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

INTRODUCTION: 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. METHODS: Eligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17. RESULTS: From April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2-18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2-10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47-0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination. CONCLUSIONS: The addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.

Phase 2 study of NAB-paclitaxel in SensiTivE and refractory relapsed small cell lung cancer (SCLC) (NABSTER TRIAL).

BACKGROUND: Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC. METHODS: In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS: Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months). CONCLUSIONS: Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met. CLINICAL TRIAL REGISTRATION: Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762.

Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non-Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial.

PURPOSE: MET-deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations. PATIENTS AND METHODS: Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts. RESULTS: From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No difference in any clinical endpoint was observed between MET-amplified and exon 14-mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts. CONCLUSIONS: Crizotinib induces response in a fraction of MET-deregulated NSCLC. Additional studies and innovative therapies are urgently needed.

[Activity and efficacy of vinflunine in third line in patients with advanced urothelial carcinoma of the renal pelvis, progressing to immunotherapy.] / Attività ed efficacia di vinflunina in terza linea in paziente con carcinoma uroteliale avanzato della pelvi renale, in progressione a immunoterapia.

The clinical case concerns a 72-years-old woman diagnosed with an urothelial carcinoma of the renal pelvis with hepatic and lymph node metastases. The disease was rapidly progressing to a first line of platinum-based chemotherapy and to a second line with immunotherapy; a clinical and instrumental benefit was then observed with vinflunine used as third line regimen.

Frequency of actionable alterations in epidermal growth factor receptor (EGFR) wild type non-small cell lung cancer: experience of the Wide Catchment Area of Romagna (AVR).

BACKGROUND: Molecular diagnostics for non-small cell lung cancer (NSCLC) has become the standard of care for personalized treatment. Epidermal growth factor receptor (EGFR) mutation and EML4-ALK translocation represent the two most important alterations in first-line treatment decision-making. However, other potentially targetable alterations are also present. METHODS: One thousand consecutive NSCLC patients with EGFR wild type (wt) tumors diagnosed by routine molecular analysis were considered. KRAS, BRAF, ERBB2, PIK3CA, NRAS, ALK, MAP2K1, RET and DDR2 gene mutations were analyzed using the multiparametric Sequenom MassARRAY® platform. EML4-ALK and ROS1 rearrangements were also assessed by fluorescent in situ hybridization. HER4 status was determined by direct sequencing. RESULTS: Three hundred and forty-eight (34.8%), 31 (3.1%), 39 (4.4%), 14 (1.8%), 6 (0.7%), 16 (1.8%), 5 (0.6%) and 9 (0.9%) patients showed an alteration in KRAS, BRAF, ALK, ROS1, NRAS, PIK3CA, MAPK1/2 and HER2 genes, respectively. Of the 657 patients for whom all markers were determined, 318 (48%) patients had at least one alteration. Eight patients showed overlapping mutations, 4 KRAS mutation/EML4-ALK translocation, one KRAS mutation/ROS1 rearrangement, 2 KRAS/PIK3CA mutations, and one BRAF/PIK3CA mutations. CONCLUSIONS: About 50% of our patients had a potentially targetable alteration, confirming the usefulness of a multiparametric approach for routine molecular diagnostics aimed at identifying potential therapeutic targets.

The Prognostic Roles of Gender and O6-Methylguanine-DNA Methyltransferase Methylation Status in Glioblastoma Patients: The Female Power.

BACKGROUND: Clinical and molecular factors are essential to define the prognosis in patients with glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status, age, Karnofsky Performance Status (KPS), and extent of surgical resection are the most relevant prognostic factors. Our investigation of the role of gender in predicting prognosis shows a slight survival advantage for female patients. METHODS: We performed a prospective evaluation of the Project of Emilia Romagna on Neuro-Oncology (PERNO) registry to identify prognostic factors in patients with GBM who received standard treatment. RESULTS: A total of 169 patients (99 males [58.6%] and 70 females [41.4%]) were evaluated prospectively. MGMT methylation was evaluable in 140 patients. Among the male patients, 36 were MGMT methylated (25.7%) and 47 were unmethylated (33.6%); among the female patients, 32 were methylated (22.9%) and 25 were unmethylated (17.9%). Survival was longer in the methylated females compared with the methylated males (P = 0.028) but was not significantly different between the unmethylated females and the unmethylated males (P = 0.395). In multivariate analysis, gender and MGMT methylation status considered together (methylated females vs. methylated males; hazard ratio [HR], 0.459; 95% confidence interval [CI], 0.242-0.827; P = 0.017), age (HR, 1.025; 95% CI, 1.002-1.049; P = 0.032), and KPS (HR, 0.965; 95% CI, 0.948-0.982; P < 0.001) were significantly correlated with survival. CONCLUSIONS: Survival was consistently longer among MGMT methylated females compared with males. Gender can be considered as a further prognostic factor.

