Previous Regimens Research Articles

Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia

Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia

A Phase 1, Open-Label, Multi-Center Study of Alteminostat (CKD-581) in Combination with Lenalidomide and Dexamethasone in Patients with Previously Treated Multiple Myeloma (MM)

Background Alteminostat (CKD-581), a novel hydroxamate-based pan-HDAC inhibitor, increases acetylation of histones and other proteins involved in multiple oncogenic pathways. It modulates gene expression involved in cell-cycle regulation, differentiation, and apoptosis. Altemonstat in combination with lenalidomide and dexamethasone demonstrated promising anti-cancer efficacy both in vitro and in vivo studies, including xenograft models of multiple myeloma (MM). In addition, it was well tolerated in patients with lymphoma and MM refractory to standard therapy. On the basis of this background, we conducted a phase I dose-finding study of alteminostat in combination with lenalidomide and dexamethasone in relapsed MM patients. Methods Subjects with MM who had relapsed after at least one prior treatment were infused alteminostat iv (90, 120, or 160 mg/m2, level 1-3, respectively once weekly for 3 weeks out of a 4-week cycle in a standard 3+3 dose-escalation, phase 1 design, combined with lenalidomide 25 mg on day 1-21 and dexamethasone 40 mg on day 1, 8, 15, 22 in a 28-day cycle Results As of July 11th, 2019 the study has enrolled 10 patients with relapsed MM to Level 3. The median age was 56 (range 46-64), and the median number of previous regimens received was 2.5 (range 1~8). Based on the data cut off day, no dose-limiting toxicities were identified. 2 patients were in progress on the maximum planned dose of 160 mg/m2. The most common (>20% of subjects) drug-related adverse events (AEs) were thromobcytopenia (80%), neutropenia (60%), anemia (50%), muscle spasms (50%), fatigue (30%), upper abdominal pain (30%), and constipation (30%). Serious adverse drug reaction was not reported. AEs related with cardiac disorder have not been observed. The most common ≥Grade 3 hematologic AEs were neutropenia (70%), thromobcytopenia (60%), and anemia (60%). The most common ≥Grade 3 non-hematologic AEs are pneumonia (40%). One patient at dose level 2 died from pulmonary embolism after pneumonia. Two of ten patients had exposed to lenalidomide before participating in this clinical trial. The median cycle was 3 in level 1, 4 in level 2 and 2 in level 3, while level 3 is still in progress. The overall response rate, defined as achieving more than partial response (PR), for all patients was 70%, including 10% stringent complete response (sCR), 10% CR, 20% very good PR and 30% PR. The median duration of response was 236 days and median progression-free survival was 232 days. Conclusions Alteminostat, a novel hydroxamate-based pan-HDAC inhibitor, can be combined safely with lenalidomide and dexamethasone, demonstrating significant clinical activity in subjects with MM. Enrollment is ongoing and full phase 1 will be updated and presented. Disclosures No relevant conflicts of interest to declare.

Real-world experiences with direct-acting antiviral agents for chronic hepatitis C treatment.

As direct-acting antiviral (DAA) agents become more readily available for the treatment of chronic hepatitis C, it is important to understand real-world treatment experiences. In order to assess the effectiveness of DAA regimens and factors that influence sustained virologic response (SVR) rates in the Veterans Affairs healthcare system, we retrospectively identified veterans with chronic hepatitis C who were treated with DAAs from January 2014 to June 2015. We determined SVR rates and collected data on demographics, genotype (GT), previous interferon-based treatment, antiviral regimens, and co-morbidities (HIV, prior solid organ transplant, haemodialysis) for analysis. Of 15720 veterans, the majority were infected with genotype 1a (GT1a, 60.5%). Excluding the special populations, the overall cohort SVR rate was 92%. Compared to treatment-experienced patients, treatment-naïve patients had significantly higher SVR rates (90% vs 92%, P=.006). Subgroups associated with lower likelihood of achieving SVR-included African Americans (OR 0.79, 95% CI 0.69-0.91), GT3 (OR 0.65, CI 0.50-0.86), and cirrhosis (OR 0.91, CI 0.84-0.99) or decompensated cirrhosis (ascites: OR 0.78, CI 0.67-0.91, variceal bleed: OR 0.75, CI 0.57-0.99). The only treatment regimen independently associated with lower SVR rates was SOF+RBV+IFN (OR 0.65, CI 0.50-0.84). Special populations achieved high SVR rates: HIV 92%, haemodialysis 93%, liver transplant 96% and renal transplant 94%. In conclusion, overall SVR rates were comparable to those reported in clinical trials and carried over to historically more difficult-to-treat patients. Several patient- and treatment-related factors were identified as independent predictors of treatment failure and suggest subgroups to target for efforts to improve therapeutic strategies.

Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

BackgroundCystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.MethodsWe conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor–tezacaftor–ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del–minimal function genotypes. Patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.ResultsA total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor–tezacaftor–ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire–Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor–tezacaftor–ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor–tezacaftor–ivacaftor group.ConclusionsElexacaftor–tezacaftor–ivacaftor was efficacious in patients with cystic fibrosis with Phe508del–minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.)

306P - Efficacy and safety of apatinib in heavily pretreated metastatic adenocarcinoma of the head and neck

BackgroundThe optimal therapy for adenocarcinoma of the head and neck with distant metastasis is very limited and controversial. Although antiangiogenic therapy is effective in advanced lung, colon, hepatic, and renal carcinomas, limited is known about its value in the carcinoma of the head and neck. Apatinib, an oral, highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been proven to be effective for the treatment of a broad range of advanced solid tumors. This prospective phase II study (NCT02989259) aims to investigate the efficacy and safety of apatinib in heavily pretreated patients with metastatic adenocarcinoma of the head and neck. MethodsThis study enrolled patients with adenocarcinoma of the head and neck, who failed in the metastatic setting at least one prior chemotherapy regimen. The primary end point was progression free survival (PFS). Secondary end points included objective response rate, disease control rate, overall survival (OS), and safety. Patients were treated with apatinib 500 mg daily until disease progression or the occurrence of intolerable toxicity. Efficacy was assessed every 8 weeks. ResultsFrom December 2016 to January 2019, twenty patients were enrolled, including 13 males and 7 females, with a median age of 61 years (26-79). The median number of previous chemotherapy regimens for the metastatic diseases was 2 (1-3). Partial response was achieved by 5 (25%) patients and stable disease exhibited by 14 (70%) patients.The median PFS and OS were 7.5 and 11.0 months, respectively. The most common adverse events (AEs) of all grade were secondary hypertension (n = 16), proteinuria(n = 10), hyperbilirubinemia (n = 10), nausea (n = 6), fatigue (n = 5) and hand-foot syndrome (n = 4). Grade 3/4 AEs were hypertension (n = 4), oral microsites (n = 3), and thrombocytopenia (n = 1). No grade 4 or 5 AE was observed in the study. ConclusionsOur results indicated that apatinib exhibited objective efficacy in heavily pretreated, metastatic adenocarcinoma of the head and neck with a manageable toxicity profile. Apatinib can be considered as a treatment option for adenocarcinoma of the head and neck with metastatic diseases. Clinical trial identificationThe trial protocol number is NCT02989259. And release date is December 2016. Legal entity responsible for the studyCAMS & PUMC, National Cancer Center, Cancer Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that can be either aggressive or indolent. Although MCL usually responds well to initial treatment with chemotherapy-based regimens, the disease often relapses or becomes refractory within a few years. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. WIthout head-to-head clinical trial data, estimation of the comparative efficacy and safety of new therapeutic entities provides valuable information for patients, clinicians, and health care payers. The objective of this analysis was to compare the efficacy and safety of acalabrutinib versus other targeted therapies employed for the treatment of relapsed/refractory MCL by using matching-adjusted indirect comparisons. Individual data from 124 patients treated with acalabrutinib in the Phase II ACE-LY-004 trial were adjusted to match average baseline characteristics of populations from studies using alternative targeted treatment regimens for relapsed/refractory MCL (for monotherapy: ibrutinib, bortezomib, lenalidomide, and temsirolimus; for combination therapies: ibrutinib+rituximab, bendamustine+rituximab, and lenalidomide+rituximab). Patient populations were matched on age, sex, race, Eastern Cooperative Oncology Group performance status, Simplified MCL International Prognostic Index score, tumor bulk, lactate dehydrogenase concentration, extranodal disease, bone marrow involvement, and number of previous treatment regimens. Outcomes assessed included overall response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), and adverse events. After matching, acalabrutinib was associated with significant increases in ORR and CR rate (estimated treatment difference [95% CI]) versus ibrutinib (ORR, 9.3% [0.3-18.3]; CR, 14.9% [5.4-24.3]), bortezomib (ORR, 50.6% [40.2-61.0]; CR, 18.8% [9.1-28.5]), lenalidomide (ORR, 38.1% [27.1-49.1]; CR, 43.5% [34.8-52.3]), and temsirolimus (ORR, 40.7% [31.0-50.4]; CR, 27.1% [19.2-35.0]). PFS (hazard ratio [95% CI]) with acalabrutinib was significantly increased versus bortezomib (0.36 [0.26-0.51]), lenalidomide (0.65 [0.48-0.89]), lenalidomide+rituximab (0.57 [0.35-0.93]), and temsirolimus (0.33 [0.24-0.45]). Acalabrutinib was associated with significantly increased OS (hazard ratio) versus bortezomib (0.36 [0.22-0.61]) and temsirolimus (0.32 [0.23-0.44]). The overall safety profile of acalabrutinib was similar or better compared with the monotherapies; however, infection risk increased versus bendamustine+rituximab, and anemia increased risk versus lenalidomide+rituximab and ibrutinib+rituximab. This comparison of targeted therapies used in the treatment of relapsed/refractory MCL showed that acalabrutinib has the potential to provide increased response rates, with trends for increased PFS and OS, and an improved safety profile.

