RESUMEN
BACKGROUND: Based on a high incidence of genomic alteration in the cell cycle and DNA damage and response (DDR)-related pathways in small cell lung cancer (SCLC), the clinical efficacy of the DDR-targeting agent olaparib (PARP inhibitor) as monotherapy and in combination with ceralasertib (ATR inhibitor) in relapsed or refractory SCLC was evaluated. METHODS: As part of a phase 2 biomarker driven umbrella study, patients with SCLC and predefined DDR gene alterations who failed to benefit from prior platinum-based regimens were allocated to the olaparib monotherapy arm and nonbiomarker-selected patients were allocated to the olaparib and ceralasertib combination arm. RESULTS: In the olaparib monotherapy arm (n = 15), the objective response rate was 6.7% (one partial response), and the disease control rate was 33.3%, including three patients with stable disease. The median progression-free survival was 1.3 months (95% CI, 1.2-NA). In the combination arm (n = 26), the objective response rate and disease control rate were 3.8% and 42.3%, respectively, with one partial response and 10 patients with stable disease. The median progression-free survival was 2.8 months (95% CI, 1.8-5.4). Treatment was generally well tolerated except for one fatal case of neutropenic fever in the combination arm. CONCLUSIONS: Targeting DDR pathways with olaparib as a single agent or in combination with ceralasertib did not meet the predefined efficacy end point. However, disease stabilization was more evident in the combination arm. Further investigation of the combination of olaparib in SCLC should be performed with diverse combinations and patient selection strategies to maximize efficacy.
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Indoles , Neoplasias Pulmonares , Morfolinas , Neoplasias Ováricas , Piperazinas , Pirimidinas , Carcinoma Pulmonar de Células Pequeñas , Sulfonamidas , Humanos , Femenino , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inducido químicamente , Resultado del Tratamiento , Ftalazinas/efectos adversos , Neoplasias Ováricas/tratamiento farmacológicoRESUMEN
PURPOSE: AcSé-ESMART Arm C aimed to define the recommended dose and activity of the WEE1 inhibitor adavosertib in combination with carboplatin in children and young adults with molecularly enriched recurrent/refractory malignancies. PATIENTS AND METHODS: Adavosertib was administered orally, twice every day on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle, starting at 100 mg/m2/dose and AUC 5, respectively. Patients were enriched for molecular alterations in cell cycle and/or homologous recombination (HR). RESULTS: Twenty patients (median age: 14.0 years; range: 3.4-23.5) were included; 18 received 69 treatment cycles. Dose-limiting toxicities were prolonged grade 4 neutropenia and grade 3/4 thrombocytopenia requiring transfusions, leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4; no recommended phase II dose was defined. Main treatment-related toxicities were hematologic and gastrointestinal. Adavosertib exposure in children was equivalent to that in adults; both doses achieved the cell kill target. Overall response rate was 11% (95% confidence interval, 0.0-25.6) with partial responses in 2 patients with neuroblastoma. One patient with medulloblastoma experienced unconfirmed partial response and 5 patients had stable disease beyond four cycles. Seven of these eight patients with clinical benefit had alterations in HR, replication stress, and/or RAS pathway genes with or without TP53 alterations, whereas TP53 pathway alterations alone (8/10) or no relevant alterations (2/10) were present in the 10 patients without benefit. CONCLUSIONS: Adavosertib-carboplatin combination exhibited significant hematologic toxicity. Activity signals and identified potential biomarkers suggest further studies with less hematotoxic DNA-damaging therapy in molecularly enriched pediatric cancers.
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Brazo , Carcinoma , Pirazoles , Pirimidinonas , Niño , Adulto Joven , Humanos , Adolescente , Carboplatino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Proteínas Tirosina Quinasas , Proteínas de Ciclo CelularRESUMEN
BACKGROUND: Loss of PTEN function leads to increased PI3Kß signaling. AZD8186, a selective PI3Kß/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed in advanced gastric cancer with PTEN loss. METHODS: In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m2 or 80 mg/m2; days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II. RESULTS: In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m2 and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (nâ =â 18) and PIK3CB mutation (nâ =â 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility. CONCLUSION: Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.ClinicalTrials.gov Identifier: NCT04001569.
