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International audience; INTRODUCTION: Molecular profile of resected stage I-II non-small cell lung cancer (NSCLC) would help refine prognosis and personalize induction or adjuvant strategies. We sought to report the molecular profile of resected stage I-II NSCLC and analyzed the impact of epidermal growth factor receptor (EGFR) mutations on outcomes in a Western population. PATIENTS AND METHODS: Surgical cases were identified from Biomarkers France study, a nationwide prospective study including NSCLC patients screened for EGFR, HER2, KRAS, BRAF, PIK3CA, ALK alterations from 2012 to 2013. Among surgical patients, clinical charts of the largest centers were reviewed in order to analyze the prognostic impact of EGFR mutations. RESULTS: In the BMF database (n = 17.636), surgical patients (n = 854) were characterized by a higher proportion of EGFR mutations than nonsurgical patients (12.9% vs. 10.2%, P = .025), while the other molecular alterations did not differ. The proportion of EGFR mutations was 27% in women undergoing surgery. In the study group (n = 293; EGFR wild type, n = 235; usual mutation, n = 50; rare mutation, n = 8), after a median follow-up of 67 months, 215 patients (74.4%) had not relapsed. No difference was found between EGFR-mutant and EGFR-wt tumors regarding recurrence site, disease-free survival, and overall survival. The 5-year disease-free survival and overall survival after surgical resection of stage I-II EGFR-mutated tumors were 65% and 75%, respectively. CONCLUSION: In resected stage I to II NSCLC, EGFR mutations were found in 12.9% of cases, associated with a 5-year overall survival of 75%, with no impact on recurrence site, disease-free survival, and overall survival.

PDF file - 252K, TUBB3 protein expression in HBEC cells is reduced by hypoxia cells culture conditions

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We assessed the prognostic and predictive value of β-tubulin III (TUBB3) expression, as determined by immunohistochemistry, in 412 non–small cell lung cancer (NSCLC) specimens from early-stage patients who received neoadjuvant chemotherapy (paclitaxel- or gemcitabine-based) in a phase III trial (IFCT-0002). We also correlated TUBB3 expression with K-Ras and EGF receptor (EGFR) mutations in a subset of 208 cryopreserved specimens. High TUBB3 protein expression was associated with nonsquamous cell carcinomas (P < 0.001) and K-Ras mutation (P < 0.001). The 127 (30.8%) TUBB3-negative patients derived more than 1 year of overall survival advantage, with more than 84 months median overall survival versus 71.7 months for TUBB3-positive patients [HR, 1.58; 95% confidence interval (CI), 1.11–2.25)]. This prognostic value was confirmed in multivariate analysis (adjusted HR for death, 1.51; 95% CI, 1.04–2.21; P = 0.031) with a bootstrapping validation procedure. TUBB3 expression was associated with nonresponse to chemotherapy (adjusted HR, 1.31; 95% CI, 1.01–1.70; P = 0.044) but had no predictive value (taxane vs. gemcitabine). Taking account of these clinical findings, we further investigated TUBB3 expression in isogenic human bronchial cell lines only differing by K-Ras gene status and assessed the effect of K-Ras short interfering RNA (siRNA) mediated depletion, cell hypoxia, or pharmacologic inhibitors of K-Ras downstream effectors, on TUBB3 protein cell content. siRNA K-Ras knockdown, inhibition of RAF/MEK (MAP–ERK kinase) and phosphoinositide 3-kinase (PI3K)/AKT signaling, and hypoxia were shown to downregulate TUBB3 expression in bronchial cells. This study is the first one to identify K-Ras mutations as determinant of TUBB3 expression, a chemoresistance marker. Our in vitro data deserve studies combining standard chemotherapy with anti-MEK or anti-PI3K drugs in patients with TUBB3-overexpressing tumors. Mol Cancer Ther; 11(5); 1203–13. ©2012 AACR.

PDF file - 144K, Representative SiRNA K-Ras depletion in HBEC and A549 (K-Ras mutated) cells

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PDF file - 352K, TUBB3 mRNA and protein expression according to K-RAs Si-RNA

Purpose:The detection of preexisting EGFRT790M subclones and the assessment of their clinical significance in the pretreatment of patients with EGFRT790M non–small cell lung cancer (NSCLC) remain unclear.Experimental Design:A total of 179 tumor samples from patients treated or not with a first-generation tyrosine kinase inhibitor (TKI) was analyzed. The presence of ultra-low levels of preexisting EGFRT790M mutation was evaluated using ultra-sensitive droplet digital PCR (ddPCR) and the clinical implication of these mutations on first-generation TKI efficiency assessed.Results:With a ddPCR linear performance of 0.999 and an analytical sensitivity of approximately 0.001%, we observed a 66% (99/150) overall incidence of ultra-low EGFRT790M mutation. Among 82 patients harboring EGFRactivating mutations, the presence of a preexisting EGFRT790M mutation prior to any treatment was significantly associated with a longer progression-free survival (PFS; P = 0.009; log-rank test). Interestingly, longer PFS was linked to concomitant EGFRdel19 and ultra-low EGFRT790M mutations. Moreover, the presence of both EGFRdel19 and ultra-low EGFRT790M mutations was identified as the best fit for predicting the clinical outcome of patients treated with TKI compared with an ultra-low EGFRT790M mutation status or an activating mutation alone (P = 0.042 and P = 0.0071, respectively).Conclusions:We demonstrate that the detection of the ultra-low EGFRT790M mutation in TKI-naïve patients is not a rare event. We suggest that ddPCR should be used in clinical practice to distinguish patients who may respond to first- or third-generation TKIs.

Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1β. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1β inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1β inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics.Lay abstract A previous study showed that canakinumab reduced the risk of lung cancer in patients with heart disease. Canakinumab blocks an inflammatory protein called IL-1β that is involved in cancer. Anti-cancer drugs used before surgery (‘neo-adjuvant’) can improve the success rate of surgery and may help prevent the cancer from returning. Neo-adjuvant trials help us understand how the drugs work and how they affect cancer. CANOPY-N (NCT03968419) is an ongoing randomized, exploratory, Phase II clinical trial testing canakinumab and pembrolizumab (a different cancer immunotherapy), alone or combined, for patients with early non-small-cell lung cancer. The study will test whether treatment can kill most cancer cells in the surgery sample (‘major pathological response’). It will also investigate other effects on cancer biology, levels of molecules that measure possible clinical benefit (‘biomarkers’) and side effects.

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International audience; Purpose: Maintenance chemotherapy is a reasonable choice for patients with metastatic non-small cell lung carcinoma (NSCLC) not progressing after induction therapy with a platinum-based doublet. Nevertheless, there have been no studies dedicated to elderly patients.Patients and methods: We conducted a randomised trial in patients aged 70-89 years, with advanced NSCLC (with neither EGFR mutation nor ALK rearrangement), who had not progressed after four cycles of monthly carboplatin and weekly paclitaxel in order to compare maintenance with either pemetrexed (500 mg/m2 d1, 22) in patients with non-squamous cell carcinoma or gemcitabine (1,150 mg/m2 d1, 8, 22) in squamous cell carcinoma to simple observation. The patients were required to have a performance status (PS) 0-2, mini-mental score >23, and creatinine clearance ≥45 mL/min. The primary end-point was overall survival (OS).Results: 632 patients were enrolled from May 2013 to October 2016. Of the 328 (52.3%) patients randomised after induction therapy, 166 patients were assigned to the observation arm, versus 162 to the switch maintenance arm, 119 of whom received pemetrexed and 43 gemcitabine. The median OS from randomisation was 14.1 months (95% confidence interval [CI]: 12.0-17.0) in the observation arm and 14 months (95% CI: 10.9-16.9) in the maintenance arm (p = 0.72). The median progression-free survival (PFS) from randomisation was 2.7 months (95% CI: 2.6-3.1) in the observation arm versus 5.7 months (95% CI: 4.8-7.1) in the maintenance arm (p < 0.001).Conclusion: Switch maintenance therapy significantly prolonged PFS but not OS and, thus, should not be proposed to elderly patients with advanced NSCLC.

International audience; Purpose: The metabolic changes associated with cachexia – sarcopenia syndrome might down-regulate antitumor immunity. We hypothesized that this syndrome reduces efficiency of immune checkpoint inhibitors (ICPI) in non-small cell lung cancer (NSCLC).Methods: The records of 142 consecutive NSCLC patients receiving first- or second-line anti-Programmed cell death protein 1) ICPI were reviewed. Response evaluation according to Response Evaluation Criteria in Solid Tumors 1.1 was performed at the eighth week of immunotherapy. Pretreatment cachexia was defined as a body-weight loss of 5% or more in the previous 6 months. Sarcopenia was estimated with the third lumbar skeletal muscle mass index (mSMI) and was evaluated before immunotherapy and at the eighth week. A decrease by 5% or more of the mSMI was considered as an evolving sarcopenia. The endpoints were disease control rate (DCR), progression-free (PFS) and overall survival (OS).Logistic regression model and Cox model took into account others covariables known to influence ICPI efficiency, particularly Programmed Death –Ligand 1 tumor cell score, Eastern Cooperative Oncology Group performance status and common somatic mutational status.Results: In multivariate analysis, cachexia – sarcopenia syndrome reduced the probability of achieving a disease control and were associated with a shorter survival. Patients without cachexia had a better probability to achieve disease control in comparison with those who did not experience cachexia (59.9 % and 41.1 %, respectively; odds ratio 95 % (confidence interval [95 %CI]): 2.60 (1.03–6.58)). Patients with cachexia had a shorter OS when compared with those without cachexia (hazard ratios [HR] (95 %CI): 6.26 (2.23–17.57)). Patients with an evolving sarcopenia had a shorter PFS and OS, with HR (95 %CI): 2.45 (1.09–5.53) and 3.87 (1.60–9.34) respectively.Conclusion: Cachexia – sarcopenia syndrome negatively influences patients’ outcome during anti-PD-1 ICPI therapy

