Wolchok Discusses Frontline Nivolumab/Ipilimumab Combo in Melanoma

Jedd D. Wolchok, MD, discusses the unique design and goals of the CheckMate-067 trial, and what its results mean for patients with advanced melanoma going forward.

Jedd D. Wolchok, MD, PhD

Phase III results from the CheckMate-067 trial presented at the 2015 ASCO Annual Meeting demonstrated that the combination of nivolumab (Opdivo) with ipilimumab (Yervoy) reduced the risk of disease progression by 58% and 26% compared with single-agent ipilimumab and nivolumab, respectively, in patients with advanced melanoma.

Median progression-free survival (PFS) with nivolumab/ipilimumab was 11.5 months versus 2.9 months with ipilimumab alone (HR = 0.42; 95% CI, 0.31-0.57; P <.00001), after at least 9 months’ follow-up. In the study, single-agent nivolumab also significantly delayed disease progression, with a median PFS of 6.9 months, versus ipilimumab monotherapy (HR = 0.57; 95% CI, 0.43-0.76; P <.00001).

Overall survival (OS) was 57.6% in the combination arm and 43.7% in the nivolumab arm, compared with 19% in the ipilimumab arm.

OncLive spoke with lead study author Jedd D. Wolchok, MD, chief of the Melanoma and Immunotherapeutics Service, Lloyd J. Old Chair for Clinical Investigation, Memorial Sloan Kettering Cancer Center, to learn more about the unique design and goals of the CheckMate-067 trial, and what its results mean for patients with advanced melanoma going forward.

OncLive: What is the significance of the CheckMate-067 trial?

Dr Wolchok: This phase III trial, CheckMate-067, was designed based on results from a phase I trial. At the 2012 ASCO Annual Meeting, before the phase I trial had ever been publically presented, we knew that this combination would have higher activity than anyone expected.

In a midnight meeting in the lobby of the Swissotel Chicago, two of my fellows at the time, along with a former fellow and myself, sketched out our dream trial. That dream trial would accomplish several goals. It would be a way to evaluate ipilimumab against nivolumab head-to-head, and then also evaluate the combination against two prospective contemporary cohorts receiving the monotherapy. We thought we would be able to answer multiple questions at the same time. That trial was designed just 3 years ago, the phase I data were presented at ASCO 2 years ago, and the phase III data was presented at the 2015 ASCO Annual Meeting.

What does it say about the interest in these drugs that the trial process moved so quickly?

It is a very strong indication of how quickly the field is accelerating. It demonstrates a very strong commitment by the investigators and the sponsor, as well, as to find the best treatment as quickly as possible. Metastatic melanoma is not a very common disease, so being able to accrue a 945-patient trial in 1.5 years, to have available data, to have patients safely treated, and to have no treatment-related deaths is truly an outstanding accomplishment.

How were you able to accomplish this?

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.

What did you learn from this trial regarding which patients would be the best candidates for ipilimumab alone, nivolumab alone, or the combination?

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.

As patients try and make decisions, they need to be based on their frailness, comorbidities, and performance status. For the first time, we have all the information to be able to guide that. We can start to take a precision approach for the first time in immunotherapy. If a robust, young person wants the treatment that has the highest response rate, that would be the combination therapy. The trial wasn’t designed to measure that, so we can’t put a P value on it, but that is what the data say.

What are the side effects of the combination therapy?

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.

Now that we have this data, what is the role for ipilimumab in melanoma?

I think it still has a place. It will be used as part of this combination. There are patients that are being treated with PD-1 blockade alone who have never had ipilimumab, and if they don’t have an adequate response or they have a reoccurrence, ipilimumab alone would be a rational choice. We have seen patients who have received either nivolumab or pembrolizumab who have progressed and then responded to ipilimumab, so I think it continues to have a role.