Roundtable Discussion: Pavlick and Participants Review Treatment and AE Management in Melanoma

Anna C. Pavlick, DO, MSc, MBA, BSN (Moderator)

Director of Melanoma and Cutaneous Oncology

Assistant Professor of Medicine and Dermatology

Weill Cornell Medicine

New York, NY

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) 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 level of 820 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. Testing was negative for BRAF mutations.

PAVLICK: How do you think relatlimab plus nivolumab [Opdualag] compares with nivolumab alone in patients with melanoma?

ALAM: I did not have a good experience with it. I was using it in a patient and after 3 doses the patient had CNS [central nervous system] toxicity.

PAVLICK: Aseptic meningitis?

ALAM: The imaging was completely normal. The patient could not remember anything. This was early in April and May. The patient is still alive, but his memory never came back.

PAVLICK: Are you treating him now?

ALAM: Yes. We gave him steroids, too, but it didn’t change much.

PAVLICK: What are you treating him with now?

ALAM: Right now, he’s off therapy but his disease is unstable. We’re thinking maybe he has nothing else positive. We might have to go to chemotherapy, but I don’t know currently.

PAVLICK: To me this is the perfect patient for “flip-dose” nivolumab [Opdivo].

ALAM: Sure, that’s an option. The family’s a bit scared, but he’s a young guy, so that is a good point.

PAVLICK: If you start to see something, you stop it. You don’t have 4 weeks to wait.

ALAM: That’s a good point.

GILLANI: How much extra benefit do you think full-dose ipilimumab [Yervoy] adds to the nivolumab? Are you talking about more response rate, better progression-free survival, overall survival? What is the goal?

PAVLICK: The flip-dose data are not fully mature yet. It looked to be very active. I use full-dose ipilimumab and nivolumab with patients who have multiple small brain metastases because there are no data for flip-dose ipilimumab and nivolumab for brain metastases. If you look at the CheckMate 067 [NCT01844505] data at 77 months— that’s 6.5 years later—those patients have not fallen off the Kaplan-Meier curve.¹

Until I can see flip-dose ipilimumab/nivolumab survival data that are at least equivalent out to even 3 years—and we’re not out that far yet—then I’d just use standard dose because at least I know what the toxicity is and I know how to manage it. The 6.5 years of survival to me is what you must compare things with.

MEHTA: How many of your patients are you able to treat with full-dose ipilimumab and nivolumab with at least 4 cycles without toxicity interrupting your treatment?

PAVLICK: I deal with a lot of toxicity. I think I handle toxicity a little differently than most [clinicians] because I’ve been doing this for 20 years, and when we first started using ipilimumab we were using it at 10 mg/kg every 3 weeks. If you can do that, then 3 mg/kg is nothing. But I would say at least 60% of my patients will get through 4 cycles.

[As for toxicity in these patients], diarrhea, itching, and rash, and some delays for hepatic toxicity [are potential problems]. I have patients call me as soon as something happens. I want to know what their bowel patterns are. If there is any change in their bowel patterns I want to know because it’s at that point that I start modifying their diet.

For the first time [recently], I was a little worried about giving somebody full-dose ipilimumab and nivolumab. She has been my patient now for 7 years. A primary [care physician] gave her 2 cycles of adjuvant nivolumab and she wound up with the most horrible mouth sores, lost a ton of weight. I never treated her again after that in the adjuvant setting because of the toxicity [she experienced]. She went for about 4 years with no disease, then developed brain metastasis. We used Gamma Knife [radiosurgery on] her brain metastasis, then watched her. She got 2 or 3 more brain metastases and some systemic disease, so I gave her full-dose ipilimumab and nivolumab. She got through 3 cycles and then developed colitis and had complete resolution of her disease, but as far as I am concerned, I’ll deal with toxicity.

It took her a long time to get off steroids and she’s now been off all therapy probably for about 9 months. My goal was to get her to her daughter’s wedding. Her daughter got married and she calls me the day after the daughter’s wedding and says she has a bunch of little lumps on her back. When I saw her, she had multiple new subcutaneous nodules. I got her set up for a PET scan and we did a brain MRI, and she had 24 new brain metastases.

The degree of colitis that I gave this patient with full-dose ipilimumab and nivolumab was significant. She has an NRAS mutation. She wants to live; she’s only 67 years old. We counted 12 subcutaneous modules all over her and the 24 brain metastases. I have to get something into her brain, and my neurosurgeon is going to use Gamma Knife on the larger metastases, but for the little ones, I gave her full-dose ipilimumab and nivolumab recently.

MEHTA: Colitis is the main challenge that I face. Maybe I have bad luck but in the third cycle onward if they start developing colitis, I’m unable to continue the ipilimumab. At that point these patients are on steroids, and you start getting nervous even continuing the nivolumab as you already mentioned in the previous patient. That’s when I started doing the flip-dose and thinking at least I may avoid it happening. I have no doubt there is a dose-dependent efficacy from ipilimumab, but the toxicity is clearly there.

