IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer

Biliary tract cancer; Cancer immunotherapy; CholangiocarcinomaCàncer del tracte biliar; Immunoteràpia contra el càncer; ColangiocarcinomaCáncer del tracto biliar; Inmunoterapia contra el cáncer; ColangiocarcinomaBackground: Biliary tract cancers (BTCs) are heterogenous, highly aggressive tumors that harbor a dismal prognosis for which more effective treatments are needed. The role of cancer immunotherapy in BTC remains to be characterized. The tumor microenvironment (TME) of BTC is highly immunosuppressed and combination treatments are needed to promote effective anticancer immunity. Vascular endothelial growth factor (VEGF) drives immunosuppression in the TME by disrupting antigen presentation, limiting T-cell infiltration, or potentiating immune-suppressive cells. Many VEGF-regulated mechanisms are thought to be relevant to repressed antitumor immunity in BTC, making dual targeting of VEGF and programmed cell death protein 1 (PD-1)/PD-L1 pathways a rational approach. Gemcitabine and Cisplatin (Gem/Cis) can also modulate anticancer immunity through overlapping and complementary mechanisms to those regulated by VEGF. Anti-PD-L1/VEGF inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit. Methods: IMbrave 151 is a randomized, double-blind, placebo-controlled, multicenter, international phase II study to evaluate atezolizumab (a PD-L1 inhibitor) in combination with chemotherapy (gemcitabine and cisplatin) and bevacizumab (an anti-VEGF monoclonal antibody) as a first-line treatment for advanced BTC. Approximately 150 patients with previously untreated, advanced BTC will be randomized to either Arm A (atezolizumab + bevacizumab + Gem/Cis) or Arm B (atezolizumab + placebo + Gem/Cis). Randomization is stratified by the presence of metastatic disease, primary tumor location, and geographic region. The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) per RECIST 1.1. Secondary endpoints include objective response rate (ORR), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety and patient reported outcomes (PROs). Tissue, blood, and stool samples will be collected at baseline and on-treatment in order to perform correlative biomarker analyses. Discussion: IMbrave 151 represents the first randomized study to evaluate combined PD-L1/VEGF blockade on a chemotherapy backbone in BTC. Trial registration: NCT identifier: NCT04677504; EUDRACT number: 2020-003759-14The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study is funded by F. Hoffmann-La Roche Ltd

Understanding the patient experience in hepatocellular carcinoma: a qualitative patient interview study

Hepatocellular carcinoma; Quality of life; SymptomsCarcinoma hepatocelular; Calidad de vida; SíntomasCarcinoma hepatocel·lular; Qualitat de vida; SímptomesPurpose This study aimed to elucidate the patient experience of hepatocellular carcinoma (HCC) to guide patient-centered outcome measurement in drug development. Methods Patients with HCC participated in qualitative interviews to elicit disease-related signs/symptoms and impacts, using discussion guides developed from literature searches and discussions with oncologists. Interview participants rated the disturbance of their experiences (0–10 scale). A conceptual model was developed and mapped against patient-reported outcome (PRO) instruments identified from database reviews. Results Interviews were conducted with 25 individuals with HCC (68% were men; median age: 63 years; 12% Barcelona clinic liver cancer (BCLC) stage A; 32% stage B; and 56% stage C) in the USA. Fifty-one HCC-related concepts were identified from the interviews and were grouped into eight sign/symptom categories (eating behavior/weight changes; extremities [arms, legs]; fatigue and strength; gastrointestinal; pain; sensory; skin; other) and four impact categories (emotional; physical; cognitive function; other) for the conceptual model. The most prevalent and disturbing experiences across the disease stages were fatigue/lack of energy and emotional impacts such as frustration, fear, and depression. Abdominal pain and skin-related issues were particularly common and disturbing in individuals with HCC stage C. The EORTC QLQ-C30 and HCC18 were identified as commonly used PRO instruments in HCC studies and captured the relevant signs/symptoms associated with the patient experience. Conclusion Patients with HCC reported a range of signs/symptoms and impacts that negatively affect daily functioning and quality of life. Including PRO measures in HCC clinical trials can provide meaningful patient perspectives during drug development.This qualitative study was funded by AstraZeneca

Current and emerging anti-angiogenic therapies in gastrointestinal and hepatobiliary cancers

