Time-dependent efficacy of checkpoint inhibitor nivolumab : results from a pilot study in patients with metastatic non-small-cell lung cancer

Hypothesis: Prior experimental and human studies have demonstrated the circadian organization of immune cells’ proliferation, trafficking, and antigen recognition and destruction. Nivolumab targets T(CD8) cells, the functions, and trafficking of which are regulated by circadian clocks, hence suggesting possible daily changes in nivolumab’s efficacy. Worse progression-free survival (PFS), and overall survival (OS) were reported for malignant melanoma patients receiving more than 20% of their immune checkpoint inhibitor infusions after 16:30 as compared to earlier in the day. Methods: Consecutive metastatic non-small-cell cancer (NSCLC) patients received nivolumab (240 mg iv q 2 weeks) at a daily time that was ‘randomly’ allocated for each course on a logistical basis by the day-hospital coordinators. The median time of all nivolumab administrations was computed for each patient. The study population was split into two timing groups based upon the median value of the median treatment times of all patients. CTCAE-toxicity rates, iRECIST-tumor responses, PFS and OS were computed according to nivolumab timing. PFS and OS curves were compared and hazard ratios (HR) were computed for all major categories of characteristics. Multivariable and sensitivity analyses were also performed. Results: The study accrued 95 stage-IV NSCLC patients (PS 0–1, 96%), aged 41–83 years. The majority of nivolumab administrations occurred between 9:27 and 12:54 for 48 patients (‘morning’ group) and between 12:55 and 17:14 for the other 47 (‘afternoon’ group). Median PFS (95% CL) was 11.3 months (5.5–17.1) for the ‘morning’ group and 3.1 months (1.5–4.6) for the ‘afternoon’ one (p < 0.001). Median OS was 34.2 months (15.1–53.3) and 9.6 months (4.9–14.4) for the ‘morning’ group and the ‘afternoon’ one, respectively (p < 0.001). Multivariable analyses identified ‘morning’ timing as a significant predictor of longer PFS and OS, with respective HR values of 0.26 (0.11–0.58) and 0.17 (0.08–0.37). The timing effect was consistent across all patient subgroups tested. Conclusions: Nivolumab was nearly four times as effective following ‘morning’ as compared to ‘afternoon’ dosing in this cohort of NSCLC patients. Prospective timing-studies are needed to minimize the risk of resistance and to maximize the benefits from immune checkpoint inhibitors

European Lung Cancer Working Party Clinical Practice Guidelines. Non-Small Cell Lung Cancer: III. Metastatic disease

The present guidelines on the management of advanced non-small cell lung cancer (NS CLC) were formulated by the ELCWP in October 2006. They are designed to answer the following twelve questions: 1) What benefits can be expected from chemotherapy and what are the treatment objectives? 2) What are the active chemotherapeutic drugs for which efficacy has been shown? 3) Which are the most effective platinum-based regimens? 4) Which is the indicated dosage of cisplatin? 5) Can carboplatin be substituted for cisplatin? 6) Which is the optimal number of cycles to be administered? 7) Can non-platinum based regimens be substituted for platinum based chemotherapy as first-line treatment? 8) Is there an indication for sequential chemotherapy? 9) What is the efficacy of salvage chemotherapy and which drugs should be used in that indication? 10) What is the place of targeted therapies? 11) What is the place of chemotherapy in the management of a patient with brain metastases? 12) Which specific drugs can be used for the patient with bone metastases

European Lung Cancer Working Party. Clinical Practice Guidelines. Small Cell Lung Cancer: V. Extensive disease

The present guidelines on the management of extensive disease small cell lung cancer (SCLC) were formulated by the ELCWP in October 2007. They are designed to answer the following nine questions: 1) What is the definition of extensive disease? 2)What are the active drugs? 3) What is the best induction regimen? 4) Is there a role for maintenance chemotherapy? 5) Is there a role for dose-intensive chemotherapy? 6) Is there a role for the use of haemopoietic growth factors and stem cells support? 7) Is there a role for alternating or sequential chemotherapy? 8) Is there a role for biological treatments? 9) Is there a place for second-line chemotherapy

A phase II study evaluating the cisplatin and epirubicin combination in patients with unresectable malignant pleural mesothelioma

Few chemotherapeutic agents have demonstrated their efficacy in malignant mesothelioma. The cisplatin plus doxorubicin combination has one of the highest response rates. Epirubicin is an anthracyclin, analogous to doxorubicin, with a different toxicologic pattern. As there are no data on the activity of the combination cisplatin plus epirubicin in malignant mesothelioma, the European Lung Cancer Working Party (ELCWP) designed a phase II study with response rate as primary objective. Sixty-nine eligible patients with malignant pleural mesothelioma were centrally registered. The majority of the patients were male (n = 59), had a Karnofsky performance status of 80 or more (n = 62) and presented with an epithelial histologic subtype (n = 43). Median age was 62 years. In nine patients, metastases were documented at the initial work-up, mainly in bone, lung and skin. Three hundred and twenty-four cycles of chemotherapy were administered. The main toxicities were nausea and vomiting, neutropenia and alopecia. Among 63 assessable patients, response rate was 19.0% (95% confidence interval [CI] 9-29%). Median survival was 13.3 months. In multivariate analysis, poor prognostic factors for survival were neutrophil count and CALGB groups 4-6. In conclusion, cisplatin plus epirubicin appears as an effective regimen in malignant mesothelioma, with a favourable toxicity profile. However, it does not demonstrate superior activity to other active regimens in this disease. © 2005 Elsevier Ireland Ltd. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A phase II study of cisplatin (CDDP) and epirubicin (EPI) in malignant pleural mesothelioma (MPM)

ECCO 12, Copenhagen, 21-25/09/03 A study by the European Lung Cancer Working Party (ELCWP).info:eu-repo/semantics/publishedsuppl.

Chemotherapy improves low performance status lung cancer patients

The aim of the present study was to determine the potential benefit of conventional cisplatin-based chemotherapy on patients with advanced nonsmall cell lung cancer (NSCLC) and poor performance status (PS), defined as 60-70 on the Karnofsky scale. Retrospective analysis was carried out of a randomised trial performed in advanced NSCLC where 485 patients received three courses of gemcitabine+ifosfamide+cisplatin induction chemotherapy. Of the patients, 80% had good PS (Karnofsky 80-100) and 20% poor PS. Response rates were 38 and 28%, respectively. Clinical improvement, defined as achieving a good PS during chemotherapy, was observed overall in 25% of the poor PS patients, with rates of 38, 20 and 14%, respectively, in case of response, no change and progression. PS improved more quickly in the responders. Survival of patients with poor PS was significantly worse, but survival of responders was similar, irrespective of the initial poor or good PS. Although nonfatal toxicity was almost similar, there were more toxic deaths (including vascular and cardiac fatalities) in the poor PS patients (9.2 versus 2.1%). In conclusion, combination chemotherapy is associated with clinical improvement in a substantial number of patients with advanced nonsmall cell lung cancer of poor performance status.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Prevalence, distribution and predictive value of XPO1 mutation in a real‐life chronic lymphocytic leukaemia cohort

International audienceNo abstract availabl

Prevalence, distribution and predictive value of XPO1 mutation in a real‐life chronic lymphocytic leukaemia cohort

International audienc