Atkins Considers Comorbidities That Limit Use of IO Doublet in Advanced 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

EVENT REGION Minnesota and Wisconsin

PARTICIPANT LIST Raymond Lobins, DO | David Potter, MD | Mark Karwal, MD | Shahid Waheed, MD | Somasekhara R. Bandi, MD | Christiane Zoghbi, MD | Hilary Ufearo, MBBS

DISCUSSION QUESTIONS

• Beyond the absence of an actionable BRAF mutation, what factors influence first-line selection of immunotherapy (IO) monotherapy vs dual IO therapy?

ATKINS: Can the person who [chose] pembrolizumab [Keytruda] tell me why you chose that?

LOBINS: I didn’t choose pembrolizumab, but I’m a little bit surprised that nobody took the RELATIVITY-047 trial [NCT03470922] results and [chose] nivolumab [Opdivo] and relatlimab [Opdualag]. I did nivolumab plus ipilimumab [Yervoy], but I’m a little bit surprised that nobody took the RELATIVITY-047 [regimen].

POTTER: I think the progression-free survival from CheckMate 067 [NCT01844505] is a good argument [for nivolumab/ipilimumab], and it has good long-term follow-up.¹

ATKINS: For this patient, why did you choose nivolumab/ipilimumab? Do you choose that for all your patients? Was there a particular reason for this patient?

POTTER: You also are weighing the toxicity of the treatment. Certainly, nivolumab alone has activity as well. You could make an argument for nivolumab alone in someone who’s 78 years old who may have ECOG performance status 1 or 2, may not be doing quite as well, where you have a little less toxicity and you’re still getting decent efficacy.

ATKINS: You would say performance status, and comorbidities, some symptoms might lead one toward choosing anti–PD-1 monotherapy such as pembrolizumab, or nivolumab [alone], which nobody chose. What factors might influence you to choose nivolumab with ipilimumab?

KARWAL: The elevated LDH influenced me to risk the combination therapy.

ATKINS: Did the liver metastasis influence [you] at all?

POTTER: Yes, to some degree it does. You want to get the best result for your patient. You can always drop the ipilimumab if there’s too much toxicity.

ATKINS: Are there patients where one might give single-agent anti–PD-1? Which type of patients are those? What factors should one consider?

WAHEED: Single agent [could be used in a patient] with less tumor burden and high PD-L1 [expression]. If the patient has some adverse events [AEs] or poor tolerance, you could give single-agent nivolumab.

ATKINS: We don’t usually use PD-L1 expression for melanoma because even the patients with low PD-L1 [respond], but if you are getting it, that might be something that might influence you to go with single agent. What type of comorbidities would one be concerned about that might lead you to using an IO monotherapy vs a combination?

WAHEED: Any history of autoimmune disease or lung disease, [or] if patients had any kind of chronic lung disease related to pneumonitis previously or any other inflammatory process, that probably comes to mind.

ATKINS: That’s a good point, that you can give anti–PD-1 to patients who have had some autoimmune conditions, even though those patients were excluded from the trials. If somebody has a BRAF wild-type disease, the only treatment option is IO, and they have a history of something like rheumatoid arthritis, or dermatitis, or maybe a remote history of colitis that’s not active and they’re not on immunosuppressive drugs, it’s probably safer to give an anti–PD-1 monotherapy than a combination that includes ipilimumab, and sometimes you can get away with it.

KARWAL: What about if the patient [had] a liver transplant or heart transplant?

ATKINS: Unfortunately, they will die [if given IO]. They’ll lose their liver or their heart. Some people like Evan Lipson, MD, have said they’ve been able to get away with it, but I wouldn’t try it. I wouldn’t try it in someone who has a history of myasthenia gravis or some life-threatening autoimmune condition that if it were activated [would be deadly].

KARWAL: What about autoimmune hepatitis?

ATKINS: Yes.

POTTER: [What if the patient has] multiple sclerosis?

ATKINS: Multiple sclerosis has not been that much of a barrier. We’ve not seen [AEs] there as much. But it’s certainly a reason for selecting a monotherapy over a combination.

BANDI: What about inflammatory bowel disease in the intestines?

ATKINS: I’ve treated some patients with inactive inflammatory bowel disease where they’re not on any [medication] that’s immunosuppressive, and I’ve done a colonoscopy and seen that their colon or their small bowel is not inflamed. About half the time, it will bring back the autoimmune condition but sometimes you can get away with it, and sometimes those patients are very responsive to immunotherapy. Even though you cause a flare, their cancer responds at the same time. Sometimes you can even put someone on something like an anti-TNF [tumor necrosis factor] and still try anti–PD-1 if they have active disease, and sometimes you might see some activity there. There have been some reports of that, although I think that if you can get someone off the immunosuppressive regimen, you have a better chance of more fully activating their immune [response].

DISCUSSION QUESTIONS

• Discuss your comfort level in managing immune-related AEs (irAEs) in the setting of metastatic melanoma.
• How has this changed over time?
• To what extent does ease/difficulty of managing potential toxicities factor into your recommendations?

WAHEED: Over time, we have become more [experienced]. I have one patient who had very severe hepatitis, [who was treated for] renal cell carcinoma. The tertiary center didn’t want to touch it, so I used high-dose steroids and over a period, his functions came back normal. There is a problem with these endocrine [irAEs]. We don’t have much access to endocrinologists. We don’t have access to ophthalmology. Their wait time is 3 months, [but] sometimes there are AEs…that you need help to manage. But, overall, managing immune-related AEs has become much better over the years.