Colorectal cancer; Hepatobiliary tumour; NeoangiogenesisCáncer colorrectal; Tumores hepatobiliares; NeoangiogénesisCàncer colorectal; Tumors hepatobiliars; NeoangiogènesiGastrointestinal tumours are a heterogeneous group of neoplasms that arise in the gastrointestinal tract and hepatobiliary system. Their incidence is rising globally and they currently represent the leading cause of cancer-related mortality worldwide. Anti-angiogenic agents have been incorporated into the treatment armamentarium of most of these malignancies and have improved survival outcomes, most notably in colorectal cancer and hepatocellular carcinoma. New treatment combinations with immunotherapies and other agents have led to unprecedented benefits and are revolutionising patient care. In this review, we detail the mechanisms of action of anti-angiogenic agents and the preclinical rationale underlying their combinations with immunotherapies. We review the clinical evidence supporting their use across all gastrointestinal tumours, with a particular emphasis on colorectal cancer and hepatocellular carcinoma. We discuss available biomarkers of response to these therapies and their utility in routine clinical practice. Finally, we summarise ongoing clinical trials in distinct settings and highlight the preclinical rationale supporting novel combinations

Understanding Patient Experience in Biliary Tract Cancer: A Qualitative Patient Interview Study

Cáncer del tracto biliar; Estudio de entrevista; Investigación cualitativaCàncer del tracte biliar; Estudi d'entrevista; Recerca qualitativaBiliary tract cancer; Interview study; Qualitative researchIntroduction Patients living with biliary tract cancer (BTC) experience a decline in health-related quality of life (HRQoL). This study aimed to obtain a comprehensive understanding of the patient experience of BTC-related signs/symptoms and the impacts of these on daily functioning and HRQoL. Methods Patients with BTC participated in qualitative semi-structured concept elicitation interviews. Signs/symptoms and impacts of BTC were initially explored by targeted literature searches and interviews with five clinicians. Patient interviews were transcribed and coded using qualitative research software. Concept saturation was assessed over five interview waves. A sign/symptom or impact was defined as “salient” if mentioned by ≥ 50% of patients, with a mean disturbance rating of ≥ 5 (0–10 scale). A conceptual model of the patient experience of BTC-related signs/symptoms and impacts was produced. Results Twenty-three patients from the USA (78% women; median age: 54 years), diagnosed as having early (n = 3), locally advanced (n = 11) or metastatic (n = 9) disease, were interviewed. Sixty-six signs/symptoms and 12 impacts were identified. Of these, 46 signs/symptoms and 8 impacts were not identified from the targeted literature or clinician interviews. Concept saturation was reached by the fourth of five interview waves. Fourteen disease-related signs/symptoms (including fatigue/lack of energy, abdominal pain, lack of appetite, insomnia and diarrhoea) and three impacts (physical, emotional and cognitive impacts) were deemed “salient”. The conceptual model included 50 signs/symptoms and 12 impacts. Conclusion Patients with BTC reported a range of signs/symptoms and impacts that negatively affect daily functioning and HRQoL.This project was funded by AstraZeneca, Gaithersburg, MD, USA. Research and publication fees are funded by the study sponsor

Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib

Qualitat de vida relacionada amb la salut; Olaparib; Càncer de pàncreesCalidad de vida relacionada con la salud; Olaparib, Cáncer de páncreasHealth-related quality of life; Olaparib; Pancreatic cancerBackground Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. Patients and methods Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. Results Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [−2.47; 95% confidence interval (CI) −7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (−4.45 points; 95% CI −8.75, −0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). Conclusions HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer.This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and MSD (no grant number). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30-17 CA008748

Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Actividad antitumoral; Calidad de vida con cáncer; PARPActivitat antitumoral; Qualitat de vida amb càncer; PARPAntitumor activity; Quality of life with cancer; PARPBACKGROUND Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P=0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P=0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, −2.47 points; 95% CI, −7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, −0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.Supported by AstraZeneca (as part of an alliance between AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck) and by a grant (P30-17 CA008748) from the National Institutes of Health National Cancer Institute Cancer Center

Population pharmacokinetics of liposomal irinotecan in patients with cancer and exposure–safety analyses in patients with metastatic pancreatic cancer

Pharmacokinetics; Liposomal irinotecan; SafetyFarmacocinética; Irinotecán liposomal; SeguridadFarmacocinètica; Irinotecan liposomal; SeguretatLiposomal irinotecan is a liposomal formulation of irinotecan, which prolongs circulation of irinotecan and its active metabolite SN-38. A population pharmacokinetic (PK) model was developed based on data from seven studies (N = 440). Adequacy of the model was assessed using multiple methods, including visual predictive check. Associations between PK exposure and the incidence of diarrhea (grade ≥3) and neutropenia adverse events (AEs) (grade ≥3) at first event in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) were investigated using logistic regression based on data from two studies (the phase III NAPOLI-1 [N = 260] and phase I/II NCT02551991 [N = 56] trials). The PKs of total irinotecan was described by a two-compartment model with first-order elimination, with SN-38 formed directly by a first-order constant from the central compartment of irinotecan or after using a transit compartment. Clearance was 17.9 L/week (0.107 L/h) and 19,800 L/week (118 L/h) for total irinotecan and SN-38, respectively. The UGT1A1*28 7/7 homozygous genotype had no significant impact on SN-38 clearance. Model evaluation was satisfactory for both irinotecan and SN-38. The incidence of diarrhea (grade ≥3) at first event was significantly higher with increasing average concentrations of total irinotecan and SN-38; there was no significant association between an increased risk of neutropenia AEs (grade ≥3) at first event and average SN-38 concentrations. In summary, the PKs of total irinotecan and SN-38 after administration of liposomal irinotecan were well-described by the model. The UGT1A1*28 status had no significant impact on the PKs of liposomal irinotecan

