scholarly journals Efficacy of EDP ± mitotane chemotherapy in the treatment of metastatic adrenocortical carcinoma. Predictive and prognostic factors of efficacy

2021 ◽  
Vol 11 (1) ◽  
pp. 37-46
Author(s):  
Ya. A. Zhulikov ◽  
E. I. Kovalenko ◽  
V. Yu. Bohyan ◽  
M. V. Khoroshilov ◽  
M. M. Gabrava ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Adrenocortical Carcinoma ◽  
Median Overall Survival ◽  
Therapeutic Option ◽  
Objective Response ◽  
Group Versus ◽  
Progression Free Survival ◽  
Ki 67 ◽  
Free Survival ◽  
Effective Therapeutic Option

Introduction. Adrenocortical carcinoma (ACC) is an orphan disease with an unfavorable prognosis. The most effective therapeutic option in the treatment of ACC is EDP plus mitotane combination chemotherapy. However, no studies comparing the efficacy of the EDP regimen with or without mitotane have been published.Materials and methods. A retrospective analysis of health records of patients with histologically confirmed metastatic ACC, who received at least one chemotherapy cycle with EDP ± mitotane. The study included 73 patients, 49 of which received a combination of EDP and mitotane and 24 were treated with EDP chemotherapy.Results. The objective response rate was 18,4 % in the EDP + mitotane group versus 4,1 % in the EDP group. Disease control was reported in 25 (51 %) and 13 (54,2 %) patients, respectively. No significant differences were found in progression-free survival (PFS) rates between the EDP and EDP + mitotane groups; the median PFS rate was 6,5 and 6,0 months, respectively. The median overall survival (OS) in the total population was 20,9 months; no significant differences were found between the groups. However, an increase in median PFS was observed in patients who achieved a therapeutic concentration of mitotane. Moreover, the achievement of therapeutic mitotane concentrations was the only factor significantly associated with improved PFS (HR 0.44, p = 0.006). Significant unfavorable prognostic factors associated with lower OS were Ki-67 level in the primary tumor > 20 % (HR 10.5, p = 0.006) and more than 1 site of metastases (HR 3.82, p = 0.02).Conclusions. This study showed that the addition of mitotane to EDP chemotherapy does not improve the median PFS and OS in the total patient population, however, the achievement of therapeutic mitotane concentrations is significantly associated with improved progression-free survival.

Clinical implications of polymorphisms in UDP-glucuronosyl transferase (UGT) in patients with metastatic colorectal cancer (mCRC) who were treated with oxaliplatin, irinotecan, and S-1.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 503-503
Author(s):  
Sun Young Kim ◽  
Mi Song I Jang ◽  
Hyun Mi Kim ◽  
Ji Yeon Baek ◽  
Yong Sang Hong ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Objective Response ◽  
Progression Free Survival ◽  
Drug Regimen ◽  
High Rate ◽  
Free Survival ◽  
Effective Therapeutic Option ◽  
Glucuronosyl Transferase ◽  
Intensive Regimen ◽  
Selection Of

503 Background: The three-drug regimen with oxaliplatin, irinotecan and fluoropyrimidine is an effective therapeutic option for patients with mCRC, but is associated with high rate of toxicity. Pharmacogenetic profile might be helpful for selection of proper patients for this intensive regimen. Methods: Forty-two patients were enrolled to our phase II trial and were given irinotecan 150mg/m2 plus oxaliplatin 85mg/m2 on D1 and S-1 80mg/m2/day on D1-14 every 21 days as their front-line therapy for mCRC. Genomic DNA was extracted from peripheral blood, where the presence of germline polymorphisms of UGT including UGT1A1*6, UGT1A1*28, UGT1A1*60, UGT1A6*2, and UGT1A7*3 were tested. Results: Patients with UGT1A1*6 allele had a tendency of more frequent grade 2-3 vomiting (p = 0.06) compared to those without UGT1A1*6. The presence of a haplotype containing UGT1A6*2 and UGT1A7*3 was associated with grade 2-3 vomiting (p = 0.014) and grade 2-3 diarrhea (p = 0.063). Higher objective response rate (18/20, 90%) was noted in patients without UGT1A*60 compared to those with UGT1A1*60 (11/22, 50%; p = 0.008). The absence of UGT1A1*60 was also associated with marginally improved progression-free survival (10.3 mo v 7.7 mo, p = 0.081) and overall survival (26.8 mo v 15.1 mo, p= 0.044) compared to the presence of the variant allele. Conclusions: UGT1A1*6 and a haplotype containing UGT1A6*2 and UGT1A7*3 may be associated with irinotecan-related gastrointestinal toxicities. Phenotypic association of UGT1A1*60 and efficacy of the three-drug regimen requires further investigation.

