Laurence Bigay-Game

Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.

BACKGROUND Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. METHODS In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. FINDINGS 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]). INTERPRETATION Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. FUNDING Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Impact of Induction Treatment on Postoperative Complications in the Treatment of Non-small Cell Lung Cancer

Introduction: A main drawback of neoadjuvant chemotherapy is that it may increase operative morbidity and mortality. The aim of this study was to determine the impact of chemotherapy on these complications. Methods: Patient data were collected from the Epithor database. From June 2002 to June 2004, 3888 successive observations of surgery for lung cancer have been reported from 51 thoracic surgery departments throughout France. Logistic regression analysis was performed to identify preoperative clinical characteristics of patients with significant postoperative complications. Results: Of 3888 patients, 555 (14.3%) received induction chemotherapy. The groups were similar with respect to sex and the number of comorbidities. The in-hospital mortality rate was 3.01%. The multivariate analysis allows us to identify age (older than 65 years), sex (male), preoperative clinical score (moderate and severe), surgical procedure (right pneumonectomy and bilobectomy) as significantly associated with in-hospital mortality. No statistical difference was observed according to the delivery or preoperative chemotherapy. In total, 1219 patients (31.4%) had at least one postoperative complication. Using a multivariate analysis, we observed a significant correlation between morbidity and age (older than 65 years), sex (male), presence of comorbidities (two or more), clinical score (moderate), and type of operation (bilobectomy). Preoperative administration of chemotherapy did not significantly influenced postoperative morbidity. Conclusions: Preoperative chemotherapy is not associated with an increase in either the mortality rate or major surgical complications. Future randomized trials are warranted to confirm the survival benefit of this strategy.

Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study

Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK-positive non-small-cell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK-positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes. ALK -positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib. At time of analysis, 209 (65.7%) of the 318 included patients had died. Median OS with crizotinib was 16.6 months. The line of crizotinib therapy did not impact survival outcomes. Of the 263 patients with PD, 105 received best supportive care, 74 subsequent drugs other than next-generation ALKi and 84 next-generation ALKi. Next-generation ALKi treatment correlated with better survival outcomes in multivariate analysis. These patients had a median post-PD survival of 25.0 months and median OS from metastatic disease diagnosis of 89.6 months. Unselected ALK-positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

Second-line therapy in elderly patients with advanced nonsmall cell lung cancer

There is no dedicated study on second-line treatment for elderly patients with advanced nonsmall cell lung cancer (NSCLC). We report the results on second-line erlotinib therapy from our previously published phase III study comparing single-agent therapy with platinum-based doublet (carboplatin plus paclitaxel) therapy in 451elderly patients. Erlotinib was given to patients exhibiting disease progression or experiencing excessive toxicity during first-line therapy, until further progression or unacceptable toxicity. In total, 292 (64.7%) patients received erlotinib as second-line therapy. Initial performance status 0–1, stage IV NSCLC and an Activities of Daily Living score of 6 were independent factors for receiving erlotinib. Median (95% CI) overall survival was 4 (3.2–6.7) versus 6.8 (5.0–8.3) months in the single-agent and doublet arms, respectively (p=0.089). Performance status 0–1, never having smoked, adenocarcinoma and weight loss ≤5% were favourable independent prognostic factors of survival, whereas the randomisation arm had no significant impact. Among the 292 patients who received erlotinib, 60 (20.5%) experienced grade 3–4 toxic effects, the most frequent being rash. Erlotinib as second-line therapy is feasible, leading to efficacy results similar to those obtained in a previous randomised study that was not dedicated to elderly patients, with acceptable toxicity. Erlotinib is a feasible second-line therapy in elderly patients with advanced nonsmall cell carcinoma http://ow.ly/pz6ud

Erlotinib versus carboplatin and paclitaxel in advanced lepidic adenocarcinoma: IFCT-0504

The IFCT-0504 phase II trial evaluated the efficacy of erlotinib versus carboplatin–paclitaxel (CP) as first-line treatment in 130 cases of advanced lepidic-predominant adenocarcinoma (ADC). The primary objective of the study was treatment efficacy, evaluated based on an end-point of disease control at 16 weeks. The primary objective was met, with a disease control in 35 (53%) out of 66 patients treated with CP and in 25 (39.1%) out of 64 patients treated with erlotinib. Median progression-free survival (PFS) for the total population was 3.6 months. The disease control rate did not differ between either the therapeutic arms or pathological subtypes, whereas there was a strong interaction between treatment arms and tumour pathological subtypes for PFS (p=0.009). Mucinous tumour patients treated with erlotinib exhibited an increased progression risk (hazard ratio 3.4, 95% CI 1.7–6.5; p≤0.001). The PFS for nonmucinous tumour patients was similar in both arms. Median overall survival was 20.1 months and did not differ between therapeutic arms. These findings were not further elucidated by molecular analyses and the toxicity profiles were as expected. Our study demonstrated the dominant role of CP alongside erlotinib in the management of advanced lepidic ADC. Based on these findings, erlotinib should not be administered in first-line therapy to patients with lepidic ADC in the absence of an epidermal growth factor receptor mutation. Interaction between pathological subtypes and treatment (erlotinib/chemotherapy) in advanced lepidic adenocarcinoma http://ow.ly/QHA2q

