Relative Expression shows the expression levels of ABCB1 and ABCC1 determined in FFPE samples after treatment (post-treatment) relatively to baseline levels (pre-treatment) in two cases (Relative expression = post-treatment/ pre-treatment). These results are in line with the expression of both genes determined in patient blood samples and with protein expression by immunohistochemistry. Patient 07 (leiomyosarcoma) displayed the highest radiological progression.

C) Values of the kinetic parameters (Vmax and Km) in the absence (vehicle, DMSO) or presence of different concentrations of nilotinib. The constants were estimated with the Michaelis-Menten equation using the GraphPad Prism program. Each value represents the mean {plus minus} SD of three independent experiments. 1The maximal rate, Vmax reveals the number of substrate molecules being catalyzed per second. 2Km is that concentration of substrate at which half the active sites of the enzyme are filled.

SW982 cells were treated with vehicle (DMSO), nilotinib (10 µM) or doxorubicin (0.1 µM). For sequential treatment, cells were pre-treated with nilotinib (10 µM) for 72 h, and then doