RESUMEN
Antibody-drug conjugates (ADCs) are a fast-growing class of cancer drugs designed to selectively deliver cytotoxic payloads through antibody binding to cancer cells with high expression of the target antigen, thus reducing systemic exposure and minimizing off-target effects. However, ADCs are associated with various ocular adverse events (AEs) that may impact treatment administration and patient outcomes. In this review, we provide a summary of ocular AEs associated with approved and investigational ADCs, recommendations for the mitigation and management of ocular AEs, current guidelines and expert opinions, and recommendations for clinical practice. A literature search was performed, using PubMed and Google Scholar, for English-language articles published between January 1985 and January 2023 to identify studies reporting ocular AEs associated with ADC use. Search terms included generic and investigational names of all identified ADCs, and further searches were performed to identify strategies for managing ADC-associated ocular AEs. ADC-associated ocular AEs include symptoms such as blurred vision and foreign-body sensation and signs such as corneal fluorescein staining, corneal pseudomicrocysts, and conjunctivitis. Reported management strategies include ADC dose modification (eg, dose delay or reduction), cool compresses, artificial tears, topical vasoconstrictors, and topical steroids. Although ADC dose modification appears to be beneficial, the preventive and/or therapeutic benefits of the remaining interventions are unclear. Although the exact mechanisms are not fully understood, most ADC-associated ocular AEs are reversible with dose delay or dose reduction. Management of ocular AEs requires a multidisciplinary approach to minimize treatment discontinuation and optimize clinical outcomes.
RESUMEN
BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Biomarcadores/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Piperazinas/efectos adversos , Supervivencia sin Progresión , Piridinas/efectos adversos , Pirimidinas/efectos adversosRESUMEN
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Piperazinas , Piridinas , Pirimidinas , Adulto , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Lenguaje , MutaciónRESUMEN
BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Piperazinas/administración & dosificación , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas/efectos adversos , Piridinas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinéticaRESUMEN
BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hipertensión/inducido químicamente , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Mutación , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-ret/análisis , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/efectos adversos , Piridinas/efectos adversos , Transaminasas/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors may synergize with programmed cell death receptor-1 (PD-1) inhibitors to enhance adaptive and innate antitumor immune responses. In the phase 2 JASPER study (NCT04475939), the PARP inhibitor niraparib was evaluated in combination with the PD-1 inhibitor pembrolizumab in patients with metastatic and/or locally advanced non-small cell lung cancer (NSCLC). METHODS: Patients whose tumors had programmed cell death ligand 1 (PD-L1) tumor proportion scores (TPS) ≥50% (cohort 1) or 1%-49% (cohort 2) received first-line niraparib (200 mg once daily) plus pembrolizumab (200 mg every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. RESULTS: Thirty-eight patients were enrolled in cohorts 1 and 2. In cohort 1, ORR (95% confidence interval [CI]) was 56.3% (9 of 16 patients; 29.9%-80.2%); 2 of 16 patients had complete responses and 7 of 16 had partial responses (PRs). In cohort 2, ORR was 20.0% (5.7%-43.7%) with 4 of 20 PRs. In cohorts 1 and 2, the median DoR was 19.7 months (95% CI, 4.2 months to not estimable [NE]) and 9.4 months (95% CI, 4.2 months to NE), the median PFS was 8.4 months (95% CI, 3.9-22.1 months) and 4.2 months (95% CI, 2.0-6.2 months), and the median OS was NE (95% CI, 6.0 months to NE) and 7.7 months (95% CI, 4.0-12.5 months), respectively. Grade ≥3 treatment-emergent adverse events occurred in 88.2% and 85.7% of patients in cohorts 1 and 2, respectively. Safety was consistent with known profiles of single-agent niraparib and pembrolizumab. CONCLUSIONS: Niraparib plus pembrolizumab showed clinical activity in patients with advanced and/or metastatic NSCLC. LAY SUMMARY: The JASPER clinical trial studied a new combination treatment for advanced or metastatic non-small cell lung cancer (NSCLC). Pembrolizumab, a drug approved for NSCLC, was given with niraparib. Previous research showed that these 2 drugs together might work better than either drug alone. This study found that more than half of patients with high levels of a tumor marker responded to the combination, and one-fifth of patients with lower levels of the marker responded. The types of side effects from the combination were similar to side effects from both drugs alone. These results support more research on this combination.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Indazoles , Neoplasias Pulmonares , Piperidinas , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Indazoles/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Piperidinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversosRESUMEN
Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional "3 + 3" design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial.