Characteristics of Lung Cancer in Patients Younger than 40 Years: A Prospective Multicenter Analysis in France

Objectives: The aim of this study was to describe the demographic and clinico-pathological characteristics of lung cancer in patients younger than 40 years. Materials and Methods: This was a prospective study performed within the Groupe Français de Pneumo-Cancérologie. Consecutive patients diagnosed with lung cancer before the age of 40 years were eligible. Data on demographics, medical history, clinico-pathological characteristics, treatment and overall survival were analysed. Results: In total, 146 patients were included from January 2011 to December 2013. Median age was 38 years (IQR: 34–40). Women accounted for 41%. Main histological type was adenocarcinoma (77%). Only 3% had a prior history of cancer, but a family history (first- or second-degree relatives) of cancer was reported in 80 (55%) patients; 85 and 50% were current or past smokers of tobacco and cannabis, respectively; 82% had stage IIIB/IV at diagnosis. Median overall survival was 15.3 (95% CI: 8.1–24.0) months in the whole population, 10.3 (95% CI: 12.5–14.2) months in stage IV and 15 (95% CI: 8.7–35.2) months in stage III. One- and two-year overall survival rates were 57% (95 CI: 49–65) and 31.5% (95 CI: 27–43), respectively. Compared to smokers, non-smokers were significantly younger and more often females. Median overall survival was not statistically different between smokers and non-smokers.

Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non–Small-cell Lung Cancer: A Phase I Study

INTRODUCTION Because of our previous preclinical results, we conducted a phase I study associating the specific αvβ3/αvβ5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.

1208PCONTINUOUS INFUSION OF CILENGITIDE WITH RADIO-CHEMOTHERAPY IN STAGE III NSCLC: A PHASE I STUDY

ABSTRACT Aim: We have shown that avb3 integrins control radioresistance, hypoxia and angiogenesis and that co-expression of FGF-2 and avb3 integrins in the tumors of patients treated with exclusive radio-chemotherapy for stage III non-small lung carcinoma (NSCLC), was associated with a worse local control, suggesting that inhibition of avb3 integrin could induce a radiosensitization of such tumours. We designed a phase I trial associating the specific avb3/avb5 integrin inhibitor cilengitide with radio-chemotherapy in patients with stage III NSCLC. Methods: A standard 3 + 3 dose escalation design was used. Cilengitide was given in continuous infusion starting 2 weeks before and then during the whole course of the radio-chemotherapy (66 Gy combined with a Platine-Navelbine regimen), and then at a dose of 2000 mg twice a week in association with chemotherapy. Planed Cilengitide continuous infusion dose levels were 12, 18, 27 and 40 mg/h. PET-FDG and CT scan were performed before and then after the first two weeks of Cilengitide administration and then 2 months after the end of radio-chemotherapy. Patients were followed by CT scan. Toxicity for DLT was assessed during combined treatment and until 1 month after. Clinical response on CT scan and TEP was evaluated according to RECIST and PERCIST criteria. Results: Fourteen patients were included between March 2010 and July 2013. Eleven patients were evaluable for DLT. No DLT was observed at level 0, 1 and 2. One DLT, a tracheo-bronchial fistula was reported at the 40 mg/h dose. No relevant adverse event related to Cilengitide (7 grade 1 and one grade 2) was observed on the whole population. Among 11 patients evaluable for efficacy, 9 patients presented a partial response and 2 a stable disease. At 6 months after the end of radio-chemotherapy, 2 patients presented a progressive disease. At PET evaluation 2 months after radio-chemotherapy, 4 patients had a complete response and 4 patients had a partial response. Conclusions: Cilengitide given continuously with radio-chemotherapy was well tolerated and shows encouraging clinical results, suggesting that targeting avb3 integrin continuously during radio-chemotherapy in NSCLC is a promising approach to treat this disease. Disclosure: E.L. Cohen-Jonathan Moyal: E Moyal has been member of an advisory board for Merck KGaA and received a funding grant from Merck KGaA for research. All other authors have declared no conflicts of interest.

C3-04: Phase III study comparing a preoperative (PRE) and a perioperative (PERI) chemotherapy (CT) with two different CT regimens in resectable stage I-II non-small cell lung cancer (NSCLC): the IFCT 0002 protocol

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