Outcomes in older adults with metastatic esophageal and gastric carcinoma treated with palliative chemotherapy.

BACKGROUND: The incidence of esophageal and gastric carcinoma (GEC) in elderly patients is increasing, yet patients ≥75 years have historically been underrepresented in clinical trials. We sought to investigate palliative chemotherapy administration patterns and survival outcomes in older adults. MATERIALS AND METHODS: A retrospective analysis identified patients aged 65-74 (young-old) and ≥75 years (older-old) diagnosed with advanced GEC. Patient and tumor characteristics were recorded, with descriptive analysis, time-to-event data analysis using Kaplan-Meier curves and multivariate Cox proportional hazards regression analysis performed. RESULTS: One hundred and ninety-eight "young-old" and 109 'older-old' patients were identified. Patient characteristics were similar between groups except for Charlson Co-morbidity Index (CCI), with lower co-morbidities in the "young-old" compared to "older-old" cohort (P < .001; CCI = 0 in 103 (52%) "young-old" vs 31 (28%) "older-old"). The primary diagnosis in both groups was adenocarcinoma. 119 (60%) "young-old" and 25 (23%) "older-old" patients received chemotherapy (P < .001). Performance status was the primary explanation for chemotherapy non-receipt in both cohorts; age was the explanation in 21 (25%) "older-old" patients and none in the "young-old" patients. PFS for first-line systemic therapy in "young-old" patients was 6.4 (95% CI 5.9-7.6) versus 7.5 months (95% CI 5.1-11.3) in "older-old" patients (P = .69) whilst respective OS was 12.3 (95% CI 10.1-15.5) and 10.4 months (95% CI 9.0-14.6) (P = .0816). Toxicity prompted chemotherapy cessation in 17 (15%) "young-old" and 3 (13%) "older-old" patients (P = .97). Multivariate analysis identified CCI and ECOG performance status as predictive for PFS and OS, respectively. No causative relationship was identified with other variables. CONCLUSION: Our study of real-world older-adults show that significant number of "older-old" patients with GEC do not receive chemotherapy. Among "older-old" adults who do receive systemic therapy, outcomes are comparable; this underscores the importance of geriatric assessment-guided care and suggests that age alone should not be a barrier to receipt of chemotherapy in patients with advanced GEC.

Comparison of Four Clinical Prognostic Scores in Patients with Advanced Gastric and Esophageal Cancer.

BACKGROUND: Prognostic scores that can identify patients at risk for early death are needed to aid treatment decision-making and patient selection for clinical trials. We compared the accuracy of four scores to predict early death (within 90 days) and overall survival (OS) in patients with metastatic gastric and esophageal (GE) cancer. METHODS: Advanced GE cancer patients receiving first-line systemic therapy were included. Prognostic risks were calculated using: Royal Marsden Hospital (RMH), MD Anderson Cancer Centre (MDACC), Gustave Roussy Immune (GRIm-Score), and MD Anderson Immune Checkpoint Inhibitor (MDA-ICI) scores. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to analyze associations between prognostic scores and OS. The predictive discrimination was estimated using Harrell's c-index. Predictive ability for early death was measured using time-dependent AUCs. RESULTS: In total, 451 patients with metastatic GE cancer were included. High risk patients had shorter OS for all scores (RMH high- vs. low-risk median OS 7.9 vs. 12.2 months, P < .001; MDACC 6.8 vs. 11.9 months P < .001; GRIm-Score 5.3 vs. 13 months, P < .001; MDA-ICI 8.2 vs. 12.2 months, P < .001). On multivariable analysis, each prognostic score was significantly associated with OS. The GRIm-Score had the highest predictive discrimination and predictive ability for early death. CONCLUSIONS: The GRIm-Score had the highest accuracy in predicting early death and OS. Clinicians may use this score to identify patients at higher risk of early death to guide treatment decisions including clinical trial enrolment. This score could also be used as a stratification factor in future clinical trial designs.

Differential prognostic significance of sarcopenia in metastatic esophageal squamous and adenocarcinoma.

