Roundtable Discussion: Atkins and Participants Look at Dual Immunotherapy Options in Frontline Metastatic Melanoma

Michael B. Atkins, MD (Moderator)

Deputy Director

Georgetown Lombardi Comprehensive Cancer Center

Scholl Professor and Vice Chair

Department of Medical Oncology

Georgetown University Medical Center

Washington, DC

CASE SUMMARY

A 73-year-old man with a history of stage III melanoma underwent surgical resection 12 years ago; his lymph node dissection (LND) result was positive for nodal involvement. The patient declined complete LND and adjuvant systemic therapy. He has remained active since his surgery and maintains regular follow-up appointments.

On routine follow-up, the patient presented with moderate asthenia that limited his daily activities. His ECOG performance status was 1, and his physical examination was unremarkable. Notable laboratory findings included lactate dehydrogenase (LDH) level of 380 U/L (reference range, 110-240 U/L). A full-body CT scan revealed pulmonary and hepatic nodules but no evidence of brain metastases. He underwent core-needle biopsy of the largest hepatic lesion in segment IVb without any complications. Pathology revealed metastatic melanoma.

DISCUSSION QUESTION

• What type of molecular testing would you obtain for such a patient at this time?

ZAMAN: I would get next-generation sequencing [NGS] and test for BRAF and all other mutations.

BHANDARI: I would do BRAF testing only. We have a drug that is BRAF-directed. I don’t know how much more NGS I would do.

NATHAN: I would check BRAF. That’s the only mutation we have a target for.

ATKINS: The NGS will often take 3 weeks, and you want to be able to start therapy right away on this patient. He has some symptoms, and there [are] some quick ways of only getting a BRAF test. You don’t need the other tests now, and you don’t need them if he does have a BRAF mutation. You’ll know that he doesn’t have the other mutations; just a BRAF test would make sense.

GAI: At this time, oncology clinical trials have a lot of things going on with immunotherapy combinations. I try to do the NGS to know the molecular signature of a given cancer for future referencing.

ATKINS: That might be true for a lot of cancers, particularly lung cancer, but I don’t think it’s true for melanoma, where we don’t use PD-L1 staining and don’t make any decisions at the beginning except [those] based on the BRAF mutation status. It’s best to do things quick.

When I’m seeing a patient as a second opinion, it frustrates me when the tumor’s been sent out for NGS and I must wait for that to decide what I’m going to do for a patient and I can’t get access to the tumor otherwise. It’s not my view, but I could see where it’s relevant in other diseases.

CASE UPDATE

• Testing results were negative for BRAF mutations.

ATKINS: I think about 20% of patients [aged] 80 years will have BRAF mutations, [whereas] about 80% [of patients aged 20 years] will have BRAF mutations in their tumor.

DISCUSSION QUESTION

• Please discuss your reasons for your choice of first-line therapy.

ATKINS: So 80% of participants would give nivolumab [Opdivo] and ipilimumab [Yervoy]. Dr Kannarkat, would you give nivolumab and ipilimumab?

KANNARKAT: Yes, I would. I’ve had good responses and durable responses with that [combination]. I haven’t had any experience yet with nivolumab plus relatlimab [Opdualag] personally, but that may be the way things are going. Most of those responses and durable responses have been in younger patients, but some of my older patients have had a harder time tolerating nivolumab plus ipilimumab. But usually that settles down once they get to the nivolumab-only part. I’ve had overall experience and familiarity with that regimen.

KHASAWNEH: I picked ipilimumab and nivolumab. This patient is symptomatic and has [metastatic] disease. I would go with the regimen with the highest response rates because one needs to get a response as soon as possible, and this is the one that’s associated with the highest response rates and the highest long-term survival data, [meaning] durable long-term remissions. They [published] the 90-month [data] update in [2022].1

It also offers the patient the opportunity to not [receive] second-line therapy. I would present it as the No. 1 preferred regimen, with the caveat that the rates of [grade] 3 or higher adverse events [AEs] are in the range of 60% to 70% and the discontinuation rate is close to 25%. I tell my patients they will likely experience high-grade AEs. Which one and how bad? No one knows. I discuss with them the colitis, pneumonitis, skin rash, and musculoskeletal pain. If they are reluctant about this regimen, my second [option] will be nivolumab plus relatlimab based on the data comparing it with nivolumab alone.2 I would love to see longer follow-up data and see how the overall survival [OS] data mature.

ATKINS: Would anyone give nivolumab and relatlimab first, and why?

NATHAN: I would. I’ve been using ipilimumab and nivolumab all these years, but based on the recent data on nivolumab plus relatlimab, I want to give it a try.

ATKINS: Is there anything specific about this patient that would give you pause with nivolumab plus ipilimumab?

