Melanoma Brings Immunotherapy to the Forefront, But Challenges Remain

Jeffrey S. Weber, MD, PhD

It is clear that immunotherapy is a key modality for the treatment of melanoma, as well as many other cancers.

However, the potential for immunotherapy was not always widely accepted, says Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center, co-director of the Melanoma Program, and head of Experimental Therapeutics at NYU Langone Medical Center.

“When I first got into immunotherapy in cancer, the field didn’t have a lot of respect,” says Weber, who started his career as a fellow at the National Cancer Institute working with immunotherapy pioneer Steven Rosenberg, MD, PhD. “It took until the last few years when checkpoint inhibitors became a new modality with success in many different cancers, for everyone in the field to accept the fact that immunotherapy was here to stay.”

The rapid integration of immunotherapy into cancer treatment means that virtually all oncologists have to become “immunotherapists,” says Weber. This learning curve can be especially difficult for oncologists outside of melanoma, the first tumor type to adapt the use of immunotherapies.

Even within melanoma, there is still much to learn regarding patient selection for immunotherapy agents, when patients should receive them, and understanding which standard treatments immunotherapies may have the potential to replace, says Weber.

OncLive: Because melanoma was one of the first cancer types to adopt immunotherapy as a standard of care, are oncologists who treat other tumor types coming to melanoma practitioners to learn more about immunotherapy?

In an interview with OncLive, Weber discusses the role that melanoma specialists can play in educating other oncologists, immunotherapy use for BRAF-mutated patients with melanoma, and how the use of chemotherapy may evolve as immunotherapies take the forefront.Weber: We’ve been doing this for a long time. Experts in the melanoma field such as Antoni Ribas, MD (UCLA Health System), Jedd Wolchok, MD (Memorial Sloan Kettering Cancer Center), Stephen Hodi, MD (Dana-Faber Cancer Institute), Mario Sznol, MD (Yale Cancer Center), Omid Hamid, MD (Angeles Clinic), and others who have been doing this for a decade have treated 500 to 900 patients.

We each have a body of experience. Those in lung cancer, breast cancer, lymphoma, etc, will come to us to discuss how to manage the side effects because we know the ropes. So, we are out there educating them.

Do you think checkpoint inhibition will eventually displace chemotherapy in melanoma, as well as other cancers?

I was asked to do a presentation at the Society of Neuro-Oncology on the management of side effects and how to understand the patterns of response for immunotherapies, because neuro-oncologists now have to know this stuff, too.As a melanoma doctor, I have never been a big fan of chemotherapy. In fact, I hate dealing with the side effects of chemotherapy.

In our field, I do think immunotherapy will essentially replace the use of chemotherapy. I think it will drop to a fourth- or fifth-choice therapy. Chemotherapy will not disappear entirely. It will still have a place as a debulking modality and as an adjuvant therapy in breast cancer, colon cancer, and others.

The potential treatment options in first-line BRAF-mutated metastatic melanoma are growing rapidly with both targeted and immunotherapies now being considered. How do oncologists select the right treatment?

I look forward to the day when we will no longer have to deal with myelosuppression, mucositis, and all of the horrible manifestations from cytotoxic chemotherapy. It is not going to happen soon, but I think it will happen in my working lifespan.It has to be tailored to the patient. Precision medicine is the big buzzword right now and, indeed, there is good rationale for that. We need to look at each patient and really individualize the treatment to them based on their goals, persona, the characteristics of their tumor, and if their disease is rapidly or slowly progressing. BRAF mutation status must also be considered, as well as LDH levels and whether the patient is symptomatic or not.

Today, I saw a young patient who is a good example of why individualized medicine is important. Patients in their 20s are almost always BRAF-mutated but, in this particular case, I think the patient’s best option is to go with radiation of an isolated metastasis, which is thankfully all they have. Then, they follow up with immunotherapy.

This could take potential advantage of the immunologic priming induced by the radiation therapy. Could this patient have gone on BRAF plus MEK inhibitors? Possibly. However, it is likely that even a BRAF-mutated patient will have a longer median survival with immunotherapy than with targeted therapy, based on data that is out there.

However, those of us who treat these patients all agree that, if you have a BRAF-mutated patient with rapidly progressing disease that is very symptomatic, they should go on a combination of BRAF-targeted agents plus MEK inhibitors, or enroll in a BRAF/MEK trial. The big question is, “How long do you continue this treatment?” There are data from the University of Texas MD Anderson Cancer Center suggesting that, in the first 8 weeks of giving BRAF/MEK drugs, there is an influx of immune cells and the creation of an immunogenic tumor environment. That is when you may want to follow up with immunotherapy.

Are there trials investigating that question currently?

The question is, “How long should patients stay on targeted agents before switching to immunotherapy?” That is going to require a clinical trial to answer that question.Interestingly, the most important trial that addresses issues of targeted versus immunotherapy is a large randomized cooperative group trial that NYU Langone will be part of, which randomly allocates BRAF-mutated patients with metastatic melanoma to either receive initial targeted therapy with the BRAF-targeted drugs dabrafenib (Tafinlar) and trametinib (Mekinist) followed by ipilimumab (Yervoy) and nivolumab (Opdivo) when they fail, or they start with ipilimumab and nivolumab and then receive daratumumab and trametinib if they fail. All those drugs are active, so it is going to take a long time for a difference to be seen.

Regarding the issue of how long to prime with the targeted therapy before switching to an immunotherapy, there is no large trial planned that answers that question. That is tough to answer. It would require a randomized discontinuation therapy trial that would need a lot of patients. Our drugs are such a success that, to find a drug or combination that is going to go above and beyond what we already have, would really take a long time. It is great for patients, but is complicated in terms of moving the field forward.