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Neoadjuvant Anti-PD-1 Predicts Melanoma Outcomes

A single dose of neoadjuvant anti-programmed cell death 1 (PD-1) therapy was effective in some stage IIIB/C and IV melanoma patients, leading to a disease-free survival (DFS) rate of 63% and an overall survival (OS) rate of 93% at 2 years, a small phase Ib clinical trial found.

Alexander C. Huang, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues, observed a very rapid immune response in peripheral blood after PD-1 blockade, with T cell re-invigoration peaking just 7 days after treatment. Complete or major pathologic response occurred in about 30% of patients within 3 weeks.

“Notably, these patients with early complete or major pathological tumor response have 100% DFS at 24 months,” Huang and co-authors wrote in Nature Medicine. In contrast, those whose tumors showed poor pathological response at surgery had a poor prognosis, with a more than 50% risk of recurrence despite adjuvant therapy.

The final cohort in the single-center trial, launched in 2015, consisted of 27 resectable patients, with a mean age of 62 (range of 28-85) and 59% of whom were male. Stage IIIC or IV melanoma was present in 59% of patients, while the remainder had stage IIIB disease. More than a quarter had elevated levels of the tumor marker lactate dehydrogenase at baseline, and one patient had already received BRAF-directed immunotherapy. Following surgery, all patients underwent adjuvant therapy.

After a single dose of the immune checkpoint inhibitor pembrolizumab (Keytruda) at a median of 21 days (17-42) before resection, eight patients experienced a complete or major pathological response, with <10% of cancer cells remaining in tumor specimens. At a median follow-up of 25 months, all participants were disease-free.

“Knowing so 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,” Huang said in a news release.

The findings could help reshape the standard of care in resectable melanoma, which currently includes surgery followed by a year of drug treatment, possibly PD-1 inhibition, in selected high-risk patients.

The researchers found that the rapid responses of both types were associated with the accumulation of exhausted CD8 T cells in tumors at 3 weeks, with T cell re-invigoration in the blood observed as early as 1 week. Pre-existing CD8 T cell responses may drive clinical responses to anti-PD-1, the team said.

Transcriptional analysis identified a neoadjuvant immune response signature associated with clinical benefit – an accumulation of exhausted-phenotype (EomeshiTbetlow) CD8 T cells in blood. In contrast, patients who recurred showed mechanisms of resistance, including immune suppression, mutational escape, and/or tumor evolution. Among these mechanisms were adaptive tumor mutations such as B2M or TP53 as well as upregulated activity in naturally occurring immunosuppressive cells.

“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,” Huang said.

“Larger multicenter trials will be required to change our current clinical practice,” he told MedPage Today. “While we feel assured by the results in patients with early responses, we are now designing trials to address how best to treat patients who do not have optimal early responses.”

Future neoadjuvant studies, he added, should shed light on the mechanisms of resistance and may help tailor therapies and clinical trials.

Huang’s group previously found that anti-PD-1 therapy had a peak immune response in the blood at about 3 weeks, but the current analysis showed tumor cells had already been eliminated at that point, meaning that the immune response itself must have started at an earlier time. Analysis of additional groups of patients confirmed that finding, demonstrating a rapid peaking of serum immune response at 1 week.

Asked for his perspective, Michael B. Atkins, MD, of Georgetown University and the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., who was not involved in this research, said that despite the robust immune response, the neoadjuvant approach is not yet ready for clinical practice. “Before using this as a clinical tool we first would have to know if treating before resection actually produces better results in eliminating microscopic disease than treating afterwards.”

He noted that the Southwest Oncology Group has initiated the SWOG S1404 randomized trial to examine the use of adjuvant pembrolizumab versus standard adjuvant care in high-risk resected melanoma.

“The second thing is that we don’t yet know if using a single checkpoint inhibitor is the best approach to treatment, but this model from the University of Pennsylvania is a good way to test the ability of combination treatments of various types to produce responses,” Atkins said. “If more patients did better with combination agents, that would help identify the best approach earlier on instead of waiting for OS results.”

He added that definitive answers would need to be based on standardized analysis of tissue and standardized patient criteria for trial eligibility. “A working group has been formed to address these issues,” he said.

Last year, MedPage Today reported that adjuvant pembrolizumab for resectable high-risk melanoma yielded a nearly 20% absolute improvement in recurrence-free survival, irrespective of a tumor’s PD-L1 or BRAF mutation status.

Limitations of the current trial, Huang and colleagues said, were the small sample size and the lack of randomization.

Merck provided both funding for the study and the trial drug. Merck performed immunohistochemistry, immunofluorescence, and NanoString assays, and played a role in the analysis of these data but no role in any other aspect of the study. Other support was provided by the Specialized Program of Research Excellence (SPORE) in Skin Cancer, the National Cancer Institute, the National Institutes of Health, the Tara Miller Foundation, the Melanoma Research Alliance, the David and Hallee Adelman Immunotherapy Research Fund, the Heisenberg program, and the Parker Institute for Cancer Immunotherapy.

Huang reported having no competing interests; co-authors reported financial ties to or employment with companies including Merck, Roche, Roche/Genentech Pieris, Elstar, and Surface Oncology.

Atkins reported relationships with Bristol-Myers Squibb, Merck, Novartis, Genentech, and Pfizer.