Paolo Andrea Zucali

MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients

BACKGROUND MET amplification has been detected in approximately 20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to tyrosine kinase inhibitor (TKI) therapy. PATIENTS AND METHODS We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents. RESULTS HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line. CONCLUSIONS MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.

Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma

PURPOSE This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2 and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12 supplementation. Pemetrexed was provided within the Expanded Access Program. RESULTS A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible. CONCLUSION Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.

Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib (‘Iressa’, ZD1839) in non-small-cell lung cancer

Gefitinib (‘Iressa’, ZD1839) is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated antitumour activity and favourable tolerability in Phase II studies. We investigated whether EGFR expression levels could predict for response to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC), who received gefitinib (250 mg day−1) as part of a worldwide compassionate-use programme. Tissue samples were analysed by immunohistochemistry to assess membrane EGFR immunoreactivity. Of 147 patients enrolled in our institution, 50 patients were evaluable for assessment of both clinical response and EGFR expression. The objective tumour response rate was 10% and disease control was achieved in 50% of patients. Although high EGFR expression was more common in squamous-cell carcinomas than adenocarcinomas, all objective responses were observed in patients with adenocarcinoma. Response and disease control with gefitinib were not associated with high EGFR expression. Overall, median survival was 4 months, and the 1-year survival rate was 18%. Strong EGFR staining correlated with shorter survival time for all patients. Gefitinib demonstrated promising clinical activity in this group of patients with NSCLC. These results have also shown that EGFR expression is not a significant predictive factor for response to gefitinib.

Early Response Evaluation in Malignant Pleural Mesothelioma by Positron Emission Tomography With [18F]Fluorodeoxyglucose

Purpose Response evaluation with conventional criteria based on computed tomography (CT) is particularly challenging in malignant pleural mesothelioma (MPM) due to its diffuse pattern of growth. There is growing evidence that therapy-induced changes in tumor [18F]fluorodeoxyglucose (FDG) uptake as measured by positron emission tomography (PET) may predict response and patient outcome early in the course of treatment. Patients and Methods Patients with histologically proven MPM, not candidates to curative surgery, scheduled to undergo palliative chemotherapy with a pemetrexed-based regimen were eligible for this study. Patients were evaluated by FDG-PET and CT at baseline and after two cycles of therapy. A decrease of 25% or more in tumor FDG uptake as measured by standardized uptake value was defined as a metabolic response (MR). Best overall response from CT scans was determined according to previously published criteria. Results Twenty-two patients were included in the study, and 20 were assessable for ...

Minidose Warfarin Prophylaxis for Catheter-Associated Thrombosis in Cancer Patients: Can It Be Safely Associated With Fluorouracil-Based Chemotherapy?

PURPOSE The use of prophylactic low-dose oral warfarin in cancer patients with a central venous catheter (CVC) in place has an established role in the prevention of thrombotic complications and is associated with a low hemorrhagic risk. Despite the literature indicating an adverse interaction between warfarin and fluorouracil (FU), the frequency of this interaction and whether it occurs when minidose warfarin is used is unknown. We analyzed the incidence of alterations in the International Normalized Ratio (INR) and bleeding in cancer patients given minidose warfarin during treatment with continuous-infusion FU-based regimens. PATIENTS AND METHODS Between July 1999 and August 2001, 95 cancer patients were evaluated. Forty-one patients (43%) had liver metastases. Seventy-nine patients (83%) had a Groshong CVC (Bard Access System, Salt Lake City, UT), and 16 (17%) had a Port-a-Cath device (Bard Access System). All patients received oral warfarin at a dose of 1 mg/daily as prophylaxis beginning the day after the catheter was positioned. An INR of more than 1.5 was considered significantly elevated. RESULTS INR elevation occurred in 31 patients (33%), with 18 patients (19%) having an INR more than 3.0. Twelve (39%) of the 31 patients had liver metastases. Bleeding was observed in eight patients (8%); seven of these patients had elevated INR levels. We observed INR elevations in 12 of 21 patients treated with a FU, folinic acid, and oxaliplatin (FOLFOX) regimen, 11 of 40 treated with a de Gramont regimen (FU and folinic acid), and five of 19 treated with a FU, folinic acid, and irinotecan (FOLFIRI) regimen. CONCLUSION A high incidence of INR abnormalities was observed in our cohort of patients, especially those treated with FOLFOX regimen. Clinicians should be aware of this interaction and should regularly monitor the prothrombin time in patients receiving warfarin and FU.