Asunto(s)
Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Everolimus/administración & dosificación , Neoplasias/tratamiento farmacológico , Ftalazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Everolimus/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ftalazinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Answer questions and earn CME/CNE Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Enfermedades de la Médula Ósea/inducido químicamente , Caquexia/inducido químicamente , Diarrea/inducido químicamente , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/terapia , Enfermedades del Sistema Endocrino/inducido químicamente , Exantema/inducido químicamente , Cardiopatías/inducido químicamente , Hemorragia/inducido químicamente , Humanos , Hiperbilirrubinemia/inducido químicamente , Hiperlipidemias/inducido químicamente , Enfermedades del Sistema Inmune/inducido químicamente , Enfermedades Pulmonares Intersticiales/inducido químicamente , Magnesio/sangre , Trastornos del Humor/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Derrame Pleural/inducido químicamente , Trombocitopenia/inducido químicamente , Tromboembolia Venosa/inducido químicamente , Trastornos de la Visión/inducido químicamenteRESUMEN
BACKGROUND: Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations. METHODS: NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients' medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated. RESULTS: Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively). CONCLUSIONS: We found an appropriate "dose-response" relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance.
Asunto(s)
Antineoplásicos/uso terapéutico , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pruebas de Farmacogenómica/normas , Medicina de Precisión/normas , United States Food and Drug Administration/normas , Perfil Genético , Humanos , Estudios Retrospectivos , Estados UnidosRESUMEN
BACKGROUND: Mediastinoscopy is considered the gold standard for preresectional staging of lung cancer. We sought to examine the effect of concomitant mediastinoscopy on postoperative pneumonia (POP) in patients undergoing lobectomy. METHODS: All patients in our institutional database (2008-2015) undergoing lobectomy who did not receive neoadjuvant therapy were included in our study. The relationship between mediastinoscopy and POP was examined using univariate (Chi square) and multivariate analyses (binary logistic regression). In order to validate our institutional findings, lobectomy data in the National Surgical Quality Improvement Program (NSQIP) from 2005 to 2014 were analyzed for these associations. RESULTS: Of 810 patients who underwent a lobectomy at our institution, 741 (91.5%) surgeries were performed by video-assisted thoracic surgery (VATS) and 487 (60.1%) patients underwent concomitant mediastinoscopy. Univariate analysis demonstrated an association between mediastinoscopy and POP in patients undergoing VATS [odds ratio (OR) 1.80; p = 0.003], but not open lobectomy. Multivariate analysis retained mediastinoscopy as a variable, although the relationship showed only a trend (OR 1.64; p = 0.1). In the NSQIP cohort (N = 12,562), concomitant mediastinoscopy was performed in 9.0% of patients, with 44.5% of all the lobectomies performed by VATS. Mediastinoscopy was associated with POP in patients having both open (OR1.69; p < 0.001) and VATS lobectomy (OR 1.72; p = 0.002). This effect remained in multivariate analysis in both the open and VATS lobectomy groups (OR 1.46, p = 0.003; and 1.53, p = 0.02, respectively). CONCLUSIONS: Mediastinoscopy may be associated with an increased risk of POP after pulmonary lobectomy. This observation should be examined in other datasets as it potentially impacts preresectional staging algorithms for patients with lung cancer.