INTRODUCTION: Abemaciclib is an oral, selective small-molecule CDK 4 and 6 inhibitor. In preclinical models, abemaciclib synergized with programmed cell death protein-1 blockade to enhance antitumor efficacy. Here, we report the safety and anticancer activity of abemaciclib plus pembrolizumab in two cohorts with NSCLC. METHODS: This nonrandomized, open-label, phase 1b study included patients with previously untreated programmed death-ligand 1-positive, KRAS-mutant nonsquamous metastatic NSCLC (cohort A); squamous NSCLC after one previous platinum-containing chemotherapy regimen for metastatic disease (cohort B); and two breast cancer cohorts (disclosed separately). Patients received 150 mg abemaciclib every 12 hours plus 200 mg pembrolizumab intravenously on day 1 every 21 days. The primary objective was safety; secondary objectives included objective response rate, disease control rate, progression-free survival, and overall survival. Clinical Trial Number: NCT02779751. RESULTS: Each cohort enrolled 25 patients. Grades greater than or equal to 3 treatment-emergent adverse events in cohorts A and B were reported by 20 (80%) and 19 patients (76%), respectively. Six patients in cohort A (24.0%) and two patients in cohort B (8.0%) had a confirmed partial response; disease control rate was 56% and 64%, respectively. Median progression-free survival was 7.6 months (95% confidence interval [CI]: 1.6-not estimable) and 3.3 months (95% CI: 1.4-5.2); median overall survival was 27.8 months (95% CI: 9.9-not estimable) and 6.0 months (95% CI: 3.7-13.1) in cohorts A and B, respectively. CONCLUSIONS: The combination of abemaciclib and pembrolizumab in stage IV NSCLC resulted in greater toxicity compared with that previously reported for each individual treatment. Risk-benefit profile does not warrant further evaluation of the combination in this population. ispartof: JTO Clin Res Rep vol:2 issue:11 pages:100234- ispartof: location:United States status: Published online

Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.Eli Lilly.

Resume Le cancer bronchique a petites cellules represente 14 % de l’ensemble des cancers bronchiques. Il reste un defi majeur de l’oncologie car les progres realises dans les trois dernieres decennies sont modestes. Apres un rapide apercu des connaissances en matieres d’alterations genomiques somatiques, les pistes de progres sont abordees par cette mise au point: le ciblage des mecanismes de reparation des dommages de l’ADN tout d’abord: les anti-PARPs, les molecules inhibitrices de l’EZH2; la de-repression de la voie NOTCH, le Rovalbituzumab – Tesirine; l’inhibition de la kinase serine/threonine Aurora A, le Temozolomide et sa dependance de la methylation du promoteur de MGMT. Ce premier volet laisse entrevoir un debut de prise en charge personnalisee du cancer bronchique a petites cellules. Le dernier volet porte sur le developpement des agents immuno-oncologiques et les informations recueillies par les etudes de phase 1 et 2: sont evoquees, la faible intensite de l’expression tissulaire de PD-L1, la relation possible de l’activite de ces agents en fonction de la charge mutationnelle tumorale. Enfin, l’analyse de l’etude de phase 3 de la chimiotherapie avec ou sans atezolizumab est detaillee.

Introduction This randomized phase II trial aimed at evaluating the engineered programmed cell death ligand 1 (PD-L1) antibody atezolizumab in SCLC progressing after first-line platinum–etoposide chemotherapy. Methods Patients were randomized 2:1 to atezolizumab (1200 mg intravenously every 3 weeks) until progression or unacceptable toxicity, or conventional chemotherapy (up to 6 cycles of topotecan or re-induction of initial chemotherapy). Patients were not selected based on PD-L1 tissue expression. The primary endpoint was objective response rate at 6 weeks. A two-stage design with 2:1 randomization and O'Brien-Fleming stopping rules was used. The null hypothesis was rejected if more than 12 of 45 patients were responders. Results Overall, 73 patients were randomized (atezolizumab n = 49; chemotherapy n = 24). At 6 weeks, 1 of 43 eligible atezolizumab patients achieved an objective response (2.3%, 95% confidence interval [CI]: 0.0–6.8), whereas 8 others had stable disease (20.9% disease control rate; 95% CI: 8.8–33.1). Among eligible chemotherapy patients (n = 20), 10% achieved an objective response (65% disease control rate). Median progression-free survival was 1.4 months (95% CI: 1.2–1.5) with atezolizumab and 4.3 months (95% CI: 1.5–5.9) with chemotherapy. Overall survival did not significantly differ between groups. Median overall survival was 9.5 months versus 8.7 months for the atezolizumab and the chemotherapy group, respectively (adjusted hazard ratioatezolizumab : 0.84, 95% CI: 0.45–1.58; p = 0.60). Two atezolizumab patients (4.2%) experienced grade 3 fatigue, and two others grade 1 dysthyroidism. Among 53 evaluable specimens, only 1 (2%) had positive immunohistochemical PD-L1 staining (SP142 clone). Conclusions Atezolizumab monotherapy in relapsed SCLC failed to show significant efficacy. No unexpected safety concerns were observed.

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Background: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. Methods: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. Results: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49, 65.3%) and RB1 (25/49, 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. Conclusion: ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.

International audience; Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DDR1 is upregulated during chemotherapy both in vitro and in vivo. Moreover, analysis of a cohort of patients with LUAD suggested that high DDR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DDR1 inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.

Resume Objectif Dans le but de connaitre ce que les medecins specialistes attendent de la chimiotherapie du cancer du poumon (stade 3b et 4), nous les avons confrontes a un auto-questionnaire en ligne decrivant cinq situations differentes de prescription. Methode Trente specialistes experts ont ete invites ; 22 ont repondu (73 %). Pour chacune des differentes situations cliniques, il etait demande a l’expert de se positionner sur 3 items : curabilite, allongement de la survie, soulagement des symptomes. Le jugement porte sur chaque item se faisait sur une echelle de Likert impaire, entre −2 « pas du tout probable » et 2 « tout a fait probable ». Resultats Pour la curabilite, le pourcentage de reponse −2 differait significativement en fonction de la situation clinique (test de Fisher : p Conclusion Ce que les medecins specialistes attendent de la chimiotherapie differe en fonction du pronostic presuppose. A la situation de plus mauvais pronostic correspond l’attente la plus forte en termes de soulagement des symptomes et la plus faible en termes de curabilite.

