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BACKGROUND: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines. PATIENTS AND METHODS: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed. RESULTS: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest. CONCLUSION: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.
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Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.
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Adenocarcinoma , Ampolla Hepatopancreática , Neoplasias del Conducto Colédoco , Neoplasias Duodenales , Humanos , Neoplasias del Conducto Colédoco/diagnóstico , Neoplasias del Conducto Colédoco/terapia , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias PancreáticasRESUMEN
BACKGROUND: OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. METHODS: Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. RESULTS: Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. CONCLUSION: No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT02923349.
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Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Dosis Máxima Tolerada , Receptores OX40RESUMEN
INTRODUCTION: Small bowel adenocarcinomas (SBAs) are rare and frequently treated like large intestinal adenocarcinomas. However, SBAs have a very different microenvironment and could respond differently to the same therapies. Our previous data suggested that SBAs might benefit from targeting the PD-1/PD-L1 axis based on PD-L1 staining in almost 50% of SBA tissue samples tested. Thus, we designed a phase 2 study to explore safety and efficacy of avelumab in SBA. PATIENTS AND METHODS: Patients with advanced or metastatic disease were enrolled; ampullary tumors were considered part of the duodenum and allowed. Prior PD-1/PD-L1 inhibition was not allowed. Avelumab (10 mg/kg) was given every 2 weeks, and imaging was performed every 8 weeks. Primary endpoint was response rate. RESULTS: Eight patients (n = 5, small intestine; n = 3, ampullary) were enrolled, with a majority (88%) being male and a median age of 61 years. Of 7 efficacy-evaluable patients, 2 (29%) experienced partial responses; stable disease occurred in 3 additional patients (71%). Median progression-free survival was 3.35 months. Most frequent, related toxicities were anemia, fatigue, and infusion-related reaction (25% each), mostly grade ≤2; grade 3 hypokalemia and hyponatremia occurred in one patient, and another reported grade 4 diabetic ketoacidosis. CONCLUSIONS: Despite the observed benefit, accrual was slower than expected and the study was closed early due to feasibility. A general clinic observation was that patients were receiving immunotherapy off-label as the availability of these agents increased. Off-label availability and disease rarity were likely drivers of insufficient accrual.
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Adenocarcinoma , Antígeno B7-H1 , Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Intestino Delgado , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1 , Microambiente TumoralRESUMEN
BACKGROUND: Early-onset pancreatic cancer (EOPC) is relatively uncommon. It is unclear if the incidence of EOPC is evolving and how these patients are treated. METHODS: We conducted a retrospective, population-based study using SEER 2004-2016. We evaluated annual age-adjusted incidence rate (AAIR), stage at presentation, and race/ethnicity among 7802 patients plus treatment patterns in 7307 patients (excluding neuroendocrine tumors) younger than 50. RESULTS: The AAIR was higher in males while the rate increased faster in females. The AAIR was highest in Non-Hispanic Black patients and increased for all races/ethnicities over time. The percentage of patients diagnosed with distant-stage disease decreased over time but increased for localized-stage disease. Hispanic patients made up a larger proportion of patients over time compared to other groups. For localized-stage disease, primary surgery alone was the most utilized modality of therapy. For regional-stage disease, chemotherapy with radiation was the most utilized modality from 2004-2010, whereas chemotherapy alone was the most utilized from 2011-2016. For distant-stage disease, chemotherapy alone was the most utilized and used increasingly over time. Patients with EOPC received radiation and chemotherapy at similar rates to, and underwent surgery more frequently, than patients 50-69. CONCLUSIONS: The AAIR of EOPC increased over time, faster so in females. Groups who experience a higher burden of pancreatic cancer, particularly African Americans, experienced a higher burden of EOPC. Treatment of localized and regional-stage disease did not follow standard treatment guidelines for pancreatic cancer. Our findings indicate that EOPC patients received more treatment than their older counterparts.
