COMMENTARY

Response to Initial Immunotherapy Treatment Predicts Melanoma Outcomes

Jeffrey S. Weber, MD, PhD

Disclosures

September 11, 2019

This transcript has been edited for clarity.

I'm Dr Jeffrey Weber, deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health in New York City. I want to briefly describe an article by Huang and colleagues[1] that was published in March in Nature Medicine. This paper reported an interesting neoadjuvant study in patients with resectable melanoma. I should point out that neoadjuvant studies are all the rage now in melanoma and a number of other histologies that are sensitive to immunotherapy.

In this study, patients with resectable stage IIIB, IIIC, and IV melanoma were given a single dose of the programmed cell death protein 1 (PD-1) antibody pembrolizumab. Three weeks later, the patients had surgery and then received 1 year of adjuvant pembrolizumab, which is now a US Food and Drug Administration (FDA)-approved therapy.

The purpose of this preclinical study was to understand what kind of pretreatment parameters, or 3-week on-treatment parameters, were associated with outcomes after that single dose of PD-1 antibody. So far, 27 patients have been treated. The investigators report that eight of those patients had either a pathologic complete response (CR) at 3 weeks after that single dose of pembrolizumab at the time of surgery, or 90% necrosis, which they call a very good partial response. Of those eight patients, five had a pathologic CR and three had 90% necrosis or almost complete regression. The other 19 patients did not have a significant response.

Of those patients who had either a pathologic CR or 90% necrosis, none have relapsed thus far, and we're talking about more than 12 months of follow-up. At 12 months, the rate of relapse-free survival was 66%—which frankly is no better than what one would see in a similar population in the CheckMate 238 study,[2] in which patients received adjuvant nivolumab.

Almost none of the patients who had a brisk tumor-infiltrating lymphocyte (TIL) infiltrate have relapsed. Of those who had a nonbrisk TIL infiltrate at baseline, the majority have relapsed. Of the 27 patients, 10 have relapsed and two have died. None of the patients were unable to go on to surgery and the significant level of toxicity was very low, implying that a single dose of pembrolizumab was, as you would expect, very well tolerated.

The TIL cells included so-called exhausted T cells, which were CD8- positive, PD- 1–positive, CTLA4- positive cells that proliferated significantly, both in the tumor and in the periphery after treatment. Investigators found that if EOMES (eomesodermin, a transcription factor that regulates T cells) was elevated in the TILs, those patients did well. If the cells proliferated, they also did well. But if T-regulatory cells proliferated, the patients did very poorly.

They also looked at an 18-gene signature that has been found in patients with metastatic disease to be associated with a good outcome, when patients are treated with PD-1 antibodies. The investigators found that in the resected tumors in patients with stage III disease, that same 18-gene signature was very closely associated with a good outcome.

All in all, these are very important pharmacodynamic data. They suggest that even though in a very small population of 27 patients, the relapse-free survival was not any different than what we've seen in the CheckMate 238 adjuvant study. It could be that the achievement of either a 90% response or a pathologic CR with either one or a few doses of PD-1 antibody may simply be a signal that those patients are going to do well. They may never relapse if they're followed long enough. And perhaps those patients don't need further adjuvant therapy. But it's clear that those who do not achieve a 90% response or a pathologic CR will need further adjuvant therapy to do well. I believe you'll be seeing new trials coming up that will compare neoadjuvant plus adjuvant immunotherapy with adjuvant immunotherapy in resected melanoma, renal cancer, bladder cancer, lung cancer, and a variety of cancers.

This is Dr Jeffrey Weber. Please do feel free to contact us with questions. I thank you for your attention.

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