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Non-small-cell lung cancer is still considered a difficult disease to manage because of its aggressiveness and resistance to common therapies. Chemotherapy remains the gold standard in nearly 80% of lung cancers, but clinical outcomes are discouraging, and the impact on median overall survival (OS) barely reaches 12 months. At the end of the last century, the discovery of oncogene-driven tumours completely changed the therapeutic landscape in lung cancers, harbouring specific gene mutations/translocations. Epidermal growth factors receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later led new insights in lung cancer biology knowledge. The use of specific tyrosine kinases inhibitors overturned the biological behaviour of EGFR mutation positive tumours and became a preclinical model to understand the heterogeneity of lung cancers and the mechanisms of drug resistance. In this review, we summarise the employment of targeted agents against the most representative biomolecular alterations and provide some criticisms of the therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of b2 glycoprotein 1 (b2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methods: Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). Results: A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel+bavituximab arm and was 10.9 months in the docetaxel+placebo arm (HR 1.06; 95% CI 0.88-1.29; P=0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82-1.22; P=0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum b2GP1 levels≤200 μg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P=0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P=0.006). Conclusions: The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high b2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. [ABSTRACT FROM AUTHOR]

Background: The activity of ginger in the management of chemotherapy-induced nausea and vomiting (CINV) has been suggested, but design inadequacies, heterogeneity of the population, small numbers and poor quality of tested products limit the possibility to offer generalizable results. Patients and methods: We conducted a randomized, double-blind, placebo-controlled, multicenter study in patients planned to receive⩾2 chemotherapy cycles with high dose (>50 mg/m2) cisplatin. Patients received ginger 160 mg/day (with standardized dose of bioactive compounds) or placebo in addition to the standard antiemetic prophylaxis for CINV, starting from the day after cisplatin administration. CINV was assessed through daily visual-analogue scale and Functional Living Index Emesis questionnaires. The main objective was protection from delayed nausea; secondary end points included intercycle nausea and nausea anticipatory symptoms. Results: In total, 121 patients received ginger and 123 placebo. Lung (49%) and head and neck cancer (HNC; 35%) were the most represented tumors. No differences were reported in terms of safety profile or compliance. The incidence of delayed, intercycle and anticipatory nausea did not differ between the two arms in the first cycle and second cycle. A benefit of ginger over placebo in Functional Living Index Emesis nausea score differences (day 6-day 1) was identified for females (P=0.048) and HNC patients (P=0.038). Conclusions: In patients treated with high-dose cisplatin, the daily addition of ginger, even if safe, did not result in a protective effect on CINV. The favorable effect observed on nausea in subgroups at particular risk of nausea (females; HNC) deserves specific investigation. [ABSTRACT FROM AUTHOR]

Composite scales such as the Total Neuropathy Score clinical version ( TNSc©) have been widely used to measure neurological impairment in a standardized manner but they have been criticized due to their ordinal setting having no fixed unit. This study aims to improve impairment assessment in patients with chemotherapy-induced peripheral neuropathy ( CIPN) by subjecting TNSc© records to Rasch analyses. In particular, we wanted to investigate the influence of factors affecting the use of the TNSc© in clinical practice. TNSc© has 7 domains (sensory, motor, autonomic, pin-prick, vibration, strength, and deep tendon reflexes [ DTR]) each being scored 0-4. Data obtained in 281 patients with stable CIPN were subjected to Rasch analyses to determine the fit to the model. The TNSc© did not meet Rasch model's expectations primarily because of misfit statistics in autonomic and DTR domains. Removing these two, acceptable model fit and uni-dimensionality were obtained. However, disordered thresholds (vibration and strength) and item bias (mainly cultural) were still seen, but these findings were kept to balance the assessment range of the Rasch-Transformed TNSc© ( RT-TNSc©). Acceptable reliability findings were also obtained. A 5-domains RT-TNSc© may be a more proper assessment tool in patients with CIPN. Future studies are needed to examine its responsive properties. [ABSTRACT FROM AUTHOR]

