Metabolomics to Assess Response to Immune Checkpoint Inhibitors in Patients with Non-Small-Cell Lung Cancer

In the treatment of advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitors have shown remarkable results. However, not all patients with NSCLC respond to this drug treatment or receive durable benefits. Thus, patient stratification and selection, as well as the identification of predictive biomarkers, represent pivotal aspects to address. In this framework, metabolomics can be used to support the discrimination between responders and non-responders. Here, metabolomics was used to analyze the sera samples from 50 patients with NSCL treated with immune checkpoint inhibitors. All the samples were collected before the beginning of the treatment and were analyzed by NMR spectroscopy and multivariate statistical analyses. Significantly, we show that the metabolomic fingerprint of serum acts as a predictive “collective” biomarker to immune checkpoint inhibitors response, being able to predict individual therapy outcome with > 80% accuracy. Metabolomics represents a potential strategy for the real-time selection and monitoring of patients treated with immunotherapy. The prospective identification of responders and non-responders could improve NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies

GEMCITABINE (dFdC), 5-FLUROURACIL (5FU), AND FOLINIC ACID (FA) IN THE TREATMENT OF PATIENTS WITH GASTRO-ENTERIC CARCINOMAS: A CLINICAL AND PHARMACOLOGICAL STUDY.

Purpose. To perform a phase I clinical study of a combination therapy based on the Tomudex-PVI-5-FU sequence. Patients and Methods: From 07/07/97 to 15/10/99, 15 patients with ileal or colorectal cancer received 62 courses (6 planned for every patient, consisting of 2 weeks therapy followed by 1 week rest) of Tomudex (given as a single 15-nunule intravenous infusion every 3 weeks, at escalating doses from 2 to 3 mg/m2) followed by PVI-5-FU (given as a 14 days infusion every 3 weeks, at escalating doses from 200 to 300 mg/m2/die). There were 10 men and 5 women with a median age of 64 years (range, 40 to 77). Eleven patients (84,6%) had previously received chemotherapy (PVI-5-FU, FudR hepatic arterial infusion. Stop-flow, intraoperative peritoneal chemohyperthermia) for advanced malignancy. Results: only 7 courses were discontinued (3 because of biliary stent obstruction in the same patient, 1 owing to erythema, 1 because of arrhythmia, 1 because of subcutaneous port pocket infection and the last owing to personal reasons) No side effects >WH0 2° were seen, with the exception of asymptomatic rise in AST-ALT (WHO 3° in 2 courses and 4° in 1 course, in the same patient), nausea and vomiting (WHO 3° in 1 course, WHO 4° in 1 course), mucositis (WHO 4° in 1 course, after that dose reduction was required) and diarrhoea (WHO 4° in 2 course; dose reduction was required in 1 patient) Dose reductions due to toxicity were required in 2 patients (at 5-FU 300 mg/m2 step); delayed courses in 6 cases. Haematological side effects (Leucopenia WHO 1° in 1 course and WHO 2° in 1 course, anaemia WHO 1° in 7 courses), other gastrointestinal side effects (diarrhoea WHO 1° in 4 courses and WHO 2° in 8 courses, nausea and vomiting WHO 1 ° in 11 courses, WHO 2° in 1 course and WHO 3° in 1 course), mucositis (WHO 1° in 1 course and WHO 2° in 1 course) and skin erythema (WHO 1° m 6 courses and WHO 2° in 2 courses) were mild and easy manageable. Among 12 patients evaluable after 3 courses there were PR 2, MR 1, SD 6, PD 3. 6 patients are evaluable after 6 courses and we found . PR 1, MR 1, SD 1, PD 3. Conclusions The combination of TOM + PVI-5-FU is well tolerated DLT is gastrointestinal toxicity (nausea and vomiting, diarrhoea) and mucositis MTD has been established: Tomudex 3 mg/m2 and 5-FU 250 mg/m2 Clinical activity looks encouraging. Further Phase II is planne

Gemcitabine (dFdC), 5-fluorouracil (5FU) and folinic acid (FA) in the treatment of patients with gastroenteric carcinoma: a clinical and Pharmacological study.

