Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.

BACKGROUND: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma. METHODS: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272. FINDINGS: Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure). INTERPRETATION: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials. FUNDING: French Cooperative Thoracic Intergroup.

Why harmonization is needed when using FDG PET/CT as a prognosticator: demonstration with EARL-compliant SUV as an independent prognostic factor in lung cancer.

BACKGROUND: To determine EARL-compliant prognostic SUV thresholds in a mature cohort of patients with locally advanced NSCLC, and to demonstrate how detrimental it is to use a threshold determined on an older-generation PET system with a newer PET/CT machine, and vice versa, or to use such a threshold with non-harmonized multicentre pooled data. MATERIALS AND METHODS: This was a single-centre retrospective study including 139 consecutive stage IIIA-IIIB patients. PET data were acquired as per the EANM guidelines and reconstructed with unfiltered point spread function (PSF) reconstruction. Subsequently, a 6.3 mm Gaussian filter was applied using the EQ.PET (Siemens Healthineers) methodology to meet the EANM/EARL harmonizing standards (PSFEARL). A multicentre study including non-EARL-compliant systems was simulated by randomly creating four groups of patients whose images were reconstructed with unfiltered PSF and PSF with Gaussian post-filtering of 3, 5, and 10 mm. Identification of optimal SUV thresholds was based on a two-fold cross-validation process that partitioned the overall sample into learning and validation subsamples. Proportional Cox hazards models were used to estimate age-adjusted and multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals. Kaplan-Meier curves were compared using the log rank test. RESULTS: Median follow-up was 28 months (1-104 months). For the whole population, the estimated overall survival rate at 36 months was 0.39 [0.31-0.47]. The optimal SUVmax cutoff value was 25.43 (95% CI: 23.41-26.31) and 8.47 (95% CI: 7.23-9.31) for the PSF and for the EARL-compliant dataset respectively. These SUVmax cutoff values were both significantly and independently associated with lung cancer mortality; HRs were 1.73 (1.05-2.84) and 1.92 (1.16-3.19) for the PSF and the EARL-compliant dataset respectively. When (i) applying the optimal PSF SUVmax cutoff on an EARL-compliant dataset and the optimal EARL SUVmax cutoff on a PSF dataset or (ii) applying the optimal EARL compliant SUVmax cutoff to a simulated multicentre dataset, the tumour SUVmax was no longer significantly associated with lung cancer mortality. CONCLUSION: The present study provides the PET community with an EARL-compliant SUVmax as an independent prognosticator for advanced NSCLC that should be confirmed in a larger cohort, ideally at other EARL accredited centres, and highlights the need to harmonize PET quantitative metrics when using them for risk stratification of patients.

Correction to: Why harmonization is needed when using FDG PET/CT as a prognosticator: demonstration with EARL-compliant SUV as an independent prognostic factor in lung cancer.

An error occurred in the labelling of Fig. 3, where math symbols for SUV thresholds were inverted in panel b when the EARL threshold was applied to the PSF dataset and vice versa. This figure should read as follows: Fig. 3: Prognostic value of tumour SUVmax.

Association between lung cancer somatic mutations and occupational exposure in never-smokers.

Occupational exposure constitutes a common risk factor for lung cancer. We observed molecular alterations in 73% of never-smokers, 35% of men and 8% of women were exposed to at least one occupational carcinogen. We report herein associations between molecular patterns and occupational exposure.BioCAST was a cohort study of lung cancer in never-smokers that reported risk factor exposure and molecular patterns. Occupational exposure was assessed via a validated 71-item questionnaire. Patients were categorised into groups that were unexposed and exposed to polycyclic aromatic hydrocarbons (PAH), asbestos, silica, diesel exhaust fumes (DEF), chrome and paints. Test results were recorded for EGFR, KRAS, HER2, BRAF and PIK3 mutations, and ALK alterations.Overall, 313 out of 384 patients included in BioCAST were analysed. Asbestos-exposed patients displayed a significantly lower rate of EGFR mutations (20% versus 44%, p=0.033), and a higher rate of HER2 mutations (18% versus 4%, p=0.084). ALK alterations were not associated with any occupational carcinogens. The DEF-exposed patients were diagnosed with a BRAF mutation in 25% of all cases. Chrome-exposed patients exhibited enhanced HER2 and PIK3 mutation frequency.Given its minimal effects in the subgroups, we conclude that occupational exposure slightly affects the molecular pattern of lung cancers in never-smokers. In particular, asbestos-exposed patients have a lower chance of EGFR mutations.

