
Single-Agent PD-1 Blockade Therapy Improves Responses in Desmoplastic Melanoma
Single-agent pembrolizumab achieved an ORR of 89%, with a 37% CR rate, in patients with advanced desmoplastic melanoma in the phase 2 SWOG S1512 trial.
Single-agent PD-1 blockade therapy with pembrolizumab (Keytruda) demonstrated high response rates, but a numerically higher incidence of toxicities, in patients with advanced desmoplastic melanoma, according to results from the 2-cohort phase 2 SWOG S1512 trial (NCT02775851) published in Nature Medicine.
The complete response (CR) rate was 37% (95% CI, 19%-58%), which was superior compared with the null hypothesis CR rate in the protocol statistical design (P <.001). The overall response rate (ORR) was 89% (95% CI, 71%-98%) per RECIST v1.1; responses were deep, mostly CRs or near-CRs, and rapid, frequently being documented in the scans obtained after the first 3 cycles.
Notably, 3 patients did not achieve an objective response by radiological assessment: 1 patient stopped treatment after 5 cycles of pembrolizumab to undergo resection and was found to have a pathological CR in the resection sample, though the radiologic response was stable disease; 1 patient progressed after 3 cycles of pembrolizumab then received nivolumab (Opdivo) plus ipilimumab (Yervoy) outside of the trial protocol and achieved a clinical CR; and 1 patient withdrew from the trial prior to the scheduled restaging imaging.
In the most recent data cutoff date of May 20, 2024, 26 patients were included in the survival analyses. The 3-year progression-free survival (PFS) was 72% (95% CI, 49%-85%), and the 3-year overall survival (OS) was 84% (95% CI, 63%-94%); neither the median PFS nor OS were reached. The estimated 3-year melanoma-specific PFS was 84% (95% CI, 67%-95%), and the 3-year melanoma-specific OS was 96% (95% CI, 83%-100%).
“[P]atients with unresectable desmoplastic melanoma have a high response rate to single-agent anti-PD-1 therapy, with responses most frequently being deep and rapid, as noted in the first 9-week scans,” wrote lead study author Kari L. Kendra, MD, PhD, professor of internal medicine, chair of the Melanoma Disease Specific Committee, and attending physician for in-patient and outpatient solid tumor services at the Ohio State University Comprehensive Cancer Center. “Treatment of choice should be single-agent anti-PD-1 blockade rather than combination immune checkpoint blockade therapy with ipilimumab (anti-CTLA-4) or relatlimab (anti-LAG-3).”
Between February 6, 2017, and May 17, 2021, a total of 27 patients with desmoplastic melanoma deemed to be unresectable were enrolled into the trial and treated with 200 mg of intravenous pembrolizumab every 3 weeks for up to 2 years. Patients were split into cohort A, which was designed to evaluate the pathological CR rate in patients with resectable desmoplastic melanoma treated with neoadjuvant pembrolizumab, and cohort B, which evaluated the clinical CR rate in patients with unresectable desmoplastic melanoma treated with pembrolizumab.
Eligible patients were 18 years or older with histologically or cytologically confirmed disease measurable per RECIST v1.1, adequate bone marrow function, adequate liver function, and a Zubrod performance status of 2 or lower.
Exclusion criteria included prior systemic therapy for the current melanoma, active autoimmune disease requiring systemic treatment within 2 years of study entry, and any history of brain metastasis.
The primary end point of the trial was the clinical CR rate. Secondary end points included PFS, OS, and safety and tolerability.
Regarding safety, 89% of patients reported experiencing a treatment-related adverse event (TRAE) of any grade; 37% of patients experienced an AE of grade 3 or 4. Immune-related AEs of any grade occurred in 67%, and of grades 3 to 5 in 30%.Any-grade serious AEs occurred in 22%, and grade 3 to 5 serious AEs in 19%. Treatment was discontinued due to adverse events by 33% of patients, and no patients died from an AE.
The most common any-grade TRAEs were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%).
Reference
Kendra KL, Bellasea SL, Eroglu Z, et al. Anti-PD-1 therapy in unresectable desmoplastic melanoma: the phase 2 SWOG S1512 trial. Nat Med. Published online August 14, 2025. doi:10.1038/s41591-025-03875-5
Newsletter
Stay up to date on recent advances in the multidisciplinary approach to cancer.