Trecc: Re-challenge therapy with anti-EGFR in metastatic colorectal adenocarcinoma (mCRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 683-683
Author(s):  
Amanda Karani ◽  
Tiago Felismino ◽  
Lara Azevedo Diniz ◽  
Mariana Petaccia Macedo ◽  
Larissa Machado ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Median Overall Survival ◽  
Colorectal Adenocarcinoma ◽  
Univariate Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Free Survival ◽  
Free Interval

683 Background: Anti-EGFR plus chemotherapy (CT) promotes high response rates (RR) and median overall survival (OS) surpasses 30 months in RASwt/BRAFwt mCRC. After disease progression (PD), resistance mechanisms have been described. The aim of our study was to evaluate efficacy of anti-EGFR re-challenge (TRECC). Methods: We retrospectively analyzed a cohort of patients (pts) with mCRC. All pts had received anti-EGFR plus CT and were discontinued for different reasons. During the treatment, there was re-challenge with an anti-EGFR + CT. We aimed to evaluate progression-free survival (PFS) and OS after re-challenge and prognostic factors associated with PFS. Results: Sixty eight pts met the study criteria. Median follow-up after re-challenge was 39.3m. Discontinuation after first exposure was 25% due to PD; 75% for other reasons. Median anti-EGFR free interval was 10.5m. At re-challenge, main CT regime was: FOLFIRI 58.8%, Cetuximab and Panitumumab were used in 59 and 9 pts respectively. mPFS after re-challenge was 6.6m; mOS was 24.4m. Objective response rate (CR + PR) at re-challenge was 42.6%. In an univariate analysis, adverse prognostic factors related to PFS were: absence of objective response at 1st EGFR exposure (HR 2.12, CI:1.20-3.74 p = 0.009); PD as reason for 1st discontinuation (HR 3.44, CI:1.88-6.29 p < 0.0001); re-challenge at fourth or later lines (HR 2,51, CI:1.49-4.23 p = 0.001); panitumumab use (HR 2.26 CI:1.18-5.54 p = 0.017). In a multivariate model, only PD as reason for 1st discontinuation remained statistically significant (HR = 2.63, CI:1.14-6.03 p = 0.022). mPFS was 3.3m and 8.4m and mOS was 7,5m and 33,4m in patients with PD as reason for 1st discontinuation and other reasons respectively. Conclusions: Re-challenge therapy is commonly used due to paucity of effective lines of treament for mCRC. In our analysis, pts that stopped 1st anti-EGFR therapy due to PD have shorter survival, suggesting these pts do not benefit from TRECC. However, interruption due to treatment holiday after PR/CR resulted in longer PFS. In conclusion, for a selected group of pts, TRECC could be considered a strategy of treatment. Due to the limited number of pts, our data should be evaluated in a prospective cohort of patients.

scholarly journals Effectiveness of nivolumab affected by prior cetuximab use and neck dissection in Japanese patients with recurrent or metastatic head and neck cancer: results from a retrospective observational study in a real-world setting

2021 ◽  
Author(s):  
Shin Kariya ◽  
Yasushi Shimizu ◽  
Nobuhiro Hanai ◽  
Ryuji Yasumatsu ◽  
Tomoya Yokota ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Dissection ◽  
Neck Cancer ◽  
Median Overall Survival ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Free Survival

Abstract Background To examine the effect of prior use of cetuximab and neck dissection on the effectiveness of nivolumab, we conducted a large-scale subgroup analysis in Japanese patients with recurrent/metastatic head and neck cancer. Methods Data on the effectiveness of nivolumab were extracted from patient medical records. All patients were analyzed for effectiveness by prior cetuximab use. In the analyses for prior neck dissection, only patients with locally advanced disease were included. Results Of 256 patients analyzed, 155 had received prior cetuximab. Nineteen of 50 patients with local recurrence underwent neck dissection. The objective response rate was 14.7 vs 17.2% (p = 0.6116), median progression-free survival was 2.0 vs 3.1 months (p = 0.0261), and median overall survival was 8.4 vs 12 months (p = 0.0548) with vs without prior cetuximab use, respectively. The objective response rate was 23.1 vs 25.9% (p = 0.8455), median progression-free survival was 1.8 vs 3.0 months (p = 0.6650), and median overall survival was 9.1 vs 9.9 months (p = 0.5289) with vs without neck dissection, respectively. Conclusions These findings support the use of nivolumab for patients with recurrent/metastatic head and neck cancer regardless of prior cetuximab use or neck dissection history. Trial registration number UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436)

scholarly journals Expression of SOAT1 in Adrenocortical Carcinoma and Response to Mitotane Monotherapy: An ENSAT Multicenter Study

2020 ◽  
Vol 105 (8) ◽  
pp. 2642-2653 ◽  
Author(s):  
Isabel Weigand ◽  
Barbara Altieri ◽  
Amanda M F Lacombe ◽  
Vittoria Basile ◽  
Stefan Kircher ◽  
...  
Keyword(s):  
Protein Expression ◽  
Treatment Response ◽  
Adrenocortical Carcinoma ◽  
Advanced Disease ◽  
Hormone Secretion ◽  
Single Agent ◽  
Objective Response ◽  
Drug Effects ◽  
Progression Free Survival ◽  
Free Survival

Abstract Context Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. Objective To investigate SOAT1 protein expression as a marker of treatment response to mitotane. Patients A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. Setting Retrospective study at 12 ACC referral centers. Main outcome measure Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). Results Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different. Conclusions SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.

scholarly journals Lenvatinib and pembrolizumab in the treatment of metastatic endometrial cancer: literature review and case report

2021 ◽  
pp. 124-128
Author(s):  
A. A. Rumyantsev
Keyword(s):  
Endometrial Cancer ◽  
Endometrial Carcinoma ◽  
Objective Response Rate ◽  
Response Rate ◽  
Therapeutic Option ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Effective Therapeutic Option ◽  
High Level

In 2019 in Russia endometrial carcinoma was diagnosed in 27151 patients, 6820 women died from the disease. The standard of frontline therapy for patients with advanced endometrial carcinoma is platinum and taxane-based chemotherapy with satisfactory efficacy – the median progression-free survival is about 13 months, and up to 50% of patients achieve objective response to therapy. On the other hand, for patients with recurrent endometrial cancer after frontline chemotherapy the results of chemotherapy remained generally unsatisfactory, the objective response rate to standard treatment was about 10 to 15%. During the last few years there significant progress has been made in this area – studies identified a subgroup of patients with a high level of microsatellite instability (MSI-high) highly sensitive to pembrolizumab therapy. In this subset of patients, who account for up to 25% of patients with metastatic endometrial cancer, the objective response rate to pembrolizumab monotherapy is up to 57%. Further studies have shown that the addition of lenvatinib to pembrolizumab therapy may be a highly effective therapeutic option for patients without MSI-high. This article describes a clinical case of the successful therapy of a patient with platinumresistant endometrial carcinoma with a combination of pembrolizumab and lenvatinib. 

Eficacy and safety of first-line TKI in elderly with metastatic renal cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 588-588 ◽  
Author(s):  
Luciana de Moura Leite ◽  
Jose A. Rinck ◽  
Aldo A. Dettino ◽  
Stenio Cassio Zequi ◽  
Alexandre Andre B. A. Da Costa ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Median Overall Survival ◽  
Kinase Inhibitors ◽  
Cox Regression ◽  
Progression Free Survival ◽  
The Elderly ◽  
Metastatic Renal Cancer ◽  
Free Survival ◽  
Exact Test ◽  
Background Data

