Immunotherapy Combinations in the Treatment of Advanced Melanoma

Michael A. Postow, MD

Today, at the American Society of Clinical Oncology (ASCO) Annual Meeting held May 29 to June 2 in Chicago, we are speaking with Michael A. Postow, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, who specializes in the treatment of patients with melanoma. Dr. Postow has taken part in melanoma clinical trials, including those testing both monotherapy and combination immunotherapy agents.

 -Interviewed by Anna Azvolinsky 

Cancer Network:Dr. Postow, the data from the phase III trial of the combination of two immune checkpoint antibodies, ipilimumab and nivolumab, in advanced melanoma patients were presented at the plenary session. Can you briefly describe what the results showed?

Dr. Postow: Absolutely. Thank you. The phase III study of nivolumab and ipilimumab was tested against ipilimumab alone, and in addition to that test, nivolumab as monotherapy was tested against ipilimumab alone, with two co-primary endpoints of the study, overall survival and progression-free survival. The progression-free survival was reported at the plenary session at this year’s ASCO meeting, showing that both nivolumab alone and nivolumab in combination with ipilimumab significantly improved progression-free survival compared with ipilimumab monotherapy in patients with advanced melanoma. In addition to significantly improving progression-free survival, the objective response rates in both of the nivolumab groups-as monotherapy and in combination with ipilimumab-were better than ipilimumab monotherapy. But, the progression-free survival was the most important finding.

What we’ve learned from this is that this again demonstrates superiority of an anti–PD-1 antibody, nivolumab in this case, over the CTLA-4–blocking antibody, ipilimumab. These data built upon prior data that we had heard at the [American Association for Cancer Research] AACR meeting, in which pembrolizumab significantly improved overall survival compared with ipilimumab. We are still trying to understand the differences between the combination of nivolumab and ipilimumab vs nivolumab alone, as that was not a statistically powered endpoint of this particular study.

Cancer Network:The study also differentiated between melanoma patients whose tumors express PD-L1, the ligand of PD-1, and those that don’t. This has also been done with other immunotherapy studies, including the pembrolizumab study you mentioned. What is the prospect of this as a potential biomarker for patient response?

Dr. Postow: Certainly it would be wonderful if we could use a biomarker such as PD-L1 to really understand which patients should be treated with which agent. But, unfortunately, we don’t have a perfect biomarker yet and PD-L1 is not a perfect biomarker to allow treatment selection for patients. But, what we did learn from this phase III combination study was that the progression-free survival among the patients who were PD-L1–positive seemed similar, whether the patients received nivolumab monotherapy or nivolumab in combination with ipilimumab. However, for patients who were PD-L1–negative, the progression-free survival appeared numerically higher for patients who got nivolumab in combination with ipilimumab compared with nivolumab monotherapy.

However, it is important to understand that this is a subset analysis from the overall study and, therefore, at this time we are not yet ready to use PD-L1 to select patients for combination immune checkpoint blockade with nivolumab plus ipilimumab vs nivolumab monotherapy. What is also important is that regardless of PD-L1 status, both PD-1 treatment arms significantly improved outcomes compared with the ipilimumab monotherapy arm. So, again, PD-L1 can’t be used to choose people to get ipilimumab or nivolumab, nor can it be used to distinguish patients who had gotten the combination of nivolumab and ipilimumab vs nivolumab alone.

However, it is intriguing that the progression-free survival was improved in the combination checkpoint blockade for patients who are PD-L1–negative, and if further validated with overall survival information when that is ultimately more mature, it may be a sign of an immune-mediated tumor microenvironment that is immune active and perhaps will justify more aggressive combination therapy for particular patients, possibly those who are PD-L1–negative, but we need more research to validate these intriguing early findings.

Cancer Network:Lastly, is there another clinical trial that was presented at the meeting, particularly one that may be practice-changing that you want to highlight?

Dr. Postow: The other main study on the targeted therapy side in melanoma at this year’s ASCO meeting was the demonstration that dabrafenib and trametinib significantly improved overall survival compared with dabrafenib monotherapy. These are data that were presented by Georgina Long, MD, and again, this demonstrates that the BRAF and MEK combination now has shown improved overall survival not only compared with dabrafenib monotherapy but also previously compared with vemurafenib monotherapy. In BRAF-mutant patients where there is a decision to be made about which targeted therapy agent or combination of agents should be used, I think now that we have overall survival of dabrafenib and trametinib over both dabrafenib alone and vemurafenib monotherapy, we really need to be considering the combination for most patients in that context, unless there is a contraindication to using such a combination of a BRAF and MEK targeted therapy.

Cancer Network:Thank you so much for joining us today, Dr. Postow.

Dr. Postow: Thank you very much.