R. Rosell

Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation

Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harboured EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouring EGFR mutations was 11.7 (7.9–15.5) months, compared to 5.8 (5.2–6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2–19.7) months and 3.1 (2.5–3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed. Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.

Single nucleotide polymorphisms in MDR1 gen correlates with outcome in advanced non-small-cell lung cancer patients treated with cisplatin plus vinorelbine

UNLABELLEDnNew therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying NSCLC could influence chemosensitivity. In this study, we assessed whether the presence of polymorphisms in ERCC1, XPD, RRM1 and MDR1 genes can affect the efficacy and the tolerability of cisplatin and vinorelbine in NSCLC patients.nnnMATERIAL AND METHODSnEligible patients had histological confirmed stage IV or IIIB (with malignant pleural effusion) non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy; World Health Organization performance status (PS) 0-1. Patients received intravenous doses of vinorelbine 25 mg/m² on day 1 and 8 and cisplatin 75 mg/m² on day 1, every 21 days, for a maximum of eight cycles.nnnRESULTSn94 patients were included. Median age was 61 years; 84% were male; WHO performance status (PS) was 0 in 24%; and 88% of patients had stage IV disease. The median number of cycles was 6. Overall median survival was 10.92 months (95% CI 9.0-12.9). Overall median time to progression was 5.89 months (95% CI 5.2-6.6). Results of the multivariate analysis for time to progression showed that ECOG 0 (hazard ratio [HR] ECOG 1 vs. ECOG 0, 1.74; p=0.036), MDR13435CC (HR CT vs. CC, 2.01; p=0.017; HR TT vs. CC, 1.54; p=0.22), and decreasing age (HR of age, 0.97; p=0.016) were the most powerful prognostic factors significantly related to lower risk of progression. Whereas ECOG 0 was the only prognostic factor for survival (HR ECOG 1 vs. ECOG 0, 3.02; p=0.001). There was no significant association between any of the SNPs analysed and the occurrence of vinorelbine and cisplatin-related toxicity.nnnCONCLUSIONnIn our results, the most important prognostic factors associated with lower risk of progression were MDR1 3435 CC genotype, PS 0 and younger age.

Three-week schedule of irinotecan and cisplatin in advanced non-small cell lung cancer: a multicentre phase II study

A phase II multicentre study of a 3-week schedule of irinotecan (CPT-11) and cisplatin providing the highest recommended dose intensity of both agents in combination, was conducted in patients with advanced non-small cell lung cancer (NSCLC). Seventy-four stage IIIB (not suitable for radiotherapy) or stage IV NSCLC patients were enrolled to receive CPT-11 200 mg/m(2) i.v. and cisplatin 80 mg/m(2) i.v. on day 1 every 3 weeks. Relative dose-intensities for CPT-11 and cisplatin were 92 and 95%, respectively. No complete responses were observed. Twenty-five patients out of 73 obtained a partial response (34.2%). Partial responses were confirmed in 18 patients (24.7%: 95% CI, 15.3-36.1%). Median survival overall was 8.2 months, 9.7 months for patients with baseline performance status (PS) 0 and 1, and 4 months for patients with PS 2. The 1-year survival rate was 31%. Major clinical toxicities were grade 3 and 4 delayed diarrhoea (29% of patients) and febrile neutropenia (14% of patients). In conclusion, the present once-every-3-week schedule of CPT-11 and cisplatin is feasible and active in PS 0-1 advanced NSCLC patients, but results do not seem superior to those reported with other schedules.