Small cell lung cancer accounts for 14% of all lung cancers. It remains a major challenge for oncology as the progresses made in the past three decades are modest. After a rapid overview of current knowledge regarding somatic genomic alterations, this state-of-art addresses pathways to improve small-cell lung cancer outcome such as the targeting of DNA damage repair mechanisms firstly anti-PARPs, inhibitory molecules of EZH2, derepression of the NOTCH pathway, rovalbituzumab-tesirine, inhibition of serine/threonine Aurora A kinase, temozolomide and its dependence on methylation of the MGMT promoter. This first chapter suggests the beginning of precision medicine in small cell lung cancer. The last section focuses on the development of immuno-oncological agents and the information collected from phase 1 and 2 studies: the low intensity of PD-L1 tissue expression and the possible relationship of the activity of these agents as a function of tumor mutational burden are pointed out.

Background: Complete surgical resection is the standard treatment for patients with stage I-IIIA non-small cell lung cancer (NSCLC). Five-year survival rates in this population range from 19% to 50%, with most patients dying from distant recurrence. As neoadjuvant/adjuvant chemotherapy yields a modest 5% absolute overall survival benefit for these patients with NSCLC, new treatment options are needed. Preliminary data with PD-1 or PD-L1 inhibitors as neoadjuvant therapy have shown major pathologic responses (MPRs) or pathologic complete responses in patients with resectable NSCLC. In the CANTOS study, reduced incidence of NSCLC and decreased lung cancer–related mortality were observed in a dose-dependent manner in patients with atherosclerosis who received canakinumab (interleukin 1β inhibitor) versus those who received placebo. In preclinical NSCLC humanized models, treatment with canakinumab ± anti–PD-1 inhibitor has shown promising activity, and a synergistic effect was observed with this combination, which may enhance the efficacy of PD-1 inhibition by modulating pro-tumor inflammation in the tumor microenvironment. In this context, the CANOPY-N study was designed to evaluate the effect of canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant treatment for patients with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a Phase II, randomized, open-label study evaluating the effect of canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant treatment in patients with resectable NSCLC. Patients with histologically confirmed stage IB-IIIA NSCLC (excluding N2 and T4 tumors), no prior systemic therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and eligibility for surgery with a planned resection in approximately 4-6 weeks after first dose of study treatment are eligible to participate. An archival (if obtained up to 6 months before first day of treatment) or new biopsy is required. Approximately 110 patients will be randomized in a 2:2:1 ratio (stratified by histology [squamous/nonsquamous]) to receive a total of 2 doses (200 mg every 3 weeks) of canakinumab alone (n=44) or in combination with pembrolizumab (n=44) or pembrolizumab alone (n=22), with safety follow-up up to 130 days from last study-drug dose. The primary endpoint is MPR rate (≤10% of residual viable tumor cells at time of surgery), and secondary endpoints include overall response rate per RECIST 1.1, MPR rate based on local assessment, surgical feasibility rates, safety, incidence of antidrug antibodies, pharmacokinetic parameters, and assessment of the relationship between blood- or tissue-based biomarkers and MPR. As of May 27, 2021, there are 44 active study locations. Citation Format: Jay M. Lee, Jean-Louis Pujol, Pilar Garrido, Edward S. Kim, Masahiro Tsuboi, Rafael Caparica Bitton, Jiawei Duan, Cecile Blin, Alexander Savchenko, Tony Mok. Canakinumab or Pembrolizumab as Monotherapy or in Combination as Neoadjuvant Therapy in Patients With Resectable Non-Small Cell Lung Cancer: CANOPY-N Trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA035.

Introduction: This study aimed at generating a new simplified prognostic score (SPS) using common clinical and biological variables to discriminate a limited number of subgroups of patients with SCLC differing by their overall survival (OS). Methods: The SPS was developed exploring the Montpellier University Hospital retrospective database of 401 patients over a 16-year period. All patients had received etoposide - platinum-based chemotherapy as first-line treatment. The SPS development took into account significant determinants of OS in the Cox model, weighted by their regression β coefficients. Validation of the consequent SPS has been done separately in a combined population of 213 patients accrued from two different published trials (NCT03059667 and NCT00930891). Results: The significant independent determinants of OS included the following: (1) American Joint Committee on Cancer TNM stage IV (hazard ratio [HR]: 2.52; 95% confidence interval [CI]: 1.91–3.33); (2) Eastern Cooperative Oncology Group performance status greater than 1 (HR: 2.27; 95% CI: 1.79–2.87); (3) the presence of liver metastases (HR: 1.66; 95% CI: 1.29–2.15); and (4) neutrophil-to-lymphocyte ratio greater than 4 (HR: 1.39; 95% CI: 1.11–1.92). The SPS generated with these four variables, segregated three groups (good, intermediate, and poor prognosis) with respective median OS of 26.9 months (95% CI: 20.1–38.9), 11.5 months (95% CI: 9.8–13.0), and 6.8 months (95% CI: 5.8–8.3; log-rank p < 10–4). Harrell's C statistic estimate was 0.68 ± 0.012, suggesting goodness of calibration. In the validation cohort, the SPS segregated the aforementioned three subgroups in a nearly similar manner, with respective median OS: 27.2, 12.3, and 8.6 months (log-rank p < 10–3; Harrell’s C statistic: 0.58 ± 0.02). Conclusions: The SPS is easy to calculate in real-life practice and efficiently discriminates three populations with different prognoses. This study deserves further validation of this score in patients with SCLC receiving immunochemotherapy.