This paper show the results of a clinical study conducted in Italy on the efficacy of the adjuvant chemotherapy in operable gastric cancer. The study shows conclusively that an intensive polychemotherapy given as postoperative treatment achieves the same results, in terms of disease-free and overall survival, of a monotherapy with fluorouracil. The strength of the study is in the large number of patients included over a limited period, making it one of the most significant in the western world.Background Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients and methods Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m2 day 1, LV 100 mg/m2 as 2 h infusion and 5-FU 400 mg/m2 as bolus, days 1 and 2 followed by 600 mg/m2/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). Results From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. Conclusions A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. Clinical trial registration ClinicalTrials.gov Identifier: NCT01640782. [ABSTRACT FROM AUTHOR]

Background. Vinorelbine (VRB) and capecitabine (CAPE) are demonstrated to be active in pretreated metastatic breast cancer patients. Different studies have demonstrated that the metronomic treatment is active with an acceptable toxicity profile. We designed a Phases I-II study to define the MTD of oral metronomic, VRB, and CAPE. Patients and Methods. Phase I: fixed dose of CAPE was 500 mg thrice a day, continuously. Level I of VRB was 20 mg/tot thrice a week for 3 weeks (1 cycle). Subsequent levels were30mg/tot and 40 mg/tot (Level III), respectively, if no Grades 3-4 toxicity were observed in the previous level. Phase II: further 32 patients received the MTD of VRB plus CAPE for a total of 187 cycles to confirm toxicity profile. Results. 12 patients were enrolled in Phase I and 22 in Phase II. Phase I: the MTD of VRB was 40 mg. Phase II: 187 cycles were delivered, observing 5.9% of Grades 3-4 toxicity. 31 patients are evaluable for efficacy, obtaining a clinical benefit rate of 58.1%. Conclusion. MTD of VRB with fixed dose of CAPE was 40 mg thrice a week and was the recommended dose for the ongoing Phase II multicenter study. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing, non-pemetrexed doublet. The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin. METHODS: In this double-blind, multicentre, phase 3, randomised placebo-controlled trial, patients with advanced non-squamous NSCLC aged 18 years or older, with no previous systemic chemotherapy for lung cancer, with at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 participated. Before randomisation, patients entered an induction phase which consisted of four cycles of induction pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) on day 1 of a 21-day cycle. Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage (IIIB or IV), ECOG performance status (0 or 1), and induction response (complete or partial response, or stable disease), and randomly assigned (2:1 ratio) to receive maintenance therapy with either pemetrexed (500 mg/m(2) every 21 days) plus best supportive care or placebo plus best supportive care until disease progression. Randomisation was done with the Pocock and Simon minimisation method. Patients and investigators were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00789373. FINDINGS: Of the 1022 patients enrolled, 939 participated in the induction phase. Of these, 539 patients were randomly assigned to receive continuation maintenance with pemetrexed plus best supportive care (n=359) or with placebo plus best supportive care (n=180). Among the 359 patients randomised to continuation maintenance with pemetrexed, there was a significant reduction in the risk of disease progression over the placebo group (HR 0·62, 95% CI 0·49-0·79; p<0·0001). The median progression-free survival, measured