Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).

Effect of capmatinib on the pharmacokinetics of substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with MET-dysregulated solid tumours.

BACKGROUND: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. METHODS: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator. RESULTS: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (Cmax ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast ), respectively, with no change in Cmax . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. CONCLUSION: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.

Pharmacokinetics of capmatinib in participants with hepatic impairment: A phase 1, open-label, single-dose, parallel-group study.

AIMS: Capmatinib, a mesenchymal-epithelial transition factor tyrosine kinase inhibitor, is metabolized by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. In individuals with hepatic impairment, alterations in hepatobiliary excretion and metabolism could lead to higher capmatinib exposure. We compared the pharmacokinetics of a single oral dose of capmatinib 200 mg administered to participants with varying degrees of hepatic impairment vs. matched controls with normal hepatic function. METHODS: This phase 1, multicentre, open-label, parallel-group study enrolled adult participants with normal hepatic function and mild, moderate and severe hepatic impairments. Eligible participants received a single oral dose of 200 mg capmatinib. The pharmacokinetic parameters of capmatinib were analysed and compared across participants with impaired and normal hepatic function. RESULTS: Of 31 enrolled participants, 29 had an evaluable pharmacokinetic profile: normal (n = 9); mild (n = 6); moderate (n = 8); severe (n = 6). Compared with the normal group, geometric mean (GM) maximum (peak) observed plasma drug concentration after single-dose administration decreased by 27.6% in the mild group (GM ratio [GMR] = 0.724; 90% confidence interval [CI]: 0.476-1.10), by 17.2% in the moderate group (GMR = 0.828; 90% CI: 0.563-1.22) and remained unchanged in the severe group (GMR = 1.02; 90% CI: 0.669-1.55). Compared with the normal group, GM area under the plasma concentration-time curve from time zero to infinity decreased by 23.3% in the mild group (GMR = 0.767; 90% CI: 0.532-1.11), by 8.6% in the moderate group (GMR = 0.914; 90% CI: 0.652-1.28) and increased by 24% in the severe group (GMR = 1.24; 90% CI: 0.858-1.78). CONCLUSION: Mild, moderate and severe hepatic impairment did not have a clinically relevant impact on capmatinib pharmacokinetics. No new safety findings are reported in this study.

Effect of capmatinib on the pharmacokinetics of digoxin and rosuvastatin administered as a 2-drug cocktail in patients with MET-dysregulated advanced solid tumours: A phase I, multicentre, open-label, single-sequence drug-drug interaction study.

AIMS: Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic nonsmall cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin in patients with MET-dysregulated advanced solid tumours. METHODS: This was a multicentre, open-label, single-sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET-dysregulated advanced solid tumours on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug-drug interaction assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated. RESULTS: Thirty-two patients were enrolled. Compared to digoxin alone, the geometric mean ratios (90% confidence interval) of area under the concentration-time curve from time zero to infinity and maximum concentration for digoxin plus capmatinib were 1.47 (1.28, 1.68) and 1.74 (1.43, 2.13), respectively. Compared to rosuvastatin alone, the geometric mean ratios (90% confidence interval) of area under the curve to infinity and maximum concentration for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral oedema and pyrexia. Most frequent Grade 3/4 adverse events (≥5%) were anaemia, pulmonary embolism, asthenia, dyspnoea, nausea and vomiting. CONCLUSION: This study demonstrated that capmatinib is an inhibitor of P-gp and BCRP transporters, with clinically relevant drug-drug interaction potential. Capmatinib was well-tolerated and no unexpected safety concerns were observed.

Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts.

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).

Evaluation of the Pharmacokinetic Drug Interaction of Capmatinib With Itraconazole and Rifampicin and Potential Impact on Renal Transporters in Healthy Subjects.