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer

BackgroundPatients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.MethodsIn this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E–mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.ResultsThe median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.ConclusionsA combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.)

Outcomes With First-line PD-1/PD-L1 Inhibition in Advanced Urothelial Cancer: A Single Institution Experience

First-line PD-inhibition in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer represents a novel clinical setting, with uncertainty concerning second-line outcomes. Specifying second-line treatment and outcomes will provide guidance in this new sequence. We performed a retrospective chart review to document the outcomes of these patients treated at our institution. Our cohort consisted of 43 patients with advanced urothelial cancer receiving first-line checkpoint inhibition. Baseline factors, programmed death-ligand 1 (PD-L1) status, treatments, and outcomes during and beyond the first line were obtained. Response was scored using Response Evaluation Criteria in Solid Tumors, version 1.1 criteria. Log rank tests were used to compare outcomes in prognostic subgroups, and outcome associations with PD-L1 status were analyzed with Fisher exact tests. A total of 43 patients received first-line atezolizumab or pembrolizumab from June 2014 until June 2018. The median age was 76.8 years, and the population was 74% male, with 60% having visceral metastases. Reasons for cisplatin ineligibility were Eastern Cooperative Oncology Group performance status 2%, 30%; renal insufficiency, 44%, and both, 21%. First-line objective response rate (ORR) was 30%, and complete response was 14%. The median overall survival was 11.7 months. Of 29 patients progressing, 17 received second-line treatment (most commonly, gemcitabine/carboplatin [10 patients]). The second-line response rate was 33%, and the ORR was 11%. The second-line median overall survival was 6.2 months. No association was found between PD-L1 status and outcomes. Outcomes with first-line immunotherapy are consistent with historical outcomes. The ORR after first-line checkpoint inhibition falls short of historical comparators; however, the response rate compares favorably to those of chemotherapies used in previous second-line regimens. The older age and poorer performance status may have contributed to second-line outcomes.

Efficacy and Safety of Trifluridine/Tipiracil Treatment in Patients With Metastatic Gastric Cancer Who Had Undergone Gastrectomy

Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC. To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy. This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018. Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle. The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups. Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups. The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy. ClinicalTrials.gov identifier: NCT02500043.

