RESUMEN
PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.
Asunto(s)
Adenocarcinoma , ADN Tumoral Circulante , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Receptor ErbB-2/genética , Estudios Retrospectivos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/uso terapéuticoRESUMEN
Standard-of-care, first-line therapy for patients with advanced HER2+ gastric/gastroesophageal junction adenocarcinoma is chemotherapy plus trastuzumab, a monoclonal antibody (mAb) targeting HER2. Margetuximab is an Fc-optimized mAb that binds HER2. Retifanlimab, a humanized IgG4 mAb, binds to PD-1 and blocks its interaction with PD-L1/2. Tebotelimab, an IgG4κ bispecific DART® molecule, binds PD-1 and lymphocyte activation gene 3 concomitantly, disrupting these nonredundant inhibitory pathways to further restore exhausted T-cell function. Here, we describe the design and rationale of the randomized, open-label, Phase II/III MAHOGANY trial evaluating margetuximab plus retifanlimab with/without chemotherapy and margetuximab plus tebotelimab with chemotherapy in first-line unresectable metastatic/locally advanced gastroesophageal junction adenocarcinoma. Primary end points include objective response rate, overall survival and safety/tolerability. Clinical trial registration: NCT04082364 (ClinicalTrials.gov).
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Adenocarcinoma/mortalidad , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Neoplasias Esofágicas/mortalidad , Femenino , Humanos , Masculino , Estadificación de Neoplasias , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/etiología , Neoplasias Gástricas/mortalidad , Resultado del TratamientoRESUMEN
Bemarituzumab is an afucosylated monoclonal antibody against FGFR2b (a FGF receptor) with demonstrated monotherapy clinical activity in patients with late-line gastric cancer whose tumors overexpress FGFR2b (NCT02318329). We describe the rationale and design of the FIGHT trial (NCT03343301), a global, randomized, double-blind, placebo-controlled Phase III study evaluating the role of bemarituzumab in patients with previously untreated, FGFR2b-overexpressing advanced gastroesophageal cancer. Patients are randomized in a blinded fashion to the combination of mFOLFOX6 and bemarituzumab or mFOLFOX6 and placebo. Eligible patients are selected based on the presence of either FGFR2b protein overexpression determined by immunohistochemistry or FGFR2 gene amplification determined by circulating tumor DNA. The primary end point is overall survival, and secondary end points include progression-free survival, objective response rate and safety.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos Clínicos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Unión Esofagogástrica/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Biomarcadores de Tumor , Neoplasias Esofágicas/diagnóstico , Unión Esofagogástrica/patología , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Amplificación de Genes , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Proyectos de Investigación , Neoplasias Gástricas/diagnósticoRESUMEN
Gastroesophageal adenocarcinomas (GEAs) harbor recurrent amplification of KRAS, leading to marked overexpression of WT KRAS protein. We previously demonstrated that SHP2 phosphatase, which acts to promote KRAS and downstream MAPK pathway activation, is a target in these tumors when combined with MEK inhibition. We hypothesized that SHP2 inhibitors may serve as a foundation for developing novel combination inhibitor strategies for therapy of KRAS-amplified GEA, including with targets outside the MAPK pathway. Here, we explore potential targets to effectively augment the efficacy of SHP2 inhibition, starting with genome-wide CRISPR screens in KRAS-amplified GEA cell lines with and without SHP2 inhibition. We identify candidate targets within the MAPK pathway and among upstream RTKs that may enhance SHP2 efficacy in KRAS-amplified GEA. Additional in vitro and in vivo experiments demonstrated the potent cytotoxicity of pan-ERBB kinase inhibitions in vitro and in vivo. Furthermore, beyond targets within the MAPK pathway, we demonstrate that inhibition of CDK4/6 combines potently with SHP2 inhibition in KRAS-amplified GEA, with greater efficacy of this combination in KRAS-amplified, compared with KRAS-mutant, tumors. These results suggest therapeutic combinations for clinical study in KRAS-amplified GEAs.
Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Mutación , Línea Celular TumoralRESUMEN
BACKGROUND: CEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8(+) T cell response. METHODS: Patients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 µg (arm A), 100 µg (arm B) or 1000 µg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression. RESULTS: Sixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 10(4) CD8(+) cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease. CONCLUSIONS: The T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts. TRIAL REGISTRATION: ClinicalTrials.gov NCT00203892.