REZNIKOFF: With the brain metastases, if you’re going to use Gamma Knife or give steroids, does that impact your immunotherapy?

PAVLICK: The answer is it depends on the dose of the steroids. My patient was completely asymptomatic. She did not have any edema, so she did not need steroids for her brain metastases. However, if you look at the CheckMate 204 trial [NCT02320058], which was the trial we did with full-dose ipilimumab and nivolumab, we divided it into arm A and arm B.

Arm A was patients who had multiple brain metastases that were small and asymptomatic, and arm B was for patients who had larger brain metastases and were symptomatic. Although we saw a positive effect from the ipilimumab and nivolumab, it was significantly less than in those patients who were asymptomatic and got full-dose ipilimumab and nivolumab.²

We try to stay away from steroids if we can. If you’re dealing with toxicity, you have to do what you have to do. Once I get their dose of prednisone down to 10 mg, I’ll start treating again. When you’re talking about brain metastases, you have patients who are on dexamethasone…. The only good thing about treating patients on dexamethasone is you don’t have any toxicity to worry about.

If you have never used nivolumab and relatlimab, any particular reason why? Are you just comfortable with single-agent PD-1 inhibitors?

GILLANI: I just haven’t had a chance to use it in anybody yet. I think the RELATIVITY-047 study [NCT03470922] data look exciting.³ It seems like the combination of a LAG-3 inhibitor and nivolumab in a fixed dose is convenient, doesn’t add substantial toxicity, and opens another option for our patients, so I will be using it in the right patient.

PAVLICK: Good. It’s certainly not like ipilimumab and nivolumab toxicity, but it does have a little bit more toxicity than single-agent PD-1 inhibitors, whether it be nivolumab or pembrolizumab [Keytruda].

D’SILVA: I think that it’s time to use dual therapies more than single monotherapy in patients who are not candidates for ipilimumab and nivolumab.

DISCUSSION QUESTIONS

• What is your comfort level with managing immune-related adverse events (AEs) in the setting of metastatic melanoma?
• To what extent does ease/difficulty of managing potential toxicities factor into your recommendations?

MEHTA: [I am] much more comfortable over the years than before just from using it, holding doses, starting steroids, and identifying all the subtle AEs, including hypopituitarism or a drug rash…. We previously may have been a little alarmed, and not making too many changes based on that. Things like these just need strategizing in terms of which one should we be acting on and which ones are dealbreakers involving subspecialists who are also now getting trained in management of immunotherapy-related AEs. We have GI [gastrointestinal] specialists who know how to manage AEs by checking calprotectin levels and monitoring patients for that. Same thing with endocrinology getting involved earlier on, so it helps.

PAVLICK: Yes, I think the more that you have subspecialists who have a true interest in immuno-oncology [IO] toxicity, the easier your life gets. I know right from the beginning I feel like I used the gastroenterologists and the endocrinologists all at the same time. It’s nice now that many endocrinologists are comfortable with adrenal insufficiency and managing the thyroid disorders or the hypopituitarism that comes with this. I think at least for me in general, most patients have become much more comfortable because we’re using IO in so many different types of malignancies that you have no choice but to learn how to manage AEs.

Does anybody still use the wallet cards that [drug companies] provided? I used to give those out like water. Now, not so much for the simple reason that I think many of the ED [emergency department] doctors are much more familiar with immunotherapy and know that if somebody comes in with diarrhea you can do a quick infectious disease check on their stool, but they probably have IO toxicity and need steroids.

For the patients you wind up having to send to the ED, how familiar or how comfortable are your ED doctors with managing these toxicities, especially diarrhea? That is what frustrates me the most because everybody is assumed to have Clostridioides difficile because they’re an oncology patient and everybody gets metronidazole [Flagyl] before they get steroids. Anybody have a different experience?

GILLANI: Maybe I’m alone but I don’t think people understand or realize these toxicities very well in the community. I think frequently even the hospitalists don’t recognize that diarrhea doesn’t equate Clostridioides difficile colitis or infectious colitis in these individuals, so I think it’s going to be a learning curve for everybody.

PAVLICK: It’s not only the communities. I have this issue in academia. Patients go to the ED with profuse bloody diarrhea, and they are put in a room [alone] and get oral vancomycin [Vancocin]. They need to give the patient steroids. At least when they get a room on the floor, I can give them steroids but it’s very rare that a patient will get intravenous steroids, which is what they need as soon as they hit the ED when they’ve got bloody colitis, but it’s very rare that they get it.

GILLANI: How often do you have to use second-generation medications like tocilizumab [Actemra]? We are comfortable using steroids, but I think once it goes beyond steroids it becomes a little bit nerve-racking.

PAVLICK: Tocilizumab is an interleukin 6 inhibitor and so you’re going to use that more for cytokine release syndrome. If you have somebody who is steroid refractory, you’re going to use your tumor necrosis factor inhibitors like infliximab [Remicade].

_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, Forsyth PA, Hodi FS, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021;22(12):1692-1704. doi:10.1016/S1470-2045(21)00545-3}

_{3. 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}