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Melanoma Immunotherapy FAQ
Experts Address Questions on the Use of Immunotherapy for Resectable and Unresectable Melanoma in Today’s Practice

Released: July 19, 2023

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Key Takeaways
  • Neoadjuvant immunotherapy is becoming the standard of care for patients with resectable melanoma.
  • Sequencing therapies after progression on combination immunotherapy is challenging, as currently available therapies have limited efficacy in later-line settings.
  • Anti‒PD-1 monotherapy is still an option for certain patients, such as those with poorly controlled autoimmune conditions or organ transplant recipients.

In this commentary, Allison Betof Warner, MD, PhD, facilitates a discussion with Evan J. Lipson, MD, and Michael Postow, MD, addressing questions submitted by a healthcare professional audience during a live webinar focused on immunotherapy options for resectable and unresectable melanoma.

Are there additional therapies, such as nivolumab plus ipilimumab, that are effective in the neoadjuvant setting?

Evan J. Lipson, MD:
In addition to pembrolizumab, other therapies have shown efficacy in the neoadjuvant setting, including nivolumab plus ipilimumab or relatlimab. The studies are relatively small, and we do not have head to head data on the combination regimens. For example, the nivolumab plus relatlimab study was a single-arm study.

What should the time frame be from diagnosis to starting neoadjuvant therapy?

Michael Postow, MD:
I think there is no specific time frame, but once someone has a biopsy-proven melanoma recurrence in a lymph node or an in transit metastasis, it is generally best to start neoadjuvant therapy as quickly as possible. There is no reason to wait because we are not going to surgery right away, but rather starting with systemic therapy. If you are a medical oncologist and you are seeing a patient who has biopsy proven, resectable, high risk melanoma, it is reasonable to start neoadjuvant therapy. On the other hand, if the patient already has had surgery and their melanoma is all resected, we usually want to start adjuvant therapy within 3 months of surgery. If you have a patient who is 4 or 5 months out from surgical resection and want to think about adjuvant therapy, that is not a setting where we have data.

How do you manage a patient who has progressive disease after neoadjuvant immunotherapy followed by adjuvant immunotherapy?

Evan J. Lipson, MD:
The question really is about sequencing therapy for patients. Let me start with the simplest of those scenarios, which is when somebody progresses through anti‒PD 1 monotherapy. There are some data to suggest that relatlimab plus nivolumab can generate antitumor responses in 9% to 12% of patients after anti‒PD 1 monotherapy. We also have data on ipilimumab by itself and in combination with nivolumab in this population, and that trial demonstrated that the combination was superior for patients refractory to anti‒PD 1. It is important to have a conversation with the patient about risk of toxicity and potential benefits of combination immunotherapy.

Michael Postow, MD:
I agree. I think this is an area where we really need new drugs, new ideas, and new combinations, as well as a better understanding of why patients progress on anti‒PD 1 therapy. For sequencing therapy, it is important to consider what therapy they received up front—anti‒PD 1 alone, PD 1 and CTLA 4 blockade, or anti‒PD 1 plus anti‒LAG 3—and then decide next steps. I think the other relevant point is knowing how the disease has progressed. Is this 1 isolated lesion that appeared 1.5 years after the completion of adjuvant therapy where resection might be an option, or is this a patient progressing after 4 or 5 doses of adjuvant anti‒PD 1 needing additional systemic therapy?

Allison Betof Warner, MD, PhD:
I think both the number of lesions and location matter. I think of in-transit disease very differently from progression in the liver or bone. I do not think it is ever too early in this setting to send a patient to a referral center and consider a clinical trial. Because response rates to all of our approved agents in the anti‒PD 1 refractory setting are poor, I think many of us who work at those referral centers want to see those patients as early as we can.

Evan J. Lipson, MD:
This is a good time to discuss deciding on therapy in the setting of a patient who has liver disease, for instance, or just a small in transit metastasis. One approach that I take is what I call “the number of shots on goal.” If I think that I have multiple opportunities to treat the patient, I am comfortable starting with something a bit less aggressive and less toxic, knowing that I can move on to something else that is perhaps more toxic. In a patient for whom I think there are limited opportunities to treat—for instance, a patient with brain or liver metastases or bulky disease—then I might start with ipilimumab plus nivolumab because we have the most data on it.

Are there patients who should be getting single-agent anti‒PD-1 therapy vs combination immunotherapy?

Evan J. Lipson, MD:
There are patients for whom I still use anti‒PD 1 monotherapy. For example, for a patient with metastatic melanoma and low-volume disease and a history of ulcerative colitis that is well controlled on medications, I start with anti‒PD 1 by itself and can add to that later. I am very cautious with patients who have immunologic comorbidities such as organ transplants and almost always start with anti‒PD 1. We plan to test dual agent therapy, but for now we are as gentle as we can be.

How do you manage a patient who has progressed on first-line immunotherapy, particularly one who has progressed on combination immunotherapy?

Evan J. Lipson, MD:
There is always an option to administer whatever immunotherapy combination they did not get or, if given monotherapy, switch to a combination. The likelihood of a response there is somewhere between 10% and 25%, depending on the previous therapy and which study we are examining. Data from the LEAP-004 study of pembrolizumab plus lenvatinib in advanced melanoma following progression on a PD-1 inhibitor found an overall response rate of 21.4%, but the concern is that the responses are often short-lived at 8.3 months. Combination therapy either with another immune checkpoint drug or something like lenvatinib is reasonable, but my choice is to enroll the patient on a clinical trial.

Do you routinely perform screening, lab work, or imaging for potential myocarditis as an adverse event associated with immunotherapy?

Evan J. Lipson, MD:
We do not. We do obtain cardiac labs for patients when we suspect there is an issue. In the past, we have had surveillance cardiac labs as patients initiate therapy that actually confused the situation rather than adding clarity. For instance, it was often confusing to see a slightly elevated troponin but not know what to do with that information.

Allison Betof Warner, MD, PhD:
I check troponin before I start so that I can see if they have mildly elevated troponin at baseline. I use that as a mitigation strategy for the panic that happens when we see an elevated level later, but I do not screen.

Michael Postow, MD:
Certainly, myocarditis is one of the scariest adverse events that can happen, but fortunately, it is also one of the rarest. If you consider screening tests, you will be screening all kinds of patients, most of whom will never have myocarditis. There is potential for a lot of false positives, uncertainty in what to do, and sending patients for extra workup. I would not recommend screening other than considering baseline troponin for the reasons we mentioned. We had experience checking troponin levels for patients receiving ipilimumab plus nivolumab, and it did not help capture myocarditis early in a way that was clinically meaningful.

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