Novel Combinations Continue to Advance Melanoma Field

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.

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

In an interview with OncLive® at the 2017 State of the Science Summit^TM on Melanoma, Sznol discussed overall advances in the field of melanoma, as well as novel treatments with the potential to change the treatment paradigm.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 the nivolumab-plus-ipilimumab combination has shown promise, can you describe some other combinations with PD-1 inhibitors that are creating similar excitement?

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. 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.

With so many agents to choose from, when is the appropriate time to choose T-VEC over other therapies?

We also heard about biomarkers. We want to know who requires the combination of ipilimumab and nivolumab, and who might get by with just anti—PD-1 alone, either nivolumab or pembrolizumab. That is very important because when you use combinations, you introduce additional toxicity that may not be necessary in the subsequent patients.We don't know. The real question is whether T-VEC will add something when ipilimumab or IDO inhibitors do not. One of the reasons you think about an intratumoral therapy is that you are trying to generate an immune response that is not already there and might not be expanded by the standard immune checkpoint inhibitors. However, we are not sure if one should give T-VEC and pembrolizumab upfront or wait until the patient develops resistance.

What is the design of the adjuvant nivolumab trial, and what were the significant findings?

For a patient to receive T-VEC, they need to have a lesion that is close to the surface. T-VEC would be something for patients with locally advanced disease who do not require a toxic therapy, but we want to add to their activity. We do not know who is the right patient for T-VEC. For example, at our institution, we have not treated many patients with T-VEC at all since we have not found a need for it at this point.Nivolumab was compared with ipilimumab in patients with at least stage IIIB melanoma. It also included patients who had stage IV resected disease. Patients were randomized to receive either nivolumab or ipilimumab. The ipilimumab dose was the standard dosage of 10 mg/kg every 3 weeks for 4 doses, and every 12 weeks for up to 1 year, which is quite toxic.

As we have learned, nivolumab was not only less toxic than ipilimumab, but also improved progression-free survival (PFS) by very significant amounts. It will be the SOC within a few months. I do not think people will be using ipilimumab in the adjuvant setting anymore.

The other interesting part of this story is that there was also a randomized trial demonstrating that BRAF/MEK inhibitors, such as dabrafenib (Tafinlar) or trametinib (Mekinist), were also effective in the adjuvant setting. Now, when you have a patient who has a BRAF mutation with fully resected, locally advanced, stage III disease, you need to ask the question, “Am I going to give this patient immunotherapy, or am I going to give them targeted therapy?” It is very different from the conversations that we have with advanced disease.

What role do you envision for surgery in the future?

What is remarkable about the targeted therapy trial is that we expected the PFS curves would separate and would come back together quickly, because we do not consider those agents to be curative. However, that is not what happened. The curve significantly separated through treatment at 1 year, but when treatment was over they did not come back together. They stayed separated for up to 3 years, coming back together slightly but not completely. There was a significant number of patients who received durable benefit from just 1 year of dabrafenib and trametinib. That does not tell us that these agents are curative in patients with low-volume disease. It is a remarkable finding, so we are going to have a very interesting discussion about which agent to use first in a patient who has a BRAF mutation in the adjuvant setting. Surgery will not go away for a variety of reasons, starting with metastatic disease. Even in patients who have very significant benefits from immunotherapies, some of those patients do not get a CR if they have a small number of residual lesions. Some of those patients can have a substantial benefit if you resect those lesions. They remain progression-free for long periods of time. Sometimes, a patient will need surgery even if you have effective systemic therapies. For example, if a patient comes in with a bowel lesion and is bleeding, you may need to resect that before they start their treatment since they may not respond as quickly.

Is there anything else you would like to add?

Surgery, even in metastatic disease, still has a major role. If you go back to the primary setting, we will be doing wide local incisions. There is still a role for SLNB since it gives prognostic information, even though it doesn’t prolong survival. It is going to be important, even if we don't do the complete lymph node resection. There are a lot of subtleties in the treatment of melanoma. Even though it seems straightforward, every individual has a slightly different approach. This is a conference where physicians can get together and talk about these interesting recent findings. There are cases that we will discuss and how we might differ in the way we manage patients.

It is important for practicing physicians to learn about the management of melanoma. There are a lot of interesting new drugs. We will hear a talk about new drugs in melanoma and which regimens are more near-term and those that are further out and earlier in clinical development. Those drugs are important to learn about because a physician might want to refer a patient for a clinical trial.

Perez RP, Riese JM, Lewis KD, et al. Epacadostat plus nivolumab in patients with advanced solid tumors: Preliminary phase I/II results of ECHO-204. J Clin Oncol. 2017;35 (suppl; abstr 3003).