Topotecan in the treatment of relapsed small cell lung cancer

Small cell lung cancer (SCLC) represents about 15% to 20% of all lung cancers. Chemotherapy is the cornerstone of the treatment, cisplatin–etoposide combination being the most used combination as first-line therapy. Despite high initial chemosensitivity, most SCLC patients will experience relapse sooner or later. Unfortunately, second-line chemotherapy does not result in a high response rate like first-line therapy, most patients having developed wide chemoresistance. This chemoresistance is far more important in refractory patients, ie, those who never responded to first-line therapy or who relapsed within 3 months after the end of chemotherapy, than in sensitive patients, ie, those who relapse more than 3 months after the end of chemotherapy. Topotecan, a topoisomerase I inhibitor, is the most studied drug in this second-line setting and has proved its efficacy as a single agent and in combination. A phase III trial comparing oral topotecan to best supportive care (BSC) in relapsed SCLC demonstrated a significant survival benefit as well as a better quality of life. Although the usual schedule is 1.5 mg/m2, days 1–5 intravenously, it is not convenient for patients with relapsed SCLC, especially those who are refractory because of their short survival expectation. Oral topotecan is of similar efficacy and much more convenient with limited stay in a treatment unit and has a comparable toxicity profile for these patients with short expected survival. Combination of topotecan with platinum salts or taxanes does not seem to improve further the outcome of the patients and thus single-agent therapy with topotecan is the standard treatment for relapsed SCLC

Systemic Therapy of Bronchioloalveolar Carcinoma: Results of the First IASLC/ASCO Consensus Conference on Bronchioloalveolar Carcinoma

Introduction:Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma of the lung with unique pathological, clinical, and molecular characteristics.Methods:This consensus conference group reviewed studies performed specifically in BAC and data from patients with BAC who were included in clinical trials of all non–small-cell lung cancer (NSCLC) subtypes.Results:Although BAC as defined by the World Health Organization represents less than 5% of adenocarcinomas, as many as 20% of adenocarcinomas have BAC features. These latter tumors are more likely to have mutations in the epidermal growth factor receptor (EGFR) gene and to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Although most patients are men and have a history of smoking cigarettes, proportionally more are women and never smokers. Patients with BAC are routinely treated with drugs and regimens appropriate for patients with all subtypes of adenocarcinoma of the lung; four studies have been performed specifically in this disease.Conclusions:There is insufficient evidence to confirm or refute the assertion that the sensitivity of BAC to chemotherapy is different from that of other lung cancer histologic types. The unique clinical and molecular characteristics associated with BAC led this panel to conclude that future clinical trials should be designed specifically for persons with BAC. Recommendations for trial design and research questions are proposed

A Phase II Study of Tg4010 (Mva-Muc1-Il2) in Association with Chemotherapy in Patients with Stage III/IV Non-small Cell Lung Cancer

BackgroundTG4010 is a recombinant viral vector expressing both the tumor-associated antigen MUC1 and Interleukine-2. This vector is based on the modified virus of Ankara, a significantly attenuated strain of vaccinia virus. TG4010 has been designed to induce or amplify a cellular immune response directed against tumor cells expressing MUC1.MethodsA multicenter, randomized phase II study has explored two schedules of the combination of TG4010 with first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1, TG4010 was combined upfront with cisplatin (100 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy until disease progression, followed by TG4010 plus the same chemotherapy as in Arm1. Response rate was evaluated according to RECIST. Median time to progression and median overall survival were calculated according to the Kaplan–Meier method.ResultsSixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in accordance with the two stage Simon design of the statistical plan. In Arm 1, partial response was observed in 13 patients out of 37 evaluable patients (29.5% of the intent to treat population, 35.1% of the evaluable patients). In Arm 2, two patients experienced stable disease for more than 6 months with TG4010 alone (up to 211 days), in the subsequent combination with chemotherapy, one complete and one partial response were observed out of 14 evaluable patients. Arm 2 did not meet the criteria for moving forward to second stage. The median time to progression was 4.8 months for Arm 1. The median overall survival was 12.7 months for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60% for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions. A MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology.ConclusionsThe combination of TG4010 with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress

366 Combined exploratory immunophenotyping and transcriptomic tumor analysis in patients treated with OSE2101 vaccine in HLA-A2+ advanced non-small cell lung cancer (NSCLC) from the ATALANTE-1 trial

