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BackgroundAnti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.Patients and methodsWe conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation.ResultsWe studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).Conclusions: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

Francesco Facchinetti,1,2 Antonin Levy,3,4 Samy Ammari,5 Charles Naltet,6 Pernelle Lavaud,6 Mihaela Aldea,6 Damien Vasseur,7 David Planchard,6 Benjamin Besse2,6 1Predictive Biomarkers and Novel Therapeutic Strategies in Oncology, Inserm U981, Gustave Roussy Cancer Center, Villejuif, France; 2Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France; 3Department of Radiation Oncology, Institut d’Oncologie Thoracique (IOT), Gustave Roussy Cancer Center, Villejuif, France; 4INSERM U1030, Molecular Radiotherapy, Gustave Roussy, Université Paris-Saclay, Villejuif, France; 5Department of Radiology, Gustave Roussy Cancer Center, Villejuif, France; 6Department of Medical Oncology, Institut d’Oncologie Thoracique (IOT), Gustave Roussy Cancer Center, Villejuif, France; 7Department of Medical Biology and Pathology, Gustave Roussy Cancer Center, Villejuif, FranceCorrespondence: Benjamin BesseDepartment of Medical Oncology, Institut d’Oncologie Thoracique (IOT), Gustave Roussy Cancer Center, Villejuif, FranceEmail benjamin.besse@gustaveroussy.frBackground: ROS1 tyrosine kinase inhibitors (TKIs) have showed activity and efficacy in ROS1-rearranged non-small cell lung cancer (NSCLC). In the clinical practice, besides the utilization of crizotinib, less is known about the best treatment strategies involving additional, new-generation TKIs for the sequential treatment of ROS1-positive NSCLC patients.Case Presentation: A patient suffering from a ROS1-rearranged lung adenocarcinoma, after receiving cisplatin-pemetrexed chemotherapy, was treated with entrectinib, a new-generation ALK/ROS1/NTRK inhibitor. After 16 months, central nervous system (CNS) metastases appeared, without extra-cerebral disease progression. Stereotactic brain radiotherapy was performed and entrectinib was maintained, due to the global systemic disease control. Approximately one month after radiotherapy, thoracic and meningeal progressions were detected, the latter highly symptomatic with neurocognitive disorders, visual hallucinations and worsening of psycho-motor impairment. A lumbar puncture was positive for tumor cells and for an EZR-ROS1 fusion. The administration of lorlatinib (a third-generation ALK/ROS1 inhibitor) prompted an extremely rapid improvement of clinical conditions, anticipating the positive results observed at radiologic evaluation that confirmed the disease response still ongoing after nine months since treatment start.Discussion: With the expanding availability of targeted agents with differential activity on resistance mechanism and on CNS disease, choosing wisely the best treatment strategies is pivotal to assure the best clinical outcomes in oncogene-addicted NSCLC patients. Here we have reported lorlatinib reverted an almost fatal meningeal carcinomatosis developing during entrectinib in a ROS1-positive NSCLC patient.Keywords: tyrosine kinase inhibitors, TKI, central nervous system, CNS, brain, lung cancer, radiotherapy

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. 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 (H 0 : 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. 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. 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. • APPLE trial demonstrated that serial monitoring of T790M status by ctDNA is feasible in patients with EGFR -mutant NSCLC for informing treatment decissions. • Serial monitoring of ctDNA identified 17% of patients with molecular progression before RECIST progression leading to an earlier switch to osimertinib with a clinically meaningful 18-month PFS of 67%. • More sensitive techniques for the assessment of molecular resistance in ctDNA are needed in prospective clinical trials assessing sequential targeted therapy treatment strategies. [ABSTRACT FROM AUTHOR]

