Pembrolizumab Yields High Response Rates for Patients With Unresectable Metastatic Desmoplastic Melanoma

Patients with unresectable metastatic desmoplastic melanoma, a rare amelonotic subtype of cutaneous melanoma, achieved high response rates when treated with single-agent pembrolizumab (Keytruda) in the SWOG S1512 trial (NCT02775851), according to data presented during the 2023 AACR Annual Meeting.¹

“Based on these data, single-agent, anti-PD1 immunotherapy should be considered the first-line treatment of choice for most patients with unresectable desmoplastic melanoma,” Kari Kendra, MD, PhD, said in a presentation. Kendra is a a professor of medicine and the director of cutaneous oncology at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Patients with unresectable disease in cohort B (n = 27) experienced an overall response rate (ORR) of 89% (95% CI, 71%-98%), with 9 complete responses (CRs; 33%; 95% CI, 17%-54%; P < 0.001), meeting the study’s primary end point of clinical CR assessed per RECIST 1.1 by passing the prespecified threshold of a 20% CR rate. Additionally, 1 patient had stable disease and stopped treatment after 5 cycles to undergo resection and the patient achieved a pathologic CR.¹

Data as of Match 17, 2023, showed a 2-year progression-free survival (PFS) rate of 74% (95% CI, 53%-87%) and a 2-year overall survival (OS) rate of 89% (95% CI, 69%-96%). There were 8 deaths—6 due to other comorbidities, 1 due to progression within the central nervous system (CNS), and 1 due to an unknown cause.

Additionally, 1 patient had progressive disease and following 3 cycles of treatment with pembrolizumab, received nonprotocol nivolumab (Opdivo) and ipilimumab (Yervoy) and achieved a clinical response. Further, 1 patient on the trial was nonevaluable and withdrew prior to a follow-up scan and died 2.6 months after registration.¹

Adverse events (AEs) were consistent with previously reported data in metastatic melanoma and any grade AEs occurred in 93% of patients with grade 1, grade 2, grade 3, and grade 4 events occurring at rates of 11%, 44%, 30%, and 7%, respectively. The most common AEs were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). The grade 4 events that occurred, each in 1 patient, were lipases increase and lung infection/sepsis.

Desmoplastic melanoma, which makes up approximately 4% of cutaneous melanomas, is most commonly diagnosed among those located in highly sun exposed areas, in the elderly, and in men. Kendra noted that high UV damage from the sun results in a high tumor mutational burden for patients with this disease.¹

Among enrolled patients in SWOG S1512, the median age was 75 years (range, 59-90) and the majority were men (93%) with an ECOG performance score of 0 (70%) or 1 (30%). Patients had disease sites of head or neck (63%), extremity (19%), and torso (19%). Staging according to American Joint Committee on Cancer were M0 (29%), M1a (4%), M1b (41%), and M1c (26%). Baseline lactate dehydrogenase was elevated in 22% of patients and normal in 78%.

Patients received pembrolizumab monotherapy at 200 mg every 3 weeks for 2 years or until disease progression or unacceptable toxicity and as of March 17, 2023, 2 patients remain on treatment. The median number of cycles received was 15 (range 1-34), which Kendra noted is approximately 45 weeks of therapy.¹

Additionally, adult patients eligible for enrollment were required to have received no prior PD-1 blockade therapy, adequate organ function, and no central nervous system (CNS), autoimmune disease, or steroid use of over 10 mg of prednisone. If a patient’s tumor was converted from an uresectable state to a resectable state, resection was allowed.

Four patients completed the protocol treatment and those who discontinued treatment (n = 21) did so because of an AE (n = 9), progression (n = 4), patient refusal (n = 1), physician/patient refusal following a CR (n = 1), dyspnea that was unrelated to treatment (n = 1), or physician decision (n = 3), with 1 patient undergoing resection and 1 undergoing radiation following a PR.1

In a discussion of the trial’s data, Zeynep Eroglu, MD, noted that the ongoing analyses of tumor samples from SWOG S1512 may help to determine why desmoplastic melanoma is so responsive to treatment with immunotherapy and if factors such as high tumor mutational burden, NF-1 driven tumors, desmoplasia, and/or the tumor microenvironment have a role in this. In SWOG S1512, the median tumor mutational burden was 49.7 mut/mb (4.1-159.2), with NF1 loss-of-function mutations reported in 67% of patients.

Eroglu, who is a medical oncologist in the Department of Cutaneous Oncology at Moffitt Cancer Center and an assistant professor in the Department of Oncologic Sciences at the University of South Florida Morsani College of Medicine, explained that in a retrospective review for which she was the lead author, showed that prior to SWOG S1512, across 10 academic centers, 60 cases of desmoplastic melanoma were identified.2 Among those who had not received prior systemic therapy, the ORR was 70% with a 32% CR rate. The 1- and 2-year PFS rates were 66% (95% CI, 53%-77%) and 63% (95% CI, 49%-74%), respectively. The 1- and 2-year OS rates were 84% (95% CI, 72%-92%) and 74% (95% CI, 60%-84%), respectively.²

Results from cohort A of SWOG S1512 were previously presented at the 2022 American Society of Clinical Oncology Annual Meeting.3 These data showed that among 29 patients who received neoadjuvant pembrolizumab, the complete pathologic response rate was 55% (95% CI, 36%-74%), meeting the primary end point of that cohort.³

When asked about the role of radiation therapy, Kendra said oncologists need to question if upfront radiation therapy is needed as the response rates are high with single-agent anti–PD-1 therapy or if radiation should be saved for more challenging cases where a response has not been seen.

Disclosure: Dr Kendra is an advisor for Pfizer, OncoSec, Regeneron,Genentech, Novartis, Natera, replimmune, Regeneron, Sanofi, BMS, regeneron, Merck, Iovance Biotherapeutics, Genzyme, Novartis, Nektar, Castle Biosciences, Instil Bio, and the NCCN (via Pfizer). She is on the scientific advisory board for Advaxis, Appia, Apricity, Arcus, Compugen, Highlight, ImaginAb, ImmPact, ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, Pluto.

References

1. Kendra K, Bellasea S, Eroglu Z, et al. High response rate with single agent anti-PD-1 in patients with metastatic desmoplastic melanoma. Cancer Res. 2023;83(suppl 8):CT009. doi:10.1158/1538-7445.AM2023-CT009
2. Eroglu Z, Zaretsky JM, Lieskovan SH, et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature. 2018;553(7688):347-350. doi:10.1038/nature25187
3. Kendra KL, Moon J, Eroglu Z, et al. Neoadjuvant PD-1 blockade in patients with resectable desmoplastic melanoma (SWOG 1512). J Clin Oncol. 2022;40(suppl 16):9502. doi:10.1200/JCO.2022.40.16_suppl.9502