Cost-effectiveness of switching to insulin degludec from other basal insulins in real-world clinical practice in Italy

Aims: The costs associated with insulin therapy and diabetes-related complications represent a significant and growing economic burden for healthcare systems. The aim of this study was to evaluate the cost-effectiveness of switching to insulin degludec (degludec) vs continuing previous basal insulin, in Italian patients with type 1 (T1D) or type 2 (T2D) diabetes, using a long-term economic model.Materials and methods: Data were retrieved from a real-world population of patients from clinical practice in Italy. Clinical parameters included in the base-case model were change from baseline in HbA1c, rates of hypoglycemia, and basal and bolus insulin dose, at 6 months following switch to degludec. Costs of treatments were taken from official Italian pharmaceutical list prices and costs of hypoglycemia were based on the literature. The data were used to populate a long-term (lifetime) IQVIA CORE Diabetes Model to evaluate the incremental cost-effectiveness ratio (ICER) – cost per quality-adjusted life-year (QALY). The robustness of these results was tested with extensive sensitivity analyses by varying the time horizons and abolishing each of the treatment differences and previous basal insulins.Results: The total incremental cost for degludec vs previous basal insulin was €–6,310 and €–2,682 for patients with T1D and T2D, respectively; the switch to degludec resulted in a QALY gain of 0.781 and 0.628. The long-term ICER for degludec vs continuing the previous basal insulin regimen showed that degludec was dominant for both T1D and T2D, meaning that patient health was improved in terms of QALYs with lower healthcare costs. Sensitivity analyses showed that degludec remained dominant in most scenarios including after elimination of any benefit in non-severe hypoglycemia and insulin dose, in both T1D and T2D.Conclusions: Under routine care, switching to degludec is dominant, compared with continuing previous basal insulin, in Italian patients with T1D or T2D.

Efficacy of nivolumab for advanced gastric cancer

Abstract Backgrounds In ATTRACTION-2 trial, nivolumab (NIVO) showed better outcome compared with best supportive care in advanced gastric cancer (AGC) patients (pts) at least two previous regimens. (NIVO has changed the treatment of AGC in Japan.) Methods: From Nov 2017 to Feb 2019, we retrospectively investigated 25 pts with AGC who received NIVO. Results: The patient demographics were as follows: median age, 67 (range, 39-82); male/female ratio, 18:7; performance status (PS) 0/1/2, 9/14/2; unresectable /recurrent, 20 /5; HER2 positive, 3; deep vein thrombosis, 3; intestinal type /diffuse type, 13 /12; primary site EGJ/UML/UM/ML/U/M/L, 2/2/1/3/5/4/8; site of metastases lymph node /liver /peritoneum /ovary, 13 /8 /9 /1; and previous treatment regimens 2 regimens /3 regimens /≥4 regimens, 9 /10 /6. Response rate (RR) was 12% and disease control rate (DCR) was 28%. The median progression free survival (PFS) was 4.1 months (95% confidence interval [CI], 2.8-NA) and the median overall survival (OS) was 11.8 months (95% CI, 8.2-12.8). In histologic subtypes and PS, there were no difference in PFS and OS between pts with intestinal type and diffuse type as well as between those with PS of 0 and 1-2. As for the number of previous treatment regimens, there was no difference in PFS between pts who received ≥3 regimens and pts who received 2 regimens. However, the former had significantly longer OS compared with the latter. Ten patients (40%) developed immune-related adverse event (ir-AE) and four (16%) did severe ir-AE (≥grade 3). Conclusions: The current study showed better results and longer OS for AGC pts who received NIVO with acceptable toxicities. The limitation is a small number of patients accompanied by a potential of selection with retrospective manner, thus warrants a further studies.

Efficacy of chemotherapy following nivolumab in metastatic gastric cancer

Abstract Background Immuno-checkpoint inhibitors, nivolumab targeting programmed cell death 1 (PD-1) can result in significant benefit to gastric cancer. Some recent data about non-small cell lung cancer suggest anti-PD-1 therapy may enhance sensitivity to subsequent chemotherapy. To date, there are no reports on treatment efficacy after failure of PD-1 blockade in advanced gastric cancer. Therefore, we aimed to report the efficacy of chemotherapy after progressive disease on nivolumab. Methods We have retrospectively reviewed data of all patients in metastatic gastric cancer who received chemotherapy in our hospital and investigated the efficacy and adverse events of chemotherapy after progression on nivolumab. Results Between September 2017 and January 2019, 29 patients received nivolumab for metastatic gastric cancer. 11 patients received subsequent treatment following nivolumab. The median age was 70. Performance status (0/1/2); 2/8/1. Previous treatment regimens (2/3/4/5); 4/3/2/1. Chemotherapy regimen (irinotecan / nab-paclitaxel±ramcirumab / CAPOX±trastuzumab / SOX+trastuzumab); 3/5/2/1. Overall Response rate was 27%. 2 patients for nab-PTX+ramcirumab and 1patient of CAPOX+trastuzumab had a PR, 1patient for nab-PTX+ramcirumab had a SD, 5 patients had a PD and 1 patient had a NE. Median PFS was 3.3 (95% CI. 0.8-5.5) months. Median OS was 8.0 (95%CI. 2.3-11.6) months. One patient developed Gr3 dysfunction of liver maybe due to nivolumab. Other adverse events were mild. Conclusions We evaluated the efficacy of chemotherapy after progression on nivolumab. Further investigation is warranted to reveal an immunotherapy-induced chemosensitization effect.