While radiomics analysis has been applied for localized cancer disease, its application to the metastatic setting involves a non-exhaustive lesion subsampling strategy which may sidestep the intrapatient tumoral heterogeneity, hindering the reproducibility and the therapeutic response performance. Our aim was to evaluate if radiomics features can capture intertumoral intrapatient heterogeneity, and the impact of tumor subsampling on the computed heterogeneity. To this end, We delineated and extracted radiomics features of all visible tumors from single acquisition pre-treatment computed tomography of patients with metastatic lung cancer (cohort L) and confirmed our results on a larger cohort of patients with metastatic melanoma (cohort M). To quantify the captured heterogeneity, the absolute coefficient of variation (CV) of each radiomics index was calculated at the patient-level and a sensitivity analysis was performed using only a subset of all extracted features robust to the segmentation step. The extent of information loss by six commonly used tumor sampling strategies was then assessed. A total of 602 lesions were segmented from 43 patients (median age 57, 4.9% female). All robust radiomics indexes exhibited at least 20% of variation with significant heterogeneity both in heavily and oligo metastasized patients, and also at the organ level. None of the segmentation subsampling strategies were able to recover the true tumoral heterogeneity obtained by exhaustive tumor sampling. Image-based inter-tumor intra-patient heterogeneity can be successfully grasped by radiomics analyses. Failing to take into account this kind of heterogeneity will lead to inconsistent predictive algorithms. Guidelines to standardize the tumor sampling step and/or AI-driven tools to alleviate the segmentation effort are required. [ABSTRACT FROM AUTHOR]

According to the results of this multi-tumour, multi-institutional Simon two-stage design phase II study the aurora kinase inhibitor danusertib was found to have only limited anti-tumour activity in heavily pre-treated patients with breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer.Background This multi-centre phase II trial assessed the activity, safety (CTCAE 3.0) and pharmacokinetics (PK) of the pan-Aurora kinase inhibitor danusertib hydrochloride (PHA-739358) in breast (BC), ovarian (OC), pancreatic (PC), colorectal (CRC), small-cell (SCLC) and non-small-cell lung (NSCLC) cancers. Methods Consenting adult patients with good performance and organ function with advanced/metastatic tumours who had failed systemic therapy were treated in independent, disease-specific cohorts with danusertib 500 mg/m2 given as 24-h i.v. infusion every 14 days with until progression or unacceptable toxicity. A two-stage design was applied. Primary end point was the progression-free rate (PFR) at 4 months (RECIST1.1). Results A total of 223 patients were enrolled with 219 actively treated. The median relative dose intensity of danusertib was similar for all tumour types (84.6%–99.6%). The median number of biweekly treatment cycles ranged from 3 to 4/patient (maximum 5–40 cycles/entity) and the median treatment duration varied between 7.6 and 10.0 weeks per histotype. Danusertib did not meet pre-specified protocol criteria for clinically relevant activity in any of the treated cancers. The PFR at 4 months was 18.4% in BC, 12.1% in OC, 10.0% in PC, 10.4% in NSCLC (all histotypes), 16.1% in squamous NSCLC and 0% in SCLC and CRC. Some radiological and/or biochemical indication of antitumor activity was seen in BC, OC, PC and NSCLC, including two confirmed partial responses. The most frequent drug-related non-laboratory adverse events (AEs) were fatigue/asthenia, nausea, diarrhoea, anorexia, vomiting, alopecia, constipation and pyrexia. Common laboratory AEs included haematological toxicity, hypalbuminaemia and increases in liver enzymes. Treatment was discontinued due to AEs in only 5.5% of patients. Plasma concentrations of danusertib were in line with results from earlier studies. Conclusion Single-agent danusertib did show only marginal anti-tumour activity in common solid tumours after failure of prior systemic therapies. The safety and PK profile was consistent with previous experience. Clinical trial number 2006-003772-35. [ABSTRACT FROM PUBLISHER]

