PD-1/PD-L1 inhibitor activity in patients with gene-rearrangement positive non-small cell lung cancer-an IMMUNOTARGET case series.

BACKGROUND Prior IMMUNOTARGET registry data had suggested that responses to immune [anti PD(L)1] monotherapy in gene-arranged non-small cell lung cancer (NSCLC) were rare or absent, depending on the specific oncogene. METHODS IMMUNOTARGET sites reporting prior registry data or new individual cases of gene rearranged NSCLC seeming to benefit from immune monotherapy were explored in detail looking to both validate their diagnosis of a functional gene rearrangement and to look for features potentially differentiating them from other such cases associated with low response rates. RESULTS Five cases of NSCLC with a gene rearrangement with reported responses or prolonged stabilization from immune monotherapy were identified in total. All had little or no prior smoking history and had programmed death-ligand 1 (PD-L1) values ranging from zero to 100%. A confirmed rearrangement partner was reported in only 2 of the cases (CD74-ROS1 and KIF5B-RET), however in one of the other three cases [analplastic lymophoma kinase (ALK)], significant benefit from a relevant prior targeted therapy was noted, also consistent with the rearrangement status being correctly assigned. CONCLUSIONS Not all driver oncogene subtypes of NSCLC are equally responsive to immune monotherapy, however even among patients with well-validated gene rearranged NSCLC which has traditionally been considered immune hyporesponsive, objective responses can occur. Additional explorations of the features associated with and underlying the immune hypo-responsiveness of most, but not all, cases of gene-rearranged NSCLC are required

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer

Summary Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m2) or S-1 (30 mg/m2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71–1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80–2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016

Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.)

Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas

The discovery of epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) has allowed the identification of a subset of patients whose tumours are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs). Despite the efficacy and superiority of EGFR TKIs over chemotherapy as first-line therapy, all patients will ultimately develop progressive disease, with a median of 9–13 months progression-free survival. A better understanding of the molecular mechanisms underlying resistance to EGFR TKIs can help design new drugs and therapeutic strategies to overcome resistance. This has been illustrated by the new generation TKIs that are effective on the T790M mutation, which is the most frequent mechanism of acquired resistance to EGFR TKIs. In this article, we will address the main molecular mechanisms of primary and acquired resistance to EGFR TKIs in EGFR-mutant NSCLC

Osimertinib (Tagrisso®) : activité, indication et modalités d’utilisation dans les cancers bronchiques non à petites cellules

International audienceThe acquisition of a resistance EGFR mutation in exon 20 (T790M) occurs in half of the cases of secondary resistance to EGFR tyrosine kinase inhibitors (TKI), given in first-line treatment in advanced EGFR-mutated non-small cell lung cancers (NSCLC). Osimertinib (AZD9291, Tagrisso®) is a third-generation, irreversible EGFR TKI, active in case of T790M mutation. A large phase I trial showed the efficacy of osimertinib after failure of first-generation EGFR TKI (erlotinib, gefitinib), with response rate at 51% and up to 61% in case of T790M mutation. Progression-free survival was 9.6 months in case of T790M. Toxicity profile was acceptable, with mainly digestive (diarrhea) and skin (rash) side effects. Preliminary data from a phase II trial confirmed these efficacy and safety data. Screening of T790M mutation at the time of progression with TKI can be performed in circulating tumor DNA in plasma, with good diagnostic performances.L’acquisition d’une mutation EGFR de résistance au niveau de l’exon 20 (T790M) est responsable de plus de la moitié des cas de résistance secondaire aux inhibiteurs de tyrosine kinase (ITK) de l’EGFR, prescrits en 1re ligne dans les cancers bronchiques non à petites cellules (CBNPC) de stade localement avancé ou métastatique, mutés EGFR. L’osimertinib (AZD9291, Tagrisso®) est un inhibiteur irréversible d’EGFR de 3e génération, actif en cas de mutations activatrices et mutation T790M. Un essai de phase I avec extension de cohorte a montré son efficacité après échec des ITK de l’EGFR de 1re génération (erlotinib, gefitinib), avec des taux de réponse de 51 %, et jusqu’à 61 % en cas de mutation T790M. La survie sans progression en cas de mutation T790M était de 9,6 mois. Le profil de toxicité est acceptable, avec essentiellement une toxicité digestive (diarrhées) et cutanée (rash). Des données préliminaires d’un essai de phase II ont confirmé ces résultats d’efficacité et de tolérance. La prescription d’osimertinib est conditionnée à la mise en évidence d’une mutation T790M dont la recherche au moment de la progression sous ITK peut être faite sur l’ADN tumoral circulant dans le plasma, avec des performances diagnostiques intéressantes ce qui en fait une alternative à la rebiopsie