SUSTAINED VIROLOGIC RESPONSE RATE IN CHRONIC HEPATITIS C PATIENTS THROUGH DIRECT-ACTING ANTIVIRALS THERAPY.

In recent years the management of hepatitis C virus infection and the possibility of its eradication have been researched due to the importance that they represent in the health of the world population. Obtaining data that help to cope with this pathology improves the quality of life of those affected by it. The present study evaluated the effectiveness of direct-acting antiviral therapies provided by the Brazilian Ministry of Health in accordance to the Clinical Protocol and Therapeutic Guidelines of 2015. To evaluate the epidemiological profile of patients with chronic hepatitis C and the rate of sustained virologic response using direct-acting antivirals of all individuals that attended the referral service for the treatment of chronic hepatitis C at the Hospital of the Federal University of Rio Grande. This was an observational, retrospective/prospective study with all patients with chronic hepatitis C who had their treatments available from December 2015 to August 2017 according to the criteria of the Clinical Protocol and Therapeutic Guidelines of 2015. In the first phase, the clinical and demographic variables of all individuals enrolled in a treatment for hepatitis C were selected and collected from the Reference Service database. In the second phase, treatment data were collected. The outcome variable, sustained virologic response, was defined as an undetectable viral load on the blood test three months after the end of treatment. The descriptive and bivariate analyzes were performed with Pearson's chi-square and Fisher's Exact test, adopting a P value ≤0.05 in the SPSS 20 software. Of the 252 participants in the study, 228 (90.5%) had a sustained virologic response, 55.2% were male with an average age of 58.6 years (SD±9.1). Genotype 1 was the most prevalent, observed in 54.4% of the participants, and 87.4% of the patients had moderate/advanced hepatic fibrosis. After the statistical analysis, it was observed that the individuals with genotype 3 and moderate/advanced hepatic fibrosis had lower sustained virologic response rate (P=0.05 and P=0.04, respectively). It was observed that the use of direct-acting antivirals, in comparison to previous therapeutic regimens, increases the sustained virologic response, reaching all patients with mild fibrosis. This study provides information that helps in the hepatitis C treatment by showing that prescribing early treatment for patients without hepatic fibrosis and/or genotype 3 virus could increase therapeutic effectiveness.

2501 A Rare Case of Sofosbuvir/Velpatasvir/Voxilaprevir Failure in a Patient With Hepatitis C Virus Infection and Previously Undiagnosed Hepatocellular Carcinoma

INTRODUCTION: The advent of direct acting antiviral (DAA) agents has revolutionized the treatment for chronic hepatitis C virus (HCV) infection with greater than 95% success rate. In 2017, a combination of sofosbuvir, velpatasvir, and voxilaprevir (sof-vel-vox) was approved after clinical trials demonstrated a 97-100% sustained virological response (SVR) rate in patients who had failed a previous NS5A inhibitor regimen. We present a rare case of treatment failure with sof-vel-vox in a non-cirrhotic patient with previously undiagnosed hepatocellular carcinoma (HCC). CASE DESCRIPTION/METHODS: The patient is a 68-year-old African-American male with a history of HCV-G1b infection who had previously failed treatment with a 12-week regimen of sofosbuvir/ledipasvir. He was subsequently retreated with 12 weeks of sof-vel-vox. He had an end of treatment response but had a viral relapse at 3 months post-treatment. He denied hepatitis exposure in the interim and repeat genotyping was G1b. He was compliant with his medications. He was referred to Hepatology for salvage treatment options. Prior labs and images did not show evidence of cirrhosis and he did not have a history of hepatic decompensations. Combined HIV Ab/Ag and Hepatitis B Core Ab were negative. A Fibrosure test revealed F3 fibrosis but unfortunately, he did not undergo HCC surveillance. At our initial evaluation a contrast MRI was ordered and revealed a 4.6 cm right lobe enhancing lesion with delayed washout consistent with HCC. Resection was not possible due to the location of the lesion, so he underwent locoregional therapy and is currently listed for liver transplantation with MELD exception. DISCUSSION: Treatment failure with sof-vel-vox is a rare event. Underlying HCC is known to be associated with lower SVR rates in patients treated with DAAs. Some have surmised a protection from eradication due to immunologic changes in cancer patients. We hypothesize that the presence of HCC was the most likely factor for this treatment failure. With sof-vel-vox as the last available option in the treatment paradigm, failure of this regimen in previous NS5A treated patients leads to a situation where there is not an available proven treatment regimen for salvage therapy. As such, we suggest that patients being considered for sof-vel-vox have “up to date” advanced imaging of the liver even in the absence of documented cirrhosis. If treatment failure does occur, one should consider the possibility of an underlying diagnosis of HCC.

