Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.

Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial.

BACKGROUND: The APPLE trial aimed to evaluate the feasibility of longitudinal plasma epidermal growth factor receptor (EGFR) T790M monitoring for the best sequencing strategy of gefitinib and osimertinib. METHODS: APPLE is a randomized, non-comparative, phase II study in patients with common EGFR-mutant, treatment-naive non-small-cell lung cancer including three arms: arm A (osimertinib upfront until RECIST progression, PD), arm B [gefitinib until emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR test v2 or RECIST PD], and arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms. The primary endpoint is the progression-free survival (PFS) rate 'on osimertinib' at 18 months (PFSR-OSI-18) after randomization in arm B (H0: PFSR-OSI-18 of ≤40%). Secondary endpoints include response rate, overall survival (OS), and brain PFS. We report the results of arms B and C. RESULTS: From November 2017 to February 2020, 52 and 51 patients were randomized into arms B and C, respectively. Most patients were females (70%) and had EGFR Del19 (65%); one-third had baseline brain metastases. In arm B, 17% of patients (8/47) switched to osimertinib based on the emergence of ctDNA T790M mutation before RECIST PD, with a median time to molecular PD of 266 days. The study met its primary endpoint of PFSR-OSI-18 of 67.2% (84% confidence interval 56.4% to 75.9%) in arm B versus 53.5% (84% confidence interval 42.3% to 63.5%) in arm C, with a median PFS of 22.0 months versus 20.2 months, respectively. The median OS was not reached in arm B versus 42.8 months in arm C. Median brain PFS in arms B and C was 24.4 and 21.4 months, respectively. CONCLUSIONS: The serial monitoring of ctDNA T790M status in advanced EGFR-mutant non-small-cell lung cancer during treatment with first-generation EGFR inhibitors was feasible, and a molecular progression before RECIST PD led to an earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.

Chemotherapy (platinum and pemetrexed) in combination with erlotinib in non-small cell lung cancer induces major gastrointestinal toxicity: two case reports from the FLARE/GFPC 03-2013 study.

WHAT IS KNOWN AND OBJECTIVE: A randomized phase III study was designed to assess the efficacy and safety of second-line platinum-based chemotherapy with or without erlotinib in non-small cell lung cancer (NSCLC) with EGFR-activating mutation after secondary resistance to EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors). CASE SUMMARY: We report herein two of the first three patients who presented with major gastrointestinal toxicities in the experimental arm of the trial. WHAT IS NEW AND CONCLUSION: Pending further data, it would seem safer to administer EGFR-TKIs and chemotherapy sequentially rather than concomitantly.

Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3.

Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-type EGFR or unknown status received docetaxel), compared with initiation with no patient selection (strategy reference). A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed. The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to €5,020 and €5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results. The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds.

High-dose chemotherapy with peripheral blood progenitor cell support for patients with non-small cell lung cancer: the experience of the European Group for Bone Marrow Transplantation (EBMT) Solid Tumours Working Party.

We report the experience of the EBMT Solid Tumours Working Party (STWP) using high-dose chemotherapy (HDCT) with PBPC support in patients with non-small cell lung cancer (NSCLC). Between 1989 and 2004, 36 NSCLC patients (27 men and 9 women), median age 53.5 years (range: 24-62) were treated with 63 HDCT courses. A high-dose carboplatin-based regimen was used in 53% of the cases. Thirty-two patients had relapsed/metastatic disease, while four classified as stage IIIB received HDCT followed by radiotherapy. No treatment-related death occurred. Of 25 patients who were planned to receive multi-cycle HDCT, 4 cases (16%) interrupted the treatment early due to prolonged severe toxicities and 4 (16%) due to progressive disease. Of 36 evaluable patients, 3 (8%) achieved a complete remission and 13 (36%) had a partial remission at an overall response rate of 44%. Of these, one patient with stage IIIB and one with stage IV are alive disease free at 71+ and 149+ months, respectively. After a median follow-up of 48 months (range: 6-149), median survival was 7 months (range: 1-149). Despite one anecdotal case, HDCT did not show significant activity, but induced relevant morbidity in NSCLC patients.

Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer.

We report the results of a randomised phase II trial of docetaxel tested as a single agent in patients with recurrent head and neck cancer using methotrexate as a control arm to validate the results. Eligibility criteria included: histologically-confirmed squamous cell carcinoma, measurable disease, adequate haematological, renal and hepatic functions, no prior chemotherapy for recurrent cancer, signed informed consent. 40 mg/m2 methotrexate was given as a short weekly bolus i.v. injection, and 40 mg/m2 docetaxel was administered as a one hour weekly infusion. A total of 57 patients were randomised based on a ratio of 2/1:37 and 20 patients received docetaxel and methotrexate, respectively. Patient characteristics included 49 males and 8 females; the median age was 59 years (range: 43-82 years). Twenty-eight patients had a local-regional relapse and 29 had distant metastasis, the median disease-free interval was 7.9 months (range: 0-165 months). For patients treated with docetaxel, the following grade 3-4 toxicities occurred: neutropenia (12.5%) with febrile neutropenia in one patient (1%), anaemia (19%) mucositis (9%) and ungueal toxicity (9%). In the methotrexate arm, the grade 3-4 toxicities were: anaemia (15%) and mucositis (5%). The response rate was significantly higher in the docetaxel arm with 27% (95% confidence interval (CI): 21.7-32.3%) of objective responses versus 15% (95% CI: 11.2-18.8%) in the methotrexate arm. Overall survival and time to progression were super-imposable between the docetaxel and methotrexate treatments. Docetaxel given as a weekly infusion has a high activity in patients with head and neck cancer. A phase III trial is needed to test if this translates into a survival benefit for docetaxel use.