Background: We recently demonstrated that excision repair cross-complementing group 1 protein (ERCC1) is predictive of adjuvant cisplatin-based chemotherapy benefit in resected non-small-cell lung cancer (NSCLC). Non-squamous cell carcinomas (non-SCCs) carry an increased risk of brain metastases (BMs). We hypothesised that there might be an increased incidence of BMs in ERCC1-negative non-SCCs when treated with adjuvant cisplatin-based chemotherapy.Patients and methods: Incidence of BMs and histoclinical parameters were analysed in a population of 761 patients enrolled in the International Adjuvant Lung Cancer Trial. A subgroup analysis was carried out in patients with ERCC1-negative non-SCCs.Results: Of 761 patients, 98 developed BMs alone or in association with other metastatic sites, with a 5-year incidence rate of 18.0% (14.7%-21.8%). In the multivariate analysis, the clinical parameters associated with the occurrence of BMs were the nodal status (P = 0.02) and histological type [give hazard ratio (HR) for non-squamous to quantify introduction assertion, P = 0.002]. Chemotherapy had no effect on BMs [HR = 1.4 (0.90-2.1), P = 0.14]. In patients with non-SCC histology (n = 335), adjuvant chemotherapy was associated with an increased risk of BMs [HR = 2.1 (1.01-4.3), P = 0.04] for ERCC1-negative tumours, whereas there was no evidence of an effect on BMs for ERCC1-positive tumours [HR = 1.1 (0.38-3.0), P = 0.90]. Nevertheless, these two effects are not different (P = 0.30 for interaction) possibly due to a lack of power in this subgroup.Conclusions: This study suggests that adjuvant cisplatin-based chemotherapy is associated with an increased risk of BMs in patients with resected chemosensitive non-SCCs. If confirmed, these data could provide a rationale for new follow-up and/or prophylactic strategies. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented which discusses the status of the KRAs mutations in the non-small-cell lung cancer (NSCLC) patients along with the effectiveness of the anti-epidermal growth factor receptor (EGFR) antibodies.

approximately 30% of lung carcinomas are resected and these cases are candidates for adjuvant treatments. The PORT meta-analysis reported in 1999 that postoperative radiotherapy had a detrimental effect for pathological N0 and N1 patients, and a debatable effect for N2 patients. Following the results of the 1995 meta-analysis on the role of chemotherapy (CT) in non-small-cell lung cancer (NSCLC), many randomized, controlled trials were launched to evaluate the effect of adjuvant cisplatin-based CT after the complete resection of NSCLC. The Lung adjuvant Ciplatin Evaluation pooled analysis included a total of 4584 patients recruited in five recent cisplatin-based adjuvant trials. It confirmed that adjuvant CT was associated with an absolute 5-year survival benefit of 5.3% (P = 0.0043). In addition, it showed that adjuvant cisplatin-based CT is detrimental in cases of stage Ia resected NSCLC; it also suggested that the combination of vinorelbine and cisplatin was of more benefit than older two and three drug combinations. The individual data-based meta-analysis was also updated with a total of over 10 000 patients. It confirmed the substantial effect of postoperative CT, with or without postoperative radiotherapy, with a substantial overall benefit of 4% at 5 years. Recent results of biological programs suggest that evaluating the expression of various tumor markers, including excision repair cross-complementation group 1, may allow the identification of patients most likely to benefit from CT. If these results are confirmed, tailored therapy might be the next step forward for resected NSCLC. [ABSTRACT FROM AUTHOR]

The article focuses on the main targeted therapies in lung cancer. It describes the cell growth pathways, programmed cell death and neo-angiogenic factors in patients with lung cancer. The role of epidermal growth factor receptor, farnesyl transferase inhibitors (FTI) and mammalian target of rapamycin (mTOR) in lung cancer treatment is examined. The article also discusses cell cycle, apoptosis and angiogenesis targeting.

The article presents clinical recommendations of the European Society for Medical Oncology (ESMO) for the diagnosis, treatment and follow-up of non-small-cell lung cancer. Its pathological diagnosis is in accordance to the World Health Organization classification. Staging and risk assessment may include a complete history and physical examination, chest x-ray and computed tomography. Its treatment includes cisplatin-based adjuvant chemotherapy, postoperative radiotherapy and platinum-based chemotherapy.