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EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFR(T790M) and EGFR(C797S). It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (p-STAT3) in EGFR(T790M) and EGFR(C797S) tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a p-STAT3–dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we showed that tyrosine kinase inhibitor–resistant tumors, with EGFR(T790M) and EGFR(C797S) mutations, were highly responsive to the combined treatment of Notch inhibitors with gefitinib or osimertinib, respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib-treated patients after disease progression.

RASSF1 gene methylation predicts longer disease-free survival (DFS) and overall survival (OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neo-adjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according to the randomized Phase 3 IFCT (Intergroupe Francophone de Canc&eacute, rologie Thoracique)-0002 trial. To better understand these results, this study used four human bronchial epithelial cell (HBEC) models (HBEC-3, HBEC-3-RasV12, A549, and H1299) and modulated the expression of RASSF1A or YAP-1. Wound-healing, invasion, proliferation and apoptosis assays were then carried out and the expression of YAP-1 transcriptional targets was quantified using a quantitative polymerase chain reaction. This study reports herein that gemcitabine synergizes with RASSF1A, silencing to increase the IAP-2 expression, which in turn not only interferes with cell proliferation but also promotes cell migration. This contributes to the aggressive behavior of RASSF1A-depleted cells, as confirmed by a combined knockdown of IAP-2 and RASSF1A. Conversely, paclitaxel does not increase the IAP-2 expression but limits the invasiveness of RASSF1A-depleted cells, presumably by rescuing microtubule stabilization. Overall, these data provide a functional insight that supports the prognostic value of RASSF1 gene methylation on survival of early-stage lung cancer patients receiving perioperative paclitaxel-based treatment compared to gemcitabine-based treatment, identifying IAP-2 as a novel biomarker indicative of YAP-1-mediated modulation of chemo-sensitivity in lung cancer.

Purpose: The detection of preexisting EGFRT790M subclones and the assessment of their clinical significance in the pretreatment of patients with EGFRT790M non–small cell lung cancer (NSCLC) remain unclear. Experimental Design: A total of 179 tumor samples from patients treated or not with a first-generation tyrosine kinase inhibitor (TKI) was analyzed. The presence of ultra-low levels of preexisting EGFRT790M mutation was evaluated using ultra-sensitive droplet digital PCR (ddPCR) and the clinical implication of these mutations on first-generation TKI efficiency assessed. Results: With a ddPCR linear performance of 0.999 and an analytical sensitivity of approximately 0.001%, we observed a 66% (99/150) overall incidence of ultra-low EGFRT790M mutation. Among 82 patients harboring EGFRactivating mutations, the presence of a preexisting EGFRT790M mutation prior to any treatment was significantly associated with a longer progression-free survival (PFS; P = 0.009; log-rank test). Interestingly, longer PFS was linked to concomitant EGFRdel19 and ultra-low EGFRT790M mutations. Moreover, the presence of both EGFRdel19 and ultra-low EGFRT790M mutations was identified as the best fit for predicting the clinical outcome of patients treated with TKI compared with an ultra-low EGFRT790M mutation status or an activating mutation alone (P = 0.042 and P = 0.0071, respectively). Conclusions: We demonstrate that the detection of the ultra-low EGFRT790M mutation in TKI-naïve patients is not a rare event. We suggest that ddPCR should be used in clinical practice to distinguish patients who may respond to first- or third-generation TKIs.

International audience

Background: Complete surgical resection is the standard treatment for patients with stage I-IIIA non-small cell lung cancer (NSCLC). Five-year survival rates range from 19% to 50%, with most patients dying from distant recurrence. Neoadjuvant or adjuvant chemotherapy improves overall survival (OS) by only 5% in patients with NSCLC, and new treatment options are needed. Preliminary data for PD1 or PD-L1 inhibitors as neoadjuvant therapy have shown major pathologic responses (MPRs) or pathologic complete responses (pCRs) in patients with early-stage NSCLC. The CANTOS study demonstrated reduced incidence of NSCLC and decreased lung cancer-related mortality with canakinumab (interleukin 1β inhibitor) versus placebo, in a dose-dependent manner for patients with atherosclerosis. In preclinical NSCLC humanized models, treatment with canakinumab ± anti-PD-1 inhibitor could lead to antitumor activity. Combination of canakinumab and pembrolizumab is expected to enhance the efficacy of PD-1 inhibition by inhibiting dysregulated inflammation in the tumor microenvironment. Based on available evidence, the CANOPY-N study was designed to evaluate the effect of canakinumab and pembrolizumab as monotherapy or in combination as neoadjuvant treatment for patients with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a Phase II, randomized, open-label study evaluating the effect of canakinumab and pembrolizumab as monotherapy or in combination as neoadjuvant treatment in patients with resectable NSCLC. Patients with histologically confirmed stage IB-IIIA NSCLC (excluding N2 and T4 tumors), no prior systemic therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and eligibility for surgery and with a planned surgical resection in approximately 4-6 weeks (after first dose of study treatment) are eligible to participate. An archival (if obtained up to 6 months before first day of treatment) or new biopsy is required. Approximately 110 patients will be randomized in a 2:2:1 ratio (stratified by histology [squamous/nonsquamous]) to one of the treatment arms to receive a total of 2 doses (200 mg every 3 weeks) of canakinumab alone (n=44) or in combination with pembrolizumab (n=44) or pembrolizumab alone (n=22), with safety follow-up up to 130 days from last study drug dose. The primary endpoint is MPR rate (≤10% of residual viable tumor cells at time of surgery), and secondary endpoints include determination of overall response rate, MPR rate based on local review, surgical feasibility rates, incidence of antidrug antibodies, and pharmacokinetic parameters. As of October 19, 2020, there are 36 active study locations. Citation Format: Jay M. Lee, Tony Mok, Pilar Garrido, Edward S. Kim, Çağatay Arslan, Masahiro Tsuboi, Tuochuan Dong, Cecile Blin, Vanessa Rodrik-Outmezguine, Bijoyesh Mookerjee, Vanessa Passos, Jean-Louis Pujol. Canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant therapy in patients with surgically resected non-small cell lung cancer: CANOPY-N trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT237.

