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MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting. In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 108 plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL (≤ or > the upper limit of normal [ULN]) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01383148. Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 [50%]; placebo and chemotherapy 111 [50%]). In the whole population, median progression-free survival was 5·9 months (95% CI 5·4–6·7) in the TG4010 group and 5·1 months (4·2–5·9) in the placebo group (HR 0·74 [95% CI 0·55–0·98]; one-sided p=0·019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 0·75 (0·54–1·03); the posterior probability of the HR being less than 1 was 98·4%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 0·77 (0·42–1·40); the posterior probability of the HR being greater than 1 was 31·3%, and the primary endpoint was not met. We noted grade 1–2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 [26%], grade 4 13 [12%] in the TG4010 group vs grade 3 22 [21%], grade 4 11 [10%] in the placebo group), anaemia (grade 3 12 [11%] vs grade 3 16 [15%]), and fatigue (grade 3 12 [11%], grade 5 one [1%] vs grade 3 13 [12%]; no grade 4 events). TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part. Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques (ADNA), and OSEO.

Studies have shown improved tolerability with once-weekly versus three-weekly docetaxel in the second-line treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the tolerability of nintedanib plus weekly docetaxel in patients with NSCLC. This phase I, open-label, dose-escalation study (NCT02668393) enrolled patients with locally advanced/metastatic adenocarcinoma NSCLC that had progressed on first-line platinum chemotherapy. The primary endpoint was to determine the maximum tolerated dose of nintedanib (up to 200 mg twice daily [BID]) combined with weekly docetaxel (35 mg/m.sup.2) on days 1, 8, and 15 based on the occurrence of dose-limiting toxicities (DLTs) over a 28-day treatment cycle. Adverse events (AEs) were also evaluated. The trial terminated prematurely due to recruitment challenges. At termination, seven patients had received nintedanib 150 mg BID and seven nintedanib 200 mg BID, in combination with weekly docetaxel. In the first treatment cycle, DLTs were reported for 1/6 evaluable patients (16.7%) in each group. The disease control rates were 57.1% and 42.9%, respectively. Grade [greater than or equal to]3 treatment-related AEs affected three patients in each group (42.9%); neutropenia was reported in one patient (14.3%) in each group. Treatment-related serious AEs were reported in three patients (42.9%) receiving nintedanib 150 mg, and two patients (28.6%) receiving nintedanib 200 mg. Overall, nintedanib plus weekly docetaxel was well-tolerated in patients with locally advanced or metastatic lung adenocarcinoma who progressed on first-line platinum-based chemotherapy, without loss of efficacy. DLTs were manageable.

Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC. In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I–IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling. Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4–9·6] in the minimal follow-up group vs 10·3 years [8·1–not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83–1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable–not estimable] in the minimal follow-up group vs 4·9 [4·3–not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99–1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported. The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology. For the French translation of the abstract see Supplementary Materials section.

Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70–89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0–2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30·3 months (range 8·6–45·2). Median overall survival was 10·3 months for doublet chemotherapy and 6·2 months for monotherapy (hazard ratio 0·64, 95% CI 0·52–0·78; p<0·0001); 1-year survival was 44·5% (95% CI 37·9–50·9) and 25·4% (19·9–31·3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48·4%] vs 28 [12·4%]; asthenia 23 [10·3%] vs 13 [5·8%]). Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Introduction Routine Electronic Monitoring of Health-Related Quality of Life (HRQoL) (REMOQOL) in clinical care with real-time feedback to physicians could help to enhance patient-centered care. We evaluated the feasibility of REMOQOL in the French context in the QOLIBRY study. The primary objective was to assess the patients’ compliance with REMOQOL. Methods The QOLIBRY study was a single-center, prospective study conducted in the University Hospital of Besançon (France). Eligible patients were those treated with systemic therapies for breast, lung or colorectal cancer at any stage. Patients were invited to complete the EORTC QLQ-C30 questionnaire and cancer-site-specific modules before each visit on tablets and/or computers in the hospital or at home. During the consultation, physicians had real-time access to visual summaries of HRQoL scores. Compliance was assessed as adequate if at least 66% of HRQoL assessments were completed during the 4 months of follow-up. Results Between March 2016 and October 2018, 177 patients were included in the QOLIBRY study. Median age was 64 years (IQR 54–71). The proportion of patients with an adequate compliance rate was 95.5% ( n  = 63) in the breast cancer cohort, 98.2% ( n  = 55) in the colorectal cancer cohort, and 90.9% ( n  = 50) in the lung cancer cohort. The physicians checked the HRQoL results in 73.1% of visits and prescribed supportive care and adapted patient management in 8.3% and 5.2% of visits, respectively. Conclusion & perspectives The results of QOLIBRY study suggest that REMOQOL is feasible in the French context. However, information about HRQoL monitoring, training of the physicians in the use of the software, and recommendations for using HRQoL results to guide care are essential and must be improved.