Background: Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC).Methods: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy.Results: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53.Conclusions: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.). [ABSTRACT FROM AUTHOR]

Discoveries in non-small-cell lung cancer (NSCLC) led to the approval of multitude of tyrosine kinase inhibitors (TKI). Elevation of pancreatic enzymes (EPE), lipase and amylase, is frequently seen after TKI introduction. It is not always clear whether EPE in this setting has clinical relevance, and recommendations on pancreatic enzymes assessment are not standardized. Our hypothesis was that EPE associated with TKI did not have clinical implication most of the time. The aim of this study was to establish the risk of clinical pancreatitis associated with TKIs, and if routine assessment of pancreatic enzymes was needed. In a monocentric retrospective study, we examined medical records of adult patients with metastatic NSCLC and genetic alterations in ALK, ROS, BRAF, RET, or NTRK, treated with TKI at Gustave Roussy, Villejuif (France) between 2011-2023. Patients having pancreatic enzymes assessed at least twice after treatment introduction were included. Clinical symptoms; blood levels of amylase, lipase, calcium and triglyceride levels; radiological findings and confirmed pancreatitis diagnosis were reported at baseline and at the moment of toxicity. Paired T-test and Paired Wilcoxon test were performed for comparative analyses. We reviewed medical records of 231 patients with NSCLC treated with TKI. Out of the total patient population, 75 had at least two pancreatic enzymes assessment. EPE was found in 34 patients (45% of tested cases). One case of clinical pancreatitis was confirmed in a patient treated with dabrafenib/trametinib, with favorable evolution after treatment suspension, hydration and analgesia. Treatment could be resumed with no new complication. EPE was attributed to TKI in 29/34 cases, 1/34 to primary pancreatic tumor and 4/34 unknown cause. EPE was found in 9 patients before initiation of TKI. Radiological assessment did not show signs of pancreatitis in any of the patients with EPE. Crizotinib was the drug most frequently linked to EPE (38%), followed by lorlatinib (26%), ceritinib (12%), entrectinib (8%), dabrafenib/trametinib (6%), repotrectinib (6%) and brigatinib (3%). Median time to EPE occurred after 42 days, with a range between four days and five years. Mean amylase at the time of toxicity was 141 U/l (Upper Limit Normal (ULN) =100 U/l), with a mean raise of 50 U/l, while mean lipase was 98U/l (ULN =67 U/l), with a mean raise of 79U/l. No significant differences in calcium and triglycerides were found in the TKI-treated entire population nor in the crizotinib subgroup. There was a limited but significant increase in mean triglyceride levels in patients treated with lorlatinib, raising from 1.7 mmol/l to 2.4 mmol/l (p = 0.027). Despite frequent EPE after TKI introduction, clinical pancreatitis are rare. Based on these results, we conclude that no routine assessment of pancreatic enzyme is required when introducing TKI treatment. To our knowledge, this is the first retrospective study about EPE linked to TKI in NSLC. [ABSTRACT FROM AUTHOR]

• Second-line therapy of stage IV SCLC is heterogeneous among European experts. • After 6 months from first-line treatment, 92 % recommend platinum re-challenge. • 3–6 months after first-line treatment no consensus was found. • In very early recurrence CAV for fit & topotecan for unfit patients was recommended. Stage IV small cell lung cancer (SCLC) is associated with short survival and progression after first-line systemic therapy frequently occurs within months. Although topotecan is approved for second-line treatment, its efficacy is limited, and treatment heterogeneity exists. The decision-making patterns for second line treatment of 13 European medical oncologists with expertise in SCLC were analyzed. The two criteria most relevant to decision-making were the performance status and the interval of recurrence since first-line treatment. With an interval of less than 3 months since the end of first-line chemotherapy, 62 % of the experts recommended cyclophosphamide, doxorubicin and vincristine (CAV) for fit patients and 54 % recommended topotecan for unfit patients. For an interval of more than 6 months, a clear consensus for a re-challenge with a platinum doublet was achieved (92 %). However, there was no consensus on the second-line therapy with an interval of 3–6 months since the end of first-line therapy. Real world practice may differ from recommendations in general guidelines and cannot always be directly derived from trial results as other factor such as habits, patient's preference, convenience or costs have to be factored in. [ABSTRACT FROM AUTHOR]

