Progression on Adjuvant Therapy

Transcript: Jeffrey S. Weber, MD, PhD: OK, so let me ask you this, if we can switch gears a very small amount. We all agree the adjuvant therapy has really changed how we treat our melanoma patients or the availability of adjuvant BRAF/MEK, dabrafenib-trametinib, nivolumab, pembrolizumab. What do you do when they fail? Because this was never an issue before. Now it’s an issue in clinical practice. What happens? Ryan, what happens when you see a patient who has had adjuvant nivolumab or pembrolizumab, and they progress? Does the rapidity of progression impact on what you recommend? And is there an obvious first recommendation for them?

Ryan J. Sullivan, MD: It’s the question that we’re having to answer more frequently now that we’re offering adjuvant immunotherapy in patients who are relapsing. There’s no great answer to it. I think the first thing we need to define is when patients relapsed, did they relapse because they developed resistance to the therapy? Or did they relapse sort of on a time line that they would have relapsed anyway? For example, if somebody is receiving nivolumab or pembrolizumab in the adjuvant setting and then relapses while on it, I’m not going to give them a single-agent PD-1 [programmed cell death protein 1] inhibitor in the metastatic setting or unresectable setting.

But if they relapsed several years later, I might consider offering single-agent therapy or a combination immunotherapy for that patient. I think the timing of relapse does matter. The earlier the relapse, the more likely that we’re dealing with a truly resistant situation and we need to escalate therapy.

The best therapy? We don’t know. I think by convention, if a patient is not a candidate for a clinical trial, we typically offer the combination of ipilimumab and nivolumab thinking that we’re escalating the checkpoint inhibitor therapy and hopefully getting somewhere. If that patient is BRAF mutated, I might think that that might be a good time to think about either a frontline BRAF/MEK plus clinical trial, or even a BRAF-targeted therapy as a commercially available option.

Vernon K. Sondak, MD: Let’s not forget that in this current era of not doing a node dissection, many patients receiving adjuvant therapy fail in the regional lymph nodes or at the local site and still have the surgical option. In that setting, that should be the first choice.

Ryan J. Sullivan, MD: Absolutely.

Vernon K. Sondak, MD: It may be a context of neoadjuvant therapy, but most of the time it’s going to be surgery. We don’t want to see somebody who has been on adjuvant anti—PD-1, has a single lymph node develop in their axilla, and then gets escalated to ipilimumab-nivolumab. That’s the wrong answer in that case. That patient should have surgery and then be reevaluated in a more thoughtful way.

Ryan J. Sullivan, MD: Excellent point.

Jeffrey S. Weber, MD, PhD: That’s true, and in the CheckMate 238 trial, of the relapses that occurred by the end of the second year, about a quarter of them actually were locoregional and thus potentially amenable to surgery. Jason, you were going to say something?

Jason J. Luke, MD, FACP: I think this really emphasizes the concept of a multidisciplinary team here because I think we really don’t understand the patterns of relapse. We changed our surgical paradigms. We changed our staging system. We don’t necessarily know what to expect, so we don’t want to miscite factors as Vernon was just mentioning. If you started a PD-1 and the patient recurs in a locoregional lymph node basin within 3 months, you’d probably want to resect that. You might even want to keep going with the therapy. These are nuance questions that I think you really need to have the whole team thinking about.

Transcript Edited for Clarity