588 Background: Data on 1st line treatment with tyrosine kinase inhibitors (TKI) in elderly patients(pts) with metastatic renal cell carcinoma (mRCC) is controversial, and there is rationale for inferior outcomes due to multiple comorbidities and polypharmacy. We aimed to compare the efficacy and safety between the elderly (E) and non-elderly (NE) in 1st line therapy, and to explore factors influencing survival and toxicity. Methods: We retrospectively reviewed all medical records of mRCC pts treated with 1st line TKI at our institution (2007 – 2018). Categorial variables were compared by Fisher’s exact test and continuous, Mann–Whitney. Survival was estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: From 171 eligible pts, 64 (37.4%) had ≥ 65years old, with median age of 70.5 for E and 56 for NE. In both groups most were male, had clear cell histology, good/intermediate IMDC risk, prior nephrectomy and > 1 metastatic (mets) site. Sites of mets were evenly distributed. E pts had more diabetes (35.9 vs16.8%, p.009) , hypertension (67.2 vs 46.7%, p.01), cardiovascular disease (15.6 vs 6.5%, p.06), moderate/severe renal dysfunction (62.5 vs 28.8%, p < 0001), high Charlson Comorbidities Index (CCI≥3, 48.4% vs 20.8%, p < .0001), polypharmacy (34.4 vs15.9%, p.008), worst ECOG (≥2, 28.2 vs 12.3%, p.01), and a trend to worst nutrition (weight loss 35.9 vs 22.5%, p.07). Sunitinib was used for 60.9 vs 79.4%, Pazopanib 35.9 vs 18.7%, Sorafenib 3.1 vs 1.9%, comparing E and NE pts. Median overall survival (OS) and progression free survival (PFS) was 23.7 vs 25.6m (p.8) and 9.3 vs 10.9m (p.7), respectively. After adjusting for prognostic factors, age continues not to influence OS (HR 1.17, IC95 0.77-1.78, p.45). Grade (G) 3/4 toxicity was seen in 59.4 vs 53.3%, dose reduction in 54.7 vs 53.3% and suspension due to toxicity 25 vs 13.3% for E and NE, respectively. In the E, none of the comorbidities, CCI or polypharmacy impaired OS or toxicity, but pts using sunitinibe had greater G3/4 toxicity than with pazopanib (71.8 vs 39.1%, p.02). Conclusions: Elderly had similar outcomes to NE pts, despite greater comorbidities and polypharmacy, hence efficacious therapies shouldn’t avoided. Pazopanib seems to be safer in this subgroup.

Efficacy of chemotherapy for patients with unresectable or recurrent pancreatic adenosquamous carcinoma: A multicenter retrospective analysis.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 647-647 ◽  
Author(s):  
Yukio Yoshida ◽  
Akira Fukutomi ◽  
Makoto Ueno ◽  
Keita Mori ◽  
Kazuo Watanabe ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Adenosquamous Carcinoma ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Ductal Adenocarcinoma ◽  
Poor Survival ◽  
Free Survival ◽  
Metastatic Sites

647 Background: Pancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). Although unresectable or recurrent PASC is usually treated by systemic chemotherapy, there are few reports which show the efficacy of chemotherapy. The aim of this study was to evaluate the efficacy of chemotherapy for patients (pts) with unresectable or recurrent PASC. Methods: We collected data retrospectively from 24 Japanese institutions. The selection criteria were as follows: 1) histologically or cytologically proven PASC (non-surgical specimens were eligible if squamous cell carcinoma (SCC) was detected), 2) unresectable or recurrent disease treated with 1st line chemotherapy between April 2001 and December 2017. Results: This study included 138 pts with median age of 66 years (range: 36-85). About 60% of pts were diagnosed with biopsy and only SCC was detected in 13.0% of pts. Median overall survival (mOS) was 6.7 months (M), median progression free survival (mPFS) was 2.8 M, and the 1-year survival rate (1YSR) was 26.7%. For the 102 metastatic or distal recurrent pts with PS of 0-1, patient characteristics were as follows: ≥76 years old, 9 (8.8%); PS of 0, 39 (38.2%); number of metastatic sites ≥2, 25 (24.5%). The treatment efficacies (The objective response rates(%)/mPFS(M)/mOS(M)/1YSR(%)) of the 5 major regimens were Gemcitabine(GEM) (n=45, 4.4%/2.2M/4.8M/28.1%), GEM+nab-PTX (n=24, 29.2%/2.9M/7.6M/23.1%), GEM+S-1 (n=9, 11.1%/5.1M/9.9M/25.4%), FOLFIRINOX (n=7, 14.3%/2.5M/7.5M/14.3%), and S-1 (n=7; 28.6%/2.6M/5.0M/28.6%), respectively. One patient with liver metastasis underwent conversion surgery after GEM+nab-PTX and achieved long survival. CRP ≥3.0mg/dl, CA19-9 ≥1000 U/ml, residual primary site, and monotherapy had a significant correlation with poor survival in multivariate analysis. Conclusions: Although combination chemotherapy regimens such as FOLFIRINOX and GEM+nab-PTX are now available, the prognosis of metastatic PASC remains poor. Development of more effective treatment options is required.

scholarly journals Immune Checkpoint Inhibitors in Advanced Acral Melanoma: A Systematic Review

