Checkpoint Inhibitors Move to the Adjuvant Setting in Melanoma

Nikhil I. Khushalani, MD

Over the last several years, a number of advances have taken place in the treatment landscape for patients with melanoma. In particular, more trials are looking at the use of checkpoint inhibitors in the adjuvant setting.

Most recently, nivolumab [Opdivo], an anti-PD-1 agent, was approved as an adjuvant treatment option for patients with resected stage III melanoma or resected stage IV melanoma. This agent has been able to reduce the risk of relapse in these patient populations.

For patients withBRAF-positive tumors, dabrafenib (Tafinlar) and trametinib (Mekinist) have also been approved as adjuvant treatment options. Other agents and treatment sequences continue to be investigated further for this patient population.

“With melanoma, we still have a long way to go,” said Nikhil I. Khushalani, MD. “We’ve certainly scratched the surface now and opened up a Pandora’s box where we have seen that patients can respond, and patients with advanced disease can potentially be cured.”

In an interview withTargeted Oncology,Khushalani, medical oncologist and vice chair of the cutaneous oncology program at Moffitt Cancer Center, discussed the role of adjuvant therapy in patients with melanoma across various subtypes. He also highlights a number of melanoma trials he is involved with at Moffitt Cancer Center.

TARGETED ONCOLOGY:What are some of the latest advancements in the treatment of patients with melanoma?

Khushalani:With melanoma, a variety of advances that have taken place in the last 5 to 7 years were primarily related to immunotherapy, particularly checkpoint inhibitors where we have defined that checkpoint inhibitors are the mainstay for the treatment of advanced disease, so primarily metastatic disease. Now what we are recognizing is that we are moving these same drugs into the adjuvant [setting], after definitive surgical resection to reduce the risk of recurrence. Now trials are currently underway and recently published trying to move them even [more] ahead of time prior to planned surgery to increase the incidence of what’s referred to as pathologic complete response and hopefully the durability of treatment and cure.

TARGETED ONCOLOGY:What does the adjuvant therapy setting currently look like?

Khushalani:In adjuvant therapy right now for melanoma, there are several available options. The most recent options to be added to the armamentarium for adjuvant therapy for melanoma from a checkpoint standpoint was nivolumab, and nivolumab, as you know, is an anti-PD-1 agent currently approved for the treatment of patients with resected stage III melanoma and selected resected stage IV patients with melanoma as well. That has clearly shown to reduce the risk of relapse. In addition to that, for those patients withBRAF-positive orBRAFV600 tumors, adjuvant dabrafenib and trametinib, which are MAP kinase-targeted agents, have also been approved for 1 year prior to reduce the risk of relapse.

Longer-term data that is now emerging has demonstrated that the survival curve to those patients treated with these agents is indeed very encouraging, hopefully raising the bar for cure. Our older agents that are approved, for example, high-dose pegylated interferon and ipilimumab (Yervoy), in my mind, should no longer be used now that we have better drugs that are far better tolerated and certainly have greater efficacy.

Another drug I suspect will soon be on the heels of nivolumab is pembrolizumab (Keytruda), based on the EORTC data which demonstrated an improvement in relapse-free survival and overall survival for patients treated with adjuvant pembrolizumab compared to placebo.

TARGETED ONCOLOGY:What are some of the challenges we still need to overcome?

Khushalani:With melanoma, we still have a long way to go. We’ve certainly scratched the surface now and opened up a Pandora’s box where we have seen that patients can respond, and patients with advanced disease can potentially be cured. That being said, we still have a large number of patients who either have primary resistance to the current drugs that we have, meaning they don’t respond at all, or during the course of their treatment, they develop secondary resistance, meaning they had an initial response and now the disease has started to progress again. We are still trying to figure out the pathways of resistance, so we can then develop potentially rational combinations of agents that can overcome this resistance and hopefully raise the bar.

The burning question in my mind for the treatment of melanoma is specifically for those who have an actionable mutation such asBRAF. The question that still remains unanswered is should we use targeted therapy first for those individuals, or should we start with immunotherapy? What is the optimal sequencing of these agents, is a second important question that I think deserves to be answered and is currently being answered in clinical trials.

Finally, in the adjuvant setting, particularly for patients who areBRAF-mutant, because we have both options, I think the issue becomes should we treat those patients with BRAF-targeted drugs for 1 year versus an anti-PD-1 for 1 year? That’s an unanswered [question] as well.

TARGETED ONCOLOGY:Can you discuss some of the melanoma clinical trials currently ongoing at Moffitt Cancer Center?

Khushalani:We have several trials currently underway at our institution. Some of these are industry sponsored, and some of these are trials we have designed and developed ourselves. We have a rational combination of an anti-PD-1 agent with an immunomodulatory agent that is currently in the works that we hope to open up at our site very soon.

For targeted therapy, we have a very innovative adaptive design study where we are actually utilizing real-time laboratory-based data from the patient that we are treating and trying to modulate the amount of time the patient is on or off therapy. This is with regard to the combination of BRAF and MEK inhibition in those patients. We are really trying to tailor the treatment to the patient and his or her response.

We are also participating in several trials with industry, for example, a combination of nivolumab with BMS-986016 (Relatlimab) versus nivolumab alonefor the first-line setting and a combination of nivolumab plus NKTR-214 versus nivolumab alone. Then one [trial] that I have been personally involved with the development of is nivolumab plus HBI-8000, which is an inhibitor of histone deacetylase inhibitors, or HDAC, believing that there is epigenetic modulation that occurs in these tumors, and epigenetic modulation can actually enhance the response to anti-PD-1 therapy.