1248PA PHASE IB OPEN LABEL CLINICAL TRIAL OF CONTINUOUS ONCE DAILY ORAL AFATINIB (A) PLUS SIROLIMUS (S) IN PATIENTS (PTS) WITH EGFR MUTATION POSITIVE (EGFR M+) NSCLC AND/OR DISEASE PROGRESSION FOLLOWING PRIOR ERLOTINIB (E) OR GEFITINIB (G)

ABSTRACT Aim: Preclinical data show that A, an irreversible ErbB family blocker, combined with an mTOR inhibitor such as S, may restore sensitivity in EGFR M+ NSCLC pts who progress after E/G. This trial was conducted to identify the maximum tolerated dose (MTD) of A + S. Methods: Pts with stage IIIB/IV NSCLC who failed ≥1 prior treatment, and whose tumour was EGFR M + , or negative/unknown, but had progressive disease after response or stable disease (SD) for ≥6 months on prior E/G were eligible. Pts received run-in treatment with sirolimus for 8 days before starting the combination therapy. Definition of MTD was initially based on dose-limiting toxicities (DLTs) in cycle (C) 1 (28 days) but with an amendment this was extended to C1 and 2. EGFR mutation was assessed (from blood and archival tumour) and PK sampling was performed. Tumour assessment was performed at week 4, 8, 12, then every 8 weeks. Results: 39 pts were treated: median age 61y (range: 32-81); male: 15; ECOG 0/1/2: 16/21/1; adeno/squamous/large cell carcinoma: 33/3/3. All had prior E/G; 32 had ≥1 prior chemotherapy. Median treatment duration: 103 days (range: 10-367). Pts were treated at 6 dose levels (A, mg/S, mg): 30/1 (n = 12), 40/1 (n = 3), 30/3 (n = 9), 30/5 (n = 9), 30/10 (n = 3), 40/5 (n = 3), with 30/1 defined as MTD. DLTs (C1 and 2) were seen in 12 pts (Table). The most frequent (≥20%, all grades) drug-related adverse events were: diarrhoea, mucositis, rash, asthenia, decreased appetite and nausea. The best response was partial response (PR) in 4 pts (2 at 30/5, 2 at 40/5); 23 had stable disease (SD) (median duration [days]: 105, range: 51-337). PK, tumour and blood mutation results will be presented. DLTs (grade [n]) by dose level 30/1 40/1 30/3 30/5 30/10 40/5 Diarrhoea – G3 (1) G3 (1) – G3 (2)* G3 (1) Mucositis – – G3 (1) G3 (2) G3 (1) G3 (2) Raised CPK – G4 (1) – – – – *1 pt had G3 diarrhoea, asthenia, anorexia and iliac fossa pain. Conclusions: A + S combination had limited tolerability in pts with EGFR M+ NSCLC progressing on E/G mainly due to overlapping DLTs of diarrhoea and mucositis. A 30u2003mg + S 1u2003mg was defined as MTD. PRs were observed at doses exceeding MTD; SD was observed at all doses. Disclosure: M. Majem: Membership on an advisory board for Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer; N. Reguart: Membership on an advisory board for Roche, Lilly, Boehringer Ingelheim and Pfizer; C.P. Lee: Employee of Boehringer Ingelheim; S. Kraemer: Employee of Boehringer Ingelheim; D. Schnell: Employee of Boehringer Ingelheim. All other authors have declared no conflicts of interest.

5IN ESMO NON-SMALL-CELL LUNG CANCER (NSCLC) CONSENSUS ON PATHOLOGY AND MOLECULAR TESTING

K. O’Byrne1, R. Rosell2, P. Baas3, K. Kerr4, M. Taron5, T.S.K. Mok6, P. Janne7, F. Blackhall8, F. Ciardiello9, E. Felip10, R.A. Stahel11 1St. James’s Hospital and Trinity College, Dublin, Ireland, 2Medical Oncology Service, Inst. Catala d’Oncologia, Badalona, Spain, 3Antoni Van Leeuwenhoek Hospital, The Netherlands Cancer Institute, Amsterdam, Netherlands, 4Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom, 5Medical Oncology Service, Institut Catala d’Oncologia, Badalona, Barcelona, Spain, 6Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China, 7Oncology, Dana Farber Cancer Institute, Boston, United States of America, 8Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom, 9Internistica Clinica e Sperimentale “Magrassi Lanzara”, Second University of Naples, Naples, Italy, 10Oncology Department Vall d’Hebron University Hospital, Barcelona, Spain, 11Division of Oncology University Hospital, Zurich, Switzerland

1148 POSTER DAB2 Interactive Protein (DAB2IP) Methylation in Serum DNA of Non-Small-Cell Lung Cancer (NSCLC) Patients (p) With Epidermal Growth Factor Receptor (EGFR) Mutations