9015 Background: Human epidermal growth factor receptor 2 ( HER2) exon 20 insertions and mutations are oncogenic drivers found in 1-2% of NSCLC. However, there are no approved therapies for these patients. Many studies suggest that the use of HER2 inhibitors developed for breast cancer patients might be of interest in this setting. The aim of this trial was to prospectively evaluate the interest of a combination of two antibodies against HER2 (trastuzumab and pertuzumab) with docetaxel. Methods: IFCT-1703 R2D2 trial is a multicenter, non-randomized phase 2 study with a two-stage design, a power of 90% and an alpha risk at 5% (one-sided). HER2 mutational status was assessed locally in certified molecular genetic centers. Main other inclusion criteria were advanced NSCLC, progression after ≥ 1 platinum-based chemotherapy, asymptomatic brain metastases, left ventricular ejection fraction (LVEF) ≥ 50%, and PS 0-2. Patients were treated every 3 weeks with pertuzumab at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at a loading dose of 8 mg/kg and 6 mg/kg thereafter; and docetaxel at 75 mg/m². Treatment was given until toxicity or disease progression. The primary outcome was overall response rate (ORR). Other endpoints included duration of response, progression-free survival and safety. NCT number: NCT03845270. Results: From May 2019 to October 2020, 45 patients were enrolled in 17 centers and received study treatment. Median age was 64.5 years (range 31–84), 72% females, 35% smokers, 100% non-squamous histology and 15% with ECOG PS 2. 31.1% patients had brain metastases. PD-L1 was expressed ≥ 1% and ≥ 50% in 36% and 7% of the patients, respectively. No other oncogene driver was found associated with HER2 exon 20 mutation. With a median follow-up of 12 months, 44 (98%) patients were evaluable for the primary endpoint. Overall response rate was 29% (n = 13), stable disease 56% (n = 26). Median PFS was 6.8 months (95% CI[4.0-8.5]). Median duration of treatment in patients with confirmed response (n = 13) was 10 months (95% CI[2.7-14.9]). At the time of data cut-off, 15 patients (33%) were still under treatment. Grade 3/4 treatment-related adverse events (AEs) were observed in 64% of patients. No patient experienced treatment discontinuation because of toxicity. One sudden death was possibly related to treatment. Most frequent grade ≥ 3 AEs were neutropenia (33%), diarrhea (13%) and anaemia (9%). Grade 1/2 dyspnea was observed in 3 (6.7%) patients. No ILD were reported. Variation LVEF was -1.72% on average (min: -18 %; max: 10 %). Conclusions: The triplet trastuzumab, pertuzumab and docetaxel is feasible and active in HER2 pretreated advanced NSCLC. These results confirm the activity of HER2 antibodies-based strategy which should be considered in these patients. Clinical trial information: NCT03845270.

Les Interventions Non Medicamenteuses (INM) sont devenues des solutions incontournables pour ameliorer la qualite de vie et la sante. Elles presentent dans certains cas un impact positif sur la duree de vie et des benefices sociaux et economiques. Leur usage augmente sans cesse. Une plateforme universitaire collaborative basee a Montpellier, la Plateforme CEPS, reflechit aux manieres de les evaluer. Cet article presente plus en detail ses activites.

