Pembrolizumab and all-trans retinoic acid combination treatment of advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9536-9536
Author(s):  
Martin McCarter ◽  
Richard P. Tobin ◽  
Dasha T. Cogswell ◽  
Victoria M. Vorwald ◽  
Dana Davis ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Checkpoint Inhibitors ◽  
Stage Iv ◽  
Suppressor Cells ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Melanoma Patients ◽  
Poor Outcomes

9536 Background: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) reduces MDSC frequency. This analysis seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in advanced melanoma patients. Methods: This single arm, single institution, phase I/II study (NCT03200847) enrolled 24 patients diagnosed with stage IV melanoma. Eligible patients were over the age of 18 and had not been previously treated anti-PD-1 therapy. Treatment consisted of 200mg Q3W pembrolizumab plus the supplemental treatment of 150 mg/m2 ATRA orally for 3 days surrounding each of the first four infusions of pembrolizumab, with patients continuing pembrolizumab for up to two years until confirmed disease progression or unacceptable toxicity. The primary endpoints were safety and reduction in circulating MDSCs. Secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) according to RECIST v1.1. Results: At data cut off (Feb, 2021) 22 patients were evaluable for tumor response. Median follow-up was 1.0 years (0.3-2 years). In general, the combination of pembrolizumab and ATRA was well tolerated. The most common treatment-related adverse events (AEs) were grade 1 or 2, including headache (22 pts, 92%), fatigue (18 pts, 75%), rash (16 pts, 66%), and nausea (8 pts, 33%), most of which corresponded with the 3-day course of ATRA treatment. Ten patients had grade 3 or higher AEs with most being common ICI-related AEs. The ORR was 60% and DCR was 83%. Six-month PFS rate was 62%. Excluding patients diagnosed with uveal melanoma (n = 2) the ORR was 72%, DCR was 86%, and the six-month PFS rate was 68%. Paired analysis showed sustained decreases in absolute numbers ( p = 0.002) and percentage ( p = 0.007) of circulating MDSCs (CD3-CD19-CD56-CD11b+CD33+HLA-DR-/low) 4-6 weeks after stopping ATRA. The study is ongoing and further data will be presented in the future. Conclusions: This study demonstrates that the combination of ATRA and pembrolizumab is well tolerated and suggests that reducing MDSCs with ATRA may enhance the efficacy of pembrolizumab. This strategy of targeting MDSCs in combination with pembrolizumab warrants further development. Research Funding: Merck. Clinical trial information: NCT03200847.

Targeting MDSCs using ATRA: a phase I/II clinical trial combining pembrolizumab and all-trans retinoic acid for metastatic melanoma

2021 ◽  
Author(s):  
Richard Tobin ◽  
Dasha Cogswell ◽  
Victoria Vorwald ◽  
Dana Davis ◽  
Jessica Borgers ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Stage Iv ◽  
Suppressor Cells ◽  
Progression Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Melanoma Patients

Abstract Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) alters their activity and reduces MDSC frequency. This trial seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in metastatic melanoma patients. In 24 stage IV melanoma patients, treatment with pembrolizumab Q3W plus the supplemental treatment of ATRA orally for three days surrounding each of the first four pembrolizumab infusions effectively lowered the frequency of circulating PMN-MDSCs and enhanced melanoma-specific T cell activity. The combination was well tolerated. Median progression free survival was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response. Targeting MDSCs remains a promising mechanism to enhance the efficacy of anti-PD-1 therapies and this combination merits further investigation.

scholarly journals Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab

2018 ◽  
Vol 63 ◽  
pp. 282-291 ◽  
Author(s):  
Richard P. Tobin ◽  
Kimberly R. Jordan ◽  
William A. Robinson ◽  
Dana Davis ◽  
Virginia F. Borges ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Melanoma Patients

scholarly journals Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors

2019 ◽  
Vol 8 (4) ◽  
pp. e1568812 ◽  
Author(s):  
Arielle Elkrief ◽  
Layal El Raichani ◽  
Corentin Richard ◽  
Meriem Messaoudene ◽  
Wiam Belkaid ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Melanoma Patients

scholarly journals Novel Use of All-Trans-Retinoic Acid in A Model of Lipopolysaccharide-Immunosuppression to Decrease the Generation of Myeloid-Derived Suppressor Cells by Reducing the Proliferation of CD34+ Precursor Cells

Shock ◽  
2017 ◽  
Vol 48 (1) ◽  
pp. 94-103 ◽  
Author(s):  
Daiana Martire-Greco ◽  
Nahuel Rodriguez-Rodrigues ◽  
Luis A. Castillo ◽  
María Belén Vecchione ◽  
Marcelo de Campos-Nebel ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Suppressor Cells ◽  
Precursor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1666 ◽  
Author(s):  
Sandra Huynh ◽  
Laurent Mortier ◽  
Caroline Dutriaux ◽  
Eve Maubec ◽  
Marie Boileau ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Real Life ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Tumor Control ◽  
Wild Type ◽  
Multicenter Cohort Study ◽  
Melanoma Patients