BACKGROUND: Sarcopenia indicates poor prognosis in various malignancies. We evaluated the association of sarcopenia with overall (OS) and progression-free survival (PFS) in metastatic esophageal cancer (MEC) patients, a population often presenting with poor nutritional status. METHODS: In newly diagnosed MEC patients managed at the Princess Margaret (PM) Cancer Centre (diagnosed 2006-2015), total muscle area, visceral adiposity (VA), and subcutaneous adiposity (SA) were quantified on abdominal computed tomography at L3. Sarcopenia was determined using published cutoffs, based on sex and height. RESULTS: Of 202 MEC patients, most were male (166/82%), < 65 years (116/57%), and had adenocarcinoma histology (141/70%); 110/54% had recurrent MEC after initial curative-intent treatment; 92/46% presented with de novo MEC. At stage IV diagnosis, 20/10% were underweight, 97/48% were normal-weight and 84/42% were overweight/obese; 103/51% were sarcopenic. Sarcopenia was associated with worse median OS (4.6 vs. 7.9 months; log-rank p = 0.03) and 1-year survival, even after adjusting for other body composition variables (e.g., BMI, VA, and SA): adjusted-HR 1.51 [95% CI 1.1-2.2, p = 0.02]. In post hoc analysis, sarcopenia was highly prognostic in adenocarcinomas (p = 0.003), but not squamous cell carcinomas (SCC). In patients receiving palliative systemic treatment (104/51%), sarcopenia was associated with shorter PFS (p = 0.004) in adenocarcinoma patients (75/72%). CONCLUSIONS: In metastatic esophageal adenocarcinomas, sarcopenia is associated with worse PFS and OS. In metastatic esophageal SCC, there was a non-significant trend for worse PFS but no association with OS. In order to offset the poor prognosis associated with sarcopenia particularly in metastatic esophageal adenocarcinoma patients, future research should focus on possible countermeasures.

Optimism Bias in the Design of Phase III Randomized Control Trials Evaluating PD-1/PD-L1 Targeting Monoclonal Antibodies.

BACKGROUND: Many randomized control trials (RCTs) evaluating programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) targeting monoclonal antibodies (mAbs) have been completed or are in progress. We examined hypothesized hazard ratios (HHRs) and observed hazard ratios (OHRs) from published RCTs evaluating these mAbs. METHODS: Publications of RCTs evaluating at least one PD-1/PD-L1 targeting mAbs approved by the US Food and Drug Administration were identified through PubMed searches. The primary reports of RCTs were retrieved. Two investigators extracted HHR, OHR for the primary endpoint among other data elements independently. The differences (∆HR) in HHR and OHR were analyzed statistically. A separate search was conducted for secondary reports after longer follow-ups, the updated OHR was extracted. RESULTS: Forty-nine RCTs enrolling 36 867 patients were included. The mean HHR and OHR were 0.672 and 0.738 respectively. The mean ∆HR was 0.067 (range: -0.300 to 0.895; 95% confidence interval (CI), 0.003-0.130). HHR was met or exceeded in 22 (45%) RCTs. OHR was ≥ 1.0 in 6 RCTs (12%). PD-L1 expression was not associated with the magnitude of effect. Of 18 RCTs with follow-up reports, the magnitude of benefit decreased in 8 RCTs with extended follow-ups. CONCLUSION: The majority of published RCTs evaluating PD-1/PD-L1 targeting mAbs did not achieve their hypothesized magnitude of benefit. The optimism bias requires attention from the cancer clinical research community given the number of these agents in development and the intense interest in evaluating these agents in a variety of disease settings.

Impact of Sites of Metastatic Dissemination on Survival in Advanced Gastroesophageal Adenocarcinoma.

INTRODUCTION: Metastatic gastroesophageal adenocarcinoma (GEA) is a heterogeneous disease with an overall poor prognosis. The impact of sites of metastatic dissemination on survival is not well characterized. This study aimed to evaluate whether certain sites of metastatic disease impacts survival. METHODS: A retrospective analysis of 375 patients with metastatic GEA treated at the Princess Margaret Cancer Centre from 2006 to 2016 was performed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to assess the association between sites of metastases and OS adjusting for baseline patient characteristics. RESULTS: Median duration of follow-up was 47.8 months. Median OS in this cohort was 11.8 months (95% CI: 10.2-12.9 months). Patients with lymph node only disease, compared to those with other sites of metastases, had the longest median OS (20.4 vs. 10.6 months; p < 0.001) and PFS (11.4 vs. 6.3 months; p < 0.001). On multivariable analysis adjusting for relevant clinical factors including age, sex, and Eastern Cooperative Oncology Group performance status, the presence of lung (HR 1.67, 95% CI: 1.23-2.26; p < 0.001) or bone metastases (HR 1.84, 95% CI: 1.31-2.59; p < 0.001) were independently associated with shorter OS. The majority of patients (68%) were treated with palliative intent first-line platinum-based chemotherapy. DISCUSSION/CONCLUSION: Patients with metastatic GEA have an overall poor prognosis. The presence of lung or bone metastases is an independent risk factor for decreased survival. Prognostic models incorporating sites of metastasis should be considered in the clinical evaluation of metastatic GEA.

