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Novel Combinations Continue to Advance Melanoma Field

Danielle Bucco
Published: Monday, Jan 29, 2018

Dr. Mario Sznol
Mario Sznol, MD
Combination regimens continue to push the field of melanoma further, following the success that has been seen with nivolumab (Opdivo) and ipilimumab (Yervoy), according to Mario Sznol, MD.

That successful combination has led to PD-1 inhibitors being studied in combination with other agents, such as IDO or LAG-3 inhibitors. For example, the ongoing phase III KEYNOTE-252/ECHO-301 study is exploring the efficacy, safety, and tolerability of the PD-1 inhibitor pembrolizumab (Keytruda) with the IDO1 inhibitor epacadostat.

“The phase II data for the IDO and PD-1 inhibitors are exciting, and suggest that there is an advantage with the combination over anti–PD-1 alone and, therefore, led to the phase III study,” said Sznol, a professor of medicine, and co-director of the Cancer Immunology Program at Yale Cancer Center.

Findings of the multi-arm, open-label, phase I/II ECHO-204 trial of nivolumab and epacadostat in patients with advanced solid tumors demonstrated an objective response rate of 63% and a complete response rate of 5% for patients with treatment-naïve melanoma. Based on the projected 2-year survival data, the combination could represent a new and less toxic frontline standard of care (SOC) for patients with melanoma.

However, as with many novel therapies, better biomarkers are needed to determine which patients should receive a combination compared with single-agent therapy. Currently, the BRAF mutation is the most predictive biomarker; however, further research is needed to improve those data, Sznol added.

In an interview with OncLive® at the 2017 State of the Science SummitTM on Melanoma, Sznol discussed overall advances in the field of melanoma, as well as novel treatments with the potential to change the treatment paradigm.

OncLive: What exciting advancements have we recently seen in the field of melanoma?

Sznol: Currently, the SOC is either single-agent anti–PD-1 or the combination of ipilimumab and nivolumab. In the future, it could involve different combinations, mostly centered around anti–PD-1. Those potential combinations are being studied in many ongoing phase III trials. We will be discussing the design of those studies and the new agents that might be approved within the next 1 or 2 years for the treatment of metastatic melanoma. 

For targeted therapy, the SOC also involves the use of BRAF and MEK inhibitors. We spoke about how we integrate targeted therapy and immunotherapy in the treatment of patients who have BRAF mutations. 

We also spoke about the future of therapies. We will have a talk on adjuvant therapy in melanoma. Previously, interferon was approved, and following that, ipilimumab was approved. Now, there is a new trial that shows that nivolumab is even more effective than ipilimumab and less toxic. We heard about the appropriate use of adjuvant treatment in patients with regionally advanced but fully resected melanoma. 

In the second half of the program, we discussed controversies related to the surgical management of melanoma, because based on recent data, complete lymph node resection is no longer part of the SOC. Patients undergo resection to the primary tumor and undergo sentinel lymph node biopsies (SLNBs). However, based on a recent phase III trial, complete lymph node resection is no longer recommended. 

Since systemic therapies are so effective, this gives us options to be able to treat patients with regionally advanced disease with systemic therapies. We discussed whether one should approach these patients with surgery, systemic therapy, or both. We have case presentations that we will present, along with some of the controversies on how different physicians manage patients with metastatic melanoma. 

Since the nivolumab-plus-ipilimumab combination has shown promise, can you describe some other combinations with PD-1 inhibitors that are creating similar excitement?

One of the combinations is with an IDO inhibitor. That phase III trial with pembrolizumab and epacadostat is ongoing. The results will be available sometime [in 2018]. We will discuss the phase II data that set up this trial.

There is a phase III trial with intratumoral talimogene laherparepvec (T-VEC; Imlygic) and pembrolizumab versus pembrolizumab alone. Again, intratumoral therapies are an interesting approach in melanoma. It is not yet clear how they will fit in with the overall treatment paradigm. I am not sure when the data from this trial will be available.

There are other agents that are being studied, such as 4-1BB ligands. There are promising data with anti–LAG-3 inhibitors in combination with PD-1 inhibitors in patients who had already progressed on anti–PD-1. There are different combinations that are moving into the clinic and are coming into phase III trials that could impact how we treat patients with melanoma. The advances have been so rapid that the SOC seems to change every 6 months. Maybe that pace will continue over the next 2 years.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
Medical Crossfire®: What Does Data Tell Us About How to Optimize Checkpoint Inhibitor Strategies Across Lines of Care for Patients with Melanoma?Nov 30, 20191.5
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