Longer Time Until Recurrence Associated With Better Melanoma Outcomes

Among patients with advanced melanoma, a longer time until disease recurrence was associated with post-recurrence progression and survival benefits, researchers have found.

“It essentially means that if you are on an adjuvant [postsurgical] immunotherapy, then the longer that you have until relapse, obviously that sets you up for a much better long-term outcome,” said Dr. Jason Luke, associate director of clinical research of the UPMC Hillman Cancer Center in Pittsburgh and a member of the CURE® advisory board, in an interview.

Study findings published in the Journal of Clinical Oncology from the phase 3 CheckMate 238 trial analyzed patients with stage 3B-C/4 melanoma who were assigned to receive treatment with either Opdivo (nivolumab) or Yervoy (ipilimumab) for a year or until disease recurrence, unacceptable toxicity and withdrawal of consent. Patients were assessed for progression-free survival (PFS, the time a patient lives without their disease spreading or worsening) and overall survival (OS, the time a patient lives, regardless of disease status) from the start of subsequent systemic therapy (SST). Patients who recurred within one year were considered to have early recurrence, while patients who recurred after a year were designated as having late recurrence.

Researchers reported recurrences in 198, or 44%, of the 453 patients treated with Opdivo, 122 of which were early recurrences and 76 of which were late recurrences. Recurrences were reported in 232, or 51%, of the patients who received Yervoy, 160 being early recurrences and 72 being late recurrences.

The median PFS on next-line therapy for patients treated with Opdivo was 4.7 months for those who recurred early versus 12.4 months for those who recurred late, while the median OS was 19.8 versus 42.8 months.

“Post-recurrence survival was longer for patients who recurred [at more than] 12 months,” researchers noted in the abstract of the study. “Patients on [Opdivo] who recurred early benefitted from SST but had better survival with [Yervoy]-based regimens or targeted therapy compared with anti–PD-1 [Opdivo] monotherapy.”

Luke spoke with CURE® about the study, its findings and their usefulness in making treatment decisions.

CURE®: What do you think should be the big takeaway from these findings?

Luke: Well, I think these findings confirm what we've kind of assumed in the field for a long time, which is that there's like a knock-on effect. We don't really know the answer. Actually, it's either that if you get immunotherapy and it works, it makes subsequent treatments work better, or it means that there are certain patients who are going to do well to everything, and the fact that they did well to immunotherapy first is just happenstance, because they would.

... My personal opinion is it's actually the latter, is that there are certain patients who are queued up to kind of do well, and there are certain people who aren't. But these data from a large phase 3 trial emphasize the point that, here it was relapse-free survival interval, the longer that goes as an initial period, the more likely you are to have a long-term outcome that's good. I think that kind of intuitively makes some sense.

Was there anything in the paper that you found particularly surprising?

Not really surprising, but another point that came out of it that I think is probably useful is in the trial that was analyzed, the patients either got [Opdivo (nivolumab] anti-PD-1 or anti-CTLA4 with [Yervoy (ipilimumab)] ... and in a not particularly surprising consequence, what they showed was that patients who got anti-PD-1 first did better if they got [Yervoy] second, which probably seems kind of obvious. But again, I think the important take-home point out of that is there has been a question in the field about whether or not keeping PD-1, keep re-treating with a PD-1 antibody, whether or not that's an important part of things. And I think these data don't really support that that's true.

So, once you kind of have gone after anti-PD-1, you don't need to keep getting it later, on and on and on. In other words, retreatment doesn't seem to have a great effect, is the point. It's not to say that it can't be tried, but these data would suggest that changing the mechanism of the treatment is more important than continuing the same thing you're doing.

In patient-friendly terms, the two different treatments that were studied in in this study, what are the basic mechanisms through which they work?

The first drug was a drug called [Yervoy (ipilimumab)], anti-CTLA4 antibody. It was the first checkpoint inhibitor that was approved for melanoma, now dating back almost 15 years ago, that works by blocking the high-level off switch on immune cells. So the off switch is off, and therefore immune cells can be more on. On a broader scale, anti-CTLA4 has the effect of expanding immune responses. So in that way, your immune system is more on, and more immune cells can come to try to fight the cancer, but it's not as much of a really specific treatment on individual immune cells that have already seen the cancer.

And that's in contrast with the other treatment, [Opdivo (nivolumab)] is an anti-PD-1 antibody, and canonically, we think the way that it works is that certain patients have immune cells that have gotten to the cancer, but the immune cells have been blocked by the tumor via the interaction of PD-1 and PD-L1. So by giving [Opdivo], you're interrupting that interaction, and that is an antigen specific, that's a T cell-specific interaction. In other words, there are already immune cells that want to kill the cancer, and by blocking that, you're allowing them to wake up.

So [Yervoy] makes everything bigger, and in that context, can generate immunity, whereas anti-PD-1 goes right after that last step and releases immune cells to try to kill cancer. And what we've seen in many different kinds of cancer is that that antigen-specific approach with anti-PD-1 is much more potent because you're releasing cells that already know what the cancer looks like.

How should these findings inform patient conversations with their doctors, especially as they're keeping things like recurrence in mind, and being watchful for that?

I think these data are pretty useful in updating now to our modern scenario, where we've learned that some of the newer treatments that are coming along, like TIL therapy or adoptive cell transfer, seem to actually work the best in patients where they had the least amount of benefit from anti-PD-1.

So, one might think, 'OK, well, I got my immunotherapy after surgery.' If one recurs very quickly, these data would suggest that further treatment with checkpoint inhibitors is unlikely to be super successful, and that would emphasize then transitioning to some of these newer treatments that we have, like the TIL therapy that was just recently approved. So that's certainly how I would use these data in my clinical practice, which would be to say, if people are progressing early, not making it to a year, then we want to quickly get them over to a different kind of treatment, like adoptive cell transfer. Whereas, if people are doing very well and they're going more than a year on treatment in [the] adjuvant [setting], well then we might be able to re-challenge them with immune checkpoint inhibitor combinations, and not necessarily have to go to immediately to TIL therapy.

Transcript has been edited for clarity and conciseness.

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