Utility of serum anti-cetuximab immunoglobulin E levels to identify patients at a high risk of severe hypersensitivity reaction to cetuximab.

AIM: Cetuximab is an anti-epidermal growth factor receptor antibody used for the treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions (HSRs) are associated with cetuximab use. The aim of the study was to evaluate the utility of anti-cetuximab immunoglobulin E (IgE) detection in order to identify patients at risk of HSR to cetuximab. METHODS: We included patients ready to receive a first cetuximab infusion in a prospective cohort carried out at nine French centres. Pretreatment anti-cetuximab IgE levels were measured. We compared the proportion of severe HSRs in the low anti-cetuximab IgE levels (≤29 IgE arbitrary units) subgroup with that in a historical cohort of 213 patients extracted from a previous study. RESULTS: Of the 301 assessable patients (mean age: 60.9 ± 9.3 years, head-and-neck cancer: 77%), 66 patients (22%) had high anti-cetuximab IgE levels, and 247 patients received cetuximab (including 38 with high anti-cetuximab levels). Severe HSRs occurred in eight patients (five grade 3 and three grade 4). The proportion of severe HSRs was lower in the low anti-cetuximab IgE levels subgroup vs. the historical cohort (3/209 [1.4%] vs. 11/213 [5.2%], odds ratio, 0.27, 95% confidence interval, 0.07-0.97), and higher in high vs. low anti-cetuximab IgE levels subgroup (5/38 [13.2%] vs. 3/209 [1.4%]; odds ratio, 10.4, 95% confidence interval, 2.4-45.6). Patients with severe HSRs had higher anti-cetuximab IgE levels than patients without reaction (median, 45 vs. 2 IgE arbitrary units, P = 0.006). CONCLUSIONS: Detection of pretreatment anti-cetuximab IgE is feasible and helpful to identify patients at risk of severe cetuximab-induced HSRs.

18F-FDG PET/CT heterogeneity quantification through textural features in the era of harmonisation programs: a focus on lung cancer.

PURPOSE: Quantification of tumour heterogeneity in PET images has recently gained interest, but has been shown to be dependent on image reconstruction. This study aimed to evaluate the impact of the EANM/EARL accreditation program on selected 18F-FDG heterogeneity metrics. METHODS: To carry out our study, we prospectively analysed 71 tumours in 60 biopsy-proven lung cancer patient acquisitions reconstructed with unfiltered point spread function (PSF) positron emission tomography (PET) images (optimised for diagnostic purposes), PSF-reconstructed images with a 7-mm Gaussian filter (PSF7) chosen to meet European Association of Nuclear Medicine (EANM) 1.0 harmonising standards, and EANM Research Ltd. (EARL)-compliant ordered subset expectation maximisation (OSEM) images. Delineation was performed with fuzzy locally adaptive Bayesian (FLAB) algorithm on PSF images and reported on PSF7 and OSEM ones, and with a 50 % standardised uptake values (SUV)max threshold (SUVmax50%) applied independently to each image. Robust and repeatable heterogeneity metrics including 1st-order [area under the curve of the cumulative histogram (CHAUC)], 2nd-order (entropy, correlation, and dissimilarity), and 3rd-order [high-intensity larger area emphasis (HILAE) and zone percentage (ZP)] textural features (TF) were statistically compared. RESULTS: Volumes obtained with SUVmax50% were significantly smaller than FLAB-derived ones, and were significantly smaller in PSF images compared to OSEM and PSF7 images. PSF-reconstructed images showed significantly higher SUVmax and SUVmean values, as well as heterogeneity for CHAUC, dissimilarity, correlation, and HILAE, and a wider range of heterogeneity values than OSEM images for most of the metrics considered, especially when analysing larger tumours. Histological subtypes had no impact on TF distribution. No significant difference was observed between any of the considered metrics (SUV or heterogeneity features) that we extracted from OSEM and PSF7 reconstructions. Furthermore, the distributions of TF for OSEM and PSF7 reconstructions according to tumour volumes were similar for all ranges of volumes. CONCLUSION: PSF reconstruction with Gaussian filtering chosen to meet harmonising standards resulted in similar SUV values and heterogeneity information as compared to OSEM images, which validates its use within the harmonisation strategy context. However, unfiltered PSF-reconstructed images also showed higher heterogeneity according to some metrics, as well as a wider range of heterogeneity values than OSEM images for most of the metrics considered, especially when analysing larger tumours. This suggests that, whenever available, unfiltered PSF images should also be exploited to obtain the most discriminative quantitative heterogeneity features.

