Article Text
PDF
Abstract
Background The primary analysis of the phase I/II clinical trial combining the anti-PD-1 agent pembrolizumab with all-trans retinoic acid (ATRA) for patients with metastatic melanoma demonstrated a well-tolerated new treatment strategy to enhance the efficacy of pembrolizumab by reducing the frequency and attenuating the function of immunosuppressive myeloid-derived suppressor cells (MDSCs).1 The initial report, with a median follow-up time of 15 months (3–34 months), noted an overall response rate (ORR) of 71% and a disease-control rate (DCR) of 88%, with a progression-free survival (PFS) rate of 20.3 months. The median overall survival (OS) rate was not reached. Here, we report 5-year OS and PFS rates for all patients included in this trial.
Methods A total of 24 patients with metastatic melanoma were enrolled in this monocenter, single arm, phase I/II trial (NCT03200847) between 10/2017-07/2020. Eligible patients were ≥18 years of age and had not been exposed to anti-PD-1. Study treatment consisted of pembrolizumab 200 mg Q3W combined with ATRA 150mg/m2 orally for three days surrounding the first four pembrolizumab doses, followed by single-agent pembrolizumab for up to two years until confirmed disease progression or unacceptable toxicity. Endpoints included safety and MDSC reduction (primary), and ORR, DCR and PFS (secondary).
Results At data cut-off (May 14, 2024), all patients had completed the protocol-defined treatment (ATRA + pembrolizumab for up to two years), and 58% of the patients (n=14) were still alive with a median follow-up time of 48 months (range 3–77). The updated 5-year OS is 54.7% (95%CI 36.4–82.1), with the median not reached. The 5-year PFS is 36.1% (95%CI 21.0–62.2), with 33% of patients (n=8) having an ongoing complete remission.
Conclusions Updated OS and PFS data from this trial underscore the long-term clinical benefit of combining anti-PD-1 with ATRA, with survival rates similar to those seen with combination treatment anti-PD-1 with anti-CTLA-4 yet with overall lower toxicity.2 This forms the rationale to further explore this well-tolerated first-line treatment strategy for patients with metastatic melanoma. Furthermore, these results indicate that targeting MDSCs prior to and during checkpoint inhibition may enhance the efficacy of current and next generation immunotherapies for melanoma and other indications.
Acknowledgements We would like to thank all the patients who participated in this trial.
Trial Registration NCT03200847.
References
Tobin, et al. Targeting MDSC differentiation using ATRA: a phase I/II clinical trial combining pembrolizumab and all-trans retinoic acid for metastatic melanoma. Clin Cancer Res 2023 Apr 3;29(7):1209–1219. doi: 10.1158/1078-0432.CCR-22-2495. PMID: 36378549; PMCID: PMC10073240.
Larkin, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019 Oct 17;381(16):1535–1546. doi: 10.1056/NEJMoa1910836. Epub 2019 Sep 28. PMID: 31562797.
Ethics Approval Colorado Multiple Institutional Review Board (COMIRB #16-1080).
Consent All patients provided written informed consent.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.