Nomogram for predicting survival in patients treated with liposomal irinotecan plus fluorouracil and leucovorin in metastatic pancreatic cancer

NAPOLI-1; Liposomal irinotecan; Survival outcomesNAPOLI-1; Irinotecan liposòmic; Resultats de supervivènciaNAPOLI-1; Irinotecan liposomal; Resultados de supervivenciaNAPOLI-1 (NCT01494506) was a phase III study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This post hoc analysis of NAPOLI-1 aimed to develop a predictive nomogram for overall survival (OS) at 6 and 12 months. Analyses were derived from all patients in NAPOLI-1 randomized to receive nal-IRI+5-FU/LV, nal-IRI monotherapy, or 5-FU/LV combination therapy. OS was associated with baseline factors using univariate and multivariable Cox analyses. A predictive nomogram was derived and validated using a concordance index and calibration plots. The univariate analyses identified 21 independent factors that contributed to OS, with eight factors significantly associated with OS. The Karnofsky Performance Score contributed the largest number of points (100), followed by presence of liver metastasis (98) and randomization to nal-IRI+5-FU/LV (96). The other baseline factors showing effects were albumin (g/dL), neutrophil/lymphocyte ratio, carbohydrate antigen 19-9 (U/mL), disease stage at diagnosis, and body mass index (kg/m2). The nomogram was used to predict the 6- and 12-month survival probability. The mean absolute errors between the observed and predicted probabilities for OS at 3, 6, and 9 months were 0.07, 0.08, and 0.07, respectively. This nomogram, based on NAPOLI-1, provides additional insight to aid decision-making for patients with mPDAC after previous gemcitabine-based therapy.This study (NCT01494506) was supported by Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA. Analysis sponsored by Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA

Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer - A subgroup analysis of the pivotal NAPOLI-1 trial

Irinotecan liposomal; Pacients grans; Càncer de pàncreesIrinotecán liposomal; Pacientes mayores; Cáncer de páncreasLiposomal irinotecan; Older patients; Pancreatic cancerObjectives Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial ( NCT01494506 ) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients. Materials and Methods This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [ .25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69% <75 years required a dose delay or reduction due to toxicities (43% versus 32% dose reductions). Discussion Results suggest that older patients with metastatic pancreatic adenocarcinoma that progressed on prior gemcitabine-based treatment can benefit from second-line therapy, supporting nal-IRI + 5-FU/LV treatment in older patients.The NAPOLI-1 trial (ClinicalTrials.govidentifier: NCT01494506) was sponsored by Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA; Medical writing support was provided by Laura McMahon of Physicians World Europe GmbH, Mannheim, Germany, and funded by Shire International, Zug, Switzerland. Correction and publication costs were funded by Global Medical Affairs, Servier, Suresnes, France

Targeting DNA Damage Repair Mechanisms in Pancreas Cancer

BRCA1/2; Inhibición de PARP; Adenocarcinoma ductal pancreáticoBRCA1/2; Inhibició DE PARP; Adenocarcinoma ductal pancreàticBRCA1/2; PARP inhibition; Pancreatic ductal adenocarcinomaImpaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, BRCA1/2, PALB2, ATM, MSH2, MSH6 and MLH1. Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline BRCA1/2-mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations in DDR genes beyond BRCA1/2 might be beneficial, but there is a lack of data, and consequently, no clear recommendations are provided in the field. Therefore, an expert panel was invited by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and significance of DDR as a target in PDAC treatment. The aim of this virtual, international expert meeting was to elaborate a set of consensus recommendations on testing, diagnosis and treatment of PDAC patients with alterations in DDR pathways. Ahead of the meeting, experts completed a 27-question survey evaluating the key issues. The final recommendations herein should aid in facilitating clinical practice decisions on the management of DDR-deficient PDAC.This congress paper received no external funding. Additional research funding is declared: L.P. (DFG PE 3337/1-1), A.K. (DFG KL 2544/1-1, 1-2, 5-1, 6-1, 7-1, Baden-Württemberg-Foundation ExPoChip, German Cancer Aid 111879, INDIMED-Verbund PancChip, HEIST RTG DFG GRK 2254/1 and Excellence grant Else-Kröner-Fresenius-Stiftung), E.M.O. (Cancer Center Support Grant/Core Grant P30 CA008748)