Morganna Freeman, DO

Many patients with advanced melanoma respond to anti-PD-1 therapy; however, not all patients benefit. If you look across trials, about 40% of patients respond, but not all of them maintain a prolonged response. Cancer specialists recognize a concept of ‘tumor escape’ from the immune system, where eventually melanoma (and other cancers) can regrow and those patients will relapse. We can run into difficulties determining the next line of therapy for these patients, especially if their melanoma does not harbor a BRAF mutation.

What’s interesting about HDAC inhibitors is they can increase PD-L1 expression and make that melanoma more vulnerable to immunotherapy, so it’s very smart to look at them as an option for relapsed patients. We may even end up thinking about them as an option for patients as a first line of therapy, so that when combining them with anti-PD-1 therapy, we can take that 40% response rate and maybe bring it closer to 50% or 60%, as we’ve seen with combination CTLA-4 checkpoint inhibitors.

To select patients for dual upfront therapy, one suggested mechanism is to test PD-L1 expression because the HDAC inhibitors increase PD-L1. A patient who is a low expressor or has a “cold” tumor might be selected for HDAC plus PD-1, whereas a patient who is a high PD-L1 expressor and thus more likely to respond to treatment may not need dual therapy. We don’t typically test for PD-L1 in melanoma, but this may end up changing our perspective if that’s the biomarker we should be using based on clinical trials.

This trial enrolled a small number of patients, and it would be important to look at this combination in a larger group to see if the study results remain consistent. We learned that lesson from indoleamine 2,3 dioxygenase, or IDO, plus PD-1 inhibitors in melanoma, which looked very promising in phase II trials but showed no difference in terms of PFS or OS when tested in in a larger phase III trial. This combination of HDAC and PD-1 inhibitors appears very promising and is a combination therapy that has a favorable toxicity profile compared with other combinations tested in melanoma, but we need to see how it shakes out in a larger number of patients to know if it’s going to clinically benefit the majority. There is always a lot of excitement and enthusiasm when new data come out of these meetings, but from a practical standpoint and patient counseling standpoint, I always try to take these early data with a grain of salt. As with any clinical trial of cancer therapy, we need to look at long-term outcomes as they pertain to safety, tolerability and efficacy in a large cohort of patients in order to extrapolate that data for the greater good.

As with any new melanoma therapy, although we might see some responses early on, do we know that is going to translate into durable responses later? Are we recapturing that immune response in a way that the tumor will stay in remission for a long time?

Another important question is whether HDAC inhibitors could have any long-term toxicities for patients. Traditionally, HDAC inhibitor drugs have a risk for myelosuppression, so we would want to know whether these patients develop hematologic toxicities later, after many months of drug exposure.

Lastly, I would like to know whether Dr. Sullivan and colleagues are thinking about using this in noncutaneous melanomas, such as mucosal melanoma or ocular melanoma, where we don’t see as robust of an immune response. Although this is a smaller number of patients, both are also orphan disease states, so it would be interesting to see if we can apply the same concept.

Anthony Olszanski, MD, RPh

Checkpoint inhibitors have revolutionized the treatment of many cancers, including melanoma; but, not all patients respond. For such patients, there remains a high unmet medical need to find therapies that can help such patients.

Dr. Sullivan and his colleagues report on the potential benefit of adding HDAC inhibitors to checkpoint inhibitors in an effort to enhance the response to checkpoint inhibition, coaxing the patient's immune system to attack the cancer. These preliminary results are encouraging, with nearly 20% of patients responding to the combination despite the failure of prior single-agent checkpoint inhibition.

Importantly, responses also appear to be durable, lasting about 1 year on average. New combinations which may enhance the effects of PD-1 inhibitors or reverse resistance to these agents is of paramount importance and offer hope to those patients who have not responded. This study offers promise and will spur further study in this situation.