Jeffrey S. Weber, MD, PhD
A standard course of the immunotherapy ipilimumab (Yervoy) is well defined and, to many patients with melanoma, surprisingly short: just 4 infusions given at 3-week intervals. That’s enough to provide lasting benefit to most responders and, if the benefit fades from lack of treatment, a second round of 4 infusions will often bring it back.
There is some evidence that relatively short treatment courses might also be appropriate for the other 3 checkpoint inhibitors approved for treating some cancers, but the data are fairly sparse. The relatively mild adverse effect profiles of those newer antibodies obviated any need to minimize treatment times for most patients, so trials have typically treated patients for as long as they seemed to benefit and avoided any comparisons of different durations of therapy. There is also very little published information about responsive patients who discontinue treatment, see their conditions deteriorate, and then reinitiate treatment.
This is, to some degree, a product of time. Nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq) are still new drugs. Hundreds of additional trials are underway and many more are at various stages of planning. These studies will provide far more information about all 3 antibodies, including information about initial responders who stop and then restart treatment. At least 1 of them—a trial designed to determine whether it’s safe to stop nivolumab after 1 year—will even provide some comparative data on treatment duration. There are, however, no plans for trials that would establish optimal treatment times for each medication with any degree of certainty.
“There are certainly indications that relatively short treatments may provide as much benefit as longer treatments, at least for many patients. For example, some trial patients who respond to these medications but stop taking them because of adverse effects seem to fare about as well as patients who undergo the full duration of scheduled therapy on protocols,” said Jeffrey S. Weber, MD, PhD, a prolific immunotherapy investigator who is deputy director of the Perlmutter Cancer Center at NYU Langone Medical Center.
“Indications aren’t proof, though. A trial that definitively compared outcomes among patients receiving treatments lasting, say, 6 months, 1 year, and 2 years could require thousands of subjects. Such trials may eventually be done by cooperative groups, but there is certainly no incentive for the companies that used ongoing treatments to gain their approvals to spend untold millions proving that 6-month treatments work just as well.”
T cells that fight disease are covered with receptors that help them distinguish normal cells from foreign invaders. They also have inhibitory receptors that check T-cell action and prevent the immune response from spiraling out of control. Among the most important of these receptors are programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4).
When T cells encounter normal human cells, PD-1 binds with the programmed death receptor-ligand-1 (PD-L1) that’s expressed on the outside of healthy human cells, and that connection signals the T cell to stand down. When T cells encounter cells that lack PD-L1, they attack and call other T cells for backup. Many tumors evade that immune response, presumably because they express some PD-L1 and thus convince T cells to accept them as normal. Both nivolumab and pembrolizumab are anti- PD-1 antibodies that encourage the immune system to attack cancer by preventing receptors on T cells from binding with ligands on tumors. Atezolizumab works on tumors and other immune cells rather than T cells, blocking the ligands to prevent them from binding with the PD-1 on the T cells. Ipilimumab works in a broadly similar way. It attaches itself to CTLA-4 on the surface of T cells and prevents CD80 or CD86 ligands on other cells (though not usually tumor cells) from binding with the CTLA-4 and inhibiting T-cell activation and proliferation. This blockade of the CTLA-4 signaling pathway can also reduce T-regulatory cell function and (it is thought) increase T-cell response to tumors and other perceived threats.
A number of clinical trials of ipilimumab have supplemented the 4-infusion course of treatment with maintenance doses, administered every 12 weeks for various durations. Most such trials gave maintenance to all ipilimumab patients, but a few of them have randomized ipilimumab patients between genuine maintenance and placebo. Investigators continue to follow outcomes in several cases, but results to date have yet to show any significant benefit to ongoing ipilimumab.