790P - A multicenter phase II study of TAS-114 in combination with S-1 in patients with pre-treated advanced gastric cancer (EPOC1604)

BackgroundHigh deoxyuridine triphosphatase (dUTPase) in tumor tissue, as a gatekeeper enzyme for 5-fluorouracil (5-FU), is associated with 5-FU resistance. TAS-114 is an oral dUTPase inhibitor which enhance antitumor activity with 5-FU or fluoropyrimidines. Phase I study of TAS-114 in combination with S-1 showed its tolerability and preliminary antitumor signals for patients (pts) with non-small cell lung cancer and advanced gastric cancer (AGC). This phase II study has been conducted to evaluate efficacy and safety of TAS-114 and S-1 combination in pts with AGC. MethodsThe main eligibility criteria is pts with AGC after two or more previous chemotherapy regimens containing fluoropyrimidines, platinum agents, and taxanes or irinotecan. The primary endpoint is objective response rate (ORR) by investigators’ judgement. Using Simon’s optimal two-stage design, 29 pts were required, with one-sided a=5% and power=80%. The threshold and expected ORRs were 5% and 25%. Protein expression levels of dUTPase and BRCA1 in tumor samples were determined by immunohistochemistry. ResultsThe accrual was terminated in June 2018. Of all 20 enrolled pts, the ORR and disease control rate were 5.0% (95% confidence interval [CI], 0.1-24.9%) and 70.0% (95% CI, 45.7-88.1%), respectively. The median progression-free survival (PFS) and overall survival were 2.4 months (95% CI, 1.2-3.3 months) and 7.1 months (95% CI, 5.2-9.4 months), respectively. The median PFS in the groups with high and low dUTPase protein expression in the cytoplasm was 2.8 months (95% CI, 1.4–3.9) and 1.6 months (95% CI, 0.6–2.4), respectively (hazard ratio, 0.40 [95% CI, 0.16–1.04], P=0.047). Grade 3 or higher treatment-related adverse events were anemia (20%), leucopenia (15%), neutropenia (10%), rash (10%), thrombocytopenia (5%), and Iymphopenia (5%). ConclusionsTAS-114 with S-1 showed modest antitumor activity with acceptable safety profiles for heavily pretreated pts with AGC. Legal entity responsible for the studyThe authors. FundingTaiho. DisclosureD. Takahari: Research grant / Funding (self): Taiho Pharmaceutical Co; Research grant / Funding (self): Ono Pharmaceutical Co; Honoraria (self): Eli Lilly Japan; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Yakult Honsha Co; Honoraria (self): Chugai Pharmaceutical Co., Ltd. A. Kawazoe: Honoraria (self), Research grant / Funding (institution): Taiho. K. Shitara: Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: MSD; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (self): Lilly; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Medi Science. All other authors have declared no conflicts of interest.