La chimioradiothérapie concomitante est le standard thérapeutique chez les patients atteints de cancer bronchique non à petites cellules non résécable de stade III, quels que soient leurs sous-types histologiques et leurs caractéristiques moléculaires. Dans ce cadre, seuls 15 à 30 % des patients demeurent en vie cinq ans après la chimioradiothérapie et ce chiffre n'a pratiquement pas changé malgré de multiples essais randomisés. Au cours des cinq dernières années, le blocage des points de contrôle immunitaires par anti-PD-(L)1 a révolutionné la prise en charge du cancer bronchique non à petites cellules métastatique, devenant un standard en première ligne et deuxième ligne de traitement. Plusieurs études précliniques ont mis en évidence une libération accrue d'antigènes tumoraux, une présentation améliorée de ces antigènes et l'augmentation de l'infiltration des lymphocytes T dans les tumeurs irradiées. L'immunothérapie a récemment été évaluée pour les patients atteints de cancer bronchique non à petites cellules localement évolué ayant reçu une irradiation thoracique. Suite à l'essai PACIFIC, l'anticorps anti-PD-L1 durvalumab est apparu comme un nouveau standard en consolidation pour les patients atteints de cancer bronchique non à petites cellules de stade III non résécable dont la maladie n'a pas progressé après une chimioradiothérapie concomitante à base de sels de platine. L'immunoradiothérapie apparaît donc comme une nouvelle association encourageante chez les patients atteints de cancer bronchique non à petites cellules localisées. De nombreux essais évaluent donc actuellement l'intérêt d'une immunothérapie concomitante à la chimioradiothérapie et/ou de l'ajout d'une chimiothérapie associée à l'immunothérapie de consolidation chez les patients atteints de cancer bronchique non à petites cellules localement évolué. Concomitant radiochemotherapy has been the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), irrespective of histological sub-type or molecular characteristics. Currently, only 15–30 % of patients are alive five years after radiochemotherapy, and this figure remains largely unchanged despite multiple phase III randomised trials. In recent years, immune-checkpoint blockades with anti-PD-(L)1 have revolutionised the care of metastatic NSCLC, becoming the standard front- and second-line strategy. Several preclinical studies reported an increased tumour antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumours. Immunotherapy has therefore recently been evaluated for patients with locally advanced stage III NSCLC. Following the PACIFIC trial, the anti-PD-L1 durvalumab antibody has emerged as a new standard consolidative treatment for patients with unresectable stage III NSCLC whose disease has not progressed following concomitant platinum-based chemoradiotherapy. Immunoradiotherapy therefore appears to be a promising association in patients with localised NSCLC. Many trials are currently evaluating the value of concomitant immunotherapy and chemoradiotherapy and/or consolidative chemotherapy with immunotherapy in patients with locally advanced unresectable NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Introduction Innate immunity represents the first step of activation of the immune system and dictates the quality of adaptive immune responses. Studies have reported links between systemic inflammatory or innate immune markers and prognosis in patients with lung cancer. To our knowledge, the prospective and concomitant study of these systemic markers has never been performed. Methods Advanced treatment-naive non–small cell lung cancer (NSCLC) patients eligible for first-line platinum-based chemotherapy were prospectively included from December 2012 to July 2015 (N = 148). Blood samples of patients were collected before the first cycle for fresh NK cell phenotyping. Peripheral blood mononuclear cells were cryopreserved for natural cytotoxicity receptor (NCR) genotyping as well as sera for NCR's ligand quantification. Data on leukocytes, neutrophils and monocyte counts and lactate dehydrogenase (LDH) levels were extracted from electronic medical records. Results Among all studied markers, monocytosis, neutrophilia, leucocytosis, high LDH and sBAG6 levels and reduced levels of NCR3 transcripts were associated with poor overall survival (OS) in univariate analysis. The levels of NCR3 transcripts was linked to age, number of metastatic sites, monocyte counts, LDH and sBAG6 levels. Neutrophilia was associated to high sBAG6 levels. NCR3 was the unique innate immune parameter that remained as an independent factor associated with both OS (P = 0.003) and progression-free survival (P = 0.009) in the multivariate analysis. Conclusion This study brought evidence that these biomarkers are entangled; parameters associated with an inflammatory process were related to reduced levels of NCR3 transcripts. Finally, the level of NCR3 transcripts was independently associated with outcomes in treatment-naive patients with advanced NSCLC. Highlights • Natural killer and systemic innate immune markers are entangled in non–small cell lung cancer patients. • These markers have an impact on patient's clinical outcomes, mainly NKp30 receptor. • Higher NCR3 transcript (NKp30) is an independent prognostic factor of progression-free survival and overall survival. • Lower NCR3 is related to inflammatory status and is associated with poor outcomes. • Targeting these innate immune markers could represent a good therapeutic strategy. [ABSTRACT FROM AUTHOR]