Influence of sarcopenia, clinical data, and 2-[18F] FDG PET/CT in outcome prediction of patients with early-stage adenocarcinoma esophageal cancer.

PURPOSE: To determine the prognostic value of sarcopenia measurements done on staging 2-[18F] FDG PET/CT together with metabolic activity of the tumor in patients with adenocarcinoma esophagogastric cancer with surgical treatment. METHODS: Patients with early-stage, surgically treated esophageal adenocarcinoma and available pre-treatment 2-[18F] FDG PET/CT were included. The standard uptake value (SUV) and SUV normalized by lean body mass (SUL) were recorded. Skeletal muscle index (SMI) was measured at the L3 level on the CT component of the PET/CT. Sarcopenia was defined as SMI < 34.4cm2/m2 in women and < 45.4cm2/m2 in men. RESULTS: Of the included 145 patients. 30% were sarcopenic at baseline. On the univariable Cox proportional hazards analysis, ECOG, surgical T and N staging, lymphovascular invasion (LVI) positive lymph nodes, and sarcopenia were significant prognostic factors concerning RFS and OS. On multivariable Cox regression analysis, surgical N staging (p = 0.025) and sarcopenia (p = 0.022) remained significant poor prognostic factors for OS and RFS. Combining the clinical parameters with the imaging-derived nutritional evaluation of the patient but not metabolic parameters of the tumor showed improved predictive ability for OS and RFS. CONCLUSION: Combining the patients' imaging-derived sarcopenic status with standard clinical data, but not metabolic parameters, offered an overall improved prognostic value concerning OS and RFS.

Preoperative and Postoperative Approaches to Gastroesophageal Cancer: What is All the Fuss About.

Gastroesophageal cancers carry poor prognoses, and are a leading cause of cancer-related morbidity and mortality worldwide. Even in those with resectable disease, more than half of patients treated with surgery alone experience disease recurrence. Multimodality approaches using preoperative and postoperative chemotherapy and/or radiotherapy have been established, resulting in incremental improvements in outcomes. Globally, there is no standardized approach, and treatment varies with geographic location. The question remains of how to select the optimal perioperative treatment that will maximize benefit for patients while avoiding toxicities from unnecessary therapies. This article reviews currently available evidence supporting preoperative and postoperative therapy in gastroesophageal cancers, with an emphasis on recent practice-changing trials and ongoing areas of investigation, including the role of immune checkpoint inhibition and biomarker-guided treatment.

Impact of Definitive Chemoradiation on Quality-of-Life Changes for Patients With Anal Cancer: Long-term Results of a Prospective Study.