from randomisation, was 4·1 months (95% CI 3·2-4·6) for pemetrexed and 2·8 months (2·6-3·1) for placebo. Possibly treatment-related laboratory grade 3-4 adverse events were more common in the pemetrexed group (33 [9%] of 359 patients) than in the placebo group (one [<1%] of 180 patients; p<0·0001), as were non-laboratory grade 3-5 adverse events (32 [9%] of 359 patients in the pemetrexed group; eight [4%] of 180 patients in the placebo group; p=0·080); one possibly treatment-related death was reported in each group. The most common adverse events of grade 3-4 in the pemetrexed group were anaemia (16 [4%] of 359 patients), neutropenia (13 [4%]), and fatigue (15 [4%]). In the placebo group, these adverse events were less common: anaemia (one [<1%] of 180 patients), neutropenia (none), and fatigue (one <1%]). The most frequent serious adverse events were anaemia (eight [2%] of 359 patients in the pemetrexed group vs none in the placebo group) and febrile neutropenia (five [1%] vs none). Discontinuations due to drug-related adverse events occurred in 19 (5%) patients in the pemetrexed group and six (3%) patients in the placebo group. INTERPRETATION: Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin. FUNDING: Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a frequent, potentially severe and dose-limiting side-effect of cancer treatment. Despite its clinical relevance that limits the use of several antineoplastic agents and even the future development of new anticancer drugs, several crucial aspects of CIPN remain unsolved, one of which is how to assess its occurrence and severity in the most effective and reliable way. CIPN severity is generally assessed using Common Toxicity Criteria (CTC) scales, although it is well known that significant inter-observer disagreement exists using these scales. Moreover, most CTC scores mix impairment, disability and quality of life measures, which could lead to misinterpretation of the results and unpredictable under- or overestimation of the effect. This uncertainty may lead to different interpretations of the results of the same clinical trials by clinicians and also by regulatory agencies. The use of other types of scale based on clinical and instrumental examinations, or the use of self-administered questionnaires for patients, has not yet really improved the accuracy of CIPN assessment, although some of these tools are promising and deserve to be further validated. As a result, there is a general recognition that CIPN has still not been properly assessed and that improvements should be made. In this review, the available data regarding the different tools used to assess CIPN will be revised and their features will be critically examined, with a special focus on their reliability and reproducibility across examiners and, when available, through direct comparison. [ABSTRACT FROM AUTHOR]

Background Treatment with an EGFR TKI is the standard of care for patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC, based on findings from randomized controlled trials, but acquired resistance is inevitable. A phase IIIb study (NCT01853826) was conducted to assess outcomes with afatinib in a broad EGFRm+ NSCLC patient population, similar to real-world practice. Here we report results from a sub-study of the trial, to assess the relationship between afatinib efficacy and the presence of biomarkers associated with resistance to EGFR TKIs. Methods EGFR TKI-naïve pts with locally advanced/metastatic EGFRm+ NSCLC and ECOG PS 0–2 received afatinib starting at 40 mg/day. Tumor biopsies were performed prior to study entry; baseline T790M status (presence vs absence), and total BIM, BIMEL and mTOR mRNA expression (high vs low, according to median values) were analyzed for patients who consented to sub-study participation. Exploratory efficacy analyses were conducted. Time to symptomatic progression (TTSP) and progression-free survival (PFS) were calculated using the Kaplan–Meier method. Results A total of 113 pts were included in this sub-study (data cut-off 21 June 2018). Baseline characteristics, n (%): white race, 112 (99); female, 70 (62); 1st/2nd/≥3rd-line therapy, 94/16/3 (83/14/3); ECOG PS 0/1, 106 (94); brain metastases, 16 (14); common/uncommon mutations, 105/8 (93/7). Median time on treatment was 581 days. Objective response/disease control rates were 58%/95%. Median (95% CI) TTSP was 20.6 months (18.9–24.9) and PFS was 