The treatment of patients with metastatic melanoma has undergone a dramatic transformation since the approval of the CTLA-4 inhibitor ipilimumab in 2011.
Jedd Wolchok, MD, PhD
The treatment of patients with metastatic melanoma has undergone a dramatic transformation since the approval of the CTLA-4 inhibitor ipilimumab (Yervoy) in 2011. After this breakthrough, BRAF/MEK targeted therapies were approved followed by the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo). Now, combination approaches are looking to further capitalize on these novel agents.
To gain further insight,Targeted Oncologyinterviewed Jedd D. Wolchok, MD, who has been instrumental in the development of the immune checkpoint inhibitors. Wolchok, chief of the Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, was the primary investigator on the phase III CheckMate-067 trial, which showed that frontline nivolumab as monotherapy and in combination with ipilimumab more than doubled progression-free survival (PFS) versus ipilimumab alone in patients with advanced melanoma (Click here, to view more from this trial >>>).Wolchok: The phase I trial included multiple different dose levels, so we were literally exploring, in real time, what the best way to deliver this combination was. We were making decisions admittedly based on modestly sized cohorts of patients, but looking back, the decisions we made on how to design this trial were correct. We saw a very good balance between safety and efficacy.
Now, we can’t forget that there were 55% of patients receiving this combination that had a grade 3 or 4 adverse event, and that has been consistent throughout the trials. However, the fact that we were able to deliver this therapy in 127 sites globally to 945 patients, one-third of who received the combination with no treatment-related deaths, was very important to me. It showed that we could strike a good safety and efficacy balance.
In that combination cohort, we saw the highest response rates and the longest PFS and no drug-related deaths. Interestingly and clearly, the rules we made about when to stop treatment were good rules. We saw that in the patients who stopped treatment with the combination, which was about 37%, 67.5% of those patients had an objective response, and half of those developed that response after they stopped treatment.The side effect profile was very consistent with what we saw in the phase I and phase II trials. There were no treatment-related deaths due to the combination; there was one treatment-related death associated with each of the monotherapies. There were no signature side effects for the combination; there was nothing there that we hadn’t seen before with each of the monotherapies.
It is important to note that these patients need to be followed carefully. Fifty-five percent of patients treated with the combination will have a grade 3 or 4 adverse event, so we need to pay attention to that. More than one-third of the patients treated with the combination will have to stop treatment because of the side effects, but those patients have almost a 68% response rate. Half of those responses occur after they stop treatment.
For any individual patients, we don’t know how much treatment they will need, but we do know how to apply it safely. The idea that more drugs for a longer time equals better response is not necessarily true for immunotherapy. You have to get a patient’s immune system to the point where they can fight the tumor; toxicities can tell you when that is achieved.For the first time, the availability of the PD-L1 data really allowed us to think about having meaningful discussions with our patients on what treatment is best for them based on an assessment of risk and benefit. For example, if a patient comes in and they have a tumor with greater than 5% PD-L1 expression, and they are frail and have comorbidities, we can reassure those patients that their PFS as an early term endpoint would be the same, whether or not they received nivolumab alone or the combination.
We recognize that, as a near-term endpoint, the most important results will be OS. We can also tell patients that, regardless of PD-L1 status, the combination has the highest response rate.