BioCAST/IFCT-1002: epidemiological and molecular features of lung cancer in never-smokers.

Lung cancer in never-smokers (LCINS) (fewer than 100 cigarettes in lifetime) is considered as a distinct entity and harbours an original molecular profile. However, the epidemiological and molecular features of LCINS in Europe remain poorly understood. All consecutive newly diagnosed LCINS patients were included in this prospective observational study by 75 participating centres during a 14-month period. Each patient completed a detailed questionnaire about risk factor exposure. Biomarker and pathological analyses were also collected. We report the main descriptive overall results with a focus on sex differences. 384 patients were included: 65 men and 319 women. 66% had been exposed to passive smoking (significantly higher among women). Definite exposure to main occupational carcinogens was significantly higher in men (35% versus 8% in women). A targetable molecular alteration was found in 73% of patients (without any significant sex difference): EGFR in 51%, ALK in 8%, KRAS in 6%, HER2 in 3%, BRAF in 3%, PI3KCA in less than 1%, and multiple in 2%. We present the largest and most comprehensive LCINS analysis in a European population. Physicians should track occupational exposure in men (35%), and a somatic molecular alteration in both sexes (73%).

Cost-utility analysis of maintenance therapy with gemcitabine or erlotinib vs observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy for advanced NSCLC: IFCT-GFPC 0502-Eco phase III study.

BACKGROUND: The IFCT-GFPC 0502 phase III study reported prolongation of progression-free survival with gemcitabine or erlotinib maintenance vs. observation after cisplatin-gemcitabine induction chemotherapy for advanced non-small-cell lung cancer (NSCLC). This analysis was undertaken to assess the incremental cost-effectiveness ratio (ICER) of these strategies for the global population and pre-specified subgroups. METHODS: A cost-utility analysis evaluated the ICER of gemcitabine or erlotinib maintenance therapy vs. observation, from randomization until the end of follow-up. Direct medical costs (including drugs, hospitalization, follow-up examinations, second-line treatments and palliative care) were prospectively collected per patient during the trial, until death, from the primary health-insurance provider's perspective. Utility data were extracted from literature. Sensitivity analyses were conducted. RESULTS: The ICERs for gemcitabine or erlotinib maintenance therapy were respectively 76,625 and 184,733 euros per quality-adjusted life year (QALY). Gemcitabine continuation maintenance therapy had a favourable ICER in patients with PS = 0 (52,213 €/QALY), in responders to induction chemotherapy (64,296 €/QALY), regardless of histology (adenocarcinoma, 62,292 €/QALY, non adenocarcinoma, 83,291 €/QALY). Erlotinib maintenance showed a favourable ICER in patients with PS = 0 (94,908 €/QALY), in patients with adenocarcinoma (97,160 €/QALY) and in patient with objective response to induction (101,186 €/QALY), but it is not cost-effective in patients with PS =1, in patients with non-adenocarcinoma or with stable disease after induction chemotherapy. CONCLUSION: Gemcitabine- or erlotinib-maintenance therapy had ICERs that varied as a function of histology, PS and response to first-line chemotherapy.

Harmonizing SUVs in multicentre trials when using different generation PET systems: prospective validation in non-small cell lung cancer patients.