Despite significant progress in melanoma survival, therapeutic options are still needed in case of progression under immune checkpoint inhibitors (ICI), and resistance to targeted therapies (TT) in BRAF-mutated melanomas. This study aimed to assess the safety of combined ICI and TT as a rescue line in real-life clinical practice. We conducted a study within the prospective French multicentric MelBase cohort, including patients treated with a combination of anti-PD1 (pembrolizumab/nivolumab) and BRAF inhibitor (BRAFi: dabrafenib/vemurafenib) and/or MEK inhibitors (MEKi: trametinib/cobimetinib) for BRAF mutated or wild-type advanced melanoma. Fifty-nine patients were included: 30% received the triple combination, 34% an anti-PD1 and BRAFi, and 36% an anti-PD1 and MEKi. Grade 3–4 adverse events occurred in 12% of patients. Permanent discontinuation or dose reduction of one of the treatments for toxicity was reported in 14% and 7% of patients, respectively. In the BRAF wild-type subgroup, treatment with MEKi and anti-PD1 induced a tumor control rate of 83% and median progression-free survival of 7.1 months. The combination of anti-PD1 and BRAFi and/or MEKi was a safe rescue line for advanced melanoma patients previously treated with ICI/TT. The benefit of these combinations, specifically anti-PD1 and MEKi in BRAF wild-type melanoma patients, needs to be prospectively studied.

scholarly journals Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1027 ◽  
Author(s):  
Teresa Amaral ◽  
Olivia Seeber ◽  
Edgar Mersi ◽  
Stephanie Sanchez ◽  
Ioannis Thomas ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Checkpoint Inhibitors ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Primary Resistance ◽  
Dismal Prognosis ◽  
Significant Difference ◽  
Melanoma Patients ◽  
Stage Iv Melanoma

Background: Primary resistance to immunotherapy can be observed in approximately 40–65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p < 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

The relationship between tumor-infiltrating lymphocytes, PD-L1 expression, and clinical outcomes of Asian melanoma patients treated with anti-PD-1 antibody.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22010-e22010
Author(s):  
Soo Jung Lee ◽  
Yee Soo Chae ◽  
Jong Gwang Kim ◽  
Byung Woog Kang ◽  
Jin Ho Baek ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Blood Parameters ◽  
Clinical Feature ◽  
Asian Populations ◽  
Melanoma Patients ◽  
Infiltrating Lymphocytes

e22010 Background: Clinical feature of Asian melanoma patients are distinct from those of Western patients. Acral and mucosal melanomas, which are common in Asian populations, predominantly occur in sun-protected areas. Immune-checkpoint inhibitors are standard treatment for inoperable melanoma, however, they are less effective against acral and mucosal melanomas. The aim of our study is to investigate the expression, clinical significance and association of programmed death-ligand 1 (PD-L1) with tumor-infiltrating lymphocytes (TIL) in Asian melanoma patient treated with anti-PD-1 therapy. Methods: Patients with unresectable stage III or metastatic stage IV melanoma who began anti-PD-1 antibody therapy between February 2016 and September 2018 were enrolled. Immunohistochemistry was used to evaluate PD-L1 expression and stromal CD8+ TIL, and PD-1+ TIL densities within the intratumoral regions and associated stromal regions. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes. Results: Of the 57 cases, the most common type was acral melanoma (n = 28, 49.1%) followed by mucosal melanoma (n = 19, 33.3%) and cutaneous (n = 10, 17.5%). The overall response was 8.8 % and disease control rate was 33.3%. The median progression-free survival (PFS) was 18.0 months (95% confidence interval, 12.57 to 23.43), and there was no difference in PFS according to subtypes. Overall, 29.8% (n = 17) showed PD-L1 expression in tumor cells and 26.3% in immune cells. PD-L1, CD8+TIL, LDH and BRAFV600 statues were not associated with response or survival. NLR (≥ 5) were independent poor prognostic factors by multivariate analysis. Conclusions: In our study, anti-PD-1 therapy showed less effective compared to western patients. High NLR (≥ 5) could predict response of anti-PD-1 therapy in patients with Asian melanoma. Considering the differences in genetic backgrounds and therapeutic efficacy of immunotherapy, specialized therapeutic strategies for Asian melanoma should be established.

scholarly journals The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Chiao-En Wu ◽  
Chan-Keng Yang ◽  
Meng-Ting Peng ◽  
Pei-Wei Huang ◽  
Ching-Fu Chang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Outcomes ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Survival Outcomes ◽  
Free Survival ◽  
Asian Patients ◽  
Melanoma Patients ◽  
Experienced Grade

Abstract Background The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. Methods We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). Results: Overall, the patients who experienced grade 1–2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27–0.98; p = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24–1.02; p = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21–0.74; p = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17–0.69, p = 0.003) than patients without any of these irAEs. Conclusions Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1–2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

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