PD-1 Inhibition Requires Further Refinement in Melanoma

Suzanne L. Topalian, MD

The PD-1 inhibitor nivolumab (Opdivo) has progressed rapidly through clinical development, with an FDA approval for patients with metastatic melanoma just 2.5 years following the initial announcement of results at the 2012 ASCO Annual Meeting.

Findings from this initial study and subsequent long-term analyses were published by Suzanne L. Topalian, MD, director of the Melanoma Program at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. In this 107-patient study, the overall survival (OS) benefit in nivolumab-treated patients was 16.8 months, with a 2-year OS rate of 43%. The estimated duration of response was 2 years.

Since 2012, a number of phase III trials have also reported top-line results. In December 2014, the FDA approved nivolumab based on a 120-patient, single-arm interim analysis of the phase III CheckMate-037 trial. This study looked specifically at treatment with nivolumab in patients who were previously treated with ipilimumab (Yervoy) and a BRAF inhibitor, if BRAF-positive. The overall response rate with nivolumab was 32%.

In a second phase III study, labeled CheckMate-066, that was published by Robert et al, treatment with nivolumab improved OS and progression-free survival (PFS) compared with dacarbazine. This study enrolled 418 previously untreated patients with advanced melanoma. The 1-year OS rate was 72.9% with nivolumab versus 42.1% with chemotherapy (HR = 0.42; P <.001). The median PFS was 5.1 versus 2.2 months, for nivolumab and dacarbazine, respectively.

In an interview with OncLive, Topalian discussed the rapid advance of nivolumab and potential next-steps.

OncLive: What has longer follow-up told us about treatment with nivolumab?

Topalian: In the long-term follow-up study we showed that many of the responses we saw in patients with advanced melanoma being treated with nivolumab were quite durable. We also found that even after we stopped administering the drug to patients, those who were in response remained in response for a very long time.

When we looked at the long-term safety profile, what we found was that the side effects of nivolumab did not tend to accumulate over the two-year observation period. It seemed as if patients who did develop side effects were more likely to develop side effects within the first 6 months of treatment. Overall, the safety profile of the drug was very favorable.

Taking all of this together, we were encouraged to conduct the phase III trials in melanoma. Caroline Robert, MD, PhD, and colleagues have recently published some of the phase III study results in The New England Journal of Medicine. This study was a first-line international study with several hundred patients who either received nivolumab or standard chemotherapy.

What the study showed was that there was a significant improvement in overall survival in the patients receiving anti—PD-1 treatment. These are very exciting results. There’s a lot of promise for this drug in the first-line as well as in the second-line and higher in melanoma.

Do you see nivolumab being used in earlier settings?

So far, this drug has only been tested in patients with advanced metastatic melanoma, but of course we’re now thinking about whether it should be applied in earlier stages of disease, such as in the adjuvant setting or even the neoadjuvant setting. This will be the subject of future clinical trials—to see if the drug can provide any benefit to patients in those situations.

What combination strategies are being explored?

We are seeing durable tumor regression in a percentage of patients with melanoma, kidney cancer, lung cancer, and now bladder cancer and Hodgkins disease. But in most cases, we are still not helping about 50% of the patients. We now need to think about what is needed to get more complete responses and to see a higher percentage of patients responding to these drugs.

Combination treatment regimens are now front and center as what we feel is the most reasonable approach, and the one that is most likely to yield results to improve on what we already have. Ipilimumab combined with nivolumab is one such combination. It’s combining two different immune modulators that in a report by Wolchok et al in 2013, showed a reasonably high response rate but also a fairly high rate of serious side effects.

I’m sure that there are ways to improve upon that regimen. Different doses and sequencing are being looked at and I’m sure that this isn’t the only combination that we’re going to be hearing about in the near future.

Where does research currently stand with the discovery of a biomarker for anti—PD-1 therapies?

The PD-1 and PD-L1 blocking drugs are most active at the tumor site. This makes them very different from anti—CTLA-4 agents like ipilimumab, which has a global impact on the immune response. For the PD-1 drugs, when we’re looking for markers to help us select patients who might be more likely to respond—or even if we’re looking for other molecules that we should be co-targeting in combination regimens&mdash;we look in the tumor itself for factors that correlate with clinical outcomes.

We published early evidence showing that there was a relationship between the tumor’s expression of PD-L1 and response to anti—PD-1 therapy. PD-L1 is the binding partner for PD-1, which is expressed on activated T cells.

This marker, PD-L1, did not seem to predict responses when anti—PD-1 was combined with ipilimumab, but we might not really expect it to because ipilimumab has a global impact on the immune system and PD-L1 might not be relevant to ipilimumab. This hopefully gives you an idea of the complexity of our challenge, as we try to find markers to help us refine these treatments.

When you presented initial findings in 2012, did you expect such rapid advancement?

In 2012, we knew that we had exciting and reproducible results not only in melanoma but also in kidney and lung cancer. But I have to say, the rapid pace and the number of other anti—PD-1 and anti–PD-L1 drugs that have come into clinical testing and the pace of discovery and clinical development have really exceeded my expectations. It’s great for patients and the field.

What does the future hold for immunotherapies in melanoma?

I think in the future, we’re going to be able to push the response rate above 50% with combinations and also with new drugs that are in the pipeline now that block other family members of PD-1 and PD-L1. This appears to be a very effective treatment strategy for enhancing the patient’s own immune response against their cancer in a way that the immune system can eliminate cancer.