Capmatinib is a highly specific, potent, and selective mesenchymal-epithelial transition factor inhibitor predominantly eliminated by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. Here, we investigated the effects of a strong CYP3A inhibitor (itraconazole) and a strong CYP3A inducer (rifampicin) on single-dose pharmacokinetics of capmatinib. In addition, serum creatinine and cystatin C were monitored to assess the potential inhibition of renal transporters by capmatinib. This was an open-label, 2-cohort (inhibition and induction), 2-period (capmatinib alone and inhibition/induction periods) study in healthy subjects. In the inhibition cohort, capmatinib (400 mg/day) was given alone, then with itraconazole (200 mg/day for 10 days, 5-day lead-in before coadministration). In the induction cohort, capmatinib (400 mg/day) was given alone, then with rifampicin (600 mg/day for 9 days, 5-day lead-in before coadministration). Fifty-three subjects (inhibition cohort, n = 27; induction cohort, n = 26) were enrolled. Coadministration of itraconazole resulted in an increase of capmatinib area under the plasma concentration-time curve from time 0 to infinity by 42% (geometric mean ratio [GMR], 1.42; 90%CI, 1.33-1.52) with no change in maximum plasma concentration (GMR, 1.03; 90%CI, 0.866-1.22). Coadministration of rifampicin resulted in a reduction of capmatinib area under the plasma concentration-time curve from time 0 to infinity by 66.5% (GMR, 0.335; 90%CI, 0.300-0.374) and a decrease in maximum plasma concentration by 55.9% (GMR, 0.441; 90%CI, 0.387-0.502). After a single dose of capmatinib, a transient increase in serum creatinine was observed with no change in serum cystatin C concentration during the 3-day monitoring period. In conclusion, coadministration of itraconazole or rifampicin resulted in clinically relevant changes in systemic exposure to capmatinib. The transient increase in serum creatinine without any increase in cystatin C suggests inhibition of renal transport by capmatinib.

Improved Survival Outcomes in Patients With MET-Dysregulated Advanced NSCLC Treated With MET Inhibitors: Results of a Multinational Retrospective Chart Review.

BACKGROUND: We evaluated the disease and patient characteristics, treatment, and MET testing patterns, predictive biomarkers and survival outcomes in patients with MET-dysregulated metastatic non-small-cell lung cancer (NSCLC) in a real-world setting. PATIENTS AND METHODS: This was a multinational, retrospective, noninterventional chart review study. Data from medical records of patients with advanced/metastatic EGFR wild-type, MET-dysregulated NSCLC (December 2017-September 2018) were abstracted into electronic data collection forms. RESULTS: Overall, 211 patient charts were included in this analysis; 157 patients had MET exon 14 skipping mutations (METex14; with or without concomitant MET amplification) and 54 had MET amplification only. All patients were tested for METex14, whereas MET amplification was evaluated in 168 patients. No overlap was reported between MET dysregulation and ALK, ROS1 or RET rearrangements, or HER2 exon 20 insertions. Overall, 56 of 211 patients (26.5%) received MET inhibitor (METi) therapy in any treatment-line setting (31.2% in the METex14 cohort; 13% in the MET-amplified only cohort). In the METex14 cohort, median OS in patients receiving METi was 25.4 months versus 10.7 months in patients who did not (HR [95% CI]: 0.532 [0.340-0.832]; P = .0055). In the MET-amplified only cohort, median OS was 20.6 months in patients treated with METi compared with 7.6 months in those without METi (HR [95% CI]: 0.388 [0.152-0.991]; P = .0479). CONCLUSIONS: MET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with poor survival outcomes. Notably, METi therapies are associated with improved survival outcomes in patients with MET-dysregulated NSCLC.

Nazartinib for treatment-naive EGFR-mutant non-small cell lung cancer: Results of a phase 2, single-arm, open-label study.

INTRODUCTION: Nazartinib, a novel third-generation EGFR-tyrosine kinase inhibitor, previously demonstrated antitumor activity and manageable safety in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) who received ≤ 3 prior lines of systemic therapy. Herein, we report phase 2 efficacy and safety of first-line nazartinib. METHODS: This single-arm, open-label, global study enrolled treatment-naive adult patients with stage IIIB/IV NSCLC harboring EGFR-activating mutations (eg, L858R and/or ex19del). Patients with neurologically stable and controlled brain metastases were also eligible. Patients received oral nazartinib 150 mg once daily. The primary endpoint was Blinded Independent Review Committee (BIRC)-assessed overall response rate (ORR) per RECIST v1.1. RESULTS: Forty-five patients received ≥ 1 dose of nazartinib. The median follow-up time from enrollment to data cutoff (November 1, 2019) was 30 months (range: 25-34). The BIRC-assessed ORR was 69% (95% CI, 53-82). The median progression-free survival (PFS) was 18 months (95% CI, 15-not estimable [NE]). The median overall survival was NE. In patients with baseline brain metastases (n = 18), the ORR and median PFS (95% CIs) were 67% (41-87) and 17 months (11-21). Seventeen of 18 patients had brain metastases as non-target lesions; the CNS lesions were absent/normalized in 9 of 17 (53%). Only 2 of 27 patients without baseline brain metastases developed new brain metastases postbaseline. Most frequent adverse events (≥ 25%, any grade, all-causality) were diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough, and stomatitis (27% each). CONCLUSIONS: First-line nazartinib demonstrated promising efficacy, including clinically meaningful antitumor activity in the brain, and manageable safety in patients with EGFR-mutant NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02108964.

Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors.

PURPOSE: In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors. METHODS: This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety. FINDINGS: Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median Tmax for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUCtau and Cmax) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%). IMPLICATIONS: Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104.

Malignant pleural mesothelioma: current treatments and emerging drugs.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an uncommon disease whose incidence is increasing worldwide over the past 30 years. Surgical resection and radiotherapy represent the standard treatment in patient with resectable MPM. Chemotherapy is also necessary to reduce incidence of distant metastases, but the optimal setting of treatment (neoadjuvant, adjuvant and intrapleural) is not clarified. For the patients with unresectable MPM, the combination cisplatin and pemetrexed or ralitrexed is the standard treatment as supported by a Phase III study. Better understanding of molecular pathways involved in MPM has enabled inclusion of new drugs targeted against pathways responsible for proliferation, cell survival and angiogenesis. OBJECTIVE: This review discusses the current treatment option, the specific signal pathways activated in MPM and the novel agents under evaluation in clinical trials. METHODS: We use for this article abstracts, papers, oral presentations from ASCO and the website http://www.clinical-trials.gov. RESULTS/ CONCLUSION: This review summarizes the activity of chemotherapy and of new agents under evaluation in clinical trials. The better understanding of molecular pathways activated in MPM will hopefully provide new therapeutic options for these patients in the future.

Pathological, biological and clinical characteristics, and surgical management, of elderly women with breast cancer.

For this retrospective study, we divided 3814 patients with invasive operable breast cancer into five groups based on their age at diagnosis. Univariate analysis showed that the elderly women had larger tumours with more axillary node involvement and lymphovascular invasion, more estrogen- and progesterone-positive tumours, lower grades and proliferative indices, and were less likely to be c-erbB2 positive. They were more likely to have been diagnosed in a symptomatic state and to have undergone mastectomy, and less likely to have undergone mammary reconstruction or axillary dissection, or to have a family history of breast cancer. The multinomial regression model showed that pT, pN, ER, PgR, the type of diagnosis, and a family history were independently associated with each other. The results of this study show that elderly women are more likely to have larger and more frequently N+ tumours, but these are biologically less aggressive and usually seem to receive less invasive surgical treatment.

Mammary Paget's disease occurring after mastectomy.

BACKGROUND: Mammary Paget's disease and extramammary Paget's disease are neoplastic conditions, in which there is intraepithelial (usually intraepidermal) infiltration by neoplastic cells showing glandular differentiation. Mammary Paget's disease occurs exclusively on the nipple/areola complex from where it may spread to the surrounding skin. CASE PRESENTATION: We here describe a case of Paget's disease occurring on the thoracic wall site of a previous simple mastectomy, and also briefly summarise the most important aspects leading to a diagnosis of mammary Paget's disease. CONCLUSION: To the best of our knowledge, this is the first reported case of mammary Paget's disease occurring after mastectomy. The absence of the nipple/areola complex obviously raised some questions concerning whether it was mammary or extra-mammary Paget's disease, and how it could occur in the absence of the nipple/areola complex.

Relationship between the thymidine labeling and Ki-67 proliferative indices in 126 breast cancer patients.

