Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma
A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three...
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Published in | Clinical cancer research Vol. 29; no. 7; pp. 1209 - 1219 |
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Main Authors | , , , , , , , , , , , , , , , , |
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03.04.2023
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Abstract | A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma.
Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS).
Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs.
With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167. |
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AbstractList | A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma.
Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS).
Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs.
With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167. Abstract Purpose: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. Patients and Methods: Anti–PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). Results: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. Conclusions: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167 |
Author | Davis, Dana M Cates, Victoria M Gao, Dexiang Davila, Eduardo McCarter, Martin D Cogswell, Dasha T Medina, Theresa M Katsnelson, Elizabeth Jordan, Kimberly R Tobin, Richard P Couts, Kasey L Robinson, William A McFarland, Ross W Gonzalez, Rene Borgers, Jessica S W Lewis, Karl D Van Gulick, Robert J |
AuthorAffiliation | 1. University of Colorado Anschutz Medical Campus, Department of Surgery, Division of Surgical Oncology, Aurora, Colorado, USA 2. Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, The Netherlands 6. UCHealth Cancer Care and Hematology Clinic - Harmony Campus, Fort Collins, Colorado, USA 5. University of Colorado Anschutz Medical Campus, Pediatrics, Biostatistics and Informatics, Cancer Center Biostatistics Core, Aurora, Colorado, USA 3. University of Colorado Anschutz Medical Campus, Department of Medicine, Division of Medical Oncology, Aurora, Colorado, USA 4. University of Colorado Anschutz Medical Campus, Department of Immunology and Microbiology, Aurora, Colorado, USA |
AuthorAffiliation_xml | – name: 2. Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, The Netherlands – name: 3. University of Colorado Anschutz Medical Campus, Department of Medicine, Division of Medical Oncology, Aurora, Colorado, USA – name: 4. University of Colorado Anschutz Medical Campus, Department of Immunology and Microbiology, Aurora, Colorado, USA – name: 1. University of Colorado Anschutz Medical Campus, Department of Surgery, Division of Surgical Oncology, Aurora, Colorado, USA – name: 5. University of Colorado Anschutz Medical Campus, Pediatrics, Biostatistics and Informatics, Cancer Center Biostatistics Core, Aurora, Colorado, USA – name: 6. UCHealth Cancer Care and Hematology Clinic - Harmony Campus, Fort Collins, Colorado, USA |
Author_xml | – sequence: 1 givenname: Richard P orcidid: 0000-0003-3890-4534 surname: Tobin fullname: Tobin, Richard P organization: Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 2 givenname: Dasha T orcidid: 0000-0002-8518-5918 surname: Cogswell fullname: Cogswell, Dasha T organization: Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 3 givenname: Victoria M orcidid: 0000-0001-7803-7792 surname: Cates fullname: Cates, Victoria M organization: Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 4 givenname: Dana M orcidid: 0000-0003-1775-1057 surname: Davis fullname: Davis, Dana M organization: Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 5 givenname: Jessica S W orcidid: 0000-0002-6478-7821 surname: Borgers fullname: Borgers, Jessica S W organization: Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 6 givenname: Robert J orcidid: 0000-0002-6300-9569 surname: Van Gulick fullname: Van Gulick, Robert J organization: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 7 givenname: Elizabeth orcidid: 0000-0001-7987-3768 surname: Katsnelson fullname: Katsnelson, Elizabeth organization: Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 8 givenname: Kasey L orcidid: 0000-0002-2088-2229 surname: Couts fullname: Couts, Kasey L organization: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 9 givenname: Kimberly R orcidid: 0000-0001-8380-7157 surname: Jordan fullname: Jordan, Kimberly R organization: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 10 givenname: Dexiang orcidid: 0000-0003-3920-7060 surname: Gao fullname: Gao, Dexiang organization: Department of Pediatrics, Biostatistics, and Informatics, Cancer Center Biostatistics Core, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 11 givenname: Eduardo orcidid: 0000-0003-3943-7974 surname: Davila fullname: Davila, Eduardo organization: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 12 givenname: Theresa M orcidid: 0000-0003-0579-4121 surname: Medina fullname: Medina, Theresa M organization: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 13 givenname: Karl D orcidid: 0000-0001-9893-0537 surname: Lewis fullname: Lewis, Karl D organization: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 14 givenname: Rene orcidid: 0000-0002-7435-6208 surname: Gonzalez fullname: Gonzalez, Rene organization: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 15 givenname: Ross W orcidid: 0000-0002-9577-0176 surname: McFarland fullname: McFarland, Ross W organization: UCHealth Cancer Care and Hematology Clinic-Harmony Campus, Fort Collins, Colorado – sequence: 16 givenname: William A orcidid: 0000-0003-1875-9691 surname: Robinson fullname: Robinson, William A organization: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado – sequence: 17 givenname: Martin D orcidid: 0000-0001-8174-1713 surname: McCarter fullname: McCarter, Martin D organization: Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado |
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Snippet | A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in... Abstract Purpose: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with... |
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SubjectTerms | Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Humans Melanoma - pathology Myeloid-Derived Suppressor Cells - pathology Neoplasms, Second Primary - drug therapy Tretinoin - adverse effects |
Title | Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma |
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