Asunto(s)
Mediastinoscopía/efectos adversos , Neumonectomía/efectos adversos , Neumonía/etiología , Complicaciones Posoperatorias/etiología , Cirugía Torácica Asistida por Video/efectos adversos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumonectomía/métodos , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). METHODS: Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. RESULTS: Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). CONCLUSIONS: Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Transducción de Señal/genética , Sulfóxidos/administración & dosificación , Sulfóxidos/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/farmacocinética , Diarrea/inducido químicamente , Fatiga/inducido químicamente , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/genética , Neoplasias Ováricas/tratamiento farmacológico , Antígeno Nuclear de Célula en Proliferación/genética , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Vómitos/inducido químicamenteRESUMEN
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned.
Asunto(s)
Antineoplásicos , Neoplasias del Colon/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas , Piridonas , Pirimidinonas , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias de la Úvea/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias del Colon/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/sangre , Femenino , Humanos , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Masculino , Dosis Máxima Tolerada , Melanoma/metabolismo , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/efectos adversos , Piridonas/farmacocinética , Piridonas/farmacología , Piridonas/uso terapéutico , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Neoplasias Cutáneas/metabolismo , Resultado del Tratamiento , Neoplasias de la Úvea/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Focal adhesion kinase (FAK) is overexpressed in many types of tumours, including lung cancer. Y15, a small molecule which inhibits Y397 FAK autophosphorylation, decreases growth of human neuroblastoma, breast and pancreatic cancers. In this study, we investigated the in vitro and in vivo effects of Y15, and the underlying mechanism on non-small cell lung cancer cells. METHODS: The cytotoxic effects of Y15 targeting FAK signalling were evaluated. Gene-knockdown experiments were performed to determine the anti-cancer mechanism. Xenografts with RAS or EGFR mutations were selected for in vivo Y15 treatment. RESULTS: Y15 blocked autophosphorylation of FAK in a time- and dose-dependent manner. It caused dose-dependent decrease of lung cancer cell viability and clonogenicity. Y15 inhibited tumour growth of RAS-mutant (A549 with KRAS mutation and H1299 with NRAS mutation), as well as epidermal growth factor receptor (EGFR) mutant (H1650 and H1975) lung cancer xenografts. JNK activation is a mechanism underlying Y15-induced Bcl-2 and Mcl-1 downregulation. Moreover, knockdown of Bcl-2 or Bcl-xL potentiated the effects of Y15. The combination of various inhibitors of the Bcl-2 family of proteins with FAK inhibitors demonstrated synergy in multiple lung cancer cell lines in vitro. CONCLUSIONS: FAK inhibition demonstrated efficacy both in vitro and in vivo in lung cancers with either oncogenic RAS or EGFR mutations. In addition, FAK inhibition in combination with inhibitors of Bcl-2 family of anti-apoptotic proteins has synergistic activity in these MAPK-activated non-small cell lung cancer cell line models.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/enzimología , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Neoplasias Pulmonares/enzimología , Sistema de Señalización de MAP Quinasas , Inhibidores de Proteínas Quinasas/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Xenoinjertos , Humanos , Neoplasias Pulmonares/patología , Ratones SCID , FosforilaciónRESUMEN
BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Comorbilidad , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Europa (Continente) , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Nivolumab , Receptor de Muerte Celular Programada 1/metabolismo , Factores de Riesgo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
Background This Phase 1b study aimed to determine the recommended Phase 2 dose of LY2334737, an oral pro-drug of gemcitabine, in combination with capecitabine, an oral pro-drug of 5-fluorouracil, in patients with advanced solid tumors. In addition, pharmacokinetics (PK) and tumor response were evaluated. Patients and methods Patients with advanced/metastatic solid tumors received 650 mg/m(2) capecitabine twice daily (BID) and escalating doses of LY2334737 once daily (QD; initial dose 10 mg/day), both for 14 days followed by 7-day drug holiday. Cycles were repeated until progressive disease (PD) or unacceptable toxicity. Results Fifteen patients received a median of 2 (range 1-7) treatment cycles; 14 patients discontinued due to PD, 1 due to toxicity (pyrexia). LY2334737 doses up to 40 mg/day were explored. Three dose-limiting toxicities were reported by 2 patients (fatigue, diarrhea, hyponatremia; all Grade 3). Seven patients achieved stable disease. Enrollment was stopped after unexpected hepatic toxicities were observed with LY2334737 QD in a study of Japanese patients. PK parameters for LY2334737 were consistent with the first-in-human study of LY2334737; PK data after 14 day combination treatment revealed no drug-drug interactions between LY2334737 and capecitabine. Conclusions No drug interactions or unexpected toxicities were observed in US patients when LY2334737 at doses up to 40 mg/day was administered QD in combination with capecitabine BID; the maximum tolerated dose was not reached.