BACKGROUND: Maintaining and improving quality of life (QOL) are important goals of anal cancer management. This disease is generally curable, with many long-term survivors. OBJECTIVE: Long-term QOL after chemoradiation for patients with anal cancer was evaluated. DESIGN: This was a prospective cohort study. SETTINGS: This study used data from a prospective study of patients with anal cancer who were treated with chemoradiation between 2008 and 2013. PATIENTS: Patients with anal cancer who were treated with image-guided intensity-modulated radiation therapy were included. INTERVENTIONS: English-speaking patients completed European Organization for Research and Treatment of Cancer cancer-specific (C30) and site-specific (CR29) QOL questionnaires at baseline, at end of radiation, at 3 and 6 months, and then annually. MAIN OUTCOMES MEASURES: Long-term QOL was evaluated clinically (a change in score of ≥10 points was considered clinically significant) and statistically (using repeated-measurement analysis) by comparing the subscale scores at 1, 2, and 3 years with baseline scores. Subanalysis compared patients who received a radiation dose of 45 to 54 Gy versus 63 Gy. RESULTS: Ninety-six patients were included (median follow-up of 56.5 months). The symptom and functional scales showed a clinically significant decline at the end of treatment with improvement by 3 months after treatment. There was a long-term statistically significant decline in dyspnea, body image, bowel embarrassment, fecal incontinence, and hair loss, and there was long-term statistically and clinically significant worsening of impotence. Higher radiation dose (63 Gy) was not associated with significantly worse QOL. LIMITATIONS: Limitations included single-institution, single-arm study design, and lack of dose reconstruction (ie, analyses were based on prescribed, rather than delivered, dose). CONCLUSIONS: Patients with anal cancer treated with chemoradiation reported recovery of overall QOL to baseline levels. Specific symptoms remained bothersome, emphasizing the need to address and manage the chemoradiation-induced symptoms, during treatment and in the long term. See Video Abstract at http://links.lww.com/DCR/B905. IMPACTO DE LA QUIMIORRADIACIN DEFINITIVA EN CAMBIOS EN LA CALIDAD DE VIDA DE LOS PACIENTES CON CNCER ANAL RESULTADOS A LARGO PLAZO DE UN ESTUDIO PROSPECTIVE: ANTECEDENTES:Mantener y mejorar la calidad de vida son objetivos importantes del tratamiento del cáncer anal, ya que esta enfermedad generalmente es curable, con muchos sobrevivientes a largo plazo.OBJETIVO:Se evaluó la calidad de vida a largo plazo después de la quimiorradiación en pacientes con cáncer anal.DISEÑO:Este fue un estudio de cohorte prospectivo.ENTORNO CLINICO:Utilizamos datos de un estudio prospectivo en pacientes con cáncer anal tratados con quimiorradiación entre 2008-2013.PACIENTES:Los pacientes con cáncer anal fueron tratados con radioterapia de intensidad modulada guiada por imágenes.INTERVENCIONES:Los pacientes de habla inglesa completaron los cuestionarios de calidad de vida específicos de cáncer (C30) y específicos del sitio (CR29) de la Organización Europea para la Investigación y el Tratamiento del Cáncer al inicio, al final de la radiación, 3 y 6 meses, y luego anualmente.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluó a largo plazo la calidad de vida clínicamente (un cambio en la puntuación de ≥10 puntos se consideraron clínicamente significativo) y estadísticamente (usando análisis de medición repetida) comparando las subescalas de puntuación al 1, 2, y 3 años. Con puntuaciones de referencia. El subanálisis comparó pacientes que recibieron 45-54 Gy versus 63 Gy.RESULTADOS:Se incluyeron un total de 96 pacientes (mediana de seguimiento: 56,5 meses). La mayoría de las escalas funcionales y de síntomas mostraron una disminución clínicamente significativa al final del tratamiento con una mejoría a los 3 meses posteriores al tratamiento. Hubo una disminución estadísticamente significativa a largo plazo en disnea, imagen corporal, vergüenza intestinal, incontinencia fecal y pérdida de cabello; y hubo un empeoramiento a largo plazo estadística y clínicamente significativo en impotencia. La dosis de radiación más alta (63 Gy) no se asoció con una calidad de vida significativamente peor.LIMITACIONES:Institución única, diseño de estudio de un solo brazo y falta de recomposición de la dosis (es decir, los análisis se basan en la dosis prescrita, en lugar de la administrada).CONCLUSIÓNES:Los pacientes con cáncer anal tratados con quimiorradiación reportaron una recuperación de la QOL en general a los niveles de base. Síntomas específicos siguieron siendo molestos, lo que enfatiza la necesidad de resolver y tartar los síntomas inducidos por la quimiorradiación no solo durante el tratamiento, sino a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B905. (Traducción- Dr. Francisco M. Abarca-Rendon).

Anal Adenocarcinoma: A Rare Entity in Need of Multidisciplinary Management.

