RESUMO
BACKGROUND: Most patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA. METHODS: Investigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6). RESULTS: Twenty-seven patients were enrolled. Median age 58 years (24-87), female (nâ =â 14), ECOG 0/1â =â 13/14, GC/GEJâ =â 16/11, and non-Hispanic White/Hispanic/Asianâ =â 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in nâ =â 3 patients (hypertension, thromboembolic event, esophageal perforation; each nâ =â 1). No G5 was observed. CONCLUSIONS: The addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.).
Assuntos
Adenocarcinoma , Anilidas , Anticorpos Monoclonais Humanizados , Neoplasias Esofágicas , Inibidores de Checkpoint Imunológico , Piridinas , Neoplasias Gástricas , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/administração & dosagem , Idoso , Anilidas/uso terapêutico , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adulto , Idoso de 80 Anos ou mais , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Resistencia a Medicamentos Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto Jovem , Junção Esofagogástrica/patologiaRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC). METHODS: We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses. RESULTS: A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00-80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13-10.76]; HCC era: OR, 3.11 [95% CI, 0.95-10.16]). CONCLUSIONS: The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.
Assuntos
Testes Genéticos , Mutação em Linhagem Germinativa , Fidelidade a Diretrizes , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Testes Genéticos/normas , Testes Genéticos/métodos , Fidelidade a Diretrizes/estatística & dados numéricos , Estudos Retrospectivos , Idoso , Adulto , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/terapia , Predisposição Genética para Doença , Aconselhamento Genético/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Encaminhamento e Consulta/normas , Guias de Prática Clínica como AssuntoRESUMO
Current guidelines recommend neoadjuvant (NAC) and/or adjuvant chemotherapy for locally advanced gastric cancers (LAGCs). However, the choice and duration of NAC regimen is standardized, rather than personalized to biologic response, despite the availability of several different classes of agents for the treatment of gastric cancer (GC). The current trial will use a tumor-informed ctDNA assay (Signatera™) and monitor response to NAC. Based on ctDNA kinetics, the treatment regimen is modified. This is a prospective single center, single-arm, open-label study in clinical stage IB-III GC. ctDNA is measured at baseline and repeated every 8 weeks. Imaging is performed at the same intervals. The primary end point is the feasibility of this approach, defined as percentage of patients completing gastrectomy.
Assuntos
Terapia Neoadjuvante , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Ensaios Clínicos Fase I como Assunto , Estudos de Viabilidade , Gastrectomia/métodos , Humanos , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Immune checkpoint inhibitors represent a newly established standard of care in patients with refractory metastatic colorectal cancer with mismatch repair deficiency and microsatellite instability. However, the use of immunotherapy is unclear in recipients of liver transplants with or without concurrent liver function abnormalities. Clinical trials investigating immunotherapy have mostly excluded liver transplant recipients and patients with abnormal liver function. This report presents the first case, to our knowledge, of a liver transplant patient with mismatch repair-deficient colon adenocarcinoma with liver metastases and concurrent abnormal liver function who safely responded to immunotherapy. We also review the literature on checkpoint inhibitor use in patients with other metastatic solid tumors after liver transplant and those with baseline liver function abnormalities. An increasing body of evidence supports the safety of checkpoint inhibition in patients with cancer and solid organ transplants, but further prospective studies are warranted. Use of immunotherapy in liver transplant recipients who have metastatic colorectal cancer with microsatellite instability is feasible but should be performed in a multidisciplinary team setting.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/etiologia , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Instabilidade de Microssatélites , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transplantados , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Neoplasias Colorretais/diagnóstico , Reparo de Erro de Pareamento de DNA , Humanos , Testes de Função Hepática , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: This study determined the safety and recommended phase 2 dose (RP2D) of the multikinase inhibitor cabozantinib in combination with trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal carcinoma (mCRC). PATIENTS AND METHODS: Single institution investigator-initiated phase 1 study using 3+3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth-factor support was allowed. RESULTS: Fifteen patients were enrolled. Median age 56 years (31-80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, and weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9-6.8) and disease control rate was 86.7%. CONCLUSION: The combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging clinical activity in refractory mCRC. CLINICALTRIALS: GOV: NCT04868773.
Assuntos
Adenocarcinoma , Anilidas , Neoplasias Colorretais , Demência Frontotemporal , Neutropenia , Piridinas , Pirrolidinas , Timina , Humanos , Masculino , Pessoa de Meia-Idade , Uracila/efeitos adversos , Trifluridina , Demência Frontotemporal/induzido quimicamente , Demência Frontotemporal/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Neutropenia/induzido quimicamenteRESUMO
PURPOSE: To provide evidence-based guidance for clinicians who treat patients with locally advanced rectal cancer. METHODS: A systematic review of the literature published from 2013 to 2023 was conducted to identify relevant systematic reviews, phase II and III randomized controlled trials (RCTs), and observational studies where applicable. RESULTS: Twelve RCTs, two systematic reviews, and one nonrandomized study met the inclusion criteria for this systematic review. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RECOMMENDATIONS: Following assessment with magnetic resonance imaging, for patients with microsatellite stable or proficient mismatch repair locally advanced rectal cancer, total neoadjuvant therapy (TNT; ie chemoradiation [CRT] and chemotherapy) should be offered as initial treatment for patients with tumors located in the lower rectum and/or patients who are at higher risk for local and/or distant metastases. Patients without higher-risk factors may discuss chemotherapy with selective CRT depending on extent of response, TNT, or neoadjuvant long-course CRT or short-course radiation. For patients who are candidates for TNT, the preferred timing for chemotherapy is after radiation, and neoadjuvant long-course CRT is preferred over short-course radiation therapy (RT), however short-course RT may also be a viable treatment option depending on circumstances. Nonoperative management may be discussed as an alternative to total mesorectal excision for patients who have a clinical complete response to neoadjuvant therapy. For patients whose tumors are microsatellite instability-high or mismatch repair deficient, immunotherapy is recommended.Additional information is available at http://www.asco.org/gastrointestinal-cancer-guidelines.
RESUMO
TAS-102 is approved for treatment of refractory metastatic gastroesophageal carcinoma (mGEC). This study sought to determine whether the combination of TAS-102 with irinotecan (TASIRI) was safe and effective in previously treated mGEC. This was a single-arm phase 1b study for patients (pts) with mGEC previously treated with at least one line of fluoropyrimidine and platinum-containing regimen. TAS-102 was given at 25 mg/m2 twice daily on days 1 to 5 with irinotecan 180 mg/m2 on day 1 of a 14-day cycle. The primary endpoint was progression-free survival at 6 months ≥ 35% (PFS-6). 20 Pts were enrolled. The study met its primary endpoint. PFS-6 is 40% (95% CI 19.3-60.0). Median PFS and overall survival are 5.3 months and not reached, respectively. 17 of 20 pts had measurable disease by RECIST criteria. Of the 17, 13 had stable disease and 4 had progressive disease as best response (8 pts had tumor shrinkage < 30%). The disease control rate was 75%. In exploratory analyses, mutations in homologous recombination deficiency genes were associated with inferior PFS (P < 0.03). The most common any grade (G) treatment-related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (20%) and neutropenia (10%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls.
Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Irinotecano , Neoplasias Gástricas , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Combinação de Medicamentos , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Irinotecano/uso terapêutico , Platina/uso terapêutico , Pirrolidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Timina/uso terapêutico , Trifluridina/uso terapêuticoRESUMO
Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.