RESUMEN
PURPOSE: The purpose of this study was to evaluate clinical outcomes of standard therapies in previously treated, advanced colorectal cancer (CRC) patients. METHODS: A systematic literature review was conducted in Embase, MEDLINE, and CENTRAL databases (January 2000-July 2021), annual oncology conferences (2019-2021), and clinicaltrials.gov to identify studies evaluating the use of licensed interventions in second-line or later settings. The primary outcome of interest was objective response rate (ORR) and secondary outcomes included progression-free survival (PFS) and overall survival (OS). ORR was pooled using the Freeman-Tukey double arcsine transformation. For survival outcomes, published Kaplan-Meier curves for OS and PFS were digitized to re-construct individual patient-level data and pooled following the methodology described by Combescure et al. (2014). RESULTS: Twenty-three trials evaluating standard chemotherapies with or without targeted therapies across 4,791 advanced CRC patients contributed to our meta-analysis. In the second-line setting, the random effects pooled estimate of ORR was 22.4% (95% confidence interval (CI): 18.0, 27.1), median PFS was 7.0 months (95% CI: 6.4, 7.4), and median OS was 14.9 months (95% CI: 13.6, 16.1). In the third-line or later setting, the random effects pooled estimate of ORR was 1.7% (95% CI: 0.8, 2.7), median PFS was 2.3 months (95% CI: 2.0, 2.8), and median OS was 8.2 months (95% CI: 7.1, 9.1). CONCLUSION: Standard treatments have limited efficacy in the second-line or later setting with worsening outcomes in later lines. Given the global burden of CRC, further research into novel and emerging therapeutic options following treatment failure is needed.
Asunto(s)
Neoplasias Colorrectales , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
Robust clinical activity has been observed with the immune checkpoint inhibitor pembrolizumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). However, given the response rate of 45% and a median progression-free survival of 16.5 months with first-line pembrolizumab demonstrated in KEYNOTE-177, there is room for improvement. Targeting a second immune receptor, such as CTLA-4, LAG-3, TIGIT, or ILT-4 may improve efficacy of PD-1 inhibition. Here we describe the design and rationale for the open-label, randomized, phase II KEYSTEP-008 trial, which will evaluate the efficacy and safety of pembrolizumab-based combination therapy compared with pembrolizumab monotherapy in chemotherapy-refractory (cohort A) or previously untreated (cohort B) MSI-H/dMMR mCRC. Clinical Trial Registration: NCT04895722 (ClinicalTrials.gov).
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias del Colon/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ensayos Clínicos Fase II como AsuntoRESUMEN
Given that there are currently no clear recommendations regarding therapeutic options for rituximab refractory/relapsed follicular lymphoma patients, this study aimed to describe the real-life management of patients with refractory follicular lymphoma after systemic rituximab-containing regimens (rFL), and rFL patient characteristics. In this retrospective, national, multicentre study, descriptive analyses were mainly performed according to rituximab-containing regimen at rFL diagnosis [rituximab monotherapy (R-MONO), rituximab + chemotherapy (R-COMBO), and ongoing rituximab maintenance (R-MAINTAIN)]. The 459 analysed patients experienced rituximab-refractoriness between October 2013 and September 2015: R-MONO: 58 (13%), R-COMBO: 197 (43%), R-MAINTAIN: 204 (44%). Post-refractoriness strategies were heterogeneous: idelalisib ± rituximab (22%), without anti-lymphoma treatment (21%), rituximab-chemotherapy (21%) and stem cell transplantation (18%). Rituximab was continued in combination in 41% of cases. Chosen strategies varied according to patient age (without anti-lymphoma treatment: 28% of patients if ≥65 years vs. 12% if <65 years old; stem-cell transplantation: 4% vs. 38%), treatment line at rFL, FL International Prognostic Index score and prior treatment. This French retrospective study, the first one conducted in a large cohort of rFL patients, showed that further strategies were highly heterogeneous, depending notably on patient characteristics and previous treatment. These data are the basis for a better understanding of rFL management and for the design of clinical trials in these patients.
Asunto(s)
Linfoma Folicular/terapia , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Toma de Decisiones Clínicas , Terapia Combinada , Comorbilidad , Manejo de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Retratamiento , Estudios Retrospectivos , Rituximab/administración & dosificación , Rituximab/efectos adversos , Rituximab/uso terapéuticoRESUMEN
BACKGROUND: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. RESULTS: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (nâ¯=â¯5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (nâ¯=â¯7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. CONCLUSION: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. GOV IDENTIFIER: ClinicalTrials.gov; NCT03374254.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Neoplasias Colorrectales , Fluorouracilo , Leucovorina , Compuestos Organoplatinos , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Anciano , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Camptotecina/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Adulto , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/uso terapéutico , Inestabilidad de Microsatélites/efectos de los fármacos , Reparación de la Incompatibilidad de ADN , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Oxaliplatino/administración & dosificación , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Neoplasias Colorrectales , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Femenino , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anciano , Adulto , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Oxaliplatino/administración & dosificación , Reparación de la Incompatibilidad de ADN , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Leucovorina/efectos adversos , Inestabilidad de Microsatélites , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented. METHODS: Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200â¯mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%-46.0%) in cohort A and 34.9% (95% CI, 23.3%-48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1-8.1) in cohort A and 4.1 months (95% CI, 2.1-18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4-58.0) in cohort A and 47.0 months (95% CI, 19.2-NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response. CONCLUSIONS: Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC. CLINICAL TRIAL REGISTRY INFORMATION: ClinicalTrials.gov, NCT02460198.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Inestabilidad de Microsatélites , Reparación de la Incompatibilidad de ADN , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genéticaRESUMEN
This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years [35-89], first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Rituximab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Francia/epidemiología , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Masculino , Persona de Mediana Edad , Recurrencia , Retratamiento , Rituximab/administración & dosificación , Rituximab/efectos adversos , Resultado del TratamientoRESUMEN
Diurnal temporal variations of emotional reactivity were investigated in relationship with fluctuations of psychophysiological state, evaluated by tonic autonomic activity. Neutral and unpleasant pictures, selected to constitute seven matched sets, were evaluated by 12 participants during seven sessions in the course of daytime. Skin conductance level (SCL) was recorded at the beginning of each session, whereas skin conductance responses (SCRs), affective evaluation and emotional experience were measured during or after each session. Data show significant temporal variations for SCL, SCRs and emotional experience which follow similar patterns during the daytime. Discussion highlights the role of temporal patterns of autonomic activity as an interesting basis to better understand the emotional regulation and affective disorders.