7593 Background: DAB2IP loss promotes primary tumor growth by activating Ras and drives metastasis through NFkB, serving as a signaling scaffold to coordinately regulate these pathways. DAB2IP is frequently methylated in lung cancer, and methylation in the m2a region is a key regulatory factor for DAB2IP expression in prostate cancer. We examined DAB2IP methylation in cell lines and in serum from erlotinib-treated NSCLC p with EGFR mutations.nnnMETHODSnIn human lung, breast and colorectal cancer cell lines, we analyzed DAB2IP promoter methylation in regions m2a and m2b by methylation-specific PCR (MSP) and bisulfite genomic sequencing. In circulating serum DNA from 152 erlotinib-treated NSCLC p with EGFR mutations, we analyzed methylation in the m2a and m2b promoter regions of DAB2IP by MSP. Methylation status was correlated with clinical outcome.nnnRESULTSnMethylation was detected in the m2a region of 42 (27.63%) p, and in the m2b region in 51 (33.55%) p. There were no major differences in clinical characteristics (age, gender, smoking history, EGFR mutation type, metastatic sites) between p with methylation in the m2a region and p with methylation in the m2b region. Overall progression-free survival (PFS) was 15 months (m), and median survival (MS) 28 m for all 152 p. For the 41 p with bone metastases (mets), PFS was 14 m for 30 p without methylation in the m2a region vs 8 m for 11 p with methylation in the m2a region (P=0.01), and MS was 23 m vs 10 m, respectively (P=0.19). For the 57 p with distant mets but no lung mets, PFS was 18 m for 36 p without methylation in the m2a region vs 10 m for 21 p with methylation in the m2a region (P=0.01), and MS was 24 m vs 16 m, respectively (P=0.03). No differences in either PFS or MS were observed according to the methylation status of the m2b region.nnnCONCLUSIONSnMethylation in the m2a region of DAB2IP in serum DNA correlates with PFS and MS to erlotinib in NSCLC p with EGFR mutations with non-lung mets. Surveillance of DAB2IP methylation status in circulating DNA could be a useful tool to predict outcome to erlotinib in EGFR-mutated NSCLC p with non-lung mets.

Meeting report: 2nd meeting of the European Thoracic Oncology Platform (ETOP)

In Europe, a renewed interest in promoting and improving colaboration in clinical and translational research in lung cancer as emerged. Many investigators, representing collaborative study roups and institutions, are trying to find new ways to improve issemination of knowledge and expertise in the field of rapidly volving customized therapy. To accomplish this goal, discussions ith European investigators during one of the thoracic oncology eetings in Dublin (BTOG) were initiated in early 2008. During the econd meeting in April 2008 in Geneva, the decision was made hat a formal structure was required to achieve this goal. Rolf Stahel rom Switzerland and Paul Baas from the Netherlands took the iniiative to prepare a draft for a foundation based on the model of the nternational Breast Cancer Study Group. The idea of the European horacic Oncology Platform (ETOP) was constructed and presented o representatives of European collaborative groups and trial instiutions in September 2008 at the ESMO meeting in Stockholm. uring this 1st ETOP meeting the ideas were accepted, suggestions or members of foundation council were made, and the collection f funds by interested groups and institutions agreed on. A first eeting of the ETOP foundation council including Rolf Sahel, Paul aas, Cesare Gridelli, Ken O’Byrne and Rafael Rosell took place in anuary 2009 in Dublin during the BTOG meeting. In March 2009 he foundation, seated in Bern, Switzerland, was approved by the uthorities. Since then, 29 collaborative groups and trial institutions have oined ETOP, representing most European Countries (Fig. 1) The TOP website (www.ETOP.ch) has been activated.

Feasibility of a prospective host cell reactivation assay (HCRA) in non-small cell lung cancer (NSCLC) patients.

10586 Background: DNA repair capacity (DRC)—the ability to repair BPDE-induced DNA adducts—measured in peripheral blood lymphocytes (PBLs) by the HCRA has been shown to correlate with survival in p...