OncLive sat down with F. Stephen Hodi, director, Melanoma Center, director, Center for Immuno-Oncology, Dana-Farber Cancer Institute, to gain further insight into combination and sequencing strategies for patients with melanoma.
F. Stephen Hodi, MD
As single agents, immune checkpoints blockers nivolumab (Opdivo) and ipilimumab (Yervoy) both have demonstrated improvements in overall survival for patients with metastatic melanoma. However, when taken together, these agents have demonstrated even more impressive findings.
Earlier reported findings from a phase I dose-escalation study demonstrated that the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab demonstrated encouraging antitumor activity. Additionally, an ongoing phase III clinical trial is assessing nivolumab or ipilimumab plus nivolumab versus ipilimumab alone in previously untreated patients with advanced melanoma (CheckMate-067; NCT01844505).
At the 2015 AACR Annual Meeting, F. Stephen Hodi, MD, presented findings from the phase II CheckMate-069 trial, further validating the efficacy seen with the combination in earlier studies and providing hints at what could be expected in the phase III trial. In this analysis, nivolumab plus ipilimumab delayed disease progression by 60% compared with 11% in patients who were given ipilimumab alone (HR = 0.40; 95% CI, 0.23-0.68; P <.001). With the combination, the ORR was 61% in BRAF wild-type (WT) patients and 52% in BRAF-positive patients.
Included in the phase II CheckMate-069 study were 142 treatment-naïve patients with advanced melanoma with a median patient age of 65 years. Patients were randomized to receive ipilimumab at 3 mg/kg with either nivolumab at 1 mg/kg (n = 95) or placebo (n = 47) every 3 weeks for four doses. This was followed by nivolumab or placebo every 2 weeks until progression or unacceptable toxicity.
Between the combination and single-agent arms, the rates of all-grade adverse events (AEs) were 91% and 93%, respectively. Grade 3/4 AEs were 54% versus 24% in the dual checkpoint versus the control arm. This led to 36 and 6 discontinuations, respectively. However, 68% of patients who discontinued the combination therapy due to AEs continued to experience CRs or PRs.
OncLive spoke with Hodi, director, Melanoma Center, director, Center for Immuno-Oncology, Dana-Farber Cancer Institute, to gain further insight into combination and sequencing strategies for patients with melanoma.
OncLive: What were the most exciting findings from the phase II CheckMate-069 trial?
Dr Hodi: We found that the patients who received the combination had a significantly higher response rate, particularly in BRAF V600 wild-type population, which had an overall 61% response rate. Patients who received the combination had a 22% complete response rate, compared to no patients in the ipilimumab arm having complete responses.
Approximately half of the patients did have grade 3/4 adverse events that were manageable in the combination arm. Even of those patients that had to stop the treatment due to toxicities, 68% continued to have either partial responses or to the therapy.
In earlier studies of this combination, PD-L1 status did not seem to impact efficacy. Did this hold true in this study as well?
Yes, the same was true in this study. When we looked at PD-L1 status in the combination arm, it did not seem to influence whether a patient responded or not.
Why is this important?
It suggests that the biomarker data that has been done before may not be important when you take these two brakes off. It helps clarify patient selection need. This combination seems to benefit patients, regardless of PD-L1 or BRAF status.
How tolerable is the combination? Does the risk benefit ratio make sense?
The toxicities were overall manageable and most could be solved with, if needed, immune-suppressive agents such as steroids. In terms of deciding if this regimen fits, we are currently waiting on more mature data, including the rest of the phase III trial comparing nivolumab and ipilimumab to ipilimumab alone and nivolumab alone. If the high response rate is worth the side effects, that is a question that will need to be considered further—if and when this becomes available for patients.
How do you see PD-1 inhibitors being sequenced or used in combination with BRAF and MEK inhibitors?
There is a sequence trial that examined ipilimumab followed by nivolumab and vice versa for the other half of the patients. This will gather that information, and our phase III trial will also get us that information. I think once we get that data, it will have to be put into context with the phase I/II trials that are combining immune checkpoints with targeted therapies for BRAF. We need a little bit more mature data to really be able to answer that question.
Considering this and other studies with PD-1 and CTLA-4, how do you envision the treatment for melanoma in five years?
It will likely be all about combinations: immunotherapy combinations or targeted combinations. We will also be figuring out the sequencing of those combinations; this will need to be worked out. Our study, in a blinded randomized fashion, confirms that the two checkpoints together had a high response rate. Even now, we can begin qualifying and quantifying patients in terms of complete responses.
What can a clinical oncologist take away from the CheckMate-069 study?
This is a regimen that will likely be considered in the future, so we need to educate each other and be aware of the side effects that could potentially happen. We need to have good communication with our patients, so that their side effects can be managed effectively and efficiently.