ABSTRACT
PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.
Subject(s)
Antibodies, Monoclonal, Humanized , Bridged-Ring Compounds , Piperazines , Pyrimidines , Triple Negative Breast Neoplasms , Humans , Albumins , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/metabolism , Paclitaxel , Proto-Oncogene Proteins c-akt , Taxoids/therapeutic use , Triple Negative Breast Neoplasms/pathology , Randomized Controlled Trials as TopicABSTRACT
Patients with early-stage non-small-cell lung cancer (NSCLC) are candidates for curative surgery; however, despite multiple advances in lung cancer management, recurrence rates remain high. Adjuvant chemotherapy has been demonstrated to significantly prolong overall survival (OS), but this benefit is modest and there is an urgent need for effective new therapies to provide a cure for more patients. The high efficacy of tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor-mutated (EGFR) in patients with advanced EGFR-mutated NSCLC has led to the evaluation of these agents in early stages of the disease. Multiple clinical trials have evaluated the safety and efficacy of EGFR TKIs as an adjuvant treatment, in patients with resected EGFR-mutated NSCLC, and shown that they significantly prolong disease-free survival (DFS), but this benefit does not translate to OS. Recently, an interim analysis of the ADAURA trial demonstrated that, surprisingly, osimertinib improved DFS. This led to the study being stopped early, leaving many unanswered questions about its potential effect on OS and its incorporation as a standard adjuvant treatment in this patient subgroup. These targeted agents are also being evaluated in locally-advanced disease, with promising results, although prospective studies with larger sample sizes are needed to confirm these results. In this article, we review the most relevant studies on the role of EGFR TKIs in the management of early-stage EGFR-mutated NSCLC.
ABSTRACT
BACKGROUND: Colorectal cancer (CRC) is one of the most frequent and deadly malignancies worldwide. This specific pathology is composed of various molecular entities, with distinct immunological phenotypes. In addition to KRAS, NRAS, and BRAF mutation status, other druggable alterations such as those in HER2, MET, NTRK, ALK, and ROS1 have been identified in recent years offering new therapeutic options for some patients with CRC. AIM: This review will focus on the molecular biology, immunological fingerprints, and current clinical evidence for the use of immunotherapy in patients with CRC. RELEVANCE FOR PATIENTS: High microsatellite instability (MSI-H) and mutations in mismatch repair genes constitute a new molecular entity within CRC, which is characterized by a high mutational and neoantigen burden, frequent immune cell infiltration, and where immune checkpoint inhibitors have shown high response and survival rates compared to microsatellite stable (MSS) tumors. Indeed, the approval of pembrolizumab in MSI-H tumors was the first agnostic FDA approval in solid tumors. While monotherapy with anti-programmed cell death protein-1 agents achieves objective response rates (ORR) of around 30% and 1-year overall survival (OS) rates of 76%, anti-PD1, and anti-CTLA4 combinations achieve a 55% ORR and a 1-year OS rate of 85%. Several ongoing trials are evaluating the use of different immunotherapy combinations, both in the advanced and early settings and in MSI-h and MSS CRCs.
ABSTRACT
BACKGROUND: Colorectal cancer is one of the most frequent neoplasms worldwide, and the majority of patients are diagnosed in advanced stages. Metastatic colorectal cancer (mCRC) harbors several mutations with different prognostic and predictive values; KRAS, NRAS, and BRAF mutations are the best known. Indeed, RAS and BRAF molecular status are associated with a different response to monoclonal antibodies (Anti-epidermal growth factor receptor and anti-vascular endothelial growth factor receptor agents), which are usually added to chemotherapy in first-line, and thus allow to select the optimal therapy for patients with mCRC. Furthermore, sidedness is an important predictive and prognostic factor in mCRC, which is explained by the different molecular profile of left and right-sided tumors. Recently, microsatellite instability-high has emerged as a predictive factor of response and survival from immune checkpoint inhibitors in mCRC. Finally, several other alterations have been described in lower frequencies, such as human epidermal growth factor receptor-2 overexpression/amplification, PIK3CA pathway alterations, phosphatase and tension homolog loss, and hepatocyte growth factor/mesenchymal-epithelial transition factor pathway dysregulation, with several targeted therapies already demonstrating activity or being tested in currently ongoing clinical trials. AIM: To review the importance of studying the predictive and prognostic roles of the molecular profile of mCRC, the changes occurred in recent years and how they would potentially change in the near future, to guide physicians in treatment decisions. RELEVANCE FOR PATIENTS: Today, several different therapeutic options can be offered to patients in the first-line setting of mCRC. Therapies at present approved or under investigation in clinical trials will be thoroughly reviewed, with special emphasis on the molecular rationale behind them. Understanding the molecular status, resistance mechanisms and potential new druggable targets may allow physicians to choose the best therapeutic option in the first-line mCRC.