1000P - Efficacy and safety of oral poly (ADP-ribose) polymerase inhibitor fluzoparib in patients with BRCA1/2 mutations and platinum sensitive recurrent ovarian cancer

BackgroundFluzoparib is a potent orally administered poly(ADP-ribose) polymerase (PARP) inhibitor. The safety and tolerability of fluzoparib has been evaluated in a phase 1 trial (NCT02575651). In this study, we aim to characterize the efficacy and safety of fluzoparib in patients (pts) with germline BRCA1/2 mutations and platinum sensitive recurrent ovarian cancer who had received ≥2 prior lines of chemotherapy. MethodsThis was an open-label, multi-centre, phase 2 study of oral fluzoparib in pts with recurrent ovarian cancer. Adult pts (≥18 years) with germline BRCA1 or BRCA2 mutations and platinum-sensitive recurrent high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with two or more previous platinum-based chemotherapy regimens were enrolled. Patients were treated with fluzoparib capsule at 150mg orally twice daily up to disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. ResultsFrom April 4 2018 to March 21 2019, 113 pts at Chinese national-wide 26 sites were received the fluzoparib. At the data cutoff date (April 15, 2019), 103 pts were efficacy evaluable (follow-up ≥8 weeks). The ORR and disease control rate (DCR) were 64.1% (66/103) and 95.1% (98/103), respectively. Complete response (CR) was observed in 9 pts (8.7%). Median duration of response (DOR) and progression free survival (PFS) have not yet been reached. Any grade treatment-related AEs (TRAEs) occurred in 108 patients (95.6%). The most common (≥20%) TRAE were nausea (55.8%), fatigue (47.8%), white blood cell count decreased (44.2%), anemia or decreased hemoglobin (42.5%), neutrophil count decreased (31.9%), decreased appetite (30.1%), thrombocytopenia (29.1%), and vomiting (23.9%). The most common grade ≥3 TRAE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption and dose reduction in 31.0% and 21.1% of patients, respectively. ConclusionsFluzoparib demonstrated promising antitumor activity and acceptable safety in patients with advanced BRCA1/2-mutated ovarian cancer. And this is the first report of a PARP inhibitor in Chinese patients with BRCA1/2 mutations and recurrent ovarian cancer. Clinical trial identificationNCT03509636. Legal entity responsible for the studyJiangsu Hengrui Medicine Co. LTD, China. FundingJiangsu Hengrui Medicine Co. LTD. DisclosureJ. Zou: Shareholder / Stockholder / Stock options: Jiangsu Hengrui Medicine Co. LTD. Q. wang: Shareholder / Stockholder / Stock options: Jiangsu Hengrui Medicine Co. LTD. All other authors have declared no conflicts of interest.

P1.01-135 Salvage Chemotherapy After Immunotherapy Failure in Non-Small-Cell Lung Cancer Patients

Objective response rate (ORR) to salvage chemotherapy (sCT) in non-small-cell lung cancer (NSCLC) patients failing upfront platinum-based doublets is limited (≈5-15%). Recently, unexpected favorable outcomes have been reported for sCT upon progression to immune checkpoint inhibitors (ICIs) as compared to historical data, with ORR observed in up to 53% and 27% in Asian and Caucasian patients respectively. Few data are available regarding prior response to ICIs and sCT performance, especially in Caucasian patients. All consecutive patients with advanced NSCLC who started ICIs at our institution from Apr 2013 to Dec 2018 were retrospectively reviewed. Patients who underwent sCT after progression to ICIs and had at least one radiological response assessment were included. ORR was calculated as the percentage of complete or partial responses according to RECIST 1.1 as best response. Survivals were estimated with Kaplan-Meier method. Correlation was assessed using Spearman’s test. Out of 283 patients included, 43 received sCT after ICIs. Among them, 29 (67%) had adenocarcinoma and 14 (37%) squamous cell carcinoma. 11 (26%) patients received sCT as second line therapy and 32 (74%) as third or more advanced treatment. sCT regimens included platinum based doublets (14; 32.5%), docetaxel or paclitaxel (20; 46.5%), and other monotherapies such as gemcitabine or vinorelbine (9; 21%). ORR to sCT was 30%. Median progression free survival and overall survival were 3.6 and 8.4 months, respectively. All patients receiving taxanes as sCT had already been treated with platinum based therapy and their ORR to sCT was 40%. ORR to upfront chemotherapy was 50%, while ORR to the last chemotherapeutic regimen prior to ICIs was 35%. ORR to sCT in pretreated patients was non-inferior to that observed in chemo-naïve ones (31% and 27%, respectively). High ORR (25%) was observed even in patients receiving sCT beyond third line. Neither response to ICIs (P=0.36) nor to prior chemotherapeutic regimens (P>0.05) were associated to the likelihood of achieving tumor response to sCT. We provide further evidence that NSCLC patients progressing to ICIs might still benefit from sCT even if heavily pretreated, regardless of sensitivity to ICIs or previous chemotherapy regimens. Further investigations are needed for uncovering bases of increased sensitivity to genotoxic agents in patients with innate or acquired resistance to ICIs and exploiting optimal treatment sequence.