Correction to: Which elderly newly diagnosed glioblastoma patients can benefit from radiotherapy and temozolomide? A PERNO prospective study.

The members of the PERNO Study Group were not individually captured in the metadata of the original publication. They are included in the metadata of this publication.

Prolonged Pemetrexed Infusion Plus Gemcitabine in Refractory Metastatic Colorectal Cancer: Preclinical Rationale and Phase II Study Results.

LESSONS LEARNED: Difficulties in translating in vitro results into clinical practice are inevitable.Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged. BACKGROUND: We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial. METHODS: Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days. RESULTS: Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3-4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9-7.1) and 2.1 months (95% CI: 1.7-2.8), respectively. CONCLUSION: The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic.

Italian, Multicenter, Phase III, Randomized Study of Cisplatin Plus Etoposide With or Without Bevacizumab as First-Line Treatment in Extensive-Disease Small-Cell Lung Cancer: The GOIRC-AIFA FARM6PMFJM Trial.

Purpose Considering promising results in phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Treatment-naive patients with ED-SCLC were randomly assigned to receive either cisplatin plus etoposide (arm A) or the same regimen with bevacizumab (arm B) for a maximum of six courses. In the absence of progression, patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses. The primary end point was overall survival (OS). Results Two hundred four patients were randomly assigned and considered in intent-to-treat analyses (103 patients in arm A and 101 patients in arm B). At a median follow-up of 34.9 months in arm A and arm B, median OS times were 8.9 and 9.8 months, and 1-year survival rates were 25% and 37% (hazard ratio, 0.78; 95% CI, 0.58 to 1.06; P = .113), respectively. A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen (hazard ratio, 0.60; 95% CI, 0.40 to 0.91; P = .011). Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B, respectively ( P = .030). Regarding hematologic toxicity, no statistically significant differences were observed; for nonhematologic toxicity, only hypertension was more frequent in arm B (grade 3 or 4, 1.0% v 6.3% in arms A v B, respectively; P = .057). Conclusion The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival, which, however, did not translate into a statistically significant increase in OS. Further research with novel antiangiogenic agents, particularly in the maintenance setting, is warranted.

Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors.

Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC).Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results:TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, P < 0.001) and HR 4.75 (95% CI, 1.38-16.29, P = 0.013), respectively.Conclusions:TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 23(9); 2195-202. ©2016 AACR.

Which elderly newly diagnosed glioblastoma patients can benefit from radiotherapy and temozolomide? A PERNO prospective study.

The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly patients with glioblastoma (GBM) remains unclear. We evaluated the outcome of patients >70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. For this analysis the criteria for selecting patients enrolled in the PERNO study were: age >70 years; PS 0-3; histologically confirmed GBM; postoperative radiotherapy (RT) after surgery with or without concomitant temozolomide (TMZ) or postsurgical TMZ alone. Between January 2009 and December 2010, 76 GBM elderly patients were identified in the prospective PERNO study. Twenty-three patients did not receive any treatment after surgery, and 53 patients received postsurgical treatments (25 patients received RT alone and 28 patients RT/TMZ). Median survival was 11.1 months (95 % CI 8.8-13.5), adding temozolomide concomitant and adjuvant to radiotherapy it was 11.6 months (95 % CI 8.6-14.6), and 9.3 months (95 % CI 8.1-10.6) in patients treated with RT alone (P = 0.164). However, patients with MGMT methylated treated with RT/TMZ obtained a better survival (17.2 months, 95 % CI 11.5-22.9) (P = 0.042). No difference in terms of survival were observed if patients with MGMT unmethylated tumor received RT alone, or RT/TMZ or, in MGMT methylated tumor, if patients received radiotherapy alone. In elderly patients RT/TMZ represent a widely used approach but it is effective with methylated MGMT tumors only.