PURPOSE: We prospectively evaluated whether a strategy using point spread function (PSF) reconstruction for both diagnostic and quantitative analysis in non-small cell lung cancer (NSCLC) patients meets the European Association of Nuclear Medicine (EANM) guidelines for harmonization of quantitative values. METHODS: The NEMA NU-2 phantom was used to determine the optimal filter to apply to PSF-reconstructed images in order to obtain recovery coefficients (RCs) fulfilling the EANM guidelines for tumour positron emission tomography (PET) imaging (PSF(EANM)). PET data of 52 consecutive NSCLC patients were reconstructed with unfiltered PSF reconstruction (PSF(allpass)), PSF(EANM) and with a conventional ordered subset expectation maximization (OSEM) algorithm known to meet EANM guidelines. To mimic a situation in which a patient would undergo pre- and post-therapy PET scans on different generation PET systems, standardized uptake values (SUVs) for OSEM reconstruction were compared to SUVs for PSF(EANM) and PSF(allpass) reconstruction. RESULTS: Overall, in 195 lesions, Bland-Altman analysis demonstrated that the mean ratio between PSF(EANM) and OSEM data was 1.03 [95% confidence interval (CI) 0.94-1.12] and 1.02 (95% CI 0.90-1.14) for SUV(max) and SUV(mean), respectively. No difference was noticed when analysing lesions based on their size and location or on patient body habitus and image noise. Ten patients (84 lesions) underwent two PET scans for response monitoring. Using the European Organization for Research and Treatment of Cancer (EORTC) criteria, there was an almost perfect agreement between OSEM(PET1)/OSEM(PET2) (current standard) and OSEM(PET1)/PSF(EANM-PET2) or PSF(EANM-PET1)/OSEM(PET2) with kappa values of 0.95 (95% CI 0.91-1.00) and 0.99 (95% CI 0.96-1.00), respectively. The use of PSF(allpass) either for pre- or post-treatment (i.e. OSEM(PET1)/PSF(allpass-PET2) or PSF(allpass-PET1)/OSEM(PET2)) showed considerably less agreement with kappa values of 0.75 (95% CI 0.67-0.83) and 0.86 (95% CI 0.78-0.94), respectively. CONCLUSION: Protocol-optimized images and compliance with EANM guidelines allowed for a reliable pre- and post-therapy evaluation when using different generation PET systems. These data obtained in NSCLC patients could be extrapolated to other solid tumours.

Brigatinib for Pretreated, ALK-Positive, Advanced Non-Small-Cell Lung Cancers: Long-Term Follow-Up and Focus on Post-Brigatinib Lorlatinib Efficacy in the Multicenter, Real-World BrigALK2 Study.

Brigatinib is a next-generation ALK inhibitor (ALKi) that shows efficacy in ALK inhibitor naïve and post-crizotinib ALK+ advanced NSCLCs (aNSCLCs). The efficacy of brigatinib was retrospectively assessed in patients with aNSCLCs included in the brigatinib French Early-Access Program (1 August 2016−21 January 2019). The primary endpoint was investigator-assessed progression-free survival (invPFS) and the primary analysis was updated in 2021 with a longer follow-up, focused on post-brigatinib lorlatinib efficacy. Sixty-six centers included 183 patients: median age 60 ± 12.7 years; 78.3% never/former smokers; median of 3 ± 1 previous lines and 2 ± 0.5 ALKis; 37.1% ECOG PS 2 and 55.6% >3 metastatic sites. The median follow-up from brigatinib initiation was 40.4 months (95% CI 38.4−42.4). InvPFS was 7.4 months (95% CI 5.9−9.6), median duration of treatment (mDOT) was 7.3 months (95% CI 5.8−9.4) and median overall survival (mOS) was 20.3 months (95% CI 15.6−27.6). The median DOT and OS from brigatinib initiation tend to decrease with the number of ALK inhibitors used in previous lines of therapy. Based on the data collected, 92 (50.3%) patients received ≥1 agent(s) post-brigatinib and 68 (73.9%) of them received lorlatinib, with 51 (75%) immediately receiving it post-brigatinib, 12 (17.6%) receiving it after one and 5 (7.4%) after ≥2 subsequent treatments. The median follow-up was 29.9 (95% CI 25.7−33.1) months. Lorlatinib mDOT was 5.3 (95% CI 3.6−7.6) months with a median OS from lorlatinib initiation of 14.1 (95% CI 10.3−19.2) months. The results of the brigALK2 study confirm the efficacy of brigatinib in a population of heavily pretreated ALK+ aNSCLC patients and provide new data on the activity of lorlatinib after brigatinib.

Efficacy of Dabrafenib Plus Trametinib Combination in Patients with BRAF V600E-Mutant NSCLC in Real-World Setting: GFPC 01-2019.