BACKGROUND: Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined. OBJECTIVE: This study aimed to describe the multidisciplinary management and outcomes of patients with anal adenocarcinoma. DESIGN: This is a retrospective cohort study. SETTING: This study was conducted at a quaternary cancer center. PATIENTS: Men and women with anal adenocarcinoma treated between 1995 and 2016 were selected. INTERVENTIONS: Fifty-two patients were treated with either chemoradiotherapy or trimodality therapy including radiation therapy, chemotherapy, and surgical resection. MAIN OUTCOME MEASURES: Local failure, regional failure, and distant metastasis rates were estimated using the cumulative incidence method. The Kaplan-Meier method was used to estimate progression-free survival and overall survival. The multivariable Cox proportional hazards model was used to evaluate the clinical predictors of outcome. RESULTS: There was a higher 5-year rate of local failure in patients treated with chemoradiotherapy compared with trimodality therapy (53% vs 10%; p < 0.01). The 5-year incidence of distant metastases was 29% (trimodality therapy) versus 30% (chemoradiotherapy; p = 0.9); adjuvant chemotherapy did not reduce the incidence of distant metastases (p = 0.8). Five-year overall survival was 73% (trimodality therapy) versus 49.4% (chemoradiotherapy; p = 0.1). On multivariable analysis, factors associated with worse overall survival were treatment with chemoradiotherapy, cT3-4 category disease, and node-positive disease. LIMITATIONS: This study is limited by its small sample size and retrospective nature. CONCLUSIONS: Although treatment may continue to be tailored to individual patients, better outcomes with a trimodality therapy approach were observed. See Video Abstract at http://links.lww.com/DCR/B708.ADENOCARCINOMA ANAL: UNA ENTIDAD POCO FRECUENTE EN NECESIDAD DE UN MANEJO MULTIDISCIPLINARIO. ANTECEDENTES: El adenocarcinoma anal es una entidad clínica poco frecuente por lo que aún no se define el manejo óptimo. OBJETIVO: Describir el manejo multidisciplinario y los resultados de los pacientes con adenocarcinoma anal. DISEO: Estudio de cohorte retrospectivo. ENTORNO CLINICO: Centro de cáncer cuaternario. PACIENTES: Hombres y mujeres con adenocarcinoma anal tratados entre 1995 y 2016. INTERVENCIONES: Cincuenta y dos pacientes fueron tratados con quimiorradioterapia o terapia trimodal que incluyó: radioterapia, quimioterapia y resección quirúrgica. PRINCIPALES MEDIDAS DE VALORACION: Se estimaron las tasas de falla local, falla regional y metástasis a distancia mediante el método de incidencia acumulada. Se utilizó el método de Kaplan-Meier para estimar la supervivencia libre de progresión y la supervivencia global. Los riesgos proporcionales de multivariable Cox se utilizaron para evaluar los predictores clínicos de los resultados. RESULTADOS: Hubo una mayor tasa de falla local a cinco años en pacientes tratados con quimiorradioterapia en comparación con terapia trimodal (53% vs 10%; p < 0,01). La incidencia a cinco años de metástasis a distancia fue del 29% (terapia trimodal) versus 30% (quimiorradioterapia) (p = 0,9); la quimioterapia adyuvante no redujo la incidencia de metástasis a distancia (p = 0,8). La supervivencia global a cinco años fue del 73% (terapia trimodal) versus 49,4% (quimiorradioterapia); p = 0,1. En el análisis multivariable, los factores asociados con una peor supervivencia general fueron el tratamiento con quimiorradioterapia, enfermedad de categoría cT3-4 y enfermedad con ganglios positivos. LIMITACIONES: Este estudio está limitado por su pequeño tamaño de muestra y su naturaleza retrospectiva. CONCLUSIONES: Aunque el tratamiento puede seguir adaptándose a pacientes individuales, se observaron mejores resultados con un enfoque TTM. Conslute Video Resumen en http://links.lww.com/DCR/B708. (Traducción- Dr. Francisco M. Abarca-Rendon).

Chemoradiotherapy Using Carboplatin plus Paclitaxel versus Cisplatin plus Fluorouracil for Esophageal or Gastroesophageal Junction Cancer.

BACKGROUND: Trimodality therapy (TMT) with neoadjuvant chemoradiotherapy (nCRT) using concurrent carboplatin plus paclitaxel (CP) followed by surgery is the standard of care for locoregional esophageal or gastroesophageal junction (GEJ) cancers. Alternatively, nCRT with cisplatin plus fluorouracil (CF) can be used. Definitive chemoradiotherapy (dCRT) with CP or CF can be used if surgery is not planned. In the absence of comparative trials, we aimed to evaluate outcomes of CP and CF in the settings of TMT and dCRT. METHODS: A single-site, retrospective cohort study was conducted at the Princess Margaret Cancer Centre to identify all patients who received CRT for locoregional esophageal or GEJ cancer. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method and multivariable Cox regression model. The inverse probability treatment weighting (IPTW) method was used for sensitivity analysis. RESULTS: Between 2011 and 2015, 93 patients with esophageal (49%) and GEJ (51%) cancers underwent nCRT (n = 67; 72%) or dCRT (n = 26; 28%). Median age was 62.3 years and 74% were male. Median follow-up was 23.9 months. Comparing CP to CF in the setting of TMT, the OS and DFS rates were similar. In the setting of dCRT, CP was associated with significantly inferior 3-year OS (36 vs. 63%; p = 0.001; HR 3.1; 95% CI: 1.2-7.7) and DFS (0 vs. 41%; p = 0.004; HR 3.6; 95% CI: 1.4-8.9) on multivariable and IPTW sensitivity analyses. CONCLUSIONS: TMT with CF and CP produced comparable outcomes. However, for dCRT, CF may be a superior regimen.