Prognostic Evaluation of Disease Outcome in Solid Tumors Investigated With 64Cu-ATSM PET/CT.

PURPOSE: Cu-ATSM is a very promising PET radiopharmaceutical for tumor imaging of hypoxia. One of the advantages of this compound compared with other hypoxia-avid tracers is the high tumor-to-background signal offered, which guaranties facilitated tumor delineation. This study analyzes optimal semiquantitative and quantitative parameters obtained by Cu-ATSM PET/CT in the same cohort of patients with special focus on their correlation to disease outcome. PATIENTS AND METHODS: A prospective recruitment of 18 consecutive patients (M:F, 13:5; mean age, 60.7 years) with locally advanced non-small cell lung cancer (n = 7) or head and neck cancer (HNC) was performed. Each participant received 105 to 500 MBq of tracer according to body size and was scanned in a 3-dimensional mode PET/CT 60 minutes after tracer injection. PET images were reconstructed and visualized on a GE Advanced 4.6 workstation for the definition of semiquantitative and quantitative parameters: SUVmax, SUVratio-to-muscle, hypoxic tumor volume (HTV), and hypoxic burden (HB = HTV × SUVmean). These data were subsequently correlated to disease outcome, expressed in terms of progression-free survival calculated on a follow-up period with a median of 14.6 months. RESULTS: All patients showed a moderately to highly increased uptake of Cu-ATSM in tumor lesions, with a mean SUVmax of 5.2 (range, 1.9-8.3) and mean SUVratio of 4.4 (range, 1.6-6.8). In addition, a broad range of HTV and HB was defined as mean values of 99.3 cm (range, 2.5-453.7 cm) and 301 (4.2-1134), respectively. Receiver operating characteristic analysis identified as reference cutoffs with respect to disease outcome with the following values: SUVmax >2.5 (AUC, 0.57; sensitivity, 88.9%; specificity, 50%), SUVratio ≤4.4 (AUC, 0.60; sensitivity, 50; specificity, 83.3%), HTV >160.7 cm (AUC, 0.61; sensitivity, 55.6%; specificity, 75%), and HB >160.7 (AUC, 0.67; sensitivity, 58.3%; specificity, 83.3%). In our cohort, HB showed a statistically significant difference in terms of mean values on the analysis of variance test with respect to disease progression (P = 0.04). On univariate analysis, Cox regression confirmed these findings and showed a significant correlation to progression-free survival for HB (P = 0.05) and HTV (P = 0.02). CONCLUSIONS: In our cohort, the definition of optimal semiquantitative and quantitative parameters on Cu-ATSM PET/CT seems feasible and in line with previously published data. However, when considering the prognostic role with respect to disease outcome, the more robust parameters are represented by HTV and HB.

Nonsquamous, Non-Small-Cell Lung Cancer Patients Who Carry a Double Mutation of EGFR, EML4-ALK or KRAS: Frequency, Clinical-Pathological Characteristics, and Response to Therapy.

BACKGROUND: Epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, and echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) translocation are generally considered to be mutually exclusive. However, concomitant mutations are found in a small number of patients and the effect of these on response to targeted therapy is still unknown. PATIENTS AND METHODS: We considered 380 non-small-cell lung cancer (NSCLC) patients who underwent nonsequential testing for EGFR and EML4-ALK translocation. KRAS mutation analysis was also performed on 282 patients. RESULTS: We found 1.6%, 1.1%, and 2.5% of patients who showed a double mutation comprising EGFR and EML4-ALK, EGFR and KRAS, and EML4-ALK and KRAS, respectively. Twenty-eight patients with EGFR mutation underwent first-line therapy with a tyrosine kinase receptor; a clinical benefit was observed in 81.8% of patients with EGFR mutations only and in 67% of those who also showed an EML4-ALK translocation. Twelve patients with an EML4-ALK translocation received crizotinib and 7 of these had disease progression within 3 months (2 had a concomitant KRAS mutation and 1 had a concomitant EGFR mutation). Two patients showed stable disease, 1 of whom also had a KRAS mutation. Two patients obtained a partial response and 1 had a complete response; all harbored an EML4-ALK translocation only. The median overall survival of patients who carried an EML4-ALK translocation alone or concomitant with a KRAS mutation was 57.1 (range, 10.7-not reached) and 10.7 (range, 4.6-not reached) months, respectively. CONCLUSION: Concomitant EGFR, EML4-ALK, or KRAS mutations can occur in NSCLC. Concomitant KRAS mutation and EML4-ALK translocation represents the most common double alteration and confers a poor prognosis.

