Efficacy and Tolerability of Immunotherapies Discussed for 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

DISCUSSION QUESTION

• What data from the CheckMate 067 (NCT01844505), KEYNOTE-006 (NCT01866319), and RELATIVITY-047 (NCT03470922) trials would influence your choice of immunotherapy for metastatic melanoma?

MICHAEL B. ATKINS: Does anybody think that investigator-assessed versus blinded independent central review made a difference [in the overall response rates reported in these trials]?

LISA BADDI, MD: In most studies there's usually a difference between the investigator's [more] optimistic assessment and the independent assessment.

ATKINS: I think it's a hard question when it comes to immunotherapy. A lot of times you see things show up in a responding patient when they're getting immunotherapy and you don't know what they are. Many times, it's inflammation in the lung in the screening or something that blind independent central review might call progressive disease or a nonresponder, when an investigator is giving it the benefit of the doubt. When they give the next scan and it's gone, they're saying the patient hasn't progressed or they are a responder.

So, in some ways I think the investigators know what the X-rays mean better than [independent central reviewers] who are reviewing them without preclinical history. But they're clearly different ways and can produce different results, and therefore it makes it hard to compare data across studies.

NEERAJ MAHAJAN, MD: I never thought of that part. Intuitively, I thought it's always good to have blinded review to avoid the bias, but you're right—the investigator may know the patient and they may know their previous history such as chronic obstructive pulmonary disease orsomething else chronically [present], and they may be able to get a better assessment of those non-specific findings.

ATKINS: We can rely on the overall survival [OS] data, but there's also other treatments patients get [after] that can influence OS. We have a lot of data trying to compare across regimens at different timepoints. [The datasets from these studies are] not focused on the BRAF wild-type population, it includes the BRAF-mutant population in its data.

BADDI: I'm sometimes seeing patients who are in their 90s and it's hard. I'm pretty comfortable with giving them pembrolizumab, but when adding other agents [it can be difficult].

ATKINS: I share your concern that with someone who's 90 years old; it's great that you can offer them treatment that has a chance of working, but certainly you want to do no harm to a 90-year-old. That is more of a concern. There are comorbidities that come with being that old, and what's going on with their disease.

DISCUSSION QUESTIONS

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

ATKINS: How has your comfort level in managing AEs in metastatic melanoma changed over time?

SRI VISWANATHAN, MD: Over time, I [have become] comfortable with managing the irAEs considering immunotherapy’s use in many cancers. I'm certainly comfortable managing single-agent immunotherapy for toxicities. Ipilimumab [Yervoy] plus nivolumab [Opdivo] has a lot more immune-related toxicities, but overall, I’m very comfortable. I have not used nivolumab/relatlimab [Opdualag]. I'm anxious to learn about it because I have a potential candidate that I could start on it soon. On a scale of 0 to 10, 10 being very comfortable, I would say 10.

ATKINS: How do others feel on a scale of 1 to 10? How comfortable do you all feel with managing toxicities, and does it influence your choice of treatments [besides] some of the comorbidities?

BADDI: I have used some ipilimumab/nivolumab in the past, both for melanoma and for renal cell carcinoma [RCC], and I think that with the RCC dosing, things go a lot better from what I've experienced. I have not used nivolumab/relatlimab yet. For pembrolizumab [Keytruda] and [single-agent] nivolumab, I've used quite a bit of those because I do general oncology. I see a fair number of patients with triple-negative breast cancer also, and we use a lot of pembrolizumab.

I would say also that although I worry about somebody who's 90 years old, I feel like the younger patients tend to have more toxicity issues than the older patients. I'm saying that not so much with melanoma in mind, but with triple-negative breast cancer [where] we're using a lot of pembrolizumab now, and those [younger patients] are the ones whom I'm seeing.

They have a lot of endocrine problems and issues with adrenal insufficiency. The thyroid issues are fine, put them on levothyroxine. But some of these [toxicities] like the adrenal insufficiency can sometimes be very insidious, and some of those endocrine issues can be a little harder.

ATKINS: I agree with you that younger patients may have better immune systems and generate more toxicity, but I also feel more comfortable that I can get them through it. In someone who is 90 years old, you have to think about those things. Does anybody not feel comfortable managing ipilimumab/nivolumab toxicity to the point where you wouldn't give it even to the ideal patient?

BAIDEHI MAITI, MD: I wouldn't [avoid] giving it, but in my experience, I always sought help with the subspecialties for severe irAEs like severe colitis. The gastroenterologist would always help us. We've given immunotherapy long enough in multiple different cancer types that I think the majority of us feel comfortable picking up on the toxicities, then starting them on steroids, and getting help from the individual subspecialties, depending on the severity of the reaction.

MICHAEL NEMUNAITIS, MD: I'm probably about 8 out of 10 [comfortable]. I have had 2 patients with severe colitis on ipilimumab, so I'm always looking for a way not to use it. This combination with nivolumab and relatlimab seems quite exciting to me. I've not used it yet, but that is something I'm excited to use.

ATKINS: Colitis can sometimes take a long time to resolve with ipilimumab-containing regimens; you're often moving to infliximab [Remicade] and sometimes even vedolizumab [Entyvio]. But fortunately, if you're in tune to it, I think you can usually get it under control and don't have to do surgery. I've never had to operate on a patient with colitis.