Proliferative activity has been proposed as a prognostic and predictive marker for breast cancer; Ki-67 is one of the most frequently used markers to assess proliferative activity. In the current study, Ki-67 immunoreactivity was comparatively assessed, even in terms prognostic relevance, with 3H-thymidine labeling index as a reference standard for proliferation in 126 patients with stage I and II breast cancer. There was a significant but weak correlation between Ki-67 values and the 3H-thymidine labeling index (r = 0.19, P = 0.03). Analysis of variance showed that the mean 3H-thymidine labeling index values were not statistically different in terms of pathologic size (T1, T2. T3, T4), number of pathologically positive axillary nodes (neg, pos 1-3, pos > 3), and grading classes (1, 2, 3), but significantly and inversely correlated with estrogen receptor status (P = 0.033) and progesterone receptor status (P = 0.08). The Ki-67 values significantly correlated with N status (P = 0.041), estrogen receptor status (P < 0.001), progesterone receptor status (P < 0.001), and grading (P < 0.001). The median follow-up was 37 months. In terms of prognosis, Ki-67 was associated significantly with overall survival (P = 0.01) and marginally with disease-free survival (P = 0.095). A significant difference in prognosis was found for both disease-free survival (P = 0.024) and overall survival (P = 0.040) when a 3H-thymidine labeling index cut-off of 6.5% was used (P = 0.024). The results suggest that, although both are indicators of proliferative activity, 3H-thymidine labeling index and Ki-67 seem to identify breast cancers with different phenotypes.

Prognostic significance of laminin, laminin receptor, and bone marrow micrometastases in breast cancer patients: are these markers of aggressive behavior and metastatic potential?

Laminin is a basement membrane glycoprotein implicated in a large number of biologic activities of cancer progression, many of which are mediated by the presence of the laminin receptor (67LR) on the cell membrane. We studied the correlations of laminin and its receptor with standardized and new prognostic factors (including bone marrow micrometastases) in a series of 112 patients with operable breast cancers. Laminin-positive cells were detected in 60% of the tumors and 67LR-positive cells in 55%; both were present in 35% of the cases. No association was found between laminin or 67LR positivity and pathologic tumor size, pathologic nodal status, grading, Ki-67, estrogen receptor status, progesterone receptor status, or bone marrow micrometastases. The only statistically significant association was with menopausal status and age, with a higher percentage of 67LR-positive tumors among premenopausal and younger patients. The median follow-up was approximately 7 years. The prognosis of disease-free survival was similar in the laminin-positive and laminin-negative subjects but was significantly better in 67LR-negative patients; there were no significant differences in overall survival. The prognostic role of laminin and 67LR in disease-free survival and overall survival varied according to nodal status. In the absence of nodal involvement, the risk of relapse (and death) was greater in the patients who were positive for laminin, 67LR, or both than in those who were negative for laminin, 67LR, or both; in the case of 4 or more involved nodes, the prognostic role of laminin and 67LR was reversed. These results did not change after adjustment for age, menopausal status, tumor status, nodal status, grading, or bone marrow micrometastases.

Chemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): a critical view.

Neuroendocrine tumors (NET) are classified according to the Ki67 in low-intermediate grade (Ki67<20%) and high grade (Ki67>20%). The NET of the latter group are also known as neuroendocrine carcinoma (NEC), and their prognosis is dismail. While in the former group biotherapy and radionuclide therapy can be proposed, chemotherapy represents the only treatment usually proposed for NEC. Cisplatin/etoposide combination is usually chosen based on the rationale that NEC are clinically similar to small cell lung cancer. However, evidence for cisplatin/etoposide in NEC is poor and controversial, and different schedules and response rate have been published so far. These aspects, combined with the heterogeneous characteristics of NEC, prompt us to have some doubt in considering cisplatin/etoposide as the gold standard. Some evidence exists that carboplatin can be used instead of cisplatin and irinotecan instead of etoposide without reducing efficacy. Furthermore other drugs, as gemcitabine, oxaliplatin or temozolomide can be evaluated in NEC with non-neuroendocrine component or in mixed adenoneuroendocrine carcinomas. NEC are a category of NET that should be deeply studied to verify if the response to cisplatin/etoposide is homogeneous related to the different Ki67, different morphology and/or different primary site.

Vaccines in non-small cell lung cancer: rationale, combination strategies and update on clinical trials.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer related mortality worldwide and despite some advances in therapy the overall prognosis remains disappointing. New therapeutic approaches like vaccination have been proposed and several clinical trials are ongoing. Many tumor antigens have been identified so far and specific tumor vaccines targeting these antigens have been developed. Even if the ideal setting for vaccine therapy might be the adjuvant one, vaccines seem to be potentially beneficial also in advanced disease and combination therapy could be a promising treatment option. In the advanced setting anti-MUC-1 vaccine (belagenpumatucel) and anti-TGF-ß(2) vaccine (BPL-25) have entered in phase III trials as maintenance therapy after first line chemotherapy. In the adjuvant setting the most relevant and promising vaccines are directed against MAGE-A3 and PRAME, respectively. We will review the key points for effective active immunotherapies and combination therapies, giving an update on the most promising vaccines developed in NSCLC.