19.8 months (16.1–23.5). TTSP and PFS by biomarker status at baseline are reported in the table. Table: 483P   TTSP    PFS      Median (95% CI)  HR (95% CI)  Median (95% CI)  HR (95% CI)  T790M*          Present (n = 51) Absent (n = 60)  19.5 (14.9–25.1) 21.4 (17.7–26.3)  1.0 (0.67–1.60)  18.8 (14.1–24.0) 21.4 (15.9–26.1)  1.1 (0.7–1.7)  BIM total mRNA expression†          High (n = 35) Low (n = 35)  23.7 (14.7–37.1) 25.7 (19.3–35.8)  1.2 (0.7–2.1)  21.8 (14.1–28.5) 26.0 (18.9–35.5)  1.2 (0.7–2.1)  BIMEL mRNA expression‡          High (n = 22) Low (n = 21)  19.1 (11.9–24.8) 24.9 (14.8–42.2)  1.3 (0.6–2.7)  18.8 (11.6–23.5) 25.2 (16.1–38.6)  1.4 (0.7–2.9)  mTOR mRNA expression§          High (n = 39) Low (n = 37)  22.3 (14.8–29.5) 26.1 (19.1–35.8)  1.0 (0.6–1.7)  21.8 (14.3–29.5) 23.1 (14.5–35.5)  1.0 (0.6–1.8)    TTSP    PFS      Median (95% CI)  HR (95% CI)  Median (95% CI)  HR (95% CI)  T790M*          Present (n = 51) Absent (n = 60)  19.5 (14.9–25.1) 21.4 (17.7–26.3)  1.0 (0.67–1.60)  18.8 (14.1–24.0) 21.4 (15.9–26.1)  1.1 (0.7–1.7)  BIM total mRNA expression†          High (n = 35) Low (n = 35)  23.7 (14.7–37.1) 25.7 (19.3–35.8)  1.2 (0.7–2.1)  21.8 (14.1–28.5) 26.0 (18.9–35.5)  1.2 (0.7–2.1)  BIMEL mRNA expression‡          High (n = 22) Low (n = 21)  19.1 (11.9–24.8) 24.9 (14.8–42.2)  1.3 (0.6–2.7)  18.8 (11.6–23.5) 25.2 (16.1–38.6)  1.4 (0.7–2.9)  mTOR mRNA expression§          High (n = 39) Low (n = 37)  22.3 (14.8–29.5) 26.1 (19.1–35.8)  1.0 (0.6–1.7)  21.8 (14.3–29.5) 23.1 (14.5–35.5)  1.0 (0.6–1.8)  Non-evaluable or missing: *n=2; †n = 43; ‡n = 36; §n = 37. Table: 483P   TTSP    PFS      Median (95% CI)  HR (95% CI)  Median (95% CI)  HR (95% CI)  T790M*          Present (n = 51) Absent (n = 60)  19.5 (14.9–25.1) 21.4 (17.7–26.3)  1.0 (0.67–1.60)  18.8 (14.1–24.0) 21.4 (15.9–26.1)  1.1 (0.7–1.7)  BIM total mRNA expression†          High (n = 35) Low (n = 35)  23.7 (14.7–37.1) 25.7 (19.3–35.8)  1.2 (0.7–2.1)  21.8 (14.1–28.5) 26.0 (18.9–35.5)  1.2 (0.7–2.1)  BIMEL mRNA expression‡          High (n = 22) Low (n = 21)  19.1 (11.9–24.8) 24.9 (14.8–42.2)  1.3 (0.6–2.7)  18.8 (11.6–23.5) 25.2 (16.1–38.6)  1.4 (0.7–2.9)  mTOR mRNA expression§          High (n = 39) Low (n = 37)  22.3 (14.8–29.5) 26.1 (19.1–35.8)  1.0 (0.6–1.7)  21.8 (14.3–29.5) 23.1 (14.5–35.5)  1.0 (0.6–1.8)    TTSP    PFS      Median (95% CI)  HR (95% CI)  Median (95% CI)  HR (95% CI)  T790M*          Present (n = 51) Absent (n = 60)  19.5 (14.9–25.1) 21.4 (17.7–26.3)  1.0 (0.67–1.60)  18.8 (14.1–24.0) 21.4 (15.9–26.1)  1.1 (0.7–1.7)  BIM total mRNA expression†          High (n = 35) Low (n = 35)  23.7 (14.7–37.1) 25.7 (19.3–35.8)  1.2 (0.7–2.1)  21.8 (14.1–28.5) 26.0 (18.9–35.5)  1.2 (0.7–2.1)  BIMEL mRNA expression‡          High (n = 22) Low (n = 21)  19.1 (11.9–24.8) 24.9 (14.8–42.2)  1.3 (0.6–2.7)  18.8 (11.6–23.5) 25.2 (16.1–38.6)  1.4 (0.7–2.9)  mTOR mRNA expression§          High (n = 39) Low (n = 37)  22.3 (14.8–29.5) 26.1 (19.1–35.8)  1.0 (0.6–1.7)  21.8 (14.3–29.5) 23.1 (14.5–35.5)  1.0 (0.6–1.8)  Non-evaluable or missing: *n=2; †n = 43; ‡n = 36; §n = 37. Conclusions In this broad population of EGFR TKI-naïve pts with EGFRm+ NSCLC who were treated with afatinib, biomarker analysis indicated no notable differences in efficacy outcomes by baseline T790M status (presence vs absence), or baseline mRNA expression of BIM, BIMEL or mTOR (high vs low). Clinical trial identification NCT01853826. Editorial acknowledgement Laura Winton of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure M. Hochmair: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme, ; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Takeda; Speaker Bureau / Expert testimony: Pfizer. R. Ramlau: Advisory / Consultancy: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. J. Skrickova: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche. P. Bidoli: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: BMS ; Advisory / Consultancy: Boehringer Ingelheim. L. Clementi: Full / Part-time employment: Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. F. De Marinis: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Boehringer Ingelheim. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the previously published article discussing about the evidence pointed at the effectiveness of Imatinib treatment in platelet-derived growth factor receptor, beta-overexpressing human lung adenocarcinoma xenografts in mice.