Dabrafenib plus trametinib combination is approved in Europe for BRAF V600E-mutant metastatic non-small-cell lung cancer (NSCLC). The objective of this study was to assess efficacy and safety of this combination in a real-world setting. This retrospective multicentric study included 40 patients with advanced NSCLC harboring BRAF V600E mutation and receiving dabrafenib plus trametinib. The median progression-free survival (PFS) and overall survival (OS) were 17.5 (95% CI 7.1-23.0) months and 25.5 (95% CI 16.6-not reached) months in the entire cohort, respectively. For the 9 patients with first-line treatment, median PFS was 16.8 (95% CI 6.1-23.2) months and median OS was 21.8 (95% CI 1.0-not reached) months; for the 31 patients with second-line or more treatments, median PFS and OS were 16.8 (95% CI 6.1-23.2) months and 25.5 (95% CI 16.6-not reached) months, respectively. Adverse events led to permanent discontinuation in 7 (18%) patients, treatment interruption in 8 (20%) and dose reduction in 12 (30%). In conclusion, these results suggest that efficacy and safety of dabrafenib plus trametinib combination in patients with BRAF V600E metastatic NSCLC are comparable in a real-world setting and in clinical trials for both previously untreated and treated patients.

Management and outcomes of non-small cell lung cancer patients with rapid progression under second-or-more-line immune checkpoint inhibitors: ERORECI study (GFPC 2016-04).

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been approved as second-line therapy for advanced non-small cell lung cancers (NSCLCs) progressing after platinum-based chemotherapy. However, some patients' disease progressed rapidly and sometimes exhibited explosive tumor progression. This descriptive, prospective study aimed to assess the characteristics of nonresponders with rapid progression (RP), defined as progression-free survival (PFS) ≤2 or 2-4 months under ICIs. METHODS: This analysis included all consecutive ICI-treated (second-or-more line) patients with RP ≤4 months from 1 September 2016 to 31 August 2017 and compared the clinical characteristics, treatments, and outcomes (overall survival [OS]; responses; PFS, according to treatment line) of NSCLCs that progressed after ≤2 vs 2-4 months on ICIs. RESULTS: Comparisons of the 224 (70.2%) patients with ≤2-month and 95 (29.8%) with 2- to 4-month RP revealed the former had less frequent nonsmokers and ECOG PS = 0, more frequent stage IV disease and higher neutrophil/lymphocyte ratio. Their respective ICI PFS rates were: 1.6 [95% CI: 0.1-2] and 2.7 [2.0-4.2] months, with 16.5% and 11.6% having partial responses to first- and second-line therapies post-ICI chemotherapy. Their respective median OS rates were 6.0 and 9.0 months (P ≤ .009). Multivariate analysis retained only PFS of the first-line therapy pre-ICI and neutrophil/lymphocyte ratio at ICI onset as being significantly associated with ≤2-month RP. CONCLUSION: In the real-life setting, NSCLC RP on ICI remains a challenge. New descriptive and analytic studies are needed to identify factors predictive of RP.

Non-Small Cell Lung Cancer Patients Harboring HER2 Mutations: Clinical Characteristics and Management in a Real-Life Setting. Cohort HER2 EXPLORE GFPC 02-14.

BACKGROUND: Mutation of human receptor tyrosine kinase epidermal growth factor receptor-2 (HER2) is a rare event, found in approximately 1% non-small cell lung cancers (NSCLC). The objective was to investigate the clinical characteristics and management of HER2-mutated NSCLCs in a real-life setting. METHODS: This multicenter study described NSCLCs harboring HER2 mutations diagnosed between January 2012 and December 2014, according their clinical characteristics, management, and outcomes: response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty patients were included: 66.7% women; median age 65.2 ± 12 years; never or former smokers 73.3%. Of the stage IV patients (n = 23), 86% received first-line platin doublet chemotherapy: RR 61.5% and PFS 6.7 (95% CI 5.9-9.5) months; 52.1% received a second-line therapy: RR 18.2% and PFS 4.9 (95% CI 2.5-11.9) months. Median OS of stage IV was 10.7 months and 2-year OS was 27.2% (95% CI 11.7-63.2). All patients with stage I-III NSCLCs were alive at 2 years. CONCLUSION: The rarity of HER2-mutated NSCLCs requires specific studies.

Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study).

OBJECTIVES: Brigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib. MATERIALS AND METHODS: This retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors (mainly crizotinib then ceritinib). At brigatinib initiation, 59.1% had performance status 0-1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (95% CI, 0.06-20.7) months. Median PFS was 6.6 (4.8-9.9) months for the entire population. For patients who received 2, 3-4 and >4 lines of treatment before brigatinib, PFS was 4.3 (2.5-8.9), 10.4 (5.9-13.9) and 3.8 (0.8-7.4) months, respectively. In the 91 evaluable patients, disease control rate was 78.2%. From brigatinib start, median overall survival was 17.2 (11.0-not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Median OS from the diagnosis of NSCLC was 75.3 (38.2-174.6) months. CONCLUSION: These real-world results confirm the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC.

