Immunotherapy in Melanoma: Looking Ahead

Melanoma has been at the forefront of the immuno-oncology revolution. This trend continued at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

In results from the phase 3 CheckMate-067 trial presented at ASCO, a drug combination with the PD-1 inhibitor Opdivo (nivolumab) and the CTLA-4 inhibitor Yervoy (ipilimumab) reduced the risk of disease progression by 58 percent compared with single-agent Yervoy and 26 percent compared with Opdivo monotherapy in patients with advanced melanoma.

Beyond the immune checkpoint inhibitors, the oncolytic immunotherapy talimogene laherparepvec (T-VEC) has also shown promise. The phase 3 OPTiM study demonstrated a significant extension in durable response rates with T-VEC compared with GM-CSF, at 16 versus 2 percent, respectively. The objective response rate was 26 percent for T-VEC versus 6 percent for GM-CSF.

Opdivo and Yervoy are already FDA-approved to treat melanoma and T-VEC is nearing marketing authorization. In April, the FDA’s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) advisory panels voted to recommend approval of T-VEC in melanoma, with a final approval decision by the FDA scheduled by October 27, 2015.

In a recent interview with CURE, Howard L. Kaufman, chief surgical officer, associate director for Clinical Science, Rutgers Cancer Institute of New Jersey, provided an overview of what the future holds for immunotherapy in melanoma.

CURE: What emerging immunotherapy agents in melanoma have the most promise?

Kaufman: There are a lot of new agents that are in the pipeline that we are excited about. Many of the early trials have been reported, and there are some advanced trials where the data have recently been released. Among these are other checkpoint inhibitors that target PD-1 or PD-L1 that are currently in development for a variety of cancers, including melanoma. I think that we will have to await the results of these trials before we really know how much potential they have.

Another thing that has been very exciting is the use of oncolytic virus immunotherapy. The agent that is clearly the furthest along is T-VEC. A phase 3 trial did demonstrate an improvement in durable response rate as well as an improvement in both progression-free and overall survival for patients that had T-VEC compared to a control group that received GM-CSF. We are widely anticipating FDA approval of this therapy. In the phase 3 study, a prominent effect was seen in patients who had locally advanced disease, such as unresectable stage 3 and also patients with stage 4 M1a (metastasis to skin, subcutaneous tissue or lymph nodes in distant parts of the body) melanoma. I think this will be a particularly useful drug in that population.

There is also a lot of interest in the use of adoptively transferred T cells. This is a little bit more complicated therapeutic approach in which T cells are either taken out of the peripheral blood or directly from the tumor site and can be engineered to directly target a particular antigen in a tumor cell. A variety of approaches have been studied and are in clinical trials, and I think we have to await the results of those studies to see how effective it is.

At this year’s ASCO Annual Meeting, what data that was presented that excited you the most?

The most important data presented at ASCO, related to immuno-oncology, was the pivotal phase 3 data of the combination study looking at Yervoy plus Opdivo [CheckMate-067]. This was a 945-patient study in which patients were randomized to receive the combination or single-agent Yervoy or single-agent Opdivo. The study is reporting a significantly improved response rate and median progression-free survival in those patients who received the combination therapy. Although there was a high toxicity rate, the potential to get a very good response and a very rapid response with this approach is very compelling and I think this will become the standard of care for patients with melanoma. I think we will push the field forward in other cancers much more rapidly.

What are the next steps for immunotherapy in melanoma?

Immuno-oncology is developing very quickly. I think in the next 12 to 24 months, many of the ongoing phase 3 studies are going to come to a close. Therefore, we should have a number of reports that we hope will be positive and lead to FDA approvals.

There are a number of orphan diseases that are also under examination, such as Merkel cell carcinoma, which is a particularly difficult-to-treat type of skin cancer. A PD-L1 targeted antibody approach has shown initial promising results for that disease. I think these are going to be very important studies to take a look at.

On the five-year front, I think we are going to see immuno-oncology increasingly taking over for the treatment of many cancers. As this becomes mainstream, I think it is really important for physicians to understand the background of how the immune system works and how to manage the potential toxicities that we see with these agents, which are very different than what we’ve seen with standard therapeutics.