Big News: Adjuvant Ipi Improves Survival in Melanoma

Caroline Robert, MD, PhD


October 17, 2016

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Breakthrough in Adjuvant Therapy

Hello. I am Dr Caroline Robert, chief of dermatology at the Institut Gustave Roussy in France. Welcome to Medscape Oncology Insights. At the 2016 meeting of the European Society for Medical Oncology (ESMO), we heard exciting data in melanoma. I will share with you some of the highlights.

In melanoma, we have been living through a revolution for the past 6 years. We have two winning strategies: targeted agents for BRAF-mutant melanoma, which is about half of the patients that we take care of, and immunotherapy. Until this meeting, progress was mostly in the field of metastatic melanoma. We had not yet improved the management of patients with a high risk for relapse, and we had not really gone into the field of adjuvant therapy. Now, things have changed.

First, at this meeting, we heard the overall survival results of the EORTC trial,[1] which evaluated ipilimumab, an anti-CTLA-4 antibody, versus placebo. This trial was for patients with stage III melanoma, patients who have had a resection of their metastatic lymph nodes and who were at high risk for relapse. In this population of patients, we already knew that the duration before relapse had been significantly prolonged with ipilimumab. This actually gave rise to the authorization of ipilimumab in the United States. We have learned that we also have an overall survival benefit with ipilimumab. This is significant. The risk for death was decreased by 28%. At 5 years, there was a difference of 11% between the two arms: 65% in the patients who received ipilimumab versus 54%.

This is big news because, until now, we had only interferon for this population of patients, and the improvement in overall survival was not very consistent across all of the trials. We knew that we prolonged the duration before relapse, but we did not know that with interferon we could have an influence on overall survival. This [improvement in overall survival from ipilimumab] is a very important result. However, there were adverse events, with five deaths in the arm with patients treated with ipilimumab. This was due to immune-related adverse events. They occurred in close to 42% of the patients with a grade 3 or above. This is something that has to be prescribed by physicians who are used to treating patients with melanoma and who are used to managing these immune-related adverse events.

Metastatic Melanoma: Survival Still Climbing

Targeted Agents Yield 3-Year Survival of 45%

In the metastatic field, we have had two very important pieces of news—one in the field of targeted agents and one in the field of immunotherapy.

Targeted agents: Here, we talk about patients with BRAF-mutant melanoma. As I said before, it concerns about half of the population of patients with melanoma. We already knew that the combination of an anti-BRAF plus anti-MEK is much more effective than anti-BRAF monotherapy. We have the results of the 3-year overall survival of patients who were included in the phase 3 trial[2] evaluating the combination of dabrafenib plus trametinib, anti-BRAF plus anti-MEK, compared with vemurafenib, an anti-BRAF single agent.

We can now announce that after a median 28 months of follow-up of the patients in the combination arm, we have 45% of patients alive. This is a very significant improvement over vemurafenib, with only 32% of patients alive. This is the highest percentage of patients alive at 3 years in a randomized trial of patients with metastatic melanoma.

This is very important to note because, right now, a lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true. Combination targeted agents give the same ratio. For anti-PD-1 single agents, we will very soon have the 3-year overall survival results, and we think that it will also probably be around 40%-45%.

A lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true.

We also have patients with complete response, which was 19% in this trial of dabrafenib plus trametinib with a median duration of response of 39 months. We have long-term responses with the combination and the same percentage of patients alive at 3 years.

What is going to be extremely important is to follow these patients and to see if we arrive at a plateau. The follow-up of these patients in this arm is going to be very important. It is quite promising because we have 66 patients still on therapy who are censored in the arm of dabrafenib plus trametinib. It is always important in the Kaplan-Meier curve to look at the number of censored patients in each of the arms, especially the ones who are still on the active treatment. It is 66 patients in the dabrafenib-plus-trametinib arm and only 10 patients in the vemurafenib arm. Probably, the top curve will remain much flatter than the [vemurafenib arm].

Immunotherapy: Ipilimumab Dose Provides Unexpected Results

In the field of immunotherapy, the results that we are all looking forward to having are from the combination of anti-CTLA-4 plus anti-PD-1. We know that in terms of response and progression-free survival, it is better than an anti-PD-1 single agent,[3] but we still have to wait some months to have the overall survival results.

At this meeting, we learned some quite unexpected results. It was very interesting. Paolo Ascierto, our colleague from Italy, presented the results of ipilimumab 3 mg versus 10 mg.[4] I forgot to tell you that in the adjuvant trial, ipilimumab was given at 10 mg/kg, which is not the dose that is approved for metastatic melanoma. So it was very important to know the results of 3 mg versus 10 mg in the metastatic setting.

This trial with a long follow-up allowed us to get 3-year overall survival rates. In the 10-mg/kg arm, the benefit in terms of survival at 3 years was 31% of patients alive compared with 23% in the 3-mg/kg arm. There was significant improvement: The hazard ratio showed that the risk for death was decreased by 16%.

It actually came as a surprise to see the significant difference. We don't know today how it will impact the future, because now we all think that ipilimumab will probably more or less always be combined with an anti-PD-1 antibody. Nevertheless, this may be something that is important for other combinations. There is a dose effect of ipilimumab, with 10 mg being more effective than 3 mg in the metastatic setting.

It was quite rich in information for melanoma this year at ESMO. Thank you for joining me for this edition of Medscape Oncology Insights. This is Caroline Robert, reporting from ESMO 2016.


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