Effects of Previous Medication Regimen Factors and Bipolar and Psychotic Disorders on Breast Cancer Endocrine Therapy Adherence

BackgroundEndocrine therapy adherence remains a barrier to optimal estrogen receptor-positive breast cancer outcomes. We theorized that experience navigating difficult medication regimen factors, such as route of administration complexity, might improve subsequent adherence after stressful cancer diagnoses but not for patients with bipolar and psychotic disorders at risk of poor access and nonadherence. Materials and MethodsWe included 21,894 women aged ≥ 68 years at their first surgically treated stage I-IV estrogen receptor-positive breast cancer (2007-2013) from the Surveillance, Epidemiology, and End Results–Medicare data set, of whom 5.8% had bipolar or psychotic disorders. We required continuous fee-for-service Medicare (parts A and B) data for ≥ 36 months before and 18 months after the cancer diagnosis. The medication regimen factors in the part D claims for 4 months before included the number of all medications used, pharmacy visits, and administration complexity (medication regimen complexity index subscale). Cox regression analysis was used to model the time to initiation and discontinuation, with longitudinal linear regression for adherence to endocrine therapy. ResultsWomen with more frequent previous medication use and pharmacy visits were more likely to initiate, 4+ medications and 2+ visits versus no medication (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.33-1.63), to adhere (6.0%; 95% CI, 4.3-7.6), and to continuously use their endocrine therapy (discontinuation HR, 0.48; 95% CI, 0.39-0.59). Medication administration complexity had modest effects. Difficult medication regimens were more common for patients with bipolar and psychotic disorders but had no statistically significant effects. ConclusionsExperience with frequent previous medication use and pharmacy visits might increase the likelihood of endocrine therapy use for most patients but not for those with bipolar and psychotic disorders.

Subgroup analysis of a phase 2/3 study of rurioctocog alfa pegol in patients with severe hemophilia A: efficacy and safety in previously treated Korean patients.

BackgroundThe efficacy and safety of extended half-life, full-length, pegylated recombinant factor VIII rurioctocog alfa pegol [BAX 855, ADYNOVATE (USA)/ADYNOVI (Europe); Baxalta US Inc., a Takeda company, Lexington, MA, USA] was investigated in previously treated Korean patients with severe hemophilia A (HA).MethodsA post hoc data analysis from the international, multicenter, phase 2/3 PROLONG-ATE study of rurioctocog alfa pegol in patients with severe HA (NCT01736475) determined annualized bleeding rates (ABRs) and rates of adverse events (AEs) in Korean patients treated in this study.ResultsAll 10 enrolled Korean patients receiving rurioctocog alfa pegol (9 prophylaxis, 1 on-demand) completed the study [median (range) age, 28.0 (12–50) yr; weight, 64.8 (45–90) kg; 8 patients had ≥1 target joint at screening]. Median (range) ABR was 1.9 (0.0–14.5) for patients on prophylaxis and 62.2 for the patient receiving on-demand treatment. The hemostatic efficacy of rurioctocog alfa pegol was rated “excellent” or “good” and only single infusions were required per bleeding episode. ABRs improved in most patients compared with prestudy values. No dose adjustments were required for prophylaxis, and the dosing frequency was reduced in 8 patients, compared with their previous prophylaxis regimen. No serious AEs were reported; all 9 nonserious AEs (in 3 patients) were mild in severity and unrelated to the study treatment.ConclusionThis post hoc analysis of a small group of Korean patients with severe HA indicated that rurioctocog alfa pegol was effective, and no serious AEs were observed. For most patients, the dosing frequency was also reduced compared with their previous regimen.

Apatinib Plus Sintilimab in Advanced Gastric Cancer Refractory to at Least Two Previous Chemotherapy Regimens

Apatinib Plus Sintilimab in Advanced Gastric Cancer Refractory to at Least Two Previous Chemotherapy Regimens