BackgroundOSE2101 (Tedopi®) is an anticancer vaccine with HLA-A2+ restricted modified epitopes targeting five tumor-associated antigens (TAAs) frequently expressed in lung cancer (CEA, HER2, MAGE2, MAGE3, P53). Step-1 results of the phase III, randomized, open-label ATALANTE-1 study comparing Tedopi® vs standard treatment (SoC) showed a favorable benefit/risk of Tedopi® over SoC (HR 0.71 for overall survival OS) in HLA-A2+ NSCLC patients in 2nd or 3rd line treatment after progression on immune checkpoint blockers (ICB).1 We analyze available tumor biopsies at initial diagnosis from some patients treated with Tedopi® to determine the expression of the 5 TAAs and to identify other tumor factors associated with long-term survival.MethodsTumor biopsies were available for 8 HLA-A2+ (blood test) stage IV NSCLC patients included in the trial. Primary (<12 weeks) and secondary (≥ 12 weeks) resistance to ICB were observed in 3 (38%) and 5 (62%) of patients. Best response to Tedopi® and OS were: 1 partial response (PR) (OS of 33 months), 3 stable disease (SD) (OS of 22, 26 and 41 mo.) and 4 disease progression (PD) (OS of 3, 4, 30 and 31 mo.). HLA-class I, PD-L1, CD8 T-cells, HER2, CEA and P53 tumor expression were evaluated by immunohistochemistry (IHC). NanoString gene expression profiling was performed using the Pan Cancer Immune gene set.ResultsHLA-class I was expressed in all tumor samples. IHC analysis revealed that P53, CEA and HER2 were expressed in 6/7, 5/7 and 0/7 patients, respectively. P53, CEA, HER2, MAGE2, and MAGE3 were detected at RNA level in 5/5 tested patients (table 1). IMMUNOSCORE® IC CD8/PDL1 analysis showed High/High, High/Low and Low/Low scores for 1/7, 1/7 and 5/7 patients, respectively. The High/High IMMUNOSCORE® with a pronounced CD8+ T-cell tumor infiltration was observed in the patient with PR. High percentage of tumor cells expressing P53 (69%–97%) and overexpression of genes associated with activated macrophages (TREM2, MARCO, SLC11A1, CHIT1, SERPINB2) were observed in the PR and SD patients. High IFN-gamma and Expanded Immune Gene Signature scores were observed in long-term survivor patients with secondary resistance to ICB, even after progressive disease.Abstract 366 Table 1Summary of clinical and translational dataCEACarcinoembryonic antigen; HER2: Human Epidermal Growth Factor Receptor-2; ICB: Immune checkpoint blocker; IHC: Immunohistochemistry; ND: Not determined; OS: Overall Survival; Patient ID: Patient identification; PDL1: Programmed death-ligand 1; PFS: Progression-free survival; ssGSEA: Single-sample Gene Set Enrichment Analysis. Blue bars = Length of overall survival; Green bars = Gene Signature upregulation; Red bars = Gene Signature downregulationConclusionsThis study shows that all HLA-A2+ patients (blood test), expressed HLA class I in the tumors at initial diagnosis. Transcriptomic data in the patients that benefited from Tedopi® showed activated macrophage pathway, high IFN-gamma and Expanded Immune Gene Signatures scores. These data will be validated on larger number of patients treated with Tedopi® after the step 2 analysis.AcknowledgementsWe thank Julie Le Boulicaut, François Montestruc and Constant Josse (eXYSTAT, Malakoff, France) for the statistical analysis, and HalioDx for the IHC and NanoString analysis.Trial RegistrationEudraCT number2015-003183-36; NCT number: NCT02654587ReferenceGiaccone, et al. Activity of OSE-2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (ICI): step 1 results of phase III ATALANTE-1 randomised trial. ESMO meeting 2020, abstract #1260MO.Ethics ApprovalThe study protocol and its related documents (including the patient information and informed consent form) received approval from the Institutional Review Board (IRB), and the Competent Authority prior to study initiation.ConsentEach patient gave his/her written informed consent prior to study enrolment

Case Rep Oncol

The pretreatment detection of an activating mutation of EGFR is now routinely performed in metastatic nonsquamous non-small cell lung cancer (NSCLC). The therapeutic impact of such a detection is major, as patients with advanced NSCLC exhibiting a mutation of exon 19 or 21 will benefit from EGFR-tyrosine kinase inhibitors (TKI). The presence of an EGFR resistance mutation, such as T790M in EGFR-TKI-naïve patients, is seldom looked for and is related either to a germinal mutation or to somatically mutated subclones. It has a negative predictive impact. We present the case of a patient with a lung papillary adenocarcinoma and miliary intrapulmonary metastases whose tumor displays a somatic complex heterozygous EGFR mutation, combining L858R (exon 21) and a primary resistance mutation T790M (exon 20), both detected by direct sequencing

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC:Updated 5-Year Survival Rates and Genomic Analysis