Molecular profiling has changed the treatment landscape in advanced non-small-cell lung cancer. Accurately identifying the tumours that harbour sensitizing EGFR mutations, the most common targetable molecular alteration, as well as those with acquired resistance mutations (e.g. T790M) on treatment is a high clinical priority. The current clinical gold standard is genotyping of tumour specimens. However, the practical utility of this approach is limited by the lack of available tissue and the potential complications associated with biopsies. With the advent of newer sequencing assays, it has become feasible to assess tumour genomics via a blood sample, termed a 'liquid biopsy'. In this review, we summarize the available techniques for liquid biopsies and their applicability for detecting sensitizing and resistance EGFR mutations and how these results may be used for making treatment decisions. [ABSTRACT FROM AUTHOR]

Background Immune checkpoint inhibitors are an important tool in the therapeutic strategy against metastatic non–small cell lung cancer (NSCLC); however, radiological evaluation is challenging due to the emergence of atypical patterns of responses. Several evaluation criteria have been proposed, such as the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, immune -related RECIST (irRECIST) and iRECIST, but have not been systematically compared in a homogeneous population. Patients and methods We conducted a monocentric retrospective analysis of consecutive advanced NSCLC patients treated with an anti–programmed cell death-1 or anti–program death-ligand 1. Response patterns and the discordance between RECIST 1.1, irRECIST and iRECIST guidelines were described, and associations of response patterns and clinical outcome were explored. Results Overall, 160 patients treated between February 2013 and October 2016 were included. Atypical responses were observed in 20 patients (13%), including eight pseudoprogressions (PsPDs) (5%) and 12 dissociated responses (8%). Thirteen of the 20 patients demonstrated clinical benefit. Per the RECIST 1.1, 37 patients (23%) showed an objective response or stable disease, and 123 patients (77%) exhibited progression. Eighty progressive patients were assessable for irRECIST and iRECIST: 15 patients were assessed differently; however, only three (3.8%) mismatches with a theoretical impact on the therapeutic decision were identified. Patients with PsPD or dissociated response had higher overall survival than patients with true progression. Conclusion Atypical responses (PsPD/dissociated response) occurred in 13% of NSCLC patients under immune checkpoint inhibitors. Based on survival analyses, the RECIST 1.1 evaluation underestimated the benefit of immune checkpoint inhibitors in 11% of the progressive patients. Immune-related RECIST and iRECIST identified these unconventional responses, with a 3.8% discrepancy rate. [ABSTRACT FROM AUTHOR]

Background: Approximately 50% of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) will acquire resistance by the T790M mutation. Osimertinib is the standard of care in this situation. The present study assesses the efficacy of osimertinib when T790M status is determined in circulating cell-free tumour DNA (ctDNA) from blood samples in progressing advanced EGFR-mutant NSCLC patients. Material and methods: ctDNA T790M mutational status was assessed by Inivata InVision™ (eTAm-Seq™) assay in 48 EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKIs without a tissue biopsy between April 2015 and April 2016. Progressing T790M-positive NSCLC patients received osimertinib (80 mg daily). The objectives were to assess the response rate to osimertinib according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, the progression-free survival (PFS) on osimertinib, and the percentage of T790M positive in ctDNA. Results: The ctDNA T790M mutation was detected in 50% of NSCLC patients. Among assessable patients, osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. All responses were confirmed responses. After median follow up of 8 months, median PFS by RECIST criteria was not achieved (95% CI: 4-NA), with 6- and 12-months PFS of 66.7% and 52%, respectively. Conclusion(s): ctDNA from liquid biopsy can be used as a surrogate marker for T790M in tumour tissue. [ABSTRACT FROM AUTHOR]