Purpose Longitudinal analysis of health-related quality of life (HRQoL) remains unstandardized and compromises comparison of results between trials. In oncology, despite available statistical approaches, results are poorly used to change standards of care, mainly due to lack of standardization and the ability to propose clinical meaningful results. In this context, the time to deterioration (TTD) has been proposed as a modality of longitudinal HRQoL analysis for cancer patients. As for tumor response and progression, we propose to develop RECIST criteria for HRQoL. Methods Several definitions of TTD are investigated in this paper. We applied this approach in early breast cancer and metastatic pancreatic cancer with a 5-point minimal clinically important difference. In breast cancer, TTD was defined as compared to the baseline score or to the best previous score. In pancreatic cancer (arm 1: gemcitabine with FOLFIRI.3, arm 2: gemcitabine alone), the time until definitive deterioration (TUDD) was investigated with or without death as event. Results In the breast cancer study, 381 women were included. The median TTD was influenced by the choice of the reference score. In pancreatic cancer study, 98 patients were enrolled. Patients in Arm 1 presented longer TUDD than those in Arm 2 for most of HRQoL scores. Results of TUDD were slightly different according to the definition of deterioration applied. Conclusion Currently, the international ARCAD group supports the idea of developing RECIST for HRQoL in pancreatic and colorectal cancer with liver metastasis, with a view to using HRQoL as a co-primary endpoint along with a tumor parameter.

Background There is a paucity of data regarding the prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC). Therefore, we investigated the prognostic value of T lymphopenia in NSCLC. Materials Treatment-naive patients with a pathological diagnosis of NSCLC, at clinical stage I to IV were included in the prospective TELOCAP1 study. Lymphocytes count was evaluated in peripheral blood by flow cytometry. CD4+ and CD8+ T lymphopenia were defined as an absolute count of < 500/μL and < 224/μL respectively. The prognostic value of T lymphopenia was analyzed in the whole population, in local/loco-regional (stage I-IIIB) and in advanced (stage IV) NSCLC disease, using the Kaplan-Meier method and Cox regression models for survival curves and multivariate analysis, respectively. Results Between July 2010 and January 2014, 169 evaluable patients with clinical stage I to IV NSCLC were prospectively enrolled. The prevalence of CD4+ and CD8+ T lymphopenia was similar in the study population (around 29%). Patients with CD4+ T lymphopenia showed lower overall survival than those with CD4+ T lymphocytes count > 500/μL (median overall survival (OS) 16.1 versus 21.7 months, hazard ratio (HR): 1.616 [95% CI: 1.1–2.36], p = 0.012). This association with OS was especially marked in local/loco-regional NSCLC stages (median OS, 21.8 versus 72 months, respectively, HR: 1.88 [95% CI: 0.9–3.8], p  = 0.035). Multivariate analysis confirmed the worse prognosis associated with CD4+ T lymphopenia in local/loco-regional NSCLC, but not in metastatic patients (HR 2.028 [95% CI = 1.065–3.817] p  = 0.02). Restricted cubic spline analysis showed that patients with CD4+ T lymphocytes count ≤500/μL displayed a high risk of death regardless of NSCLC clinical stage. There was no obvious relationship between CD8+ T lymphopenia and clinical outcome. Conclusion We identified CD4+ T lymphopenia as an independent prognostic factor in local/loco-regional stages of NSCLC and CD4+ T lymphopenia is also associated with a high risk of death, regardless of NSCLC clinical stage. Trial registration EUDRACT: 2009-A00642–55. Highlights This study investigates the unknown prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC) with long-term follow-up CD4+ but not CD8 + T lymphopenia was associated with poor survival in patients with localized NSCLC The CD4+ T lymphopenia appears to be an independent prognostic factor for poor overall survival in local/loco-regional NSCLC. CD4+ T lymphocyte count ≤500/μL in peripheral blood is associated with a high risk of death in NSCLC

BackgroundThe IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC).MethodsIn a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality (NCT03030131).ResultsForty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8–41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with >10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3–5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity.ConclusionsNeoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.

Aim A systematic literature review of immuno-oncology trials was conducted to assess the potential impact of open-label vs double-blind trial design on patient-reported outcome (PRO) data. Methods A systematic search of indexed literature published from January 2009 to May 2019 was conducted using PubMed/MEDLINE, Cochrane Library, and EMBASE database. All randomized clinical trials (RCTs) of immuno-oncology therapies on advanced cancer patients reporting PRO data were identified. Descriptive analyses were performed to quantify differences at baseline and over time, by the type of study, regarding questionnaire completion rate and PRO scores. Results In total, 23 studies were retained (15 open-label, 8 blinded). At baseline, no difference in completion rate was observed between arms irrespective of trial design (absolute mean difference of 2.8% and 2.2% for open label and blinded studies, respectively). No clinically significant difference in baseline PRO scores was observed between arms. Over time, impact on PRO scores could not be identified due to the limited number of studies, heterogeneity of questionnaires and tumor types. Conclusions Trial design had no impact on PRO completion rate or baseline scores. Future research should involve analyses by specific cancer types and ideally compare individual data from two similar RCTs (blinded vs. open-label).