Phase II Study of Asparagine-Glycine-Arginine–Human Tumor Necrosis Factor α, a Selective Vascular Targeting Agent, in Previously Treated Patients With Malignant Pleural Mesothelioma

PURPOSE NGR-hTNF consists of human tumor necrosis factor alpha (hTNF-alpha) fused to the tumor-homing peptide asparagine-glycine-arginine (NGR) able to selectively bind an aminopeptidase N isoform overexpressed on tumor blood vessels. Hypervascularity is a prominent and poor-prognosis feature of malignant pleural mesothelioma (MPM). Currently, there are no standard options for patients with MPM who are failing a front-line pemetrexed-based regimen. We explored safety and efficacy of NGR-hTNF in this setting. PATIENTS AND METHODS Eligible patients had radiologically documented tumor progression and performance status < or = 2. Primary study aim was progression-free survival (PFS). NGR-hTNF 0.8 microg/m(2) was given intravenously every 3 weeks. A subsequent cohort of patients received 0.8 microg/m(2) on a weekly basis. RESULTS In the triweekly cohort (n = 43), only one grade 3 drug-related toxicity was noted, and the most common grades 1 to 2 were short-lived chills (71%). The median PFS was 2.8 months (95% CI, 2.3 to 3.3 months). Nineteen patients (44%) had disease control (one had partial response, and 18 had stable diseases) and experienced a median progression-free time of 4.4 months. In the weekly cohort (n = 14), there was no higher toxicity, and median PFS was 3.0 months (95% CI, 1.9 to 4.1 months). Seven patients (50%) had disease control (all stable diseases) and had a median progression-free interval of 9.1 months. In the overall study population (N = 57), median PFS was 2.8 months. Median progression-free time was 4.7 months in twenty-six patients (46%) who achieved disease control. Median survival was 12.1 months. CONCLUSION The tolerability and disease control of NGR-hTNF 0.8 microg/m(2) weekly warrant additional evaluation in patients with advanced MPM.

Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors

BACKGROUND Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC. MATERIALS AND METHODS pAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells. RESULTS EGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied. CONCLUSIONS Activated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients. cMET may be a target in treatment of NSCLC.

Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.

Pemetrexed‐cisplatin chemotherapy is the standard of care in the first‐line treatment of unresectable malignant pleural mesothelioma (MPM). Second‐line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first‐line setting. The objective of this study was to evaluate the activity and toxicity of the gemcitabine‐vinorelbine combination in pemetrexed‐pretreated patients with MPM.

Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. Clin Cancer Res; 17(8); 2581–90. ©2011 AACR.

Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma

The role of second-line therapy in patients with malignant pleural mesothelioma (MPM) progressing after first-line pemetrexed-based chemotherapy (PBC) is currently undefined. Recent case series have suggested a possible role of re-treatment with PBC. In this observational study, the activity and safety of this therapeutic option was assessed in a consecutive series of cases. Patients with complete response (CR), partial response (PR) or stable disease (SD) lasting for at least 3 months after first-line PBC were retreated with PBC, either as second-line (2L) or further-line (>2L) therapy. Descriptive analyses of progression-free survival (PFS), overall survival (OS), response rate and toxicity are reported. Between October 2004 and July 2009, 31 patients (21 males and 10 females) received re-treatment with PBC as 2L (18 patients) or beyond 2L therapy (13 patients). Median age was 65 years (range 37-81). Fifteen patients were re-treated with pemetrexed alone, and 16 with a pemetrexed/platinum combination. An objective response was achieved in 6 patients (one CR and 5 PRs), for a response rate of 19%. Nine patients (29%) had SD after treatment. Overall, the disease control rate (DCR) was 48%. Median PFS and overall survival (OS) after re-treatment with PBC were 3.8 months and 10.5 months, respectively. PFS and OS after re-treatment with PBC were correlated with PFS achieved after first-line PBC (FL-PFS). Patients with a FL-PFS >12 months had a median PFS after re-treatment of 5.5 months, while patients with a FL-PFS ≤12 months had a median PFS after re-treatment of 2.5 months; no patient in this group was progression-free at 1 year. Toxicity was mild, with grade 3 or 4 hematological toxicity occurring in 9.7% of patients. In conclusion, re-treatment with PBC should be considered as second-line therapy in MPM patients achieving a durable (>12 months) disease control with first-line PBC. Further prospective evaluation of this therapeutic option is warranted.