2020 ◽  
Vol 10 ◽  
Author(s):  
Qingyue Zheng ◽  
Jiarui Li ◽  
Hanlin Zhang ◽  
Yuanzhuo Wang ◽  
Shu Zhang
Keyword(s):  
Systematic Review ◽  
Combination Therapy ◽  
Objective Response Rate ◽  
Median Overall Survival ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Therapeutic Effects ◽  
Free Survival

IntroductionAcral melanoma (AM) has different biological characteristics from cutaneous melanoma. Although systemic therapeutic strategies for advanced AM resemble those for advanced cutaneous melanoma, the evidence of the clinical use of immune checkpoint inhibitors (ICIs) for AM is still inadequate. We aimed to systematically analyze the therapeutic effects and safety profile of ICI treatments in advanced AM.MethodsThis systematic review was conducted in line with a previously registered protocol. Three electronic databases, conference abstracts, clinical trial registers, and reference lists of included articles were searched for eligible studies. The primary outcomes were therapeutic effects, and the secondary outcomes were the safety profiles.ResultsThis systematic review included six studies investigating anti-CTLA-4 immunotherapy, 12 studies investigating anti-PD-1 immunotherapy, one study investigating the combination therapy of anti-CTLA-4 and anti-PD-1, and one study investigating anti-PD-1 immunotherapy in combination with radiotherapy. In most studies investigating ipilimumab, the anti-CTLA-4 antibody, the objective response rate ranged from 11.4 to 25%, the median progression-free survival ranged from 2.1 to 6.7 months, and the median overall survival was more than 7.16 months. For studies discussing anti-PD-1 immunotherapy with nivolumab, pembrolizumab, or JS001, the objective response rate ranged from 14 to 42.9%, the median progression-free survival ranged from 3.2 to 9.2 months, and the median overall survival was more than 14 months. The combination therapy of anti-CTLA-4 and anti-PD-1 immunotherapy showed better efficacy with an objective response rate of 42.9% than single-agent therapy. The retrospective study investigating the combination therapy of anti-PD-1 immunotherapy and radiation showed no overall response. Few outcomes regarding safety were reported in the included studies.ConclusionsICIs, especially anti-CTLA-4 monoclonal antibodies combined with anti-PD-1 antibodies, are effective systematic treatments in advanced AM. However, there remains a lack of high-level evidence to verify their efficacy and safety and support their clinical application.

scholarly journals Efficacy of Regorafenib in Hepatocellular Carcinoma Patients: A Systematic Review and Meta-Analysis

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 36 ◽  
Author(s):  
Antonio Facciorusso ◽  
Mohamed A. Abd El Aziz ◽  
Rodolfo Sacco
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Adverse Events ◽  
Therapeutic Option ◽  
Controlled Trial ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Sensitivity Analyses ◽  
Free Survival

Regorafenib showed promising results as a second-line agent after sorafenib failure in hepatocellular carcinoma patients. The aim of this meta-analysis was to evaluate the efficacy and safety of regorafenib in hepatocarcinoma patients. A computerized bibliographic search was performed on the main databases. The primary outcome was overall survival. Secondary outcomes were progression-free survival, tumor response, and the adverse events rate. Outcomes were pooled through a random-effects model and summary estimates were expressed in terms of median and 95% confidence interval or rates, as appropriate. One randomized-controlled trial and seven non-randomized studies with 809 patients were included. The great majority of recruited patients were in Child-Pugh A and ECOG 0 stage. Median overall survival was 11.08 months (9.46–12.71) and sensitivity analyses confirmed this finding, with a median survival ranging from 10.2 to 13.8 months. Duration of regorafenib therapy was 3.58 months, whereas median progression-free survival was 3.24 months (2.68–3.86). The pooled objective response rate was 10.1% (7.8–12.5%) while the disease control rate was 65.5% (61.3–69.7%) with no evidence of heterogeneity (I2 = 0%; Diarrhea, fatigue, and hand-foot skin reaction were the most frequent adverse events. The current meta-analysis shows that regorafenib represents a valuable and relatively safe therapeutic option in intermediate/advanced hepatocellular carcinomapatients who progress on sorafenib.

scholarly journals The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lars Ny ◽  
Henrik Jespersen ◽  
Joakim Karlsson ◽  
Samuel Alsén ◽  
Stefan Filges ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Median Overall Survival ◽  
Objective Response ◽  
Progression Free Survival ◽  
Epigenetic Therapy ◽  
Phase 2 ◽  
Free Survival ◽  
Phase 2 Study ◽  
Phase 2 Clinical Trial ◽  
Registration Number

AbstractPreclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016). EudraCT registration number: 2016–002114-50.

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