Purpose The impact of epidermal growth factor receptor (EGFR) and KRAS genotypes on outcomes with erlotinib or gefitinib therapy continues to be debated. This study combines patient data from five trials in predominantly Western populations to assess the impact of EGFR and KRAS mutations on first-line therapy with an EGFR–tyrosine kinase inhibitor (TKI) and compare clinical versus molecular predictors of sensitivity. Experimental Design Chemotherapy-naïve patients with advanced non–small cell lung cancer and known EGFR mutation status treated with erlotinib or gefitinib monotherapy as part of a clinical trial were eligible for inclusion. Patients received daily erlotinib (150 mg) or gefitinib (250 mg) until disease progression or unacceptable toxicity. Data were collected in a password-protected web database. Clinical outcomes were analyzed to look for differences based on EGFR and KRAS genotypes, as well as clinical characteristics. Results Patients (223) from five clinical trials were included. Sensitizing EGFR mutations were associated with a 67% response rate, time to progression (TTP) of 11.8 months, and overall survival of 23.9 months. Exon 19 deletions were associated with longer median TTP and overall survival compared with L858R mutations. Wild-type EGFR was associated with poorer outcomes (response rate, 3%; TTP, 3.2 months) irrespective of KRAS status. No difference in outcome was seen between patients harboring KRAS transition versus transversion mutations. EGFR genotype was more effective than clinical characteristics at selecting appropriate patients for consideration of first-line therapy with an EGFR-TKI. Conclusion EGFR mutation status is associated with sensitivity to treatment with an EGFR-TKI in patients with advanced non–small cell lung cancer. Patients harboring sensitizing EGFR mutations should be considered for first-line erlotinib or gefitinib.

Purpose: Erlotinib has proven activity in pretreated patients with advanced non–small cell lung cancer (NSCLC). We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome. Experimental Design: In this phase II study, chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurred. Tumor response was assessed every 6 weeks, and samples were analyzed for potential molecular markers of treatment response and survival. The primary end point was the proportion of patients without disease progression after 6 weeks of treatment. Results: Fifty-three patients were eligible. The overall rate of nonprogression at 6 weeks was 52.8% (28 of 53 patients). Tumor response rate was 22.7%, with 1 complete response, 11 partial responses, and 16 cases of stable disease. Responses were seen across most patient clinical characteristics. The median duration of tumor response was 333 days; median overall survival was 391 days; and median time to disease progression was 84 days. Erlotinib was well tolerated, the main treatment-related adverse events being mild-to-moderate rash and diarrhea. Histologic material for biological studies was available in 29 cases. Four of five responders and one patient with stable disease had a classic epidermal growth factor receptor tyrosine kinase mutation. Two progressing patients exhibited epidermal growth factor receptor point mutations (one with T790M mutation), and K-ras mutations were detected in 10 nonresponders. Conclusions: Erlotinib shows significant antitumor activity in the first-line treatment of advanced NSCLC and may be a viable alternative to chemotherapy. Patient selection cannot easily be based on clinical or biological variables.

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.

BackgroundTumor immune escape and angiogenesis contribute to tumor progression, and gangliosides and activation of signal transducer and activator of transcription (STAT)-3 are implicated in these processes. As both are considered as novel therapeutic targets, we assessed the possible association of ganglioside GM3 expression and STAT3 activation with suppression of dendritic cell (DC) activation and angiogenesis in non-small cell lung cancer (NSCLC).MethodsImmunohistochemistry was performed on a tissue array to determine N-glycolyl GM3 (GM3) and phosphorylated STAT3 (pSTAT3) expression in 176 primary NSCLC resections. Median values of GM3 and pSTAT3 expression were used as cut off. Microvessel density (MVD) was determined by CD34 staining and morphology. CD1a and CD83 were used to determine infiltrating immature and mature dendritic cells, respectively.Results94% and 71% of the NSCLC samples expressed GM3 and nuclear pSTAT3, respectively. Median overall survival was 40.0 months. Both low GM3 expression and high pSTAT3 expression were associated with a worse survival, which reached near significance for GM3 (P = 0.08). Microvessel density (MVD), determined by CD34 staining and morphology, was lower in NSCLC samples with high GM3 expression. CD1a+ cells (immature DCs) were more frequent in NSCLC tissues as compared to peritumoral lung tissue, while CD83+ cells (mature DCs) were more frequent in peritumoral lung tissue. CD83+ DCs were less frequent in NSCLC tissues with high GM3 expression.ConclusionGM3 and pSTAT3 are widely expressed in NSCLC. Based on CD83 expression, GM3, but not pSTAT3, appeared to be involved in tumor-induced DC suppression. pSTAT3 expression was not associated with MVD, while GM3 might play an anti-angiogenic role.

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Introduction and objectives : Plitidepsin is a cyclic depsipeptide originally isolated from the marine tunicate, Aplidium albicans. It appears very potent against multiple myeloma (MM) cells. Specifically, it was observed that it was active against a broad panel of 35 human MM cell lines, which included MM cells resistant to conventional anti-MM agents and novel agents (i.e. thalidomide, bortezomib). Plitidepsin also induced cell death in primary MM tumor cells freshly isolated from patients resistant to thalidomide or its analogs and/or proteasome inhibitors. Phase I has been completed exploring 4 different schedules of administration. Muscle and liver (transaminases and/or alkaline phosphatase) toxicities were the main DLTs. Hematological toxicity was not observed at the recommended dose. The aim of this trial was to explore the activity of plitidepsin in patients with previously treated refractory/relapsed MM. Material and Methods: This is a non-randomized two-stage Phase II, multicenter, clinical and pharmacokinetic trial, with Aplidin® (APLD) 5 mg/m2 as a 3 h intravenous infusion every 2 weeks, with antiemetic and antihistaminic prophylaxis. In the first stage 16 patients evaluable for efficacy were included. At least one response was requested in order to proceed with the second stage, in which a total of 37 patients will be included. Results: Between June’04 and June’05, 19 patients have been enrolled and data are available for 18 patient (7 men and 11 women, median age was 65.7y, range 48–82). Patients were previously relapsed/refractory. Prior treatments included: stem cell transplantation 64.7%, thalidomide 35.28% and bortezomib 17.64%. The median previous chemotherapy lines received were 3, range 1–6. The APLD median number of cycles received 4, range 1–16. Thirteen patients are currently evaluable for efficacy. One patient (7.7%) achieved a partial response (PR) with a 70% reduction in M-component lasting 8 months. Stable disease lasting between 3–5 months was observed in 3 patients (23.0%). In 2 patients (15.38%) a stabilization lasting 2.5 months was stated and the remaining 7 patients (53.8%) progressed. NCI-CTC grade 3–4 related toxicities were reported for n=17 patients and were mainly fatigue in 2 patients (11.8%), myalgia in 1 patient (5.9%), elevation of CPK in 1 patient (5.9%) and transient transaminases increase in 9 patients (52.9%). Significant hematological toxicity did not occurred in spite of 2 patients included and treated with thrombopenia grade 3–4 and 2 patient with neutropenia grade 3. Conclusions: First stage data shows that APLD presents hints of activity in patients with refractory/relapsed MM, with acceptable toxicity profile, thus meeting the criteria for proceeding to second stage recruitment. The absence of significant hematological toxicity is a well known feature of this drug and is being confirmed in this trial.