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Paclitaxel , Neoplasias Gástricas , Humanos , Compuestos de Anilina/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cromonas/farmacología , Dosis Máxima Tolerada , Paclitaxel/farmacología , Proteínas Represoras , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
BACKGROUND: Targeting the DNA damage repair (DDR) pathways is an attractive strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral kinase inhibitor of ataxia telangiectasia and Rad3 related protein, which is a master regulator of DDR. We conducted a phase II trial of ceralasertib plus durvalumab in patients with previously treated advanced gastric cancer (AGC) to demonstrate the safety, tolerability, and clinical activity of the combination. METHODS: This phase II, open-label, single-center, non-randomized study was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with AGC. The study drug regimen was ceralasertib (240 mg two times a day) days 15-28 in a 28-day cycle in combination with durvalumab (1500 mg) at day 1 every 4 weeks. The primary end point was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (V.1.1). Exploratory biomarker analysis was performed using fresh tumor biopsies in all enrolled patients. RESULTS: Among 31 patients, the ORR, disease control rate, median progression-free survival (PFS), and overall survival were 22.6% (95% CI 9.6% to 41.1%), 58.1% (95% CI 39.1% to 75.5%), 3.0 (95% CI 2.1 to 3.9) months, and 6.7 (95% CI 3.8 to 9.6) months, respectively. Common adverse events were manageable with dose modification. A subgroup of patients with a loss of ataxia telangiectasia mutated (ATM) expression and/or high proportion of mutational signature attributable to homologous repair deficiency (sig. HRD) demonstrated a significantly longer PFS than those with intact ATM and low sig. HRD (5.60 vs 1.65 months; HR 0.13, 95% CI 0.045 to 0.39; long-rank p<0.001). During the study treatment, upregulation of the innate immune response by cytosolic DNA, activation of intratumoral lymphocytes, and expansion of circulating tumor-reactive CD8 +T cell clones were identified in responders. Enrichment of the tumor vasculature signature was associated with treatment resistance. CONCLUSIONS: Ceralasertib plus durvalumab has promising antitumor activity, with durable responses in patients with refractory AGC. Thus, a biomarker-driven trial is required. TRIAL REGISTRATION: NCT03780608.
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Inhibidores de Proteínas Quinasas , Neoplasias Gástricas , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/genética , Humanos , Indoles/administración & dosificación , Indoles/uso terapéutico , Morfolinas/administración & dosificación , Morfolinas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfóxidos/administración & dosificación , Sulfóxidos/uso terapéuticoRESUMEN
PURPOSE: Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS: Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS: Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION: We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.
RESUMEN
BACKGROUND: A high percentage of small cell lung cancer (SCLC) cases harbor cell cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study. METHODS: The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co-alterations were allocated to adavosertib (SUKSES protocol C [SUKSES-C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES-D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non-biomarker-selected arm: adavosertib (SUKSES-N1; 21 patients) or AZD2811NP (SUKSES-N3; 15 patients). RESULTS: Patients in the SUKSES-C and SUKSES-N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES-C and 6 patients in SUKSES-N1. The median progression-free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES-C and 1.2 months (95% CI, 1.1-1.4 months) for SUKSES-N1. Patients in the SUKSES-D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES-N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9-1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES-C and SUKSES-N1 arms and 50.0% in the SUKSES-D arm. Target-related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule. CONCLUSIONS: To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/genética , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Benzamidas/administración & dosificación , Biomarcadores de Tumor/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Amplificación de Genes/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Morfolinas/administración & dosificación , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Platino (Metal)/efectos adversos , Supervivencia sin Progresión , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Pirimidinonas/administración & dosificación , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patologíaRESUMEN
The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RICTOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. SIGNIFICANCE: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility.This article is highlighted in the In This Issue feature, p. 1325.
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Biomarcadores de Tumor , Genómica , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , ADN Tumoral Circulante , Toma de Decisiones Clínicas , Biología Computacional/métodos , Manejo de la Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genómica/métodos , Humanos , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Resultado del TratamientoRESUMEN
MET amplification is a frequently observed genomic aberration in solid tumors. We conducted a phase I trial to evaluate dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) for the combination therapy. The following dose levels were tested in this single-arm phase I study: docetaxel as an intravenous infusion over 1â¯hour at 60â¯mg/m2 once every 3â¯weeks of a 21-day schedule plus savolitinib (level 1, 200â¯mg qd; level 2, 400â¯mg qd; level 3, 600â¯mg qd; level 4800â¯mg qd). In total, there were 17 patients enrolled on to this study [7 gastric cancer (GC) patients, 5 melanoma patients, 3 sarcoma patients, and 2 rectal cancer patients]. Most of the patients (14 of 17) were heavily pretreated (≥third line or greater lines of treatment). For the first 3 cohorts (200â¯mg savolitinib + docetaxel 60â¯mg/m2, 400â¯mg savolitinib + docetaxel 60 mg/m2, 600â¯mg savolitinib + docetaxel 60â¯mg/m2), there were no DLTs. In the fourth dose cohort (800â¯mg savolitinib + docetaxel 60â¯mg/m2), one DLT occurred with generalized edema grade 3 that required intensive management. One GC patient with both MET overexpression (3+) and MET amplification (MET/CEP7 ratio, 7.3) achieved a durable partial response for 297â¯days, and another MET-amplified GC patient (MET/CEP7 ratio, 7.6) achieved stable disease for 86â¯days. Due to the higher incidence of G4 neutropenia in cohort 4 (800 mg), we recommend savolitinib 600â¯mg qd in combination with docetaxel 60â¯mg/m2 as the RP2D for phase II trial. The combination therapy demonstrated a very promising antitumor activity with durable responses in MET amplified GC patients.