A Phase I study of olaparib and irinotecan in patients with colorectal cancer: Canadian Cancer Trials Group IND 187.

Background Olaparib is an orally available inhibitor of PARP-1. In pre-clinical studies, olaparib was shown to potentiate anti-tumor effects of irinotecan in colon cancer cell lines. This phase I study was conducted to evaluate the safety and tolerability of olaparib in combination with irinotecan. Patients and Methods Patients with advanced colorectal cancer whose disease progressed after at least one systemic therapy regimen were enrolled. Dose escalation and de-escalation were based on toxicity assessment. Pharmacokinetic samples were collected in Cycle 1 for olaparib, irinotecan and SN-38. Results Twenty-five patients were enrolled, 11 patients on a schedule of continuous olaparib and irinotecan every 3 weeks (Part A) and 14 patients on a schedule of intermittent olaparib and irinotecan every 2 weeks (Part B). Continuous olaparib administration was associated with higher than expected toxicities and was not considered to be tolerable. Intermittent olaparib administration was better tolerated, and the recommended phase 2 doses were olaparib 50 mg p.o twice daily days 1-5 and irinotecan 125 mg/m(2) i.v. every 2 weeks. Common toxicities included fatigue, anorexia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia and abdominal pain. Nine patients had stable disease as the best response, 2 from Part A (3 and 9 months respectively), and 7 from Part B (median duration: 7.4 months; range: 4 to 13 months). There was no pharmacokinetic interaction between olaparib and irinotecan. Conclusions Olaparib can be combined with irinotecan if administered intermittently. Both olaparib and irinotecan required significant dose reductions. The lack of anti-tumor efficacy observed in this trial makes this combination of little interest for further clinical development. Trial Registration ID NCT00535353.

Phase I trial of dacomitinib, a pan-human epidermal growth factor receptor (HER) inhibitor, with concurrent radiotherapy and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (XDC-001).

Background Curative-intent, non-surgical treatment options for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) include radiotherapy with/without chemotherapy or radiotherapy with cetuximab. This single institution phase I dose escalation trial tested the pan-human epidermal growth factor receptor (HER) oral tyrosine kinase inhibitor, dacomitinib, in combination with standard cisplatin-based chemoradiotherapy. Methods Patients received oral dacomitinib once daily at 3 protocol-defined dose levels (15 mg, 30 mg, and 45 mg). Cisplatin was given intravenously at 100 mg/m(2) every 3 weeks. Radiotherapy was delivered using intensity modulated radiation therapy (IMRT) to a dose of 70Gy in 35 daily fractions to the primary and nodal disease. Dose escalation was performed using a standard 3 + 3 design. Results Twelve patients with LA-SCCHN were enrolled between January 2013 and August 2014. No dose limiting toxicities (DLTs) were observed in the 15 mg and 30 mg dose levels. In the 45 mg dose level, one of four evaluable patients developed a DLT with intolerable grade 2 diarrhea requiring discontinuation of therapy. Adverse events (AEs) attributed to dacomitinib alone include diarrhea, hypertension, and acneiform and maculopapular rash. The most common non-hematological AEs include weight loss, diarrhea, dry mouth, mucositis, nausea, hypoalbuminemia, and hyponatremia. Frequency and severity of AEs did not increase with increasing dose levels of dacomitinib. All patients completed the full course of radiotherapy on schedule and the median dose of cisplatin was 200 mg/m(2), which is comparable to historical standards. Of the 10 patients evaluable for response, 1 patient relapsed with metastatic disease. Conclusions The triple combination has a tolerable side effect profile and dose levels 15 mg and 30 mg were cleared safely. The addition of dacomitinib did not preclude delivery of standard chemoradiotherapy. Studies testing the addition of other HER-targeted therapies to platinum-based concurrent chemo-radiotherapy in LA-SCCHN have failed to demonstrate improved patient outcomes and have reported trends towards excessive toxicities. These results generated uncertainty regarding the future of these agents in combination with chemo-radiation for the treatment of LA-SCCHN, which ultimately led to the early termination of this study.