ABSTRACT
OBJETIVO: Determinar los factores demográficos, clínicos, histopatológicos y administrativos asociados a la respuesta patológica de la quimiorradiación neoadyuvante en cáncer de recto. MATERIALES Y METODOS: Se realizó un estudio descriptivo de corte longitudinal en 42 pacientes con diagnóstico de cáncer de recto en estadios II y III, operados entre enero del 2007 y diciembre del 2012 después de recibir un tratamiento neoadyuvante con quimiorradiación en el Hospital Nacional Guillermo Almenara Irigoyen. Se recogieron de las historias clínicas los datos demográficos, clínicos, histopatológicos y administrativos asociados a la respuesta patológica del tratamiento. Se realizó una evaluación descriptiva y analítica asociando las variables estudiadas mediante el programa SPSS versión 18.0. RESULTADOS: La edad media de los pacientes fue de 59 años, con un rango entre 34 y 78 años. El 82.1 por ciento de los pacientes fueron mayores de 45 años y el 59.5 por ciento de los casos varones. La histología más importante fue el adenocarcinoma (85.7 por ciento), la mayoría fueron bien o moderadamente diferenciados (76.2 por ciento) y las localizaciones más frecuentes fueron el recto medio y bajo con 33.3 por ciento y 45.2 por ciento, respectivamente. Todos los pacientes del estudio fueron estadio II (33.3 por ciento) o III (66.7 por ciento). El 66.7 por ciento de los pacientes iniciaron el tratamiento neoadyuvante de forma tardía (5 a más semanas después del diagnóstico). Así mismo, el 52.4 por ciento de los pacientes demoraron más de 40 días en completar el tratamiento de quimiorradiación. La dosis total de RT neoadyuvante fue 50,4 Gy en todos los casos. El 5FU fue la quimioterapia más empleada con 95,2 por ciento de casos. El 73,8 por ciento de los pacientes fueron sometidos a una resección anterior baja, 19,0 por ciento a resección laparoscópica y 7,1 por ciento a resección abdominoperineal. Se observó que de 11 pacientes con tumores bajos y estadio clínico III, todos...
OBJECTIVE: Determine the demographic, clinical, histopathological and administrative factors associated to a pathologic response in neoadjuvant chemoradiation for rectal cancer. MATERIALS AND METHODS: We conducted a descriptive study of longitudinal cross sections in 42 patients diagnosed with stages Il and IU rectal cancer, operated between January 2007 and December 2012, after receiving neoadjuvant chemoradiation treatment at the National Hospital Guillermo Almenara Irigoyen. From these clinical histories, were collected the clinical, histopathological and administrative data associated with pathological response to treatment. We conducted a descriptive and analytical evaluation associating the studied variables using the program SPSS version 18.0. RESULTS: The mean age of patients was 59 years, ranging between 34 and 78 years 88.1 per cent of patients were older than 45 years and 59.5 per cent patients were male. The most important histology was adenocarcinoma (85.7 per cent), most were well or moderately differentiated (76.2 per cent) and the most common locations were the part middle and lower of the rectum with 33.3 per cent and 45.2 per cent, respectively. All study patients were stage Il (33.3 per cent) or stage In (66.7 per cent), 66.7 per cent of patients started the neoadjuvant treatment late (5 or more weeks after diagnosis). Similarly, 52.4 per cent of the patients took more than 40 days to complete chemoradiation treatment. The total dose of neoadjuvant RT was 50.4 Gy in all cases. The most used chemotherapy was 5FU with 95.2 per cent of cases. 73.8 per cent of patients underwent a low anterior resection, 19.0 per cent a laparoscopic resection and 7.1 per cent an abdominoperineal resection. It was observed that of 11 patients with low tumor and at clinical stage III, all potential candidates for abdominoperineal resection, 9 (81.8 per cent) underwent anal sphincter preservation surgery and 2 (18.2 per cent) to abdominoperineal...
