UCLA Researcher Provides Insight Into the Impact of Pembrolizumab in Melanoma

John Glaspy, MD, MPH

Last week, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with advanced or unresectable melanoma following progression on prior therapies. In the pivotal KEYNOTE-001 study, at the recommended dose for pembrolizumab of 2 mg/kg, the overall response rate was 24%, with a response duration lasting from 1.4 to 8.5 months.

Pembrolizumab is the first PD-1 inhibitor and sixth new melanoma treatment to gain approval since 2011.

Could you discuss the KEYNOTE study results and the approval of pembrolizumab?

Pembrolizumab is the 6th drug to gain approval in melanoma since 2011. What is the impact of this drug on the treatment of melanoma?

Pembrolizumab is the first PD-1 inhibitor to gain approval in the US. What will be the impact on immunotherapy as a whole?

To gain further insight into the approval of this novel agent, OncLive interviewed John Glaspy, MD, MPH, from the Jonsson Comprehensive Cancer Center and UCLA, where research into pembrolizumab was conducted.Pembrolizumab was approved because it is active for the treatment of metastatic melanoma and brings something new to the table in terms of working in patients who have had all the benefit from the other available medications. About half of melanomas have a BRAF mutation. Pembrolizumab works equally well in patients with this mutation as it does in patients who are BRAF-negative who have fewer therapeutic options.This drug is up at the top of the new drugs for melanoma for a couple of reasons. First, pembrolizumab can be used in BRAF-negative and BRAF-positive tumors. Second, it works when the other drugs have stopped working or failed to work altogether. Third, when it works, it tends to work for a very long time. These immune checkpoint inhibitors are more durable in their responses than BRAF inhibitors. I would put pembrolizumab in the top rung of those new drugs that have been approved.I think this drug will soon find community use in not just melanoma but in non-small cell lung cancer, the most common kind of lung cancer. It will find use in other cancers as well. This drug is also going to be looked at in combinations with other immune strategies and immune vaccines. As this approach, checkpoint inhibition, facilitates the continuation of an immune reaction when it otherwise might stop, treatments good at starting an immune reaction, like vaccines, need to be studied in combination with checkpoint inhibitors. Using checkpoint inhibitors in the adjuvant setting and in combination with one another will also need to be evaluated.

What side effects are important for a community oncologist to consider with a PD-1 inhibitor?

Immunotherapy clearly is going to be an important part of oncology. We are going to be working out how to integrate immunotherapies with all the other approaches to cancer treatment both in melanoma and other cancers.All their toxicities are related to their intended effect on the immune system. If the immune system has brakes, they are there for a reason. These brakes have evolved to help to make sure that the immune system is under control and does not attack normal cells.

With anti-PD drugs, we have seen autoimmunity that can be anywhere, but most commonly in the lungs, where some pneumonitis or inflammation develops. An oncologist must watch for these events and treat with drugs aimed to train the immune system to back off.

That said, these drugs are very well tolerated compared to other cancer therapies. The chance of having a significant immune attack is about 15%, which is manageable, given that melanoma poses a 100% risk to the patient.

What questions still need to be answered surrounding this agent for melanoma?

Bristol-Myers Squibb has recently filed a lawsuit with Merck, contending that the PD-1 inhibitor will infringe upon patents that Bristol-Myers holds on the technology. Do you think this could delay access?

The balance between immunity and autoimmunity is being tilted — both are occurring with more vigor. A more vigorous immune system tends to be good for many cancer patients, but autoimmunity can be a problem.I think that the ideal time to administer still needs to be worked out, as well as how early in the course of the disease to use it, and how long to continue it. It is almost certain that it is going to be better to combine it with something else than just giving it alone. It remains to be seen what agent or agents should be combined with pembrolizumab. Finally, it’s going to take a long time to sort out what other cancers can be treated with pembrolizumab.I don’t think it will. I think we are going to be able start treating patients right away. Whatever happens with Bristol-Myers Squibb and Merck, it probably will not block access, but will focus on settling revenues later on. At least I hope that’s the case. There are patients out there who are eligible for this drug — melanoma doesn’t wait.