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Importance: Despite the benefit of peptide receptor radionuclide therapy (PRRT) for patients with well-differentiated neuroendocrine tumors (WD NETs), no clinical metric to anticipate benefit from the therapy for individual patients has been previously defined. Objective: To assess whether the prognostic ability of the clinical score (CS) could be validated in an external cohort of patients with WD NETs. Design, Setting, and Participants: This multicenter cohort study's analysis included patients with WD NETs who were under consideration for peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-dotatate between March 1, 2016, and March 17, 2020. The original cohort included patients from Vanderbilt-Ingram Cancer Center. The validation cohort included patients from Ochsner Medical Center, Markey Cancer Center, and Rush Medical Center. Patients with paragangliomas, pheochromocytomas and neuroblastomas were excluded. Statistical analysis was performed from June to November 2021. Exposures: PRRT with 177Lu-dotatate or alternate therapies such as everolimus, sunitinib, or capecitabine plus temozolomide. Main Outcomes and Measures: The primary outcome was progression-free survival (PFS) and was estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusting for primary tumor site, tumor grade, and number of PRRT doses administered was used to analyze association between CS and outcomes. Results: A total of 126 patients (median age [IQR] age: 63.6 [52.9-70.7] years; 64 male individuals) were included in the validation cohort, and the combined cohort (validation and original cohorts combined) had a total of 248 patients (median [IQR] patient age: 63.3 [53.3-70.3] years; 126 male individuals). In the validation cohort, on multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.61; 95% CI, 1.64-4.16). After finding an association of the CS with PFS in the validation cohort, the original and validation cohorts were combined into the cohort for this analysis. On multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.52; 95% CI, 1.89-3.36). Conclusions and Relevance: Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT.
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Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/radioterapia , Radioisótopos/uso terapéutico , Receptores de Péptidos/uso terapéutico , Índice de Severidad de la Enfermedad , Anciano , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Valor Predictivo de las Pruebas , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Cintigrafía , Resultado del TratamientoRESUMEN
PURPOSE: Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study. PATIENTS AND METHODS: Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1). RESULTS: Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including BRAF or KRAS mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events. CONCLUSION: Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Reparación de la Incompatibilidad de ADN , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/administración & dosificación , Inestabilidad de Microsatélites , Nivolumab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Progresión de la Enfermedad , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Ipilimumab/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Nivolumab/efectos adversos , Supervivencia sin Progresión , Factores de Tiempo , Adulto JovenRESUMEN
Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Noninvasive imaging via PET may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. l-[5-11C]-glutamine (11C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of 11C-glutamine for oncologic PET imaging. Methods: Nine patients with confirmed metastatic colorectal cancer underwent PET/CT imaging. Patients received 337.97 ± 44.08 MBq of 11C-glutamine. Dynamic PET acquisitions that were centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. After the dynamic acquisition, a whole-body PET/CT scan was acquired. Volume-of-interest analyses were performed to obtain estimates of organ-based absorbed doses of radiation. Results:11C-glutamine was well tolerated in all patients, with no observed safety concerns. The organs with the highest radiation exposure included the bladder, pancreas, and liver. The estimated effective dose was 4.46E-03 ± 7.67E-04 mSv/MBq. Accumulation of 11C-glutamine was elevated and visualized in lung, brain, bone, and liver metastases, suggesting utility for cancer imaging. Conclusion: PET using 11C-glutamine appears safe for human use and allows noninvasive visualization of metastatic colon cancer lesions in multiple organs. Further studies are needed to elucidate its potential for other cancers and for monitoring response to treatment.
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GlutaminaRESUMEN
PURPOSE: PARP inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic cancers. This study evaluated the safety and efficacy of second-line treatment with veliparib and mFOLFIRI versus FOLFIRI (control) for metastatic pancreatic cancer. PATIENTS AND METHODS: This randomized phase II clinical trial led by the SWOG Cancer Research Network enrolled patients between September 1, 2016 and December 13, 2017. The median follow-up was 9 months (IQR 1-27). BRCA1/2 and homologous recombination DNA damage repair (HR-DDR) genetic defects were tested in blood and tumor biopsies. Patients received veliparib 200 mg twice daily, days 1-7 with mFOLFIRI days 3-5, or FOLFIRI in 14-day cycles. RESULTS: After 123 of planned 143 patients were accrued, an interim futility analysis indicated that the veliparib arm was unlikely to be superior to control, and the study was halted. Median overall survival (OS) was 5.4 versus 6.5 months (HR, 1.23; P = 0.28), and median progression-free survival (PFS) was 2.1 versus 2.9 months (HR, 1.39; P = 0.09) with veliparib versus control. Grade 3/4 toxicities were more common with veliparib (69% vs. 58%, P = 0.23). For cancers with HR-DDR defects versus wild-type, median PFS and OS were 7.3 versus 2.5 months (P = 0.05) and 10.1 versus 5.9 months (P = 0.17), respectively, with FOLFIRI, and 2.0 versus 2.1 months (P = 0.62) and 7.4 versus 5.1 months (P = 0.10), respectively, with veliparib plus mFOLFIRI. CONCLUSIONS: Veliparib plus mFOLFIRI did not improve survival for metastatic pancreatic cancer. FOLFIRI should be further studied in pancreatic cancers with HR-DDR defects.
