMMR tumors make up only about 5% of all metastatic colorectal cancers. For other subtypes less responsive to immunotherapy, he continued, one of the main focuses of research is how to turn these “cold” tumors, where immune cells aren’t getting to the tumors sufficiently or aren’t recognizing the tumors, into “hot” tumors that are infiltrated by immune cells and for in which immunotherapy is more likely to work.

“We are hopeful this will be the way forward [for immunotherapy],” he concluded.

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