NATHAN: If they can tolerate nivolumab and ipilimumab, they can tolerate nivolumab and relatlimab. For this patient, they have good performance status and metastatic melanoma. I think both drugs have great efficacy, so either one of them would do.

DISCUSSION QUESTIONS

• What has been your experience with nivolumab plus relatlimab?
• If you have not used nivolumab plus relatlimab yet, what is your perception of it?

BHANDARI: I have used it [for] a patient who received pembrolizumab [Keytruda] in the adjuvant setting and had progression within 5 months. I ended up using nivolumab plus relatlimab because there were no other options available.

ATKINS: Why wouldn’t you have used nivolumab plus ipilimumab in that setting?

BHANDARI: The patient had already [received immunotherapy]. I thought this [was] a novel option. I probably could have used nivolumab plus ipilimumab. The patient has cutaneous metastases, and those are shrinking; we see the response. That’s very encouraging.

ATKINS: How is he tolerating it?

BHANDARI: Very well. No diarrhea and no immune-related AEs, except for mild rash.

ATKINS: That’s good to hear. So most of you have not used this regimen. Dr Nidhiry, can you comment on your perception of this regimen?

NIDHIRY: It has a better response rate than single-agent checkpoint inhibitor therapy, but I want to see [whether] it will show an improved OS. Part of the reluctance in using it is [that] ipilimumab plus nivolumab has been established as an agent with significant long-term survival in this patient population.

Recently, I thought of using nivolumab plus relatlimab in an older patient with a poor performance status. I was concerned that the patient [would] not tolerate ipilimumab plus nivolumab. But the insurance refused to approve it because there was no OS advantage, and they said they would approve either ipilimumab plus nivolumab or single-agent checkpoint inhibitor. That is the pushback I got. Otherwise, the reason I haven’t used it is [because of] the lack of OS data.

ATKINS: That’s a surprising response from the insurance company, but maybe they were looking at the NCCN [National Comprehensive Cancer Network] guidelines and staying with their category 1 recommendations [prior to nivolumab/ relatlimab being placed in category 1].3 Does anyone have anything else to say about their understanding and perceptions of this regimen?

KHASAWNEH: I look forward to this regimen because of the RELATIVITY-047 trial [NCT03470922] data.2 The combination was superior, but what was reassuring [was] that the AE profile was comparable between the relatlimab plus nivolumab arm [and] the nivolumab-only arm. So it is a superior regimen with slightly higher rates of toxicity, [which is] not what one would expect from a combination immunotherapy regimen.

DISCUSSION QUESTIONS

• Thinking about the preferred first-line regimens for patients with non–BRAF-mutated, unresectable/ metastatic melanoma, what type of patient do you consider ideal for each one?
• For which patients do you recommend first-line single-agent immunotherapy (pembrolizumab or nivolumab)? For which patients do you recommend first-line dual immunotherapy (nivolumab plus ipilimumab or nivolumab plus relatlimab)?

ATKINS: Most of you are not in favor of monotherapy unless there are some social issues [or] a severe autoimmune issue or you’re worried about their overall performance status and ability to tolerate ipilimumab. But are there patients for whom you would consider nivolumab plus relatlimab over nivolumab plus ipilimumab?

GAI: This is the first time I have heard about it; I don’t see many patients with melanoma. It sounds like it has a different mechanism. I’d be interested to know and look at more data. I’d be willing to use it.

NATHAN: The AE profile of nivolumab plus relatlimab is almost the same as nivolumab alone. I have used nivolumab plus ipilimumab for melanoma. The kind of patient [for whom] I would choose it is one with an ECOG performance score of 0 or 1; [fewer] comorbid conditions; no history of inflammatory bowel disease, which includes ulcerative colitis or Crohn disease; and no history of a severe autoimmune disorder that requires therapy other than steroids. I could use it in anybody with extensive metastatic disease with no comorbid conditions.

ATKINS: Are their patients whom you would give nivolumab plus ipilimumab over nivolumab plus relatlimab? [There is] the issue of brain metastasis. But do you feel that if there are brain metastases, nivolumab plus ipilimumab is the choice you must use? Are there other situations [such as] elevated LDH level?

SAFA: I agree with the combination of nivolumab and ipilimumab for brain metastases.

ATKINS: Are there other conditions where you would choose nivolumab plus ipilimumab over nivolumab plus relatlimab?

SAFA: That [would be my choice for patients] with high tumor burden and high LDH [level].

ATKINS: I would agree with those things.

DRUCK: I think the issue is toxicity related, because the study was this regimen vs nivolumab alone and we’re not [using] that. The real issue is the regimen vs ipilimumab plus nivolumab. The efficacies are there [for both regimens], so the question comes down to the toxicity. For instance, [in] this study, approximately 7% [of patients had] infusion reactions. Infusion reactions are a big problem for me and the staff. I don’t know about the patient, but for me and the staff it’s a big issue. That’s a toxicity I care about. If I had a patient, [the choice] would be driven by toxicity, not efficacy.