Introduction: Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data. Methods: Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety. Results: At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5–78.5) and 16.3 (range: 0.4–80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8–80.1) and 63.9% (46.2–79.2), median progression-free survival (95% CI) was 10.2 (6.9–16.7) and 10.8 (7.0–14.5) months, and median overall survival (95% CI) was 18.2 (14.3–28.6) and 17.3 (12.3–40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation. Conclusions: Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment

Latitude, Birth Date, and Allergy

BACKGROUND: The space and time distribution of risk factors for allergic diseases may provide insights into disease mechanisms. Allergy is believed to vary by month of birth, but multinational studies taking into account latitude have not been conducted. METHODS AND FINDINGS: A questionnaire was distributed in 54 centres to a representative sample of 20- to 44-y-old men and women mainly in Europe but also including regions in North Africa, India, North America, Australia, and New Zealand. Data from 200,682 participants were analyzed. The median prevalence of allergic rhinitis was 22%, with a substantial variation across centres. Overall, allergic rhinitis decreased with geographical latitude, but there were many exceptions. No increase in prevalence during certain winters could be observed. Also, no altered risk by birth month was found, except borderline reduced risks in September and October. Effect estimates obtained by a multivariate analysis of total and specific IgE values in 18,085 individuals also excluded major birth month effects and confirmed the independent effect of language grouping. CONCLUSION: Neither time point of first exposure to certain allergens nor early infections during winter months seems to be a major factor for adult allergy. Although there might be effects of climate or environmental UV exposure by latitude, influences within language groups seem to be more important, reflecting so far unknown genetic or cultural risk factors

Novel active agents in patients with advanced NSCLC without driver mutations who have progressed after first-line chemotherapy

Despite the efficacy of a number of first-line treatments, most patients with advanced-stage non-small cell lung cancer (NSCLC) experience disease progression that warrants further treatment. In this review, we examine the role of novel active agents for patients who progress after first-line therapy and who are not candidates for targeted therapies. More therapeutic options are needed for the management of patients with NSCLC after failure of first-line chemotherapy. A PubMed search was performed for articles from January 2012 to May 2015 using the keywords NSCLC, antiangiogenic, immunotherapy, second-line, novel therapies and English language articles only. Relevant papers were reviewed; papers outside that period were considered on a case-by-case basis. A search of oncology congresses was performed to identify relevant abstracts over this period. In recent years, antiangiogenic agents and immune checkpoint inhibitors have been added to our armamentarium to treat patients with advanced NSCLC who have progressed on first-line chemotherapy. These include nintedanib, a triple angiokinase inhibitor; ramucirumab, a vascular endothelial growth factor receptor-2 antibody; and nivolumab, pembrolizumab and atezolizumab, just three of a growing list of antibodies targeting the programmed death receptor-1 (PD-1)/PD ligand-1 pathway. Predictive and prognostic factors in NSCLC treatment will help to optimise treatment with these novel agents. The approval of new treatments for patients with NSCLC after the failure of first-line chemotherapy has increased options after a decade of few advances, and holds promise for future evolution of the management of NSCLC

Professional Exposure to Goats Increases the Risk of Pneumonic-Type Lung Adenocarcinoma: Results of the IFCT-0504-Epidemio Study

Pneumonic-type lung adenocarcinoma (P-ADC) represents a distinct subset of lung cancer with specific clinical, radiological, and pathological features. Given the weak association with tobacco-smoking and the striking similarities with jaagsiekte sheep retrovirus (JSRV)-induced ovine pulmonary adenocarcinoma, it has been suggested that a zoonotic viral agent infecting pulmonary cells may predispose to P-ADC in humans. Our objective was to explore whether exposure to domestic small ruminants may represent a risk factor for P-ADC. We performed a multicenter case-control study recruiting patients with P-ADC as cases and patients with non-P-ADC non-small cell lung cancer as controls. A dedicated 356-item questionnaire was built to evaluate exposure to livestock. A total of 44 cases and 132 controls were included. At multivariate analysis, P-ADC was significantly more associated with female gender (Odds-ratio (OR) = 3.23, 95% confidence interval (CI): 1.32–7.87, p = 0.010), never- smoker status (OR = 3.57, 95% CI: 1.27–10.00, p = 0.015), personal history of extra-thoracic cancer before P-ADC diagnosis (OR = 3.43, 95% CI: 1.10–10.72, p = 0.034), and professional exposure to goats (OR = 5.09, 95% CI: 1.05–24.69, p = 0.043), as compared to other subtypes of lung cancer. This case-control suggests a link between professional exposure to goats and P-ADC, and prompts for further epidemiological evaluation of potential environmental risk factors for P-ADC