Pharmacokinetic assessment of dacomitinib (pan-HER tyrosine kinase inhibitor) in patients with locally advanced head and neck squamous cell carcinoma (LA SCCHN) following administration through a gastrostomy feeding tube (GT).

BACKGROUND: Dacomitinib is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients with recurrent/metastatic (RM) SCCHN. A Phase I trial of dacomitinib with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN patients, this study investigated the PK properties of dacomitinib when administered via GT (NCT01484847). Since patients with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN patients with GT, by giving a single dose of drug during their radiotherapy (co-administration with chemotherapy avoided). METHODS: Eligible patients were given a single dose of crushed dacomitinib at 45 mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t = 0), 30 min and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of dacomitinib given orally using Student t test. RESULTS: Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14 F Cope-loop tube (n = 3), 20 F PEG/disc retention tube (n = 3). PK study showed t1/2 of 58 h, Cmax of 17 ng/ml, Tmax of 8 h, AUC0-inf of 1185 ng*hr/ml, Vd/F of 3310 L and CL/F of 41 L/hr. CONCLUSION: Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34 % reduction in Cmax and 33-44 % decrease in AUC (all p <0.05) (Jänne et al., Clin Cancer Res 2011). Such differences were not detected when compared with the PK properties of dacomitinib administered orally in aqueous suspension (Bello et al., Cancer Chemother Pharm 2013). These differences may be attributed to aqueous suspension of dacomitinib. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs.

A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin.

BACKGROUND: In preclinical models, the proton pump inhibitor pantoprazole enhances the antitumor activity of chemotherapeutic agents by improving drug distribution and by inhibiting autophagy. METHODS: Patients with advanced solid tumors (n = 24) received doxorubicin 60 mg/m(2) and escalating doses of pantoprazole (80, 160, 240 and 360 mg) administered intravenously prior to doxorubicin. Blood samples were collected for pharmacokinetic studies. An optional biopsy was performed to evaluate doxorubicin concentration and pharmacodynamic markers of drug activity. RESULTS: Twenty-four patients participated in the study (17 in the dose escalation phase and 7 in the dose expansion). Three patients experienced a dose limiting toxicity (grade 3 fatigue in the three cases), one patient at dose level 3 (pantoprazole 240 mg) and two patients at dose level 4 (pantoprazole 360 mg). Dose level 4 was considered to exceed the maximum tolerated dose. The recommended phase II dose was pantoprazole 240 mg and doxorubicin 60 mg/m(2). The most commonly observed toxicities included fatigue, neutropenia and leukopenia. Two patients achieved a confirmed partial response. Median maximum serum concentration of pantoprazole was 84.3 µM at 1-2 h after injection of pantoprazole 240 mg. No drug-drug interaction was observed. A single on-treatment tumor biopsy showed a sharply decreasing gradient in doxorubicin concentration and associated activity markers with increasing distance from tumor blood vessels. CONCLUSION: Administration of high doses of pantoprazole in combination with doxorubicin is feasible. The recommended phase II dose of pantoprazole, 240 mg, will be evaluated in combination with docetaxel as first line in patients with castration-resistant prostate cancer.

Phase II trial of bortezomib alone or in combination with irinotecan in patients with adenocarcinoma of the gastroesophageal junction or stomach.

PURPOSE: To determine the effectiveness of bortezomib plus irinotecan and bortezomib alone in patients with advanced gastroesophageal junction (GEJ) and gastric adenocarcinoma. We also sought to explore the effect of these therapeutics on tumor and normal gene expression in vivo. METHODS: Forty-one patients with advanced GEJ (89 %) or gastric (11 %) adenocarcinoma received bortezomib (1.3 mg/m(2) days 1, 4, 8, 11) plus irinotecan (125 mg/m(2) days 1, 8) every 21 days as first line therapy (N = 29), or bortezomib alone as second line therapy (N = 12). The trial was designed to detect a 40 % response rate for the combination, and 20 % response rate for bortezomib alone. Affymetrix HU133A gene chip arrays were used for gene expression studies. RESULTS: Objective response occurred in 3 of 29 patients (10 %, 95 % confidence intervals [CI] 2 %, 27 %) treated with bortezomib plus irinotecan, and in 1 of 12 patients (8 %, 95 % CI 0 %, 39 %) with bortezomib alone. Due to the limited number of responders, there were no significant correlations with response found in the gene expression profiles of 12 patients whose tumors were sampled before and 24 h after therapy with bortezomib alone (N = 2) or the combination (N = 10). CONCLUSIONS: We conclude that bortezomib is not effective for the treatment of advanced adenocarcinoma of the GEJ or stomach, whether used alone or in combination with irinotecan, in an unselected patient population.

