COMMENTARY

'Compelling' Regimen for Resectable Advanced-Stage Melanoma

Jeffrey S. Weber, MD, PhD

Disclosures

August 16, 2018

This is Dr Jeffrey Weber. I am a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at the New York University Langone Health System in New York City. I would like to describe to you a recent article that was published in Lancet Oncology, which I thought represented a very interesting development that may, in spite of its small size, be practice-changing.

Amaria and colleagues,[1] from the MD Anderson Cancer Center, described a very small, randomized trial of neoadjuvant and adjuvant BRAF-MEK [inhibitor] therapy versus standard of care for patients with relatively high-risk stage IIIB, IIIC, and IV resectable melanoma. Patients were randomized 2:1 to receive 8 weeks of neoadjuvant dabrafenib and trametinib, followed by surgery, and then up to 44 weeks of adjuvant dabrafenib and trametinib or the alternative treatment, which was simply standard of care.

The investigators intended to randomize almost 100 patients to be able to get a good assessment of the relative efficacy of one approach versus the other; the idea was to look for event-free survival at 12 months, with an event generally being a relapse.

The trial was stopped early because it passed an O'Brien-Fleming boundary [Editor's note: According to the study authors, "The reported p value (p<0.0001) did not cross the O'Brien-Fleming stopping boundary for seven events"; however, in a predictive analysis, "the predicted probability that neoadjuvant plus adjuvant dabrafenib and trametinib would be superior to standard of care was 0.991, necessitating closure of the standard of care group."] where there was a very clear benefit for the patients, in terms of event-free survival, who received the neoadjuvant therapy followed by surgery and adjuvant therapy versus those who were in the standard-care arm.

Of interest, of the 21 patients treated, 14 had [neoadjuvant therapy–surgery–adjuvant therapy], and only seven had standard of care. Of those seven, all had surgery, but interestingly, only one had any adjuvant therapy at all, which was interferon.

The data were very compelling. Of the 12 patients out of 14 who had [neoadjuvant therapy–surgery–adjuvant therapy], seven had a pathologic complete response. A pathologic complete response with a median follow-up of around 17.5 months was clearly associated with a superior outcome.

If one compared the neoadjuvant–surgery–adjuvant arm with the standard-of-care surgery arm, the event-free survival median was 19.7 months versus 2.9 months, respectively. Interestingly, all seven of the standard surgical patients who had stage IIIB, IIIC, and IV resected disease relapsed.

The drugs were generally well tolerated in the neoadjuvant–surgery–adjuvant arm. There were no effects from surgery. It was felt by the investigators that surgery went as well as it could have, whether they received neoadjuvant therapy or not. There was no increase in surgical complications, but the usual side effects of dabrafenib and trametinib were present: mainly diarrhea, pyrexia, fatigue, fever, and headache. Most were grades 1 and 2, with a sprinkling of grade 3 toxicities.

The interesting data show that for event-free survival, the hazard ratio (HR) was a spectacular 0.016 (P < .0001); and when you look at distant metastasis-free survival, which a lot of folks think is a surrogate for overall survival (OS), the HR was 0.024 (P < .001). Interestingly, OS was not different (P = .22). But again, the main endpoint to this trial was event-free survival and distant metastasis-free survival.

A number of correlative markers were looked at and, as you would imagine, benefit was clearly associated in the seven out of 12 patients who achieved a pathologic complete response. But in the patients who benefited, who did not have an event, there was clearly a lower level of CD8 T cells that were TIM-3 positive and LAG-3 positive, reflecting fewer exhausted T cells. There was a more clonal T-cell receptor distribution that was present pre-treatment in those who benefitted versus those who did not. In general, there was significant influx of CD8 T cells in the patients who benefited the most. All of the parameters that you would expect to be present were there in the patients who did well with the neoadjuvant surgery and then adjuvant therapy.

The conclusions of this study were that neoadjuvant therapy for patients with marginally resectable stage III melanoma should be significantly explored; that those patients may well benefit; and that pathologic complete response in that scenario might be a terrific surrogate endpoint for patients who are going to do well (justifying further adjuvant therapy as we have seen in many other cancers).

Fascinating article. It is potentially practice-changing. A lot of folks have used ad hoc BRAF-MEK [inhibitors] in the marginally resectable stage III melanoma setting, and this certainly supports that idea.

This is Dr Jeffrey Weber. If you have comments, we are more than grateful to have you call in and let us know what you think. Thank you very much for listening.

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