Asunto(s)
Antineoplásicos/farmacocinética , Desoxiuridina/análogos & derivados , Neoplasias/tratamiento farmacológico , Profármacos/farmacocinética , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina/uso terapéutico , Desoxiuridina/administración & dosificación , Desoxiuridina/efectos adversos , Desoxiuridina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Profármacos/administración & dosificación , Profármacos/efectos adversosRESUMEN
Based on preclinical data demonstrating cytotoxic synergy between sorafenib and entinostat, a phase I study of this combination was conducted in patients with advanced solid tumors. Enrollment followed the traditional "3 + 3" dose escalation scheme. Entinostat was given orally once every 2 weeks, starting at a dose of 4 mg and escalating to 6 and 10 mg every 2 weeks. Sorafenib was administered as a continuous oral dose, escalating from 200 to 400 mg twice daily. A treatment cycle was 28 days. A total of 31 patients with advanced solid tumors were enrolled on the study. The three dose-limiting toxicities (DLTs) observed were grade 3 hand-foot syndrome, nausea/vomiting, and fatigue. MTD was not reached. The recommended phase II dose was defined as the full dose of the respective drugs administered individually. The most common grade 3-4 toxicities were muscle weakness (13 %), skin rash (10 %), fatigue (6 %), diarrhea (6 %), and hand-foot syndrome (3 %). One NSCLC patient achieved a partial response. Two patients (adenocarcinoma of GE junction and Hurthle cell carcinoma of the thyroid) were on the study for more than 9 months with stable disease. The combination of entinostat and sorafenib was well tolerated. Entinostat 10 mg orally once every 2 weeks in combination with sorafenib 400 mg orally twice daily, representing full single agent doses of each drug was identified as the recommended phase 2 dose (RP2D). These data support future clinical development of the combination of entinostat and sorafenib.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/farmacología , Línea Celular Tumoral , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacología , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacología , Sorafenib , Resultado del TratamientoRESUMEN
PURPOSE: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS: A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS: Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS: The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Citocromo P-450 CYP2C19/genética , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/metabolismo , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Niacinamida/farmacología , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Polimorfismo Genético , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirrolidinonas/administración & dosificación , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacología , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Quinolinas/farmacología , Sorafenib , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Complementary and alternative medicine (CAM) use has been increasing among cancer patients. This study characterizes the use of CAM among patients with thoracic malignancies. METHODS: This cross sectional study was conducted at a National Cancer Institute-designated comprehensive cancer center among adult patients diagnosed with thoracic malignancies. The primary outcome was a self-reported use of CAM, defined as the use of any type of CAM beyond routine vitamin/mineral supplementation alone. A logistic regression model was developed to explore predictors of CAM use. RESULTS: A total of 108 patients completed a standardized survey (59% response rate). Overall, 42% of respondents reported the use of at least one type of CAM. Users and non-users of CAM did not differ based upon demographics, diagnosis, staging, smoking status, quality of life, or perceived understanding of cancer diagnosis. In the multivariate analysis, patients who reported feeling fearful about their future were four times more likely to be CAM users when compared to those who did not specify this emotion (odds ratio=4.18; 95% CI=1.23-14.12; p=0.02). Commonly cited reasons for CAM use were to support one's self, boost immunity, and for improvements in emotional and/or spiritual well-being. CONCLUSIONS: Prevalence of CAM use among cancer patients in this study was similar to the general US population. Feeling fearful about the future was associated with CAM use. Results suggest that patients may be turning to CAM as a therapeutic adjunct to actively cope with emotional distress surrounding the cancer experience.