Oxaliplatin-induced bronchiolitis obliterans organizing pneumonia following hyperthermic intraperitoneal chemotherapy.

Oxaliplatin given systemically is associated with pneumonitis in less than 1% of cases. This case report describes acute respiratory failure, due to bronchiolitis organising pneumonia, in a patient with colorectal carcinoma being treated with hyperthermic intraperitoneal chemotherapy which included oxaliplatin and CPT-11 (irinotecan). The clinical course, the lack of an identifiable infectious agent and the complete response to corticosteroids suggested a drug-induced cause. After ruling out CPT-11, oxaliplatin was considered to be the causal agent. The unusual feature of this case was that pneumonitis developed after intraperitoneal administration of oxaliplatin. Oxaliplatin-associated respiratory complications can occur whatever route the drug is administered.

Safety of combined PD-1 pathway inhibition and radiation therapy for non-small-cell lung cancer: A multicentric retrospective study from the GFPC.

INTRODUCTION: Randomized prospective studies on patients with metastatic non-small-cell lung cancers (NSCLCs) showed that anti-programmed death-1 (PD-1) agents notably improved 2-year overall survival (OS) rates, compared to docetaxel. NSCLC patients now receive nivolumab and irradiation, concurrently or not. However, little is known about the safety of this combination, even though the preclinical model suggested a possible synergic effect. We analyzed NSCLC patients treated with radiotherapy and nivolumab according to former's timing. METHODS: We retrospectively reviewed records of a large series of metastatic NSCLC patients from three French centers, irradiated during the 6 months preceding, concomitantly, or 3 months after nivolumab administration to assess nivolumab tolerance and outcomes. RESULTS: Among 104 patients included (37 women; 67 men; median age 60.3 years; 67% with performance status <2; 93.2% were current or past smokers) and their 144 intra- or extracranial irradiation courses, any-grade adverse events (AEs) were observed in 62 (59.6%), with 10 (9.6%) experiencing at least one grade 3/4 toxicity and 9 (8.7%) at least one grade 3/4 immune-related AE (IRAE). Respective 1- and 2-year OS rates were 48.8% and 29.1%, while 1- and 2-year progression-free survival (PFS) rates were 20.9% and 10.1%. PFS was significantly better for patients with IRAE(s) (P = 0.038) than those without and a trend toward better OS (P = 0.06). Delivering radiation before or during/after nivolumab administration was not associated with better OS or PFS. CONCLUSION: Radiotherapy delivered during the 6 months before, during, or the three months following nivolumab for NSCLCs was not associated with an increased risk of severe or unexpected toxicities.

Phase II study assessing the benefit of cisplatin re-introduction (stop-and-go strategy) in patients with advanced non-squamous non-small cell lung cancer: the IFCT-1102 BUCiL study (a Better Use of Cisplatin in Lung cancer).

INTRODUCTION: This single-arm phase II trial aimed to evaluate a stop-and-go strategy with cisplatin-based chemotherapy and bevacizumab in advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Patients were initially treated with three cycles of pemetrexed, cisplatin plus bevacizumab (sequence 1) followed by bevacizumab maintenance and after progression, re-introduction of three cycles of pemetrexed, cisplatin plus bevacizumab (sequence 2) and pemetrexed plus bevacizumab maintenance. The primary endpoint was the proportion of patients with advanced non-squamous NSCLC receiving the complete sequence 2 without platinum dose reduction (hypothesis ≥75%). RESULTS: 120 patients with performance status ≤1 were included. Of 113 patients evaluable for efficacy, 65 (57.5%) entered in sequence 2 and 56 (86%) received the three planned cycles including 37 (56.9%, 95% CI 45.1 to 73.6) without platinum dose reduction. The median progression-free survival 1 (PFS1; inclusion to progression 1) was 5.6 months (95% CI 5.0 to 6.3) and median PFS2 (progression 1 to progression 2) was 6.8 months (95% CI 5.8 to 8.8). The median disease control duration (PFS1+PFS2; n=65) was 12.4 months (95% CI 11.2 to 14.9). The median overall survival was 17.7 months (95% CI 13.1 to 21.6) and 20.5 months (95% CI 16.9 to 26.9) for patients reaching the sequence 2 (n=65). CONCLUSION: Although the stringent primary endpoint was not met, this stop-and-go strategy with platinum-based chemotherapy plus bevacizumab continuation beyond progression compares favourably with standard schedule, deserving to be further studied in advanced non-squamous NSCLC.

Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients.

Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase (ALK) positive (ALK+) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK+ or ROS proto-oncogene 1 positive (ROS1+) tumours. Patients received oral ceritinib (750 mg·day-1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK+ NSCLC and 13 had ROS1+ NSCLC. The median age of ALK+ patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK+ NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4%) and those receiving prior crizotinib for >5 months (51.6% versus 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day-1) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK+ NSCLC.

Off-Label Use of Crizotinib as a Neoadjuvant Treatment for a Young Patient When Conventional Chemotherapy Gave No Benefits in Stage IIIA Non-Small Cell Lung Cancer.

BACKGROUND The treatment of locally advanced non-small cell lung cancer involves a combination of chemotherapy, surgery, and radiotherapy. Each case is discussed and the best strategy is chosen individually, following international guidelines. CASE REPORT A 37-year-old man was diagnosed with locally advanced broncho-pulmonary adenocarcinoma (stage IIIA). The disease was stable after 2 cycles of cisplatin plus Navelbine used as neoadjuvant therapy. FISH analysis revealed an ALK rearrangement. The patient then received unlicensed crizotinib as second-line neoadjuvant treatment, which led to an almost complete radiological and metabolic response. A left upper lobectomy was performed, followed by post-operative chemotherapy and radiotherapy. At 18 months post-surgery, the patient is still disease-free according to the last CT scan. CONCLUSIONS Targeted therapy was an alternative solution when chemotherapy was not helping. Randomized studies are needed to define its precise role in the neoadjuvant scheme.

Generating harmonized SUV within the EANM EARL accreditation program: software approach versus EARL-compliant reconstruction.

BACKGROUND: Evolutions in hardware and software PET technology, such as point spread function (PSF) reconstruction, have been shown to improve diagnostic performance, but can also lead to important device-dependent and reconstruction-dependent variations in standardized uptake values (SUVs). This may preclude the multicentre use of SUVs as a prognostic or diagnostic tool or as a biomarker of the early response to antineoplastic treatments. This study compared two SUV harmonization strategies using a newer reconstruction algorithm that improves lesion detection while maintaining comparability with older systems: (1) the use of a second reconstruction compliant with harmonization standards and (2) the use of a proprietary software tool (EQ.PET). METHODS: PET data from 50 consecutive non-small cell lung cancer patients were reconstructed with PSF reconstruction for optimal tumor detection and an ordered subset expectation maximization (OSEM3D) reconstruction to mimic a former generation PET. An additional PSF reconstruction was performed with a 7 mm Gaussian filter (PSF7, first method), and, post-reconstruction, the EQ filter (same Gaussian filter) was applied to the PSF data (PSFEQ, second method) for harmonization purposes. The 7 mm kernel filter was chosen to comply with the European Association of Nuclear Medicine (EANM) standards. SUVs for all reconstructions were compared with regression analyses and/or Bland-Altman plots. RESULTS: Overall, 171 lesions were analyzed: 55 lung lesions (32.2%), 87 lymph nodes (50.9%), and 29 metastases (16.9%). In these lesions, the mean PSF7/OSEM3D ratios for SUVmax and SUVpeak were 1.02 (95% CI: 0.93-1.11) and 1.04 (95% CI: 0.95-1.14), respectively. The mean PSFEQ/OSEM3D ratios for SUVmax and SUVpeak were 1.01 (95% CI: 0.91-1.11) and 1.04 (95% CI: 0.94-1.14), respectively. When comparing PSF7 and PSFEQ, Bland-Altman analysis showed that the mean PSF7/PSFEQ ratios for SUVmax and SUVpeak were 1.01 (95% CI: 0.96-1.06) and 1.01 (95% CI: 0.97-1.04), respectively. CONCLUSION: The issue of reconstruction dependency in SUV values that hampers the comparison of data between different PET systems can be overcome using two reconstructions for harmonized quantification and optimal diagnosis or using the EQ.PET technology. Both technologies produce similar results, EQ.PET sparing reconstruction and interpretation time. Other manufacturers are encouraged to either emulate this solution or to produce a vendor-neutral approach.