ZOGHBI: There was a learning curve with immunotherapy, but I think with us as community oncologists treating patients with so many types of cancer with IO, our [experience] has definitely improved. We have a high level of [suspicion] for even rare AEs. Now that I have several patients on IO, I see a lot of thyroid problems and adrenal insufficiency, and those are manageable and easy to pick up. The more you see patients, the more you start noticing other types of toxicity that are less prominent but even more serious. For example, I have a patient with immune-induced myositis that was bad. For a couple of patients I was concerned with hepatitis. I have a patient whose liver function test levels got up to 2500 to 3000 U/L [of alanine aminotransferase]. I haven’t had heart toxicity, but that also could be a serious one to manage. To help managing those toxicities, we need the help of other specialties. I have learned to communicate with [specialists], whether it was with a pulmonologist, endocrinologist, or a cardiologist, in managing those toxicities.

ATKINS: Does the ease or difficulty of managing these toxicities influence your choice of therapy regimen for the patient?

ZOGHBI: We try to do the best for our patients. We must take into consideration patients’ baseline issues. But always we try to give the best to the patient and try to see how we’re going to get along with toxicity. But a lot of those immune-based therapies have shown survival benefit and have [been used in] lots of patients. Those toxicities should not prevent me from giving the drug. Unless contraindicated, I still would offer the best to the patient.

ATKINS: On a scale of 1 to 10, with 10 being the hardest to manage and 1 being the easiest to manage, how would you score each of these different regimens or treatments for patients with metastatic melanoma, in terms of toxicity, ease of tolerability, and ease of management of the toxicity?

BANDI: With 10 being the toughest, I would say 8 to 9 for nivolumab/ipilimumab and 3 to 4 for pembrolizumab and nivolumab. I don’t have personal experience with nivolumab/ relatlimab. I’m assuming it’s going to be [at] 4 to 5 based on the experience [of others] and also based on the data.

How comfortable are you to rechallenge patients with anti–PD-L1 agents after hepatitis requiring steroids? Is there any situation where if the patient is otherwise stable and liver enzymes are all back to normal, if they’re doing well, [they could rechallenge], or is this an absolute contraindication?

ATKINS: Some things are an absolute contraindication like myocarditis, myositis, Guillain-Barré syndrome, or myasthenia gravis, and some neurotoxicities. But, for some toxicities, if it happened with nivolumab/ipilimumab and the patient has recovered, including hepatitis or colitis, you can often get away with single-agent anti–PD-1 once they’ve recovered.

DISCUSSION QUESTION

• Were you familiar with the data from RELATIVITY-047? What is your reaction to these data?

ATKINS: Were people familiar with the RELATIVITY-047 data? What is your reaction to those data?

KARWAL: [I think it is] too early for prime time. If you could ever figure out whom you would not want to give a CTLA-4 drug, you could consider this as the doublet instead of a single-agent PD-L1 drug.

ATKINS: If there were patients who we talked about before whom you would give PD-1 monotherapy to, would that be a group of people [for] whom you might consider nivolumab/relatlimab instead of nivolumab or pembrolizumab monotherapy?

KARWAL: Yes, potentially, but you still see more irAEs, and the reason I’m not giving the doublet initially is that I’m concerned about irAEs [From the Data²]. Does it really have that much efficacy, or it is too early [to know]? I would still favor single-agent PD-L1.

UFEARO: In some patients in whom I [would] use single agent, I think that nivolumab/relatlimab is a good alternative to single agent. I feel that the data are compelling to use that in place of single agent.

WAHEED: The drug [company] representatives usually tout it as a second-line [option], and some of the data also show [that compared] with the nivolumab/ipilimumab it is a bit inferior. Second line will be a better place for this drug.

POTTER: I’d take patient age into account. So if I had a 25-year-old in my clinic, I think I would go for nivolumab/ipilimumab.

ATKINS: What about the 78-year-old whom we were talking about in the case?

POTTER: I think nivolumab/relatlimab might be a better option [in that case].

LOBINS: Have they had any data collected where you start on nivolumab/ipilimumab and got nivolumab/relatlimab, vs if you start with nivolumab/relatlimab and got nivolumab/ ipilimumab? Do they have any of those data that would suggest you are able to salvage on second line?

ATKINS: Those trials haven’t been done. Early on, when there was just nivolumab and ipilimumab, there were some trials like that where patients would flip between them. If you started with the best treatment, that meant you did best because most of the impact of an immunotherapy is in the first 6 to 12 weeks. The things that [investigators] are looking at are trying to decide which patients should get which type of regimen and some biomarkers may help with that, but what we’re left with are clinical characteristics. Then [they are] looking at potential triplets of nivolumab/ipilimumab and relatlimab where you might be able to raise the bar for cure even higher.

LOBINS: When you look at the RELATIVITY-047 data, part of the baseline characteristics was a LAG3 [expression] score. If you have a LAG3 [expression], is relatlimab a better drug? I don’t [have experience testing for] a LAG3 score.

ATKINS: LAG3 is on immune cells, and 75% of patients had LAG3 expression on their immune cells.² They also looked for PD-L1, and there was a slight difference in patients with high PD-L1. There wasn’t much of a difference between nivolumab/relatlimab and nivolumab. But, in patients who had low PD-L1, the nivolumab/relatlimab [showed] benefit, suggesting that LAG3 expression on T cells was what was controlling or preventing the immune response against the tumor, and that blocking LAG3 helped to activate the immune system. But when you activate the immune system, PD-L1 is going to end up being expressed on the tumor cells, and therefore you must keep the PD-1 pathway blocked as well. In Europe, nivolumab/relatlimab is only approved for patients with low PD-L1. But as the data mature, I’m not sure that distinction is going to hold up.

_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}