Jeffrey S. Weber, MD, PhD

Disclosures

May 26, 2017

Hello. I am Dr Jeffrey Weber, a medical oncologist and deputy director of the Laura and Isaac Perlmutter Cancer Center at the New York University Langone Medical Center in New York City. Today I will discuss five abstracts that have been submitted for discussion at the 2017 Meeting of the American Society of Clinical Oncology (ACSO) in Chicago from June 2 to 6. I chose these melanoma abstracts because I believe that they will be important, well received, and potentially practice-changing.

Caroline Robert, from the Institut Gustave Roussy in Paris, France, will present an update, with long-term survival data, on the KEYNOTE-006 trial.[1] This is a frontline trial using a relatively high dose of the PD-1 antibody pembrolizumab given every 2 or 3 weeks versus frontline ipilimumab, which was standard at that time. With a median follow-up of 33 months in both pembrolizumab arms, the survival rates were at 50%, which suggests that the median survival is a little less than 3 years—pretty darn impressive for a frontline therapy for melanoma.

Some 9 months after finishing pembrolizumab, 98% of patients who had to stop the drug because of toxicity are still alive, as are 95% of those with complete remission, 91% of those with partial remission, and 84% of those who were simply stable. This suggests that if you stop the drug because of toxicity, you are going to do very well. If you stop because you reach 2 years, had a response, and the decision is to discontinue therapy, you are also probably going to stay in remission.

In a similar vein, Georgina Long, from the University of Sydney, Australia, will present long-term follow-up data on the dabrafenib/trametinib randomized phase 2 trial[2] in which patients received either dabrafenib/trametinib or the BRAF inhibitor dabrafenib alone. At 5 years, 20 of 100 total patients remain in the trial, with 13 in the combination arm and 7 in the dabrafenib-alone arm still receiving treatment. The overall survival rates at 4 and 5 years were 30% and 28%, respectively, suggesting that, similar to immunotherapy, there probably is a plateau on the survival curve.

Not all patients who receive upfront targeted therapy with BRAF and MEK inhibitors are going to die of disease. There will be a significant likely survival plateau at 5 years. Of note, the 5-year survival rate is 51% for patients with normal lactate dehydrogenase levels at baseline and three or fewer sites of disease—a very favorable outcome group.

Continuing the theme of BRAF and MEK inhibition, Mike Davies from MD Anderson Cancer Center in Houston, Texas, will be presenting an abstract on the COMBI-MB trial,[3] a phase 2 trial of dabrafenib/trametinib in 125 patients with brain metastases. The intracranial response rate was an impressive 58%, the extracranial response rate was 55%, and the overall response rate was 58%. Interestingly, the overall survival is only about 10.5 months, with an overall median progression-free survival of about 5.6 months, suggesting that those patients will do well but they probably do not fare as well as the patients who do not start with central nervous system (CNS) disease from the get-go, when they receive frontline BRAF plus MEK therapy.

Another abstract that will provide important and impressive data on treating patients with brain metastases from melanoma is the CheckMate 204 study.[4] The interim data will be presented by Hussein Tawbi, also from MD Anderson Cancer Center. Patients received standard FDA-approved ipilimumab—3 mg/kg plus nivolumab, 1 mg/kg at induction and every 3 weeks for four doses—followed by maintenance nivolumab, 3 mg/kg. This regimen resulted in a very impressive intracranial response rate of 56%, with a 19% complete response rate in the brain.

The rate of grade III/IV immune-related adverse events was 48%, however, but there was no obvious increase in the rate of CNS-related, immune-related, or other adverse events. This suggests that this regimen will be very well tolerated. The overall global response rate of over 40% suggests that both BRAF plus MEK inhibition and the use of ipilimumab with nivolumab can have impressive results in patients with melanoma who have disease in the brain.

Finally, in what I think will be a practice-changing result, investigators will present an interim relapse-free survival assessment of the ECOG/intergroup 1609 trial.[5] In this trial, over 1500 patients were randomly allocated to receive ipilimumab at 3 mg/kg or 10 mg/kg, or high-dose interferon. An unplanned relapse analysis at 3 years showed that the relapse-free survival rate for the 10-mg/kg arm was 54%, but for the 3-mg/kg arm it was 56%. This is very impressive data suggesting no real difference between 3 mg/kg or 10 mg/kg when ipilimumab is used as adjuvant therapy in high-risk, resected melanoma.

This result may convince a lot of folks to drop that higher dose. It will probably encourage more patients to receive adjuvant ipilimumab therapy. These are impressive data. There were eight deaths in the 10-mg/kg arm versus two in the 3-mg/kg arm. We await further data from this presentation at the ASCO meeting in a couple of weeks, as well as, of course, the follow-up survival data, but it looks quite impressive so far.

That is my impression of the important ASCO melanoma abstracts coming up. Please feel free to contact me with questions. And thank you very much for your attention.

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