Adrenal incidentalomas and subclinical Cushing syndrome: indications to surgery and results in a series of 26 laparoscopic adrenalectomies.

BACKGROUND: Casual detection of an adrenal mass, the so called incidentaloma (AI) requires an in-depth analysis of imaging phenotype together with hormonal investigation, in order to evaluate both its potential malignancy and the occurrence of a preclinical condition of hypercortisolism (Subclinical Cushing Syndrome, SCS). Aim of the present work is to evaluate surgical indications and results of surgery in patients harbouring an AI with inapparent hypercortisolism. METHODS: The study has been carried on in a series of 26 Laparoscopic Adrenalectomies (LA) performed from January 2009 and January 2015. Indications to surgery included AI (11 cases), Cushing's syndrome (7 cases), suspected metastases (5 cases) and Conn's disease (3 cases). Six patients with AI had a SCS associated with variable forms of a metabolic syndrome: they were evaluated in detail analysing cortisol secretion and values of Arterial Hypertension, Diabetes Mellitus and BMI before and after surgery. RESULTS: As far as SCS is concerned, LA was completed in 5 patients (one case converted). Pathology revealed 5 adenomas and one nodular hyperplasia. Four cases required oral cortisone administration at the discharge. At a mean follow- up of 33 months cortisol secretion returned to normal range in all patients; an improvement of metabolic condition was observed in 60, 25, and 50 per cent of hypertensive, diabetic and obese patients respectively. CONCLUSION: Indications to LA in case of AI and SCS is strongly supported by the presence of an associated metabolic syndrome. In spite of a limited number, our experience confirms the favourable results of surgery in such patients. KEY WORDS: Adrenal incidentaloma, Laparoscopic adrenalectomies, Subclinical Cushing syndrome.

Benefit of eribulin in a patient with HER2(+) breast cancer who progressed after trastuzumab and lapatinib: a case report.

We report the case of a HER2(+) breast cancer patient, with early relapse, refractory to HER2-targeted therapy and treated with eribulin mesylate. The patient progressed during two different HER2 target therapies: trastuzumab as adjuvant/first-line treatment and lapatinib as second-line treatment. The patient underwent nine cycles of eribulin (1.23 mg/m(2) days 1-8 every 3 weeks). The therapy was well tolerated. Restaging with computed tomography after the second cycle of treatment demonstrated stable disease. After nine cycles of eribulin therapy the patient experienced disease progression and she died 6 months later. This case report provides further insights regarding the use of eribulin mesylate as third-line treatment in a HER2(+) breast cancer patient.

Italian multicenter phase III randomized study of cisplatin-etoposide with or without bevacizumab as first-line treatment in extensive stage small cell lung cancer: treatment rationale and protocol design of the GOIRC-AIFA FARM6PMFJM trial.