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Neoplasias Pancreáticas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/efectos adversos , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversosRESUMEN
Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.
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Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapiaRESUMEN
LESSONS LEARNED: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation. BACKGROUND: Cediranib, a vascular endothelial growth factor receptor inhibitor, suppresses expression of BRCA1/2 and RAD51 inducing homologous recombination DNA repair deficiency (HRD) in several cancer cell lines and xenograft models [1]. Olaparib provides a clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPDAC) with germline BRCA mutation (gBRCAmt) [2]. We hypothesized that cediranib induces HRD in the absence of gBRCAmt and synergizes with olaparib, resulting in an objective response in patients with mPDAC. METHODS: Patients with mPDAC with at least one prior systemic chemotherapy were enrolled. Patients with known gBRCAmt were excluded. Patients took cediranib 30 mg daily and olaparib 200 mg twice daily, orally. The primary endpoint was objective response (OR) rate. RESULTS: Nineteen patients received the study drugs. Seven patients came off treatment before the first restaging scan: six because of clinical progression and one because of an adverse event. No OR was observed. Six patients had stable disease (SD) as a best overall response. The median duration of SD was 3.1 months. The median overall survival was 3.4 months. Common treatment-related adverse events were fatigue, hypertension, and diarrhea. CONCLUSION: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.
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Adenocarcinoma , Neoplasias Ováricas , Neoplasias Pancreáticas , Femenino , Humanos , Mutación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Ftalazinas/efectos adversos , Piperazinas , Quinazolinas , Factor A de Crecimiento Endotelial VascularRESUMEN
We developed a clinical score (CS) at Vanderbilt Ingram Cancer Center (VICC) that we hoped would predict outcomes for patients with progressive well-differentiated neuroendocrine tumors (NETs) receiving therapy with Lutetium-177 (177Lu)-DOTATATE. Patients under consideration for 177Lu-DOTATATE between March 1, 2016 and March 17, 2020 at VICC were assigned a CS prospectively. The CS included 5 categories: available treatments for tumor type outside of 177Lu-DOTATATE, prior systemic treatments, patient symptoms, tumor burden in critical organs and presence of peritoneal carcinomatosis. The primary outcome of the analysis was progression-free survival (PFS). To evaluate the effect of the CS on PFS, a multivariable Cox regression analysis was performed adjusting for tumor grade, primary tumor location, and the interaction between 177Lu-DOTATATE doses received (zero, 1-2, 3-4) and CS. A total of 91 patients and 31 patients received 3-4 doses and zero doses of 177Lu-DOTATATE, respectively. On multivariable analysis, in patients treated with 3-4 doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated hazard ratio (HR) for PFS was 2.0 (95% CI 1.61-2.48). On multivariable analysis, in patients who received zero doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated HR for PFS was 1.22 (95% CI 0.91-1.65). Among patients treated with 3-4 doses of 177Lu-DOTATATE, those with lower CS experienced improved PFS with the treatment compared to patients with higher CS. This PFS difference, based upon CS, was not observed in patients who did not receive 177Lu-DOTATATE, suggesting the predictive utility of the score.
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Tumores Neuroendocrinos , Compuestos Organometálicos , Humanos , Lutecio/uso terapéutico , Tumores Neuroendocrinos/radioterapia , Octreótido/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Tomografía de Emisión de Positrones , Radioisótopos , CintigrafíaRESUMEN
OPINION STATEMENT: Metastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from tumor tissue, to assess for the presence of DNA damage repair (DDR) defects, microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor kinase (NTRK) fusions, anaplastic lymphoma kinase (ALK) rearrangements, or human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose tumors harbor DDR defects, benefit from treatment with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and WEE1 have demonstrated promising anti-tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting therapies into rational clinical trial combinations and sequence PARP inhibitors in relation to platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for mPDA patients, in all treatment lines, so that novel therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.