Small-cell carcinoma of the esophagus: report of three cases and review of the literature with emphasis on therapy.

Primary small-cell carcinoma (SCC) of the esophagus is rare, with about 200 cases reported up till now in the literature. Like pulmonary SCC, it is an aggressive tumor associated with a poor prognosis. Between 1994 and 1997, three patients with SCC of the esophagus were treated at Besançon University Hospital and this represented 1.85% of all esophageal malignancies diagnosed during this period: one patient had a limited tumor and underwent initial surgical resection, then chemotherapy with cisplatine and etoposide, and radiotherapy for recurrences. The other patients had extensive disease at diagnosis and were treated by the same chemotherapy. This retrospective study reports our experience of patients with this particular tumor and outlines the management strategy based on the available literature.

Role of molds in farmer's lung disease in Eastern France.

Farmer's lung disease (FLD) is common in the east of France. In the absence of the primary recognized FLD agent, Saccharopolyspora rectivirgula, its etiology remains unknown. A prospective case-control study was performed to find the etiology of FLD in this area. Eleven patients were matched with 11 healthy control farmers. Twenty-two urban subjects constituted the nonexposed control group. Microorganisms from cowshed air and fodder were identified and counted. The antigens of the microorganisms most frequently isolated at the 22 farms were used for serological tests. Farms of patients with FLD contained more Absidia corymbifera than those of healthy farmers (p < 0.05 in air, p < 0.01 in fodder). Electrosyneresis, performed with A. corymbifera somatic antigen, differentiated 9 of 11 patients with FLD from control subjects (p < 0.01). Other significant results were obtained with Eurotium amstelodami (p < 0.01) and Wallemia sebi (p < 0.05). In contrast, no significant results were obtained with the other seven antigens tested, including S. rectivirgula. Absidia corymbifera and, to a lesser degree, W. sebi or E. amstelodami are likely to be the main causes of FLD in this area. Modifications in working conditions over time could explain the emergence of these new contributing etiologies.

[Respective influence of occupational and personal factors on respiratory function in dairy farmers]. / Influence respective des facteurs professionnels et personnels sur la fonction respiratoire en milieu agricole de production laitière.

Occupational and individual factors influencing respiratory function were analysed in a sample of dairy farmers. The study protocol included a medical questionnaire, an occupational questionnaire, spirometry and allergological tests (skin prick tests for a panel of inhalant allergens, serum total IgE level and Phadiatop (CAP System). Two hundred and forty-five farmers were studied (140 men, 105 women with an average age of 45.9 (11.3) years, 35 were smokers, 27 ex-smokers and 183 non-smokers). A multiple linear regression model was used to analyse the correlations between respiratory function and the different independent variables. There was a statistically significant negative correlations between smoking (expressed in pack-years) and all the respiratory function parameters (p < 0.01). Respiratory function was significantly impaired in farmers working on traditional farms (p < 0.05 for VC and for FEV1), and the respiratory function values increased proportionally with the modernisation of the farms (notably using an artificial barn drying system for hay and a ventilation system for the cow byres). No significant relationship between respiratory function and quantitative indicators of exposure (size of farm, amount of livestock, quantity of hay handled during professional lifetime) or indicators of IgE-mediated allergy was observed. In conclusion, this study suggests that traditional work conditions in farms which have little mechanisation are, along with tobacco, the determining factors for the respiratory function impairment in dairy farmers.

[Diffuse interstitial pneumonia revealing Erdheim-Chester's disease]. / Pneumopathie interstitielle diffuse révélant une maladie d'Erdheim-Chester.

Erdheim-Chester's disease is a rare form of visceral xanthogranulomatosis. We report a case of a patient aged 50 presenting with a diffuse interstitial pneumonia which revealed Erdheim-Chester's disease with localisation in the bones, peri-aortic region and also with neurological involvement. The diffuse interstitial pneumonia which progressed chronically was characterised by a diffuse thickening of the septa with subpleural cysts and bilateral apical bullae with thickening of the pleura. Respiratory function tests showed a restrictive ventilatory defect with resting hypoxaemia which was aggravating by exercise. Broncho-alveolar lavage showed a lymphocytosis (26%) also with polymorpho neutrophils (11%). The pathological diagnosis was confirmed by transbronchial lung biopsy showing an excess of foamy histiocytes in the interstitium which are characteristic of the disease. The progress of this interstitial pneumonia is stabilised without immunosuppressive drugs.