Ipilimumab improves survival in metastatic melanoma

For decades, metastatic melanoma carried a median survival measured in months, and no drug had moved that number in a randomized trial. Dacarbazine had been a standard agent since the 1970s, producing response rates around 15% with no demonstrated survival benefit. Interleukin-2 worked in a small fraction of patients but carried severe toxicity. By the late 2000s, oncologists treating stage IV disease had little to offer beyond enrollment in trials.

The drug that finally did so worked by releasing a brake on the immune system. James Allison's laboratory at the University of California, Berkeley had spent years studying CTLA-4, a protein expressed on activated T cells that dampens their response. His group first tried blocking CTLA-4 with an antibody in mice with tumors at the end of 1994, cured them, and published the result in Science in 1996. Ipilimumab, an antibody against CTLA-4, was developed for patients by Medarex and Bristol-Myers Squibb.

The 2010 phase 3 trial, led by F. Stephen Hodi at Dana-Farber Cancer Institute, enrolled 676 patients who had progressed on prior therapy and randomly assigned them to ipilimumab alone, ipilimumab plus an experimental gp100 peptide vaccine, or vaccine alone. Median overall survival reached 10.1 months in the ipilimumab monotherapy arm versus 6.4 months in the vaccine-only arm. The result that drew most attention came later: a 2015 pooled analysis of 1,861 patients from 12 studies found that the survival curve flattened at about three years, with 22% of patients alive at that point.

The trial also introduced oncologists to a class of toxicities they had not managed before. Immune-related adverse events, including colitis, hepatitis, dermatitis, and hypophysitis, required prompt recognition and corticosteroid treatment. Managing these events became a required competency in oncology, and guidelines for immune-mediated toxicity were developed across specialties. In the 2010 trial, grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients given ipilimumab, and 7 of the 14 deaths related to the study drugs were immune-related. Steven O'Day was second author of the report.

The FDA approved ipilimumab on March 25, 2011. The finding that CTLA-4 was a workable target showed that immune checkpoint blockade could help patients, and it was not long before the PD-1 pathway yielded a second class of agents with higher response rates and a better tolerability profile. Allison shared the 2018 Nobel Prize in Physiology or Medicine with Tasuku Honjo. In the CheckMate 067 trial in previously untreated advanced melanoma, reported in 2017, 3-year survival was 58% with nivolumab plus ipilimumab and 34% with ipilimumab alone.