Jason J. Luke, MD, FACP
The development of agents targeting the PD-1 immune checkpoint in the treatment of patients with advanced melanoma is progressing rapidly, with optimal sequencing and combinations emerging as the most pressing questions that researchers are seeking to answer in ongoing clinical trials, according to Jason J. Luke, MD, FACP.
Luke believes the recently approved anti-PD-1 monoclonal antibodies nivolumab (Opdivo) and pembrolizumab (Keytruda) will move quickly from second-line to frontline settings. Both agents currently are indicated for patients with unresectable or metastatic melanoma whose disease has progressed after treatment with the CTLA-4 inhibitor ipilimumab (Yervoy) and who are not candidates for drugs targeted at BRAF
sat down with Luke, an assistant professor of Medicine in the Melanoma and Developmental Therapeutics Clinic at the University of Chicago, to discuss the clinical implications of these immunotherapies during the 11th Annual International Symposium on Melanoma and Other Cutaneous Malignancies. Physicians’ Education Resource (PER) hosted the conference on March 7 in Miami.OncLive: What impact do the approvals of pembrolizumab and nivolumab have on the treatment paradigm for melanoma?Dr Luke:
The approval of PD-1 agents is highly exciting. Put it in a historical perspective where, before 2011, median life expectancy was only 9 to 12 months. We now have six or seven drugs or combinations approved. PD-1 agents are exciting because response rates are over 40% in melanoma, and there is the potential for long-term survival.
The question now becomes: What line of therapy is most appropriate? Currently, the FDA label indication is in second-line therapy after ipilimumab or a BRAF inhibitor if the patient is BRAF
-mutant. There is a lot of debate in the field on whether that is the appropriate indication. Ongoing clinical trials are likely to modify it; there are several phase III trials comparing PD-1 agents with ipilimumab. I think all of us believe that, very quickly, PD-1 antibodies will transition to frontline therapy.
The question will become: Is that enough, or will combinations of CTLA-4 and PD-1 be even better? We have to include the caveat that there appears to be more toxicity, but there are a number of other molecules in development as well that could be combined with PD-1. It is unlikely the current indication will be the case a year from now, and it’s very unknown what the case will be two years from now. Hopefully, there will be something even better.Do the adverse events differ between ipilimumab and PD-1 agents and, if so, are they managed differently?
Qualitatively, the answer is no. They are the same adverse events. Quantitatively, the answer is absolutely yes. With CTLA-4 antibodies, up to 30% of patients may have worrisome or high-grade events; in clinical trials those are more at 10% to 20%, although in clinical practice we see that high-grade adverse events might be somewhat higher.
With PD-1 antibodies, however, the rates of high-grade toxicity are much lower at about 10%. Though the adverse events are the same adverse events, which can be rash, dermatitis, colitis, and pneumonitis, they don’t happen nearly as often. The management of them is the same, and the take-home point is to be aware that there are signs of side effects, and try to get on them very quickly. Adverse events will escalate if they are not managed properly.Please discuss sequencing considerations in using ipilimumab, followed by a PD-1 inhibitor, as the labels for the new PD-1 agents indicate.
This is an area of controversy. The FDA approval indicates that ipilimumab should be given as frontline therapy, followed by a PD-1 antibody. Which approach is the best is sort of a moot point at the current time in clinical practice, in that we’re essentially required to give ipilimumab first.
It is worth noting that the NCCN has already suggested that consideration of frontline treatment with anti-PD-1 is appropriate. Whether or not payers will agree with that, given the growing and astronomical cost of these agents, is a wholly separate issue. Based on what we have seen in clinics, I would think most investigators in the field believe that PD-1 antibodies deserve to be frontline treatment already. Clinical trials will help us to understand whether or not you should give ipilimumab first. Those clinical trials actually are ongoing and accrued; we just don’t have the results yet. This is an area where we are just at the beginning.You explored ipilimumab’s mechanism of action and recently published a case report detailing the antitumor responses and toxicities experienced by a 61-year-old woman with unresectable metastatic melanoma who underwent treatment (J Clin Oncol. 2015;33(6):e32-35). Can you elaborate on your findings?