Jeffrey S. Weber, MD, PhD


May 31, 2016

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This is Dr Jeffrey Weber. I am a medical oncologist and deputy director at the Perlmutter Cancer Center at NYU Langone Medical Center. Today we'll be talking about abstracts that have recently been released as part of the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting. It may not be a revolutionary meeting, as it was for melanoma immunotherapy in 2013 or 2015, but this is an excellent year nonetheless.

We will see data from a large randomized trial called the NEMO trial,[1] in which 402 patients with metastatic NRAS-mutated melanoma received either a MEK inhibitor (binimetinib) or dacarbazine alone. There was clear superiority by response rate for binimetinib compared with chemotherapy (15% vs 7%). Progression-free survival and overall survival were also superior for the MEK inhibitor compared with chemotherapy, with a hazard ratio in the initial overall survival analysis—which is a bit premature—of 0.81, suggesting that this new drug would be reasonable for patients with NRAS-mutated melanoma who perhaps have failed immunotherapy.

We will also hear very interesting follow-up data from the KEYNOTE-001 study,[2] which was the phase 1/2 study of the PD-1 antibody pembrolizumab, given in different doses and schedules. The results suggest that across doses, schedules, and either first- or second-line therapy, 3-year survival was in the range of 38%-42%. It is a very impressive statistic, suggesting that there may now be a plateau of survival for pembrolizumab, similar to what we heard at the American Association for Cancer Research (AACR) meeting this year for nivolumab, the other PD-1 antibody. Again, these are very impressive data, and I think we're going to see the tail on the curve between 30% and 40% for that drug.

We also heard updated results from several combination studies, such as the CheckMate 067 study,[3] in which patients were randomly allocated to get ipilimumab and nivolumab versus nivolumab alone or ipilimumab alone. Longer-term follow-up from that study confirmed the excellent progression-free survival rate and the superiority in progression-free survival and response with the combination arm versus either of the other checkpoint inhibitors alone. It remains to be seen whether there will be a survival advantage with combination therapy versus nivolumab alone. We'll hear more about that, perhaps, at the European Society for Medical Oncology (ESMO) meeting later this year.

We also have follow-up data from the KEYNOTE-029 study,[4] in which patients received ipilimumab at 1 mg/kg combined with pembrolizumab at 2 mg/kg, both given every 3 weeks. The ipilimumab was stopped after 4 doses and the pembrolizumab was continued. Again, they saw an excellent 57% response rate. There are no survival data coming out yet because they're premature, but the toxicity seemed to be superior to that seen with ipilimumab/nivolumab, at a rate of about 30% for the grade 3/4 immune-related adverse events. We'll hopefully hear much more about that in coming ASCO meetings. It's a very promising combination regimen.

We will hear updates on the combination clinical trials of targeted therapy. For example, we'll hear about dabrafenib and trametinib vs dabrafenib alone, in which the BRAF V600K-mutated patients had a much higher mutational load than those who were BRAF V600E-mutated.[5] It's a very interesting finding, which in my view suggests the possibility that we would want to use targeted checkpoint inhibition in those patients.

We'll also get an update from the original BRIM7 study,[6] which was the phase 1b/2 study of vemurafenib and cobimetinib, the other BRAF+MEK combination that is already approved by the US Food and Drug Administration. We'll see an excellent median overall survival of 31-plus months—an excellent record—and a 3-year survival that is between 35% and 40%, suggesting the urban legend that the only way to get long-term survival in metastatic melanoma is with checkpoint inhibition or immunotherapy. Again, that may not be true, because in the right patient population, targeted therapies may also give you the so-called tail on the curve.

Finally, we'll hear about a randomized phase 2 trial,[7] a very interesting trial in which patients received adoptive cell therapy with tumor-infiltrating lymphocytes, which was preceded by either nonmyeloablative chemotherapy or extreme myeloablative chemotherapy with stem cell transplant and total body irradiation. The results are that no significant difference was found in progression-free or overall survival, with fairly mature data (now out past 3 years), suggesting that the very heavy toxicity of total nodal irradiation plus serious chemotherapy is probably not warranted in patients receiving tumor-infiltrating lymphocytes (TIL). We'll be hearing a lot more about TIL therapy in the next couple of ASCO meetings.

This is Dr Jeffrey Weber. Feel free to send in comments, questions, or concerns. Thank you very much for your attention.


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