From Pages to Practice
Cancer therapy continues to evolve, with the most drastic advances during the past century and even decade. The first leap came with the discovery of nonspecific anti-proliferative chemotherapeutics and radiation therapy in the 1940s through 1960s. Although these therapies improved survival, they were associated with off-target effects on nonmalignant proliferating cells. In the 1990s and early 2000s, we started to employ agents that target mutant proteins that are specifically expressed by the cancer cells, allowing better targeting of the tumors. However, these therapies were plagued by mutations that led to treatment resistance and relapse. Finally, during the last decade, immune modulation therapy entered the scene and completely changed management of multiple types of cancer, including melanoma.
Previous studies have shown that immune modulation therapies, such as nivolumab — a monoclonal antibody against programmed death 1 (PD-1) — or ipilimumab — a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) — prolong survival in patients with melanoma. Based on lessons learned from successes with antibiotics, antiviral agents, and cancer chemotherapy, researchers have explored whether combination immune modulation therapy is more effective than monotherapy.
In this week’s issue of the NEJM, Wolchok et al. report 3-year overall survival rates from the CheckMate 067 trial. This prospective trial randomized approximately 1000 patients across more than 20 countries to receive nivolumab plus ipilimumab, nivolumab and placebo, or ipilimumab and placebo. At the 3-year follow-up, the overall survival rate was 58% in the combination-therapy group versus 52% in the nivolumab-alone group and 34% in the ipilimumab-alone group. Thus, combination therapy (nivolumab plus ipilimumab) and nivolumab alone were associated with significantly longer survival than ipilimumab alone. The study was not designed to compare the two nivolumab groups, but the results favored combination therapy over nivolumab alone.
However, the survival benefits came at a cost: Combination therapy was associated with higher rates of adverse events than either treatment alone: 59% of patients in the combination group had grade 3 or 4 treatment-related adverse events versus 21% in the nivolumab group and 28% in the ipilimumab group. Most were gastrointestinal events that resolved within 3 to 4 weeks.
Overall, these results hint that a combination of immune modulator therapies can offer some survival benefit in melanoma patients, but at the cost of more adverse treatment-related events. Further study is needed to decipher whether combination therapy is truly superior to nivolumab alone. Once the success of immune modulation therapy is established, perhaps the next wave of advancement will involve combinations of immune modulators and molecular targeted therapies.