Background: HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2% of lung adenocarcinomas. There is, to date, no standard of care for these patients. We thus aim to study the therapeutic outcomes of patients harboring HER2 mutations and establish the efficacy of various drug regimens. Patients and methods: This retrospective cohort study in European centers assessed patients with advanced nonsmall- cell lung cancer (NSCLC), a known HER2 exon-20 insertion, treated with chemotherapy and/or HER2-targeted drugs. Results: We identified 101 eligible patients from 38 centers: median age 61 years (range: 30-87), 62.4% women, 60.4% never-smokers. All tumors were adenocarcinomas. Concomitant EGFR mutations, ALK translocations, and ROS translocations were observed in 5, 1, and 1 patients, respectively. The median number of treatment lines was 3 (range: 1-11). The median overall survival was 24 months. Overall response rate (ORR) and the median progression-free survival (PFS) with conventional chemotherapy (excluding targeted therapies) were 43.5% and 6 months in first-line (n = 93), and 10% and 4.3 months in second-line (n = 52) therapies. Sixty-five patients received HER2-targeted therapies: trastuzumab = 57, neratinib = 14, afatinib = 9, lapatinib = 5, T-DM1 = 1. ORR was 50.9% and PFS was 4.8 months with trastuzumab or T-DM1. Conclusion: This series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2- targeted agents. Our results should help to define the best therapeutic strategy for these patients and to orient future clinical trials. [ABSTRACT FROM AUTHOR]

Rare EGFR mutations were collected from 10117 non-small cell lung cancer samples analyzed by ERMETIC-IFCT French network. Among 1047 EGFR-mutated samples, 102 (10%) harboured rare mutations (41 in exon 18, 49 in exon 20, 12 with others). Association with smoking differed between exon 18 and 20, and control rate to EGFR-TKI was 47%, strongly varied between patients requiring individual assessment.Background There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. Patients and methods EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. Results Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12–24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08–0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6–21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). Conclusions Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment. [ABSTRACT FROM AUTHOR]

Background Despite advances in cancer therapy, mortality is still high except in early-stage tumors, and screening remains a challenge. The randomized National Lung Screening Trial (NLST), comparing annual low-dose computed tomography (LDCT) and chest X-rays, revealed a 20% decrease in lung-cancer-specific mortality. These results raised numerous questions. The French intergroup for thoracic oncology and the French-speaking oncology group convened an expert group to provide a coherent outlook on screening modalities in France. Methods A literature review was carried out and transmitted to the expert group, which was divided into three workshops to tackle specific questions, with responses presented in a plenary session. A writing committee drafted this article. Results The multidisciplinary group favored individual screening in France, when carried out as outlined in this article and after informing subjects of the benefits and risks. The target population involves subjects aged 55–74 years, who are smokers or have a 30 pack-year smoking history. Subjects should be informed about the benefits of quitting. Screening should involve LDCT scanning with specific modalities. Criteria for CT positivity and management algorithms for positive examinations are given. Conclusions Individual screening requires rigorous assessment and precise research in order to potentially develop a lung-cancer screening policy. [ABSTRACT FROM AUTHOR]

Abstract: The use of conformal radiotherapy in lung cancer has considerably evolved with the advent of improved staging technologies and methods of radiation delivery. Patients with limited disease, inoperable for medical reasons, may be treated with conformal radiotherapy alone; patients with more advanced disease are treated with combined chemo-radiotherapy. If local control may be improved by radiotherapy dose escalation according to several studies, toxicity and more particularly pulmonary toxicity seems to be related to radiation volume. Thus the use of elective nodal irradiation is being questioned. Data for early stage (stage I) non-small-cell lung cancer treated with conformal radiotherapy or stereotactic hypofractionated radiotherapy strongly supports the use of smaller fields that do not incorporate elective nodal regions; local control and survival rates approach those of surgical series. In locally advanced non-small cell lung cancer, eliminating elective nodal irradiation allows to maximize tumor dose and minimize normal tissue toxicity in combined modality treatments; results are encouraging. The use of staging modalities such as positron emission tomography and eventually oesophageal ultrasonography is increasing, allowing to encompass the tumor volume with more accuracy. Several studies have confirmed that involved-field irradiation results into a regional nodal rate of less than 10%. Further larger-scale studies would be needed to definitely establish “no elective nodal irradiation” as a standard in non-small cell lung cancer. There are very few data concerning small cell lung cancer. [Copyright &y& Elsevier]