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Adenocarcinoma/genética , Antineoplásicos/farmacología , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Neoplasias Pancreáticas/genética , Transducción de Señal/efectos de los fármacos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Ensayos Clínicos como Asunto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Terapia Molecular Dirigida , Mutación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Mutaciones Letales Sintéticas , Resultado del TratamientoRESUMEN
PURPOSE: The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC). PATIENTS AND METHODS: Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy. RESULTS: A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2-4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4-18.4], median overall survival was 9.7 m (95% CI, 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use. CONCLUSIONS: Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.
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Adenocarcinoma/tratamiento farmacológico , Albúminas/administración & dosificación , Desoxicitidina/análogos & derivados , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Receptores Acoplados a Proteínas G/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Fluorouracilo/administración & dosificación , Humanos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Wnt/antagonistas & inhibidores , GemcitabinaRESUMEN
LESSONS LEARNED: This trial evaluating a novel plant extract, PBI-05204, did not meet its primary endpoint of overall survival but did show signals of efficacy in heavily pretreated mPDA. PBI-05204 was generally well tolerated, with the most common side effects related to treatment being vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Additional trials are needed to explore the role of PBI-05204 in cancer treatment. BACKGROUND: Survival for metastatic pancreatic ductal adenocarcinoma (mPDA) is dismal, and novel agents are needed. PBI-05204 is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a cardiac glycoside that has demonstrated antitumor activity in various tumor cell lines with a mechanism involving inhibition of Akt phosphorylation and through downregulation of mTOR. METHODS: A phase II, single-arm, open-label study to determine the efficacy of PBI-05204 in patients with refractory mPDA therapy was conducted. The primary endpoint was overall survival (OS), with the hypothesis that 50% of patients would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Patients received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or patient withdrawal. Radiographic response was assessed every two cycles. RESULTS: Forty-two patients were enrolled, and 38 were analyzed. Ten patients were alive at 4.5 months (26.3%) with a median PFS of 56 days. One objective response (2.6%) was observed for 162 days. Grade ≥ 3 treatment-emergent adverse events occurred in 63.2% of patients with the most common being fatigue, vomiting, nausea, decreased appetite, and diarrhea. CONCLUSION: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate a role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy and radiotherapy. A randomized phase II trial is currently being designed.
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Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Teorema de Bayes , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Neoplasias Pancreáticas/tratamiento farmacológicoRESUMEN
PURPOSE: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. RESULTS: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. CONCLUSIONS: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.
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Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Anciano , Biomarcadores de Tumor , Quimioradioterapia , Terapia Combinada , Manejo de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Terapia Neoadyuvante , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Piridonas/administración & dosificación , Piridonas/efectos adversos , Pirimidinonas/administración & dosificación , Pirimidinonas/efectos adversos , Neoplasias del Recto/etiología , Neoplasias del Recto/metabolismo , Resultado del TratamientoRESUMEN
Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years. Improving quality of life and survival amongst these patients will require new ideas and novel therapies in a multidisciplinary approach. This review will cover the most recent advances in the comprehensive treatment of pancreatic cancer and place them within a historical context when necessary. Treatment of all disease stages will be discussed, but the focus is on systemic therapy as novel drugs and new treatment combinations enter the clinic. This will include more aggressive chemotherapy in earlier disease stages, approved uses for immunotherapy, and targetable mutations. In addition, negative trials of importance and controversial topics will be noted.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático/terapia , Humanos , Terapia Neoadyuvante , Neoplasias Pancreáticas/terapia , Calidad de VidaRESUMEN
PURPOSE: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m2 twice daily; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m2; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. RESULTS: Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m2 twice daily plus irinotecan 180 mg/m2. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months). CONCLUSIONS: Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecan-bevacizumab combination in previously treated mCRC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Combinación de Medicamentos , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Irinotecán/administración & dosificación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Seguridad del Paciente , Supervivencia sin Progresión , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Distribución Tisular , Resultado del Tratamiento , Trifluridina/administración & dosificaciónRESUMEN
INTRODUCTION: Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. MATERIALS AND METHODS: The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. RESULTS: Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. CONCLUSION: Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. IMPLICATIONS FOR PRACTICE: Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.