// Guenaelle Levallet 1 , Fatemeh Dubois 2 , Pierre Fouret 3 , Martine Antoine 4 , Solenn Brosseau 2,5,6 , Emmanuel Bergot 2,5 , Michele Beau-Faller 7 , Valerie Gounant 6,8 , Elisabeth Brambilla 9 , Didier Debieuvre 10 , Olivier Molinier 11 , Francoise Galateau-Salle 1 , Julien Mazieres 12 , Elisabeth Quoix 13 , Jean-Louis Pujol 14 , Denis Moro-Sibilot 15 , Alexandra Langlais 16 , Franck Morin 16 , Virginie Westeel 17 and Gerard Zalcman 5,6,18,19 1 Service d’Anatomie et Cytologie Pathologique, Centre Hospitalier Universitaire de Caen, Normandie Universite, Caen, France 2 Normandie Universite; UMR 1086 INSERM, Caen, France 3 Service d’Anatomie Pathologique, Pitie-Salpetriere, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 4 Service d’Anatomie Pathologique, Hopital Tenon, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 5 Service de Pneumologie et Oncologie Thoracique, Centre Hospitalier Universitaire de Caen, Normandie Universite, Caen, cedex, France 6 Service d’Oncologie Thoracique, Hopital Bichat-Claude Bernard, AP-HP, Universite Paris-Diderot, Paris, France 7 Laboratoire de Biochimie et Biologie moleculaire, Hopital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Universite de Strasbourg, BP426 Strasbourg, Cedex, France 8 Service de Pneumologie, Hopital Tenon, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 9 Service d’Anatomie Pathologique, Hopital Albert Michallon, Centre Hospitalier Universitaire de Grenoble, La Tronche, France 10 Service de Pneumologie, GHRMSA-Centre Hospitalier Eric Muller, Mulhouse, France 11 Service de Pneumologie, Centre Hospitalier du Mans, Le Mans, France 12 Service de Pneumologie, Hopital Larrey, Centre Hospitalier Universitaire de Toulouse, Universite de Toulouse III, Toulouse, France 13 Service de Pneumologie, Nouvel Hopital Civil, Hospices Civils de Strasbourg, Universite de Strasbourg, BP426 Strasbourg, Cedex, France 14 Service de Pneumologie, Centre Hospitalier Universitaire Arnaud de Villeneuve, Universite de Montpellier, Montpellier, France 15 Unite d’Oncologie Thoracique–Pneumologie, CHU de Grenoble, INSERM U823, Grenoble, France 16 Intergroupe Francophone de Cancerologie Thoracique (IFCT), Paris, France 17 Service de Pneumologie, Hopital Jean-Minjoz, Centre Hospitalier Universitaire de Besancon, Universite de Franche-Comte, Besancon, France 18 CIC INSERM 1425-CLIP2 Paris-Nord, Hopital Bichat-Claude Bernard, AP-HP, Paris, France 19 On Behalf of the IFCT (Intergroupe Francophone de Cancerologie Thoracique) Correspondence to: Gerard Zalcman, email: // Keywords : non-small cell lung cancer; neo-adjuvant chemotherapy; MSH2; BRCA1; MGMT Received : August 08, 2016 Accepted : December 05, 2016 Published : December 19, 2016 Abstract Introduction: DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks. Methods: We used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I-II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O 6 MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens. Results: Median follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [ 1 . 07 - 2 . 34 ], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [ 1 . 11 - 2 . 08 ], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high ( n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [ 1 . 45 - 4 . 33 ], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [ 0 . 31 - 0 . 83 ], p = 0.006) risk of death. Interpretation: DNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors.

Resume Les complications en chirurgie oncologique thoracique varient selon les comorbidites et le type de chirurgie. Les hemorragies, les infections et l’œdeme pulmonaire ne sont pas specifiques du type de resection mais sont plus frequemment rencontres apres pneumonectomies. Les pneumonectomies ont une morbidite due aux modifications majeures du contenu intrathoracique. L’infarctus pulmonaire et le volvulus bronchique sont des situations urgentes rencontrees apres lobectomie. Le scanner met en evidence des signes congestifs localises et la stenose ou l’occlusion d’une veine ou d’une bronche. La reconnaissance rapide d’evenements critiques, en particulier grâce a une analyse systematique du scanner, est capitale pour une prise en charge adequate au decours d’une complication postoperatoire ou retardee en oncologie thoracique.

Resume Les resections majeures correspondent aux pneumonectomies et aux lobectomies. Les resections infralobaires sont les segmentectomies et les resections atypiques. Elles sont pratiquees en chirurgie ouverte par thoracotomie ou de facon mini-invasive video-assistees pour la lobectomie et les resections infralobaires. La comprehension du geste realise permet d’interpreter les aspects postoperatoires normaux et de distinguer ces modifications anatomiques des complications postoperatoires potentielles. La chirurgie entraine une adaptation physiologique de la cavite thoracique, plus ou moins marquee en fonction du volume pulmonaire reseque, et evolutive au cours des premiers mois. La radiographie de thorax et le scanner permettent de mettre en evidence un pincement des espaces intercostaux, une ascension de la coupole diaphragmatique et un deplacement du mediastin du cote opere apres resections majeures.

International audience; A shift in mortality and morbidity has been observed in people living with human immunodeficiency virus (PLWHIV) from acquired immunodeficiency syndrome (AIDS) to non-AIDS diseases. Lung cancer has the highest incidence rates among all the non-AIDS-defining malignancies and is associated with mortality rates that exceed those of other cancers. Strategies to increase lung cancer survival in PLWHIV are needed. Lung cancer screening with chest LDCT has been shown to be efficient in the general population at risk. The objective of this review is to discuss lung cancer screening with chest computed tomography in PLWHIV. Lung cancer screening in PLWHIV is feasible. Whether PLWHIV could benefit from an age threshold for screening that is earlier than the minimum age of 55 years usually required in the general population still needs further investigation. Studies evaluating smoking cessation programs and how they could be articulated with lung cancer screening programs are also needed in PLWHIV.