BACKGROUND: Neoangiogenesis is particularly abundant in small-cell lung cancer (SCLC) and is associated with poor prognosis. As a result of the promising nature of phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line chemotherapy with cisplatin-etoposide for treatment of extensive disease SCLC. We present the treatment rationale and study design of GOIRC trial (FARM6PMFJM study), a multicenter randomized phase III study, supported by AIFA (Agenzia Italiana del Farmaco). PATIENTS AND METHODS: Patients are randomized to receive either cisplatin 25 mg/m(2) and etoposide 100 mg/m(2) intravenously on days 1 to 3 (control arm) or the same chemotherapy combined with bevacizumab 7.5 mg/kg intravenously on day 1 (experimental arm). Treatment is repeated every 3 weeks and for a maximum of 6 courses. Patients randomized to the experimental arm in the absence of disease progression after 6 cycles continue bevacizumab alone until progression or for a maximum of 18 courses. Tumor assessment is done every 3 cycles. Major eligibility criteria are: age ≥ 18 years; histologically or cytologically documented extensive disease SCLC; Eastern Cooperative Oncology Group performance status ≤ 2; adequate hematological, hepatic and renal functions; no history of grade 2 or higher hemoptysis; and no evidence of tumor cavitation. The primary end point of this study is overall survival. Secondary end points include response rate, time to progression, and toxicity. CONCLUSION: An interim futility analysis was performed by an Independent Data Monitoring Committee in September 2013 and the trial obtained approval to continue. As of July 31, 2014, 171 patients of 206 planned have been randomized.

Gene mutation analysis in EGFR wild type NSCLC responsive to erlotinib: are there features to guide patient selection?

Tyrosine kinase inhibitors (TKIs) are very efficacious in non-small-cell lung cancer (NSCLC) patients harboring activating Epidermal Growth Factor Receptor (EGFR) mutations. However, about 10% of EGFR wild type (wt) patients respond to TKI, with unknown molecular mechanisms of sensitivity. We considered a case series of 34 EGFR wt NSCLC patients responsive to erlotinib after at least one line of therapy. Responsive patients were matched with an equal number of non-responsive EGFR wt patients. A panel of 26 genes, for a total of 214 somatic mutations, was analyzed by MassARRAY® System (Sequenom, San Diego, CA, USA). A 15% KRAS mutation was observed in both groups, with a prevalence of G12C in non-responders (80% vs. 40% in responders). NOTCH1, p53 and EGFR-resistance-related mutations were found more frequently in non-responders, whereas EGFR-sensitizing mutations and alterations in genes involved in proliferation pathways were more frequent in responders. In conclusion, our findings indicate that p53, NOTCH1 and exon 20 EGFR mutations seem to be related to TKI resistance. KRAS mutations do not appear to influence the TKI response, although G12C mutation is more frequent in non-responders. Finally, the use of highly sensitive methodologies could lead to the identification of under-represented EGFR mutations potentially associated with TKI sensitivity.

Pattern of care and effectiveness of treatment for glioblastoma patients in the real world: Results from a prospective population-based registry. Could survival differ in a high-volume center?

BACKGROUND: As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. METHODS: Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. RESULTS: Two hundred sixty-seven GBM patients (median age, 64 y; range, 29-84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2-12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0-18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248-0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388-0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328-0.986; P = .0446). CONCLUSIONS: The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.

The Pan European Emesis Registry (PEER): a critical appraisal of the Italian experience.

PURPOSE: Data from a large European prospective observational study were analysed to describe the antiemetic prescribing pattern for chemotherapy-induced nausea and vomiting (CINV) in Italian clinical practice. METHODS: Post hoc analysis of the Pan European Emesis Registry in chemo-naïve adults initiating single-day highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer. RESULTS: A total of 211 eligible patients were enrolled in the Italian centres, 180 were included in the analyses for cycle 1; 50·6% received MEC. The use of guideline-consistent CINV prophylaxis (GCCP) varied substantially between acute and delayed phases (54·4% during the acute phase vs. 29·4% in the overall 120-hour study period, acute plus delayed phases). Neurokinin-1 receptor antagonist was added to the prophylaxis with dexamethasone+5-hydroxytryptamine type 3 receptor antagonists in only 11·1% of patients (vs. 57·2% of the entire European study population). In the GCCP group, the complete response rate was significantly higher than that recorded in the guideline-inconsistent CINV prophylaxis (GICP) group (75·5 vs. 53·5%, P = 0·006). CONCLUSION: The proportion of guideline-consistent antiemetic therapy was quite low in the Italian population as it was in the overall European population. The implementation of specific guidelines' recommendations for chemotherapeutic regimens administered according to standard protocols could be considered as a means to reduce the burden of CINV.