Purpose. To perform a phase I clinical study of a combination therapy based on the Tomudex-PVI-5-FU sequence. Patients and Methods: From 07/07/97 to 15/10/99, 15 patients with ileal or colorectal cancer received 62 courses (6 planned for every patient, consisting of 2 weeks therapy followed by 1 week rest) of Tomudex (given as a single 15-nunule intravenous infusion every 3 weeks, at escalating doses from 2 to 3 mg/m2) followed by PVI-5-FU (given as a 14 days infusion every 3 weeks, at escalating doses from 200 to 300 mg/m2/die). There were 10 men and 5 women with a median age of 64 years (range, 40 to 77). Eleven patients (84,6%) had previously received chemotherapy (PVI-5-FU, FudR hepatic arterial infusion. Stop-flow, intraoperative peritoneal chemohyperthermia) for advanced malignancy. Results: only 7 courses were discontinued (3 because of biliary stent obstruction in the same patient, 1 owing to erythema, 1 because of arrhythmia, 1 because of subcutaneous port pocket infection and the last owing to personal reasons) No side effects >WH0 2° were seen, with the exception of asymptomatic rise in AST-ALT (WHO 3° in 2 courses and 4° in 1 course, in the same patient), nausea and vomiting (WHO 3° in 1 course, WHO 4° in 1 course), mucositis (WHO 4° in 1 course, after that dose reduction was required) and diarrhoea (WHO 4° in 2 course; dose reduction was required in 1 patient) Dose reductions due to toxicity were required in 2 patients (at 5-FU 300 mg/m2 step); delayed courses in 6 cases. Haematological side effects (Leucopenia WHO 1° in 1 course and WHO 2° in 1 course, anaemia WHO 1° in 7 courses), other gastrointestinal side effects (diarrhoea WHO 1° in 4 courses and WHO 2° in 8 courses, nausea and vomiting WHO 1 ° in 11 courses, WHO 2° in 1 course and WHO 3° in 1 course), mucositis (WHO 1° in 1 course and WHO 2° in 1 course) and skin erythema (WHO 1° m 6 courses and WHO 2° in 2 courses) were mild and easy manageable. Among 12 patients evaluable after 3 courses there were PR 2, MR 1, SD 6, PD 3. 6 patients are evaluable after 6 courses and we found . PR 1, MR 1, SD 1, PD 3. Conclusions The combination of TOM + PVI-5-FU is well tolerated DLT is gastrointestinal toxicity (nausea and vomiting, diarrhoea) and mucositis MTD has been established: Tomudex 3 mg/m2 and 5-FU 250 mg/m2 Clinical activity looks encouraging. Further Phase II is planne

Screening for Frailty in Older Patients With Early-Stage Solid Tumors: A Prospective Longitudinal Evaluation of Three Different Geriatric Tools

Advance Access publication February 2, 2017Background: Frailty increases the risk of adverse health outcomes and/or dying when exposed to a stressor, and routine frailty assessment is recommended to guide treatment decision. The Balducci frailty criteria (BFC) and Fried frailty criteria (FFC) are commonly used, but these are time consuming. Vulnerable Elders Survey-13 (VES-13) score of ≥7, a simple and resource conserving function-based scoring system, may be used instead. This prospective study evaluates the performance of VES-13 in parallel with BFC and FFC, to identify frailty in elderly patients with early-stage cancer. Methods: Patients aged ≥70 years with early-stage solid tumors were classified as frail/nonfrail based on BFC (≥1 criteria), FFC (≥3 criteria), and VES-13 (score ≥ 7). All patients were assessed for functional decline and death. Results: We evaluated 185 patients. FFC had a 17% frailty rate, whereas BFC and VES-13 both had 25%, with poor concordance seen between the three geriatric tools. FFC (hazard ratio = 1.99, p = .003) and VES-13 (hazard ratio = 2.81, p < .001) strongly discriminated for functional decline, whereas BFC (hazard ratio = 3.29, p < .001) had the highest discriminatory rate for deaths. BFC and VES-13 remained prognostic for overall survival in multivariate analysis correcting for age, tumor type, stage, and systemic treatment. Conclusions: A VES-13 score of ≥7 is a valuable discriminating tool for predicting functional decline or death and can be used as a frailtyscreening tool among older cancer patients in centers with limited resources to conduct a comprehensive geriatric assessment.Laura Biganzoli, Anna Rachelle Mislang, Samantha Di Donato, Dimitri Becheri, Chiara Biagioni, Stefania Vitale, Giuseppina Sanna, Elena Zafarana, Stefano Gabellini, Francesca Del Monte, Elena Mori, Daniele Pozzessere, Antonella Brunello, Andrea Luciani, Letizia Laera, Luca Boni, Angelo Di Leo, and Giuseppe Mottin

Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial

Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC

Management of Italian Patients With Advanced Non-Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study.

INTRODUCTION/BACKGROUND: Patients with advanced NSCLC who experience disease progression after second-line therapy might receive further active treatment. LIFE was an Italian cohort multicenter observational study composed of a cross-sectional and a longitudinal phase. PATIENTS AND METHODS: In the longitudinal phase, described here, the primary aim was to determine the proportion of patients receiving third-line therapy among those who received second-line active treatment according to clinical practice. The proportion of patients receiving further treatment lines was also estimated. RESULTS: The longitudinal phase was conducted between January and August 2012. Of 464 patients who began second-line therapy outside of clinical trials within the baseline evaluation, 56 (12.1%) were still receiving second-line therapy at the end of the observation period and 17 (3.7%) withdrew during or after second-line therapy. Of the remaining 391 patients, 158 (40.4%) received third-line treatment outside of clinical trials: 93 received a third-line chemotherapy and 65 a targeted agent. The main reason for interrupting third-line treatment was disease progression or death. During the same observation period, 25 of 113 patients who completed a third-line therapy received a fourth line of treatment. From diagnosis of NSCLC to the end of observation, biomarkers were tested in 323 patients (59.7%): epidermal growth factor receptor mutations in 315 (58.2%), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations in 83 (15.3%) and Anaplastic lymphoma kinase (ALK) translocation in 84 (15.5%). CONCLUSION: In Italian clinical practice, the proportion of patients with advanced NSCLC receiving more than 2 treatment lines of therapy is not negligible