Objective Chemotherapy is widely prescribed for lung cancer with palliation as primary end point. This study aimed at determining how preconceptions about lung cancer and its treatment interact with medical discourse into acceptance of chemotherapy. Methods Twenty-three purposively selected patients who recently accepted chemotherapy were invited to participate in this survey consisting of semi-structured in-depth interviews. Grounded theory was applied to investigate participants' perceptions of the context that have surrounded their decision to undergo chemotherapy. Results Major drivers of social representation of illness were linked with stigma. Participants also evoked the disease itself as a stereotype representation of incurable disease. Significant others' experiences were major components of participants' knowledge of chemotherapy. Searching for information regarding lung cancer actively confronted participants with the disease and its prognosis. However, the searching process was self-limited because of the poor prognosis of the disease, insofar as complete information would have precluded from any hope. We therefore identified 3 domains that provide insights into the participant's views and attitude toward chemotherapy: (i) synthesizing preconceptions of disease and chemotherapy with personal medical case; (ii) slowly constructing complex knowledge of cancer and treatment; and (iii) accepting chemotherapy as a surrogate for acknowledging incurable disease. Conclusion Patients have preconceptions about chemotherapy that result from complex features involving social perception, stigma, and significant others' experiences. In this context, developing a personal knowledge about lung cancer and its treatment is a slow construction. This process needs time to be explained and reformulated, so that patients might give their informed consent.

Resume Parmi l’ensemble des cancers bronchiques, le cancer a petites cellules occupe une place particuliere. L’idee que ce cancer, aujourd’hui sur la voie d’un declin epidemiologique, soit en train de se retirer invaincu est omnipresente dans la litterature medicale. Il y a pourtant des avancees que je souhaiterais souligner par cette breve revue. Il s’agit de mettre en perspective la chirurgie de ces cancers, leur genotypage, et l’identification de phenotypes biocliniques particuliers. Deux axes beneficient actuellement d’un effort de recherche : l’identification de cibles genotypiques somatiques ; le controle de la maladie par l’immunotherapie.

Summary Background Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. Methods In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. Findings Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9–48·4) in the MAGE-A3 group and 39·5 months (27·9–50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2–not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7–not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89–1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6–not reached) in those in the MAGE-A3 group and 56·9 months (44·4–not reached) in the placebo group (HR 0·97, 95% CI 0·80–1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). Interpretation Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. Funding GlaxoSmithKline Biologicals SA.

Background: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p

Resume Cet article decrit les avancees recentes relatives a la prise en charge diagnostique et therapeutiques des cancers bronchiques a petites cellules. Une place particuliere est faite au developpement des inhibiteurs des proteines de controle de l’immunite. Il cite aussi les points encore debattus autour des explorations pretherapeutiques, de la radiotherapie thoracique, et de l’irradiation prophylactique cerebrale. Enfin, les pistes de therapie ciblant les anomalies de reparation des dommages de l’ADN sont evoquees. © 2020 SPLF. Publie par Elsevier Masson SAS. Tous droits reserves.

Objectives: Complete surgical resection is the standard treatment (tx) for pts with stage I-IIIA NSCLC. 5-year survival rates range from 19-50%, with most pts dying from distant recurrence. Neoadjuvant or adjuvant chemotherapy improves overall survival (OS) by only 5% in pts with NSCLC, and new tx options are needed. Preliminary data with PD-1 or PD-L1 inhibitors as neoadjuvant therapy has shown major pathologic responses (MPR) or pathologic complete responses (pCR) in pts with early stage NSCLC. CANTOS study demonstrated reduced incidence of NSCLC and decreased lung cancer-related mortality with CAN (IL-1β inhibitor) versus placebo, in a dose-dependent manner for pts with atherosclerosis. In pre-clinical NSCLC humanized models, tx with CAN±anti PD-1 inhibitor could lead to anti-tumor activity. Combination of CAN and PEM is expected to enhance the efficacy of PD-1 inhibition by inhibiting dysregulated inflammation in tumor microenvironment. Based on available evidence, CANOPY-N study was designed to evaluate effect of CAN and PEM as monotherapy or in combination as neoadjuvant tx for pts with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a phase II, randomized, open-label study evaluating effect of CAN or PEM monotherapy or in combination as neoadjuvant tx in resectable NSCLC pts. Histologically confirmed stage IB-IIIA, tx-naive, ECOG PS 0-1 NSCLC pts eligible for surgery and with a planned surgical resection in approximately 4-6 weeks (after 1st dose of study tx), are eligible to participate. An archival (if obtained up to 6 months before 1st day of tx) or new biopsy is required. Approximately 110 pts will be randomized in 2:2:1 ratio (stratified by histology [squamous/non-squamous]) to one of the tx arms to receive a total of 2 doses (200 mg Q3w) of CAN alone (n=44) or in combination with PEM (n=44) or PEM (n=22) with safety follow-up up to 130 days from last study drug dose. Primary endpoint is to determine MPR rate (≤10% of residual viable tumor cells at time of surgery), secondary endpoints include determination of ORR, MPR rate based on local review, surgical feasibility rates, anti-drug antibodies incidence and PK parameters. Citation Format: Jay M. Lee, Pilar Garrido, Edward S. Kim, Cagatay Arslan, Jean-Louis Pujol, Yuanbo Song, Cecile Blin, Vanessa Rodrik-Outmezguine, Bijoyesh Mookerjee, Vanessa Passos, Tony Mok. Randomized phase II study of canakinumab (CAN) or pembrolizumab (PEM) alone or in combination as neoadjuvant therapy in patients (Pts) with surgically resected (Stage IB-IIIA) non-small cell lung cancer (NSCLC): CANOPY-N [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT192.