Nivolumab Continues to Improve Outcomes in Advanced Melanoma

Victoria Atkinson, MD

Anti—PD-1 monoclonal antibodies, such as nivolumab (Opdivo), will become the backbone of advanced melanoma treatment, predicts Victoria Atkinson, MD, of Princess Alexandra Hospital and Gallipoli Medical Research Foundation in Queensland, Australia.

“Chemotherapy does not have a role in advanced melanoma anymore. PD-1 antibodies, whether combined with BRAF or MEK inhibitors, or other therapies like vaccines or radiotherapy, are the future for the treatment of patients with this disease,” says Atkinson, the lead study author on the phase III CheckMate-066 trial.

The CheckMate-066 trial was the basis of the recent FDA expanded approval, which compared single-agent nivolumab with dacarbazine as a frontline treatment of patients with BRAF wild-type advanced melanoma.

In updated data presented by Atkinson at the 2015 Society for Melanoma Research Congress, the 2-year overall survival (OS) rate with frontline nivolumab was 57.7% compared with 26.7% for dacarbazine. After a minimum follow-up of 15.1 months, the median OS was not yet reached for patients receiving nivolumab compared with 11.2 months in the dacarbazine arm (HR, 0.43; 95% CI, 0.33-0.57; P <.001). The 1-year OS rates were 70.7% and 46.3% for nivolumab and dacarbazine, respectively.

OncLive: How was the trial designed?

OncLive spoke with Atkinson regarding the impact of this data and nivolumab’s future as both a monotherapy and in combination with other therapies.Atkinson: This was a large randomized phase III trial of nivolumab versus dacarbazine in BRAF wild-type patients who had no previous therapy. It was randomized 1:1 to nivolumab or dacarbazine and was also blinded.

What is the significance of this long-term data for patients with melanoma?

At progressive disease, if it was in the patients’ best interest, treatment beyond progression was permitted. The duration of nivolumab was not limited to 2 years; it was allowed until progression or if patients chose not to receive therapy. Patents were stratified by metastasis stage and the treatment was given fortnightly.This trial is the longest follow-up that we have on patients from a phase III trial with a PD-1 antibody. It shows the highest 2-year survival for any PD-1 therapy in patients with advanced melanoma.

Nivolumab is a highly effective treatment, which is significantly improving the overall survival of patients with good quality of life.

Which factors should be considered for determining whether to use nivolumab alone or with ipilimumab?

What role should PD-L1 expression play in determining therapy?

What toxicities associated with nivolumab that oncologists should be aware of?

What planned additional studies are going to examine nivolumab?

How do you see immunotherapy evolving in melanoma?

This data reassures us that the responses are maintained for those who do respond to nivolumab. What we can see from this data, with the 2-year overall survival being so high, is a plateau of the curve. We hope with further follow-up we will see maintained responses.In my opinion, patients with lower burdens of disease who don’t need a rapid response or patients who are frailer should have nivolumab monotherapy. We know that nivolumab with ipilimumab does have a higher response rate, so for those patients who need a rapid response I would recommend the combination. For patients who don’t need that, we know that nivolumab is much better tolerated alone and still has a very good response rate at more than 40%.For patients with melanoma, PD-L1 should not determine whether or not we consider nivolumab monotherapy. We can see that, regardless of PD-L1 status, patients live longer with nivolumab.The highest toxicities with nivolumab are fatigue and arthralgias. These side effects are very easily managed. Moreover, we saw that the toxicity profile was better than chemotherapy. We do not see the same toxicities with combination therapy that we see with monotherapy, and that is because ipilimumab contributes to the majority of the toxicities with that combination.There will be prolonged follow-up to see if the benefit can be maintained at 4, 5, and 6 years. Other trials are looking at the combination of nivolumab with other therapies to see if we can improve response rates. Checkmate-067 is looking at the combination of nivolumab and ipilimumab.On the horizon, I see more investigation of combination immunotherapies, including combinations with oncolytic viruses and radiotherapy, taking place. Immunotherapy is going to have a PD-1 backbone, but I think it will be combined with other agents to see if we can improve that response rate. Even with the combination of nivolumab and ipilimumab, we are still only looking at response rates of approximately 55%. We need to look at other therapies to see if we can improve that so all patients are maintaining a clinically significant response from immuno-oncology. I think we are moving into an era where we are going to see even more advances in a short period of time than we have seen in the last few years.