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Single-dose pembrolizumab may induce remission in advanced melanoma
Patients with advanced melanoma appeared to experience durable remission with single-dose pembrolizumab initiated 3 weeks before surgery, according to study results published in Nature Medicine.
Additionally, researchers found that immune responses may peak as early as 7 days after initiation of pembrolizumab (Keytruda, Merck).
“Knowing much earlier whether or not patients are responding to PD-1 inhibitors may give us the ability to guide them to the most appropriate therapy with the greatest chance for success,” Alexander Huang, MD, researcher in the department of medicine at Perelman School of Medicine at University of Pennsylvania, said in a press release.
The study included 27 patients with advanced-stage melanoma treated with one dose of pembrolizumab 3 weeks before surgery. Researchers hypothesized they would detect immune reinvigoration in the tumor at 3weeks, and that this would correlate with DFS.
According to study results, 30% of patients achieved greater than 90% tumor eradication after a single dose of pembrolizumab. Moreover, all of these patients were disease-free at a median follow-up of 25 months.
“Also, for patients who did not achieve this degree of response, we identified patterns in the way the cancer can adapt to survive, meaning we may be able to guess the next move after PD-1 treatment,” Huang said in the release. “The longer into treatment we go, the more mutations and resistance mechanisms we find, but identifying the means of resistance early after starting therapy in resected tumors means the resistance mechanisms may be more predictable, which is another benefit of giving this treatment before surgery.”
HemOnc Today spoke with Huang about the study and the clinical implications of the findings.
Question: What prompted this research?
Answer: We had previously shown that immunologic responses to anti-PD-1 therapy occur rapidly, with pharmacodynamic T-cell responses detectable in blood by 3weeks among patients with melanoma. This begged the question of what the effect is in a tumor in terms of a pathologic response and an immune response. In order to answer this question, we designed this trial.
Q: How was the study conducted ?
A: We recruited 27 patients with advanced-stage resectable melanoma. These patients underwent biopsy before treatment with pembrolizumab, followed by complete resection of the tumor. Each patient also received a PD-1 blockade after surgery for up to 1 year.
Q: Can you elaborate on your findings?
A: The main finding was that approximately 30% of patients had a complete pathologic response, or greater than 90% eradication of their tumor, with single-dose pembrolizumab. They remain disease-free. However, those who did not achieve this response at 3 weeks had an overall poor prognosis, which told us that the activity of PD-1 blockade occurs early and is largely determined by 3 weeks. Indeed, when we looked at the peripheral blood, we could identify an immune response to PD-1 blockade by 7 days.
Q: Did any of your findings surprise you?
A: We found that immunotherapy treatment works a lot faster than we had imagined. This also likely means that the clinical response rates are dictated early on as well.
Q: What should clinicians do with this information?
A: The data need to be validated in a much larger trial. However, one of the most important things is that our data show the clinical utility of neoadjuvant trials — from a safety, feasibility and efficacy standpoint as well as the translational value. Also, it gives us valuable information for the design of future clinical trials.
Q: What is next for research?
A: Future studies will focus on altering adjuvant therapies based on the presurgical response to PD-1 blockade. – by Jennifer Southall
Reference:
Huang A, et al. Nat Med. 2019; doi:10.1038/s41591-019-0357-y.
For more information:
Alexander Huang, MD, can be reached at Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: alexander.huang@uphs.upenn.edu.
Disclosure: Huang reports no relevant financial disclosures.