Role of Tolerability in Using Immunotherapy for Metastatic Melanoma

April K.S. Salama, MD

Associate Professor of Medicine

Duke University School of Medicine

Durham, NC

DISCUSSION QUESTIONS

• Thinking about the preferred first-line regimens for patients with non–BRAF-mutated, unresectable/metastatic melanoma, what type of patient do consider ideal for each one?
• For what types of patients are you “on the fence” about whether to use monotherapy or dual immunotherapy?

APRIL K.S. SALAMA, MD: I’m curious about others experiences; is anyone’s interested in sharing?

LAWRENCE NEGRET, MD: When [nivolumab/relatlimab; Opdualag] first got approved, my experience was using it in the third and fourth lines, when patients have…used up a lot of their previous regimens. Initially I wasn’t seeing a lot of response, but now I’ve had a chance to use it in the first line and I do see less toxicity compared with nivolumab [Opdivo] plus ipilimumab [Yervoy[. It’s [usable] more in patients in whom you think comorbidities might play a role.

SALAMA: That’s a great point. Like anything, when there’s something new, there are a number of patients who may be waiting.

FRANTZ FRANCISQUE, MD: I just started using it on new patients, so I haven’t had any concerns with it so far. The patient is staying on cycle. I was using it in first-line metastatic melanoma.

MAGALI VAN DEN BERGH, MD: I also started using it in a couple patients already over the last year. Essentially [these were] patients where I didn’t feel comfortable giving dual immunotherapy due to comorbidities [or] advanced age. Both patients I have on it have been doing extremely well, with no adverse events [AEs]. It has become my go-to drug for first-line patients who don’t feel like are good candidates for the nivolumab/ipilimumab combination. I haven’t really encountered any AEs.

SALAMA: Thank you for sharing. I’m curious for those who haven’t used it, about their perceptions. My experience at Duke [Cancer Institute] is similar in the sense we did not participate in any of the trials. We’ve mainly used it in the standard-of-care setting. At Duke, sometimes there’s a financial barrier in review and authorization, but from a medical decision-making standpoint, it can definitely be a good regimen…for patients whom I don’t consider appropriate for therapy with nivolumab/ipilimumab.

I’m getting a sense that [we] feel like the first-line immune monotherapy group is this narrower group of patients with comorbidities or another specific situation. Are there patients whom you’re on the fence about? When your choice was PD-1 monotherapy vs nivolumab and you would’ve used monotherapy, are those patients now that you’re considering for nivolumab/relatlimab or still maybe giving them monotherapy?

CANDICE BALDEO, MD: I’m in a rural area, and pembrolizumab [Keytruda] can be given every 6 weeks, [which] is favorable for some patients who don’t have transport. I do give pembrolizumab in some cases like that because of the schedule, [as well as cases where] COVID-19 is bringing them into the clinic less.

SALAMA: That’s a great point [concerning] schedule administration and logistics. Similar issues may prevent access to prompt management of AEs. I certainly see that in my practice, even though I practice in more of an urban and suburban area. We have patients who live 6-plus hours away; there can be barriers to care. COVID-19 has prevented or limited travel for some patients.

DISCUSSION QUESTIONS

• What is your comfort level in managing immune-related AEs [irAEs] in the setting of metastatic melanoma?
• To what extent does ease/difficulty of managing potential toxicities factor into your recommendations?​
• What is your opinion on the tolerability and ease of toxicity mitigation/management of each regimen as first-line systemic therapy for metastatic melanoma?

SALAMA: I’m curious how your comfort level and managing irAEs has changed over time.

NEGRET: What was more challenging for me at the beginning were the hormone-type immunotherapy issues. We had to try to figure out if somebody had adrenal insufficiency or hypophysitis. Those were more challenging for me because we haven’t done that a lot lately. Rechecking those levels at 8 in the morning was more difficult. The dermatitis and colitis were easier to [manage]. It was the hormone-type AEs that were more difficult for me. I think I’ve done a lot better now with experience.

SALAMA: Do you primarily manage the endocrinopathies or do you have access to an endocrinologist?

NEGRET: The issue we’ve been having lately at the University of Miami is you put in a consult for endocrinologist and [may take up to] 6 months. It’s been a big difficulty. They’re going to start an immunotherapy task force, where they’re going to try to get 1 physician from each field who’s going to be accessible to be able to talk to oncologists. They’re going to have a cardiologist, endocrinologist, and rheumatologist [who are] going to cross-train and we’ll be able to use them as a means without having to put the patient in their clinic. That is something that’s being looked into.

SALAMA: It’s an issue [in my institution] as well. An interested endocrinologist and others have created a virtual consult…that helps give you some management and dosing advice until they see an endocrinology, which…can be [up to] 2 months. This is hard if your patient’s having a lot of active symptoms, so I will say that’s helped somewhat because we can usually get an answer within a day or 2 about management. I typically manage thyroid-related issues, but the hypophysitis is pretty complex. There’s a lot that goes into it. We try to reach out to the specialist in things that are uncommon like Type 1 diabetes, but I’m a few years out now from my medicine training. I always appreciate the help. It is a challenge when I talk to other colleagues at other institutions and community practices as well. In terms of subspecialty co-management of irAEs, is that an issue for you all?

PHU N. TRAN, MD: That is a big issue for us in the mid-Florida [region], especially when you try to refer them to endocrinologists or rheumatologists. It takes [approximately] 6 months. Everybody’s very busy here. It’s very hard. We end up treating these on our own. It’s difficult but you do what you have to do.

SALAMA: Absolutely. How much do these factor into decision making?

TRAN: From my standpoint, I would be worried if they have baseline autoimmune disease. That’s something I would be concerned [about]. Most of the time they already have a rheumatologist and that’s when I would consult with the rheumatologist over that. In patients who have no autoimmune history that we know of, I would be comfortable treating them with immunotherapy for most of them, especially [since] the treatment is so crucial for melanoma.

VAN DEN BERGH: Yes, I agree with you. We don’t have good alternatives for metastatic melanoma and the data are there with immunotherapy, changing the way we treat and manage melanoma, and [it has] improved significantly compared with the pre-immunotherapy era. Knowing that we can have these immune-mediated toxicities [including] endocrinopathies does not scare me away from giving immunotherapy and should not scare the patients either, because a lot of those endocrinopathies are manageable. We can continue the treatments. We all have become more comfortable managing these AEs. That’s because we use immunotherapies commonly now in many different cancers. Certain [endocrinopathies] are much easier to manage than other ones. I’m thinking of hypothyroidisms [and similar toxicities]. We all feel very comfortable managing those.

I had another patient with insulin-dependent diabetes developed from durvalumab [Imfinzi]. Some of these things can also be handled by a primary care physician. It doesn’t always require an endocrinologist to be on board because it’s an issue everywhere with endocrinology to get in timely and get an appointment. It’s the same where I practice in southwest Florida. There are long waitlists to be seen. It’s not a reason for me not to give immunotherapy. We should counsel patients the same way.

SALAMA: That’s a great point and well said. It sometimes will influence my decision to give something like nivolumab/ipilimumab now that we have other options, or [modify] the dosing…if I sense barriers to adherence or follow-up or reporting of AEs, but I agree. For melanoma, for a BRAF wild-type patient…the potential upside of immunotherapy is huge. We’ve touched on the PD-1 monotherapies having some advantages in terms of tolerability and ease, with nivolumab and ipilimumab maybe having higher AE rates.¹ Nivolumab/relatlimab is somewhere in the middle, is how I would reflect on that.²

_References:

_{1. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970}

_{2. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol. 2022;40(2):127-137. doi:10.1200/JCO.21.02229}