Asunto(s)
Terapias Complementarias/estadística & datos numéricos , Neoplasias Torácicas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Terapias Complementarias/psicología , Estudios Transversales , Recolección de Datos , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Motivación , Análisis Multivariante , Oportunidad Relativa , Autoinforme , Neoplasias Torácicas/psicología , Estados UnidosRESUMEN
Introduction: EML4-ALK is an oncogenic driver, seen in around five per cent of advanced non-small-cell lung cancer (NSCLC) patients, which can be targeted with anaplastic lymphoma kinase tyrosine kinase inhibitors with great response rates. Disease flare refers to sudden rapid disease worsening on tyrosine kinase inhibitors (TKI) discontinuation, which is associated with shorter survival and worse outcomes. Here, we review cases previously published in the literature where patients developed disease flares, and contrast this with our patients who had prolonged survival despite TKI discontinuation. Case description: We report three different patients with advanced ALK-positive NSCLC seen at our institute, who had EML4-ALK translocation variant 1 oncogenic driver on next-generation sequencing. They received treatment with several different ALK inhibitors before opting to discontinue TKI. They were able to come off TKI safely without developing disease flare and had prolonged survival. Discussion: Shorter time to progression on TKI, presence of symptoms with disease progression or central nervous system/pleural metastasis have been previously linked with development of flare, although this was not seen in our case series. Tumour response at the time of treatment discontinuation, line of therapy, overall disease burden, fusion variant and co-alteration status can affect the prognosis of these patients after ALK TKI cessation. In particular, variant 1 and wild-type TP53 status may be a suitable patient population for dose optimisation strategies. Intermittent TKI dosing strategies may help to avoid acquiring resistance mutations and prevent long-term treatment toxicities. Conclusion: It is important for clinicians to identify patients at risk for developing disease flare on TKI discontinuation to improve outcomes. Intermittent TKI dosing strategies require further investigation. LEARNING POINTS: Patients who develop disease flare after cessation have poor survival and worse outcomes.Certain phenotypic and molecular characteristics of the tumour may help clinicians identify which patients are likely and which are unlikely to develop disease flare on TKI discontinuation.Advanced ALK-positive NSCLC with variant 1 and wild-type TP53 may be a suitable patient population for intermittent TKI dosing investigations.
RESUMEN
Exosomes are nanosized extracellular vesicles released by cells to transport biomolecules such as proteins and RNAs for intercellular communication. Exosomes play important roles in cancer development and metastasis; therefore, they have emerged as potential liquid biopsy biomarkers for cancer screening, diagnosis, and management. Many exosome cargos, including proteins, RNAs, and lipids, have been extensively investigated as biomarkers for cancer liquid biopsy. However, carbohydrates, an important type of biomolecule, have not yet been explored for this purpose. In this study, we reported a new exosomal carbohydrate biomarker, α-linked Thomsen-Friedenreich glycoantigen (TF-Ag-α; Galß1-3GalNAc-α). To translate our discovery into clinical settings, we developed a surface plasmon resonance-based assay which utilized a unique mAb, JAA-F11, with high specificity to measure the levels of exosomal TF-Ag-α in blood. To the best of our knowledge, we are the first to demonstrate that exosomes carry TF-Ag-α. We detected exosomal TF-Ag-α in as low as 10 µL serum samples from patients with cancer, but in contrast, levels were negligible in those from normal controls. With a total of 233 patients with cancer and normal controls, we showed that exosomal TF-Ag-α detected lung cancer (n = 60) and breast cancer (n = 95) from normal controls (n = 78) with ≥95% and ≥97% accuracy, respectively. These results demonstrated that exosomal TF-Ag-α is a potential liquid biopsy biomarker for cancer diagnosis. SIGNIFICANCE: Exosomes or small extracellular vesicles have emerged as potent biomarkers of cancer liquid biopsy. We discovered a new exosomal carbohydrate marker, TF-Ag-α (Galß1-3GalNAc-α), and showed that exosomal TF-Ag-α detected both lung and breast cancers with >95% accuracy. Our findings demonstrated that exosomal TF-Ag-α is a promising liquid biopsy biomarker for cancer screening and early detection.