Features and prognostic factors of large node-negative non-small-cell lung cancers shifted to stage II.

BACKGROUND: During the period that randomized clinical trials were establishing the role of adjuvant therapy in tumors larger than 5 cm without lymph-node invasion, which shifted from stage IB (6th TNM) to stage II (7th TNM), we derived the rate of shifted patients in our series and analyzed the relationship between specific patient- and tumor- characteristics, and clinical outcome, to identify putative prognostic factors. METHODS: We retrospectively collected data (age, sex, smoking status, type of surgery grading, and histological type) from 467 patients who underwent radical surgery for primary 6th TNM-T2N0 non-small cell lung cancer patients between 1998 and 2009 at our institute. Categorical variables were cross-tabulated by tumor staging according to the 7th TNM edition, and they were tested both for association with stage and survival. RESULTS: One hundred and eighteen patients shifted to stage II, mainly older patients and patients with a sarcomatoid or a poorly differentiated carcinoma. Median overall survival time was significantly different across stages. Among the factors investigated, only the tumor dimension resulted in being statistically significant in multivariate analysis. CONCLUSIONS: Nearly a quarter of patients shifted from stage I (6th TNM) to stage II (7th TNM), raising a major need for information on the effects of adjuvant chemotherapy in this group of patients. Our findings suggest that randomized clinical trials aimed at addressing this topic should consider only tumor dimensions as principal selection criteria.

Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations.

INTRODUCTION: Mutations of the epidermal growth factor receptor (EGFR) have been proven to predict activity of the EGFR-tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib. Although the "common" EGFR mutations, such as the L858R point mutation in exon 21 and the in-frame deletional mutation in exon 19, have been definitively associated with response to EGFR-TKIs, the correlation with response to treatment for many other rarer mutations is still unclear. In this study, we report the results of treating patients with advanced non-small cell lung cancer harboring rare EGFR mutations treated with EGFR-TKIs. METHODS: The frequency of rare mutations has been investigated in 681 cases of non-small cell lung cancer screened between 2006 and 2010. Mutations in exons 18 and 20, uncommon mutations in exons 19 and 21, and/or the presence of different mutations in a single tumor (complex mutations) were considered rare. RESULTS: EGFR mutations were detected in 99 tumors (14.5%). Eighteen cases carried rare mutations, and 10 of these patients were treated with erlotinib or gefitinib. The clinical outcome was described case by case with references to the literature. Of note, we found two EGFR mutations never identified before and one of unknown response to EGFR-TKIs. CONCLUSIONS: Gefitinib and erlotinib have different antitumor activity according to the type of the EGFR mutation borne. Report of cases harboring rare mutations can support the decision-making process in this subset of patients.

Immunomodulatory Agents with Antivascular Activity in the Treatment of Non-Small Cell Lung Cancer: Focus on TLR9 Agonists, IMiDs and NGR-TNF.

Standard treatments for nonsmall cell lung cancer (NSCLC), such as surgery, chemotherapy, and radiotherapy, often lead to disappointing results. Unfortunately, also the various immunotherapeutic approaches so far tested have not produced satisfactory results to be widely applied in the clinical practice. However, the recent development of new immunomodulatory agents may open promising therapeutic options. This paper focuses on PF3512676, lenalidomide, and NGR-TNF, that is, drugs belonging to three different classes of immunomodulatory agents, that are also capable to affect tumor blood vessels with different mechanisms, and discusses the potential role of such agents in NSCLC treatment strategy.

Antiangiogenic strategies in breast cancer management.

Angiogenesis is considered one of the key mechanisms of tumour growth and survival. Therefore it represents an ideal pharmaceutical target. Many antiangiogenic agents have been developed so far in several solid tumours and also in breast cancer. Vascular endothelial growth factor (VEFG) is the main target and both monoclonal antibodies and small molecules belonging to the tyrosine kinase inhibitors directed against VEGF(R) have been developed. Some other therapeutic approaches have shown to exert some antiangiogenic activity, such as hormonal agents, metronomic chemotherapy, bisphosphonates and others. In this paper we provide an introduction of the current data supporting the angiogenesis in breast cancer and a review of the most relevant antiagiogenic therapies which have been investigated so far.