Circulating Oncometabolite 2-hydroxyglutarate as a Potential Biomarker for Isocitrate Dehydrogenase (IDH1/2) Mutant Cholangiocarcinoma.

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (αKG). IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of patients with IDHmt glioma and CCA. Results were validated in cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for patients with IDHmt glioma, while circulating rRS was elevated in patients with IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in patients with IDHmt CCA compare with patients with IDHwt CCA. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.

Plasma versus tissue tumor mutational burden as biomarkers of durvalumab plus tremelimumab response in patients with metastatic colorectal cancer in the CO.26 trial.

PURPOSE: Tissue derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset on which this was validated lacked colorectal cancers (CRCs), and there is limited evidence for immunotherapy benefit in CRC using this threshold. PATIENTS AND METHODS: CO.26 was a randomized phase II study of 180 patients comparing durvalumab and tremelimumab (D+T, n=119 patients) versus best supportive care (BSC, n=61 patients). ctDNA sequencing was available for 168 patients (n=118 D+T, n=50), of which 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on overall survival were determined using a minimal p-value approach. This report includes the final overall survival analysis. RESULTS: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D+T compared to BSC in microsatellite stable (MSS) metastatic CRC (HR 0.71 [95% CI:0.28-1.80], p=0.47). No tissue TMB threshold could identify a high TMB group that benefited from ICI. In contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D+T (HR=0.34 [95%CI:0.13-0.85], p=0.022), as was clonal pTMB ≥10.6 mutations/Mb (HR=0.10 [95%CI:0.014-0.79], p=0.029) and subclonal pTMB ≥25.9/Mb (HR=0.20 [95% CI:0.061-0.69], p=0.010). Higher pTMB was associated with length of time on cytotoxic agents (p=0.021) and prior anti-EGFR exposure (p=2.44x10-06). CONCLUSION: pTMB derived from either clonal or subclonal mutations may identify a group more likely to benefit from immunotherapy, though validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.

Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E.

BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.

Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D.

BACKGROUND: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. RESULTS: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. CONCLUSION: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. GOV IDENTIFIER: ClinicalTrials.gov; NCT03374254.

A phase II study of cediranib (AZD 2171) in treatment naive patients with progressive unresectable recurrent or metastatic renal cell carcinoma. A trial of the PMH phase 2 consortium.

BACKGROUND: Inhibition of angiogenesis has emerged as an effective therapeutic strategy in metastatic renal cell cancer (mRCC). In this single arm phase 2 study, we evaluated the efficacy and tolerability of cediranib (AZD2171) a potent angiogenesis inhibitor in first line mRCC. METHODS: Eligible patients who had no prior systemic therapy received cediranib 45 mg orally once daily continuously. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate (ORR plus stable disease (SD) ≥ 4 months), duration of response, progression free survival (PFS), median overall survival (OS), safety and tolerability. RESULTS: Between January 2006 and April 2008, 44 patients were accrued. The median age was 62 (range 44-83) and performance status was either 0 (22 patients) or 1 (22 patients). Of the 39 evaluable patients there were 15 (38 %) partial responses (95 % CI: 23-55 %); 18 stable disease (SD) for a clinical benefit rate of 33/39 = 85 % (95 % CI: 69-94 %) and 6 progressive disease. Median PFS was 8.9 months (95 % CI: 5.1-12.9); and median OS was 28.6 months (95 % CI: 18.2-37.3 months). The most frequent grade 3 or higher AEs included hypertension, fatigue, hand-foot syndrome and diarrhea. CONCLUSIONS: Cediranib demonstrated significant anti-tumour activity in first line, treatment-naive mRCC, with efficacy parameters comparable to the other approved agents (sunitinib and pazopanib) in this setting. The main toxicities were fatigue, diarrhea and hypertension. Based on these encouraging results, further evaluation of cediranib in mRCC at a more tolerable dose of 30 mg daily appears warranted.