ATKINS: My view of toxicity, and most but not all my patients feel this way, is [that] the biggest toxicity facing a patient you’re having this discussion with is from their melanoma not being effectively [managed]. Most of the others we can manage well, but having their melanoma not respond durably is certainly a bigger problem.

DISCUSSION QUESTIONS

• How do you feel about managing the toxicity of nivolumab plus ipilimumab now vs when the regimen was first approved?

ZAMAN: It’s a learning curve. As time passes, we are all learning. Because we are seeing unusual toxicities—not only colitis, hepatitis, pneumonitis, and adrenal insufficiency. I have seen a couple of patients, so I’m seeing more and more toxicity than when we started. I have a patient who is on ipilimumab plus nivolumab, but the patient had thrombocytopenia. I thought it was ITP [immune thrombocytopenic purpura]. He did not respond to the standard dose of IVIg [intravenous immunoglobulin] and ended up with the 1-g/kg dose, and he is responding. So it’s a learning curve. When I look at the organ involvement, that scares me. Sometimes with [minor] symptoms, one wonders whether it is immune related.

NATHAN: Did the RELATIVITY-047 trial include patients [with] BRAF-mutated [disease], whereas the CheckMate 067 trial [NCT01844505] did not?

ATKINS: All the studies included patients with BRAF- [mutated] melanoma.

ZAMAN: With the long follow-up, how many patients progressed between year 5 and 7 on average? I’m asking to know how often we should [perform imaging for] them after 5 years.

ATKINS: I don’t think we fully know about the imaging question. I’ll just tell you about the data. There are few patients who progress after 3 years. There’s a plateau.4 The numbers go down a little from progression or death, and a lot of the deaths are for other reasons. So if you make it to 3 years, particularly if you stop therapy and your disease hasn’t come back, you’re probably [in effect] cured. At the 3-year point, I scan patients twice a year, and at 5 years I stop.

DRUCK: You have seen a lot more cases than I have…[but] I’ve given up on trying to figure out when the melanoma will come back and how it will come back. I don’t tell the patient those things because I don’t believe it myself. Melanoma is such a strange disease. I’m more guided by the response rates and the [depth and durability] of response. I’m not guided at all by long-term statistics because I don’t [believe the disease is gone]. I don’t have the experience you do. You have a lot more patients with melanoma than I do, but the melanomas I’ve seen are [unpredictable], and I’m not guided by the statistics. I’m guided by the toxicities and the response rates I can see rather than [by] what’s going to happen later. I don’t believe we’re in control. It’s like breast cancer; 15 to 20 years later, it can come back.

ATKINS: Does anyone else feel the same way as Dr Druck? [Consider a] case where you gave them immunotherapy. They had a major response or complete response. You stop treatment, and they’ve been free from progression for 2 years. Does anybody think that they’re likely to be cured at that point?

KANNARKAT: I’m not sure what to think. I’ve had a few patients [experience] relapse quickly after stopping some form of immunotherapy, and I’ve had [patients] go years without any relapses.

ATKINS: We’ve got a lot of experience with this back to the IL-2 days. If you’re progression free on nivolumab and ipilimumab at 3 years, particularly if you’re off therapy for 2 years, you’re 95% likely to remain free from progression the rest of your life.1 So I think it’s a service to the patient to let them know that they beat it, [though it is] not 100% certain. They should contact you if they have new symptoms, but they should go back to their normal life. It’s amazing how wonderful it is for patients to do that when they feel that way.

KANNARKAT: For the nivolumab plus ipilimumab, nivolumab-alone, and pembrolizumab-alone trials, how long was the duration of treatment? Was it the standard 2 years?

ATKINS: For the KEYNOTE-006 study [NCT01866319], pembrolizumab was stopped at 2 years.4 The CheckMate 067 study had no termination of treatment, but the median duration of treatment was somewhere around 12 weeks because half the patients had toxicity during the nivolumab plus ipilimumab phase that caused them to stop.5 They weren’t allowed to go on nivolumab monotherapy afterward. So most of those patients who were out 5 years or more have been off treatment for over 4 years.1

Only about 5% of patients were still on nivolumab monotherapy at that point on the nivolumab plus ipilimumab arm. If you look at the 5-year period and talk about how much time the average patient [was] treatment free without progression, it’s one-third of that 60-month period. That ignores the patients who died. This is alive and treatment free, so it’s 33% of the time. You can get a sense of what that is for the patients who are responding [and] represent half the patients.

_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. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Cutaneous melanoma, version 1.2023. Accessed March 17, 2023. https://bit.ly/2UK2FST}

_{4. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532. doi:10.1056/NEJMoa1503093}

_{5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34. doi:10.1056/NEJMoa1504030}