Advances in the Treatment of Malignant Melanoma - Episode 11

I/O Dosing Schedules in Metastatic Melanoma

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Jeffrey S. Weber, MD, PhD: Let’s turn back to Ryan. Jason had alluded to a couple of scenarios where alternate doses and schedules of immunotherapy were used. At this ASCO [American Society of Clinical Oncology annual meeting], there was at least 1 very interesting oral presentation by Mike Postow. What can you tell us about the different doses and schedules? Tell us a little more about how you treat your patients in real life, off protocol.

Ryan J. Sullivan, MD: In real life, off protocol, I tend to treat patients as my colleagues do and often give single-agent PD-1 or combined immune checkpoint inhibition. The reason I don’t give combined immune checkpoint inhibition to everybody is the high toxicity rate. That’s obvious. It’s probably also why the difference in overall survival between 52% and 44% at 5 years isn’t 70% and 44%. Because the toxicity is high, a lot of patients need corticosteroids. It’s not a high percentage, but some patients certainly die from the toxicity more with combined.

There’s been a push in the field to look at alternative ways of delivering combined immune checkpoint inhibition. One way of doing it is to lower the dose of ipilimumab. Jason alluded to the CheckMate 511 study, which was comparing alternate dosing of 3 mg and 1 mg ipilimumab-nivolumab versus 1 mg and 3 mg ipilimumab-nivolumab times 4 doses and then maintenance nivolumab.

What’s clear is the toxicity is less with the flipped dose. What’s also interesting is it’s probably a little early. There was only about 18 months of follow-up to see a real difference in overall survival with that. When you think about when the overall survival advantage was seen with ipilimumab and nivolumab versus nivolumab in CheckMate 067, it was actually 2 and 3 years when you started to see those curves separate, not 1 year, not even 18 months. We can feel good about the fact that it was less toxic, and the relapse-free survival looks about the same. I don’t think we can comment much on overall survival with alternative dosing of ipilimumab until you have longer-term data.

At this ASCO, Michael Postow and his colleagues at Memorial Sloan Kettering Cancer Center presented data on a trial where they thought they could get away with 2 doses of ipilimumab and nivolumab for patients and then do a scan. If the scan looked good, meaning there wasn’t any growth, then that would be it, and they could switch to maintenance nivolumab. If patients were having some additional growth of their disease, then they would continue to receive the final 2 doses of ipilimumab and nivolumab. This is the standard dose of 3 mg/kg of ipilimumab and 1 mg/kg of nivolumab.

What was interesting about the data is essentially 2 doses was about what you’d expect with 4 doses, meaning the majority of patients had no progression at 2 doses. In fact, the 12-week response rate was slightly less than 50%. But the total response rate, when we looked out further, was 57%, which is in line with what you’d see with when you intend to give 4 doses of ipilimumab and nivolumab.

Of those patients who may have had some evidence of tumor progression after 2 doses, none had a response. That was a minority of patients. That was about one-third of the patients who fell into that category. It suggests that continuing with ipilimumab-nivolumab when you’re not seeing benefit may not actually be the right thing to do. Although quite frankly, it doesn’t seem it was the wrong thing to do, because the toxicity rate was virtually the same you would expect if you were intending to give 4 doses.

What it ultimately shows us is that response is an early phenomenon with these drugs. So is toxicity, particularly in combination. Thinking about how we can optimize therapy, just thinking about a lesser number of doses, would be fine. It’s hard to say we should change our standard of care based on that. We certainly should feel OK if all we can do is give 2 doses because the patient is not tolerating it.

This is 1 of those types of questions that can be done only at an institution, and then ultimately maybe in a cooperative group to try to change the amount of dose that we give to be less than what’s standard. It certainly is something that may be considered in the future to do a larger trial, just comparing the 2 doses.

Jeffrey S. Weber, MD, PhD: The amazing thing is that 19 of 60 patients had more than 4% growth. Why they chose 4%, I don’t know. That’s a good question. That means any evidence of growth, as opposed to stability or regression, but none of them responded. Those were all the patients who are going to do badly. I was absolutely struck by that. The median survival is not reached. They haven’t even reached median PFS [progression-free survival], as I remember.

Ryan J. Sullivan, MD: Correct.

Jeffrey S. Weber, MD, PhD: It is pretty interesting, although I assume they met median PFS, but actually, that’s surprising if they had 20 months of follow-up, and they haven’t seen the median PFS.

Ryan J. Sullivan, MD: It’s 60 patients, so it’s hard to lean on even the PFS and the OS [overall survival], but certainly the response data are fascinating, as is the toxicity.

Jeffrey S. Weber, MD, PhD: Eighty percent of patients who were alive at either 18 or 24 months. That’s pretty impressive.

Ryan J. Sullivan, MD: Yeah.

Jeffrey S. Weber, MD, PhD: Those investigators may be onto something. We’ll see. Maybe less is more.

Sunandana Chandra, MD: There also were the correlative data. They mentioned that they looked at T-cell activation and cell proliferation, and the parameters didn’t change after 2 doses. The increases they saw after 1 seemed like that was sufficient. That that data also support biologically what’s happening.

Jeffrey S. Weber, MD, PhD: They chose the 2 classic pharmacodynamic sine qua nons of getting PD-1 blockade alone or ipilimumab alone: Do the T cells proliferate, so Ki-67, and do they upregulate ICOS? I was blown away by the fact that 2 weeks later, it happened. Then you can keep going for as long as you want. Nothing changed. That’s a pretty early indication. Very interesting data.

Transcript Edited for Clarity