Atkins Assesses the Differences Between Immunotherapy Strategies in Advanced Melanoma

Michael B. Atkins, MD

MODERATOR

Deputy Director and Professor

Scholl Professor and Vice Chair, Department of Oncology

Georgetown Lombardi Comprehensive Cancer Center

Washington, DC

EVENT REGION New York

PARTICIPANT LIST Mohammed Ali, MD | Madhumathi Kalavar, MD | Tony Cheung, MD | Mubasir Mundia, MD | Yvonne Saenger, MD | Kenneth Hoffman, MD | Eric Bravin, MD | Sandeep Malik, MD | Anita Gul, MD | Ilya Blokh, MD

CASE SUMMARY

A 78-year-old man with a history of stage III melanoma underwent surgical resection 12 years ago. At the time, he was lymph node density (LND) positive for nodal involvement but declined complete LND and adjuvant systemic therapy. The patient has remained active since his surgery and maintains regular follow-up, but at a routine follow-up visit, he presented with moderate asthenia limiting his daily activities but no other relevant clinical symptoms.

He had an ECOG performance score of 1, but results of his physical examination were unremarkable. Notable laboratory findings showed lactate dehydrogenase levels of 380 U/L (reference range, 110-240). A full-body CT scan revealed the presence of pulmonary and hepatic nodules but no evidence of brain metastases.

He underwent core-needle biopsy of the largest hepatic lesion, in segment IVb, with no complications. Pathology revealed metastatic melanoma, and mutation testing showed his tumor was BRAF negative.

DISCUSSION QUESTION

• Beyond the absence of an actionable BRAF mutation, what factors influence the first-line selection of single vs dual immunotherapy in a patient like this?

ALI: I think for nivolumab [Opdivo] and ipilimumab [Yervoy] the dose of ipilimumab is 3 mg/kg.¹ It’s a higher dose associated with significant toxicity. I think if the patient’s condition and performance status [are] good, only then can we use nivolumab and ipilimumab. I know it’s an effective regimen, but at the cost of significant toxicity because of the dosage of ipilimumab, as compared [with] the single agent, [which] is easier to use.

KALAVAR: I find nivolumab and ipilimumab to be the most aggressive approach that has more toxicity, so I would use it in a very fit patient with a high tumor burden who has good social support and [is] willing to [alert us] immediately if he has toxicity. [If it’s a patient who has] low-burden disease and [is] frail or fragile who cannot tolerate ipilimumab, then I will use single-agent nivolumab or pembrolizumab [Keytruda].

ATKINS: Does anyone else want to describe a patient who they would give nivolumab or pembrolizumab monotherapy to?

CHEUNG: For a patient with CNS [central nervous system] metastases, I use a combination, so [I would use] nivolumab and ipilimumab. I think the data are there to prove it’s effective and probably the better, or the best, regimen so far for immunotherapy.

ATKINS: How about for single-agent anti–PD-1 [therapy], is there a patient who you would give that to?

MUNDIA: Again, like everyone else said, for someone on a single agent [I will put them on it if they aren’t] able to tolerate dual immunotherapy. For someone who’s older and has minimal disease, I would [give them a] single agent.

ATKINS: So far, nobody has mentioned what I would look for, which is their comorbidities.

SAENGER: For me personally, the patients I’ve treated with [the] nivolumab and relatlimab [Opdualag] combination drug…the treatment has been well tolerated. So, it’s tempted me. I don’t know what you think, but I’m curious just to give the nivolumab and relatlimab instead of the single agent, given the improvement in progression-free survival [PFS].² I’m sort of wondering what the rationale would be for the single agent now that we have nivolumab and relatlimab, unless you’re worried about autoimmune disease [developing after they take it], so you really want to go slow [From the Data²].

HOFFMAN: I think the whole issue we’ve talked around, Dr Atkins, is that with the toxicity of therapy, will the patient survive? In this case, it’s a 78-year-old gentleman who’s—I’ll call him elderly because he’s older than I am—but the fact of the matter is, he’s not 30. And so any of these major toxicities can really be life-threatening, and I think that’s what’s important [to note]. Are they near a hospital? Is someone going to be there at 2 o’clock in the morning on a Saturday or Sunday when they finally call you [with a serious toxicity]? I think that’s the biggest issue.

As far as I’m concerned, I’m probably in the minority, if the person has liver metastases and they can tolerate it, then I’m going to blast them with 2 agents, not 1. You want to get rid of the disease as fast as you can, and this individual probably only has 1 course. I don’t think he’s going to get a second line of therapy. This is one and done. If the family is willing, and he’s willing to give consent, and everybody is on board, and you’ve got a hospital that can take care of a toxicity, I’m going to give him dual therapy and hope for the best.

ATKINS: I think that’s well said. I think the only place where I’m considering anti–PD-1 monotherapy right now is for patients with a history of autoimmune disease where I have no other option but to give them the anti–PD-1 therapy. I would certainly want to avoid ipilimumab. I’m not sure what relatlimab does in that setting, but, otherwise, I think I am agreeing with Dr Saenger that there’s very little use for a single-agent anti–PD-1 currently because nivolumab and relatlimab is something I’m giving to the patients who I would have given a single agent to before.

DISCUSSION QUESTION

• To what extent does the difficulty of managing potential toxicities of immunotherapy factor into your recommendations? And how has that changed over time?

ATKINS: Please rate your comfort level in managing the immune-related events in the setting of metastatic melanoma treated with immune therapy. How has this changed over time?

BRAVIN: It’s changed tremendously over time…. At this point, I think we’ve seen almost everything. I don’t want to say everything because I keep getting surprised, but the common toxicities are very manageable now.