Perception of Lung Cancer Risk: Impact of Smoking Status and Nicotine Dependence

Background The general population is nowadays well aware that tobacco smoking dramatically increases the risk of developing lung cancer. We hypothesized that a personal history of smoking and the level of nicotine dependence in current smokers may affect the perception of this risk among healthy individuals. Methods The fourth French nationwide observational survey, EDIFICE 4, was conducted by telephone among a representative sample of individuals (N = 1602) aged between 40 and 75 years. Interviewees were asked about their smoking habits, perception of the risk of lung cancer, and nicotine dependence (Fagerstrom test). Results Regardless of their smoking status or level of nicotine dependence, the majority (96%) of our study population (N = 1463) acknowledged that tobacco smoking is a major risk factor for lung cancer. For 34% of all respondents, smoking <= 10 cigarettes per day does not carry any risk of lung cancer. Only half the current smokers considered themselves to be at higher risk of lung cancer than the average-risk population. The majority of current cigarette smokers with a nicotine dependence considered themselves to be at higher risk for lung cancer while only 37% of non-nicotine-dependent individuals had the same perception (P < 0.01). Current smokers were more likely to consider a screening examination than former smokers and never-smokers. However, the intention to undergo screening was not significantly affected by the level of nicotine dependence. Conclusions Awareness campaigns may first have to overcome misconceptions about light smoking and, secondly, to target specific populations (heavy smokers, those with a long history, highly dependent smokers)

Current and Former Smokers: Who Wants To Be Screened?

Participation is key to the success of cancer screening. Identifying the reasons for nonparticipation is therefore essential. The present analysis of the EDIFICE (etude sur le depistage des cancers et ses facteurs de compliance [survey on cancer screening and compliance factors]) surveys (n = 1463) found 36.4% of current smokers and 26.3% of former smokers intended to participate in a lung cancer screening program. Discrepancies exist between the screening program target populations and the individuals who actually intend to undergo screening. Background: Lung cancer (LC) screening (LCS) with annual low-dose computed tomography scans has been seen to reduce the specific and overall mortality in selected populations. However, participation is key to successful screening programs. The EDIFICE (etude sur le depistage des cancers et ses facteurs de compliance [survey on cancer screening and compliance factors]) nationwide observational surveys are used to assess behavior related to cancer screening programs in France. Materials and Methods: Using comprehensive multivariate stepwise logistic regression analyses of data from current and former cigarette smokers, we sought to identify the explanatory factors associated with the intention to participate in an LCS program. Results: Of the 1463 respondents with no personal history of cancer, 263 (36.4%) of the current cigarette smokers and 170 (26.3%) of the former cigarette smokers stated their willingness to participate in an LCS program. The explanatory factors differed between current cigarette smokers (already screened for LC: odds ratio PRI, 2.81; < 30 pack-years: OR, 2.69; intention to quit smoking: OR, 1.96; no social vulnerability: OR, 2.15) and former cigarette smokers (comorbidities: OR, 0.31). The usual eligibility criteria were not significantly explanatory. Conclusion: Our findings highlight the discrepancy that exists between target populations and individuals who actually intend to participate in a screening program for LC, with subsequent potential effects on the participation rates and, thus, on the efficacy of screening. (C) 2018 Elsevier Inc. All rights reserved

Beliefs and behavior regarding e-cigarettes in a large cross-sectional survey

Although e-cigarette use is increasing dramatically, numerous concerns persist regarding toxicity and their role in smoking cessation. We assessed beliefs and behavior regarding e-cigarettes in an adult French population.The 4th French nationwide observational survey, EDIFICE 4, was conducted among representative samples of 1602 laypersons (age, 40–75 years) from 12 June-10 July 2014, using the quota method. Profile, beliefs and behavior were assessed by phone interviews of the participating lay population with no history of cancer (N = 1463). Tobacco use, nicotine dependence (Fagerström test) and e-cigarette use were assessed.E-cigarette users represented 6% of the study lay population. E-cigarette users regarded e-cigarettes as helpful for quitting tobacco smoking and reducing the risk of lung cancer. Current dual users (e-cigarettes + cigarettes) were more likely to attempt to quit than current exclusively cigarette smokers (odds ratio, 3.15 [1.74–5.70]), and to consider themselves at higher risk for lung cancer (OR 3.85 [2.47–5.99]). They also considered e-cigarette vapor to be less toxic than tobacco smoke in terms of both active and passive exposure.Dual users typically consider themselves at higher risk for cancer and intend to quit smoking. Physicians should be made aware of this specific sub-population for whom e-cigarettes may be a useful trigger in the smoking cessation process. Keywords: Electronic cigarettes, Smoking cessation, Tobacco use, Lung neoplasms, Pulmonary disease, Risk factors, Smok

Decline in compliance to breast cancer screening in France: Results of the 5th EDIFICE survey

San Antonio Breast Cancer Symposium, San Antonio, TX, DEC 05-09, 201

Decline in compliance to breast cancer screening in France: Results of the 5th EDIFICE survey

San Antonio Breast Cancer Symposium, San Antonio, TX, DEC 05-09, 201