The issue for me is that I practice in a rural area, and I just need to know that I’m going to hear from the patient when they get the toxicity, or that if they live far away and they’re going to end up in another [emergency department], is the person there going to recognize the toxicity and call me? That’s a bigger problem right now than just straightforward management of diarrhea, hepatitis, and all the other things that happen.

MALIK: Because of the use of these agents in many other settings, or we could say malignancies, the comfort level has increased considerably. We could go case by case. For example, pembrolizumab is used more than the other ones, so the comfort level is [higher] with pembrolizumab. Though the data you’re [discussing] do not show that much efficacy as a single agent.³ [Regarding the] immune toxicities, I think at this point almost all of us know what to expect and how to deal with them.

ATKINS: Dr Gul, how often does your concern about being able to manage the toxicity, assuming you can trust the patient to be reliable in reporting it, factor into your decision-making as to which treatment to choose?

GUL: The comfort level has increased, but [the concern is] not down to zero. I always worry about the toxicities I have not seen, like encephalitis and those kinds of rare ones. Luckily, they don’t happen commonly, but that’s something I always worry [about]. So, the comfort level is not almost 100%, and we are always worried, especially in the first 4 months they are getting the combined treatment.

How do you think about each immunotherapy-based option in your efforts to balance efficacy, safety, patient preferences, goals of therapy, and quality of life when recommending a first-line regimen?

ATKINS: Now we’re just trying to compare nivolumab and ipilimumab vs nivolumab and relatlimab, I think. Do you have a sense of who you might [treat with] nivolumab and relatlimab compared [with] nivolumab and ipilimumab?

BLOKH: It seems like the choice is really between these 2 regimens then. I know the data in terms of ipilimumab and nivolumab recommend ipilimumab 3 mg/kg and nivolumab 1 mg/kg, specifically in melanoma.1 But my question is, is it only a choice of those 2 regimens? For example, would you at any point, despite less convincing data, use the reverse? So, nivolumab 3 mg/kg and ipilimumab 1 mg/kg, or nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg every 6 weeks? Is there some continuum of efficacy, or continuum of AE data, where you may say, “Well, I’ll take less efficacy but less toxicity, and maybe I’ll use the reverse dosing or the every-6-week dosing?” Maybe we have more choices than just those 2.

ATKINS: I’m going to throw it open to everybody, but I’m going to give a little bit of data. There was a study that was done that looked at full-dose nivolumab and ipilimumab vs reverse-dose nivolumab and ipilimumab in patients with melanoma and showed less toxicity for the reverse dose, somewhere in the range of about 28% grade 3 or 4 toxicity.⁴ Although the study was not powered to look at efficacy, the PFS and overall survival curves look like they overlap. What do people think about that? Do you ever use a different schedule of nivolumab and ipilimumab? And, if so, in what patient?

HOFFMAN: I don’t think it’s the schedule. I’m in a suburb of a major city, so for me, transportation is not an issue. I don’t know what it’s like in the middle of nowhere. But I think, out of everything we’ve talked about…the concern about toxicity is the biggest issue. And I always think the biggest question we never talk about is, what does the patient want? Is it a life-cycle event they’re trying to get to? And we’re still talking about a 78-year-old, although we’ve maybe made it generic. He may have a grandson or a granddaughter being married next year [and he wants to be there]. That’s his goal. Or he may be living alone with some family support, but really everyone around him has died, so all he wants to do is stay out of pain.

But the other question I always ask, besides functionality, is how much disease does the patient have and where is it? Because I think that plays an important role…. And I think those are, when we do these cases, as I’m sure we all do every day, there’s a lot of gray area [to consider]. It’s not as straightforward, and so I think that’s one of our problems with an older individual. OK, yes, I’d love to give him both [regimens] and I would, but the question is, [are] there any data showing one couplet vs the other? Right now [my choice is still] nivolumab and ipilimumab.

But the one question I want to ask [is], is there any research into why patients’ tumors do not respond?

ATKINS: There’s a lot of research going on. We don’t know [this] definitively, but for many patients, they just don’t have the immune cells that recognize the mutations in the tumor. They probably have [immunologically] colder tumors, or they may have a lot of hypoxia, but [the tumor] may have other immunosuppressive factors that are keeping the immune response from working, in addition to the PD-1 pathway. For some it might have been LAG3 expression. For others, maybe they don’t have enough T cells there where ipilimumab [can have an impact]. For others we don’t know, but I think that’s still something we’re trying to study.

SAENGER: Maybe you’ll disagree with me here, but I don’t feel comfortable giving the reverse dose of nivolumab and ipilimumab because [it was] originally published that there is a dose response with ipilimumab.5 So way back when, the initial dose was 10 mg/kg. And given the fact that it took 6 years to demonstrate and fully prove the survival advantage of ipilimumab and nivolumab vs nivolumab alone, because initially the overall survival data [weren’t] there even though it was looking better, I’m not convinced that it’s not inferior.¹

ATKINS: Well, my answer to that question is, if there’s a patient I would give, let’s say, anti–PD-1 monotherapy previously or now maybe nivolumab and relatlimab, but they have brain metastases, I’m going to give them reverse-ratio nivolumab and ipilimumab because I want to make sure there’s some ipilimumab there. But for a 90-year-old with brain metastases, I can’t give him full-dose ipilimumab.

SAENGER: That would be a perfect application. I would agree.

_REFERENCES

_{1. 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}

_{2. Tawbi HA, Schadendorf D, Lipson EJ, et al; RELATIVITY-047 Investigators. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970}

_{3. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853-1862. doi:10.1016/S0140-6736(17)31601-X}

_{4. Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol. 2019;37(11):867-875. doi:10.1200/JCO.18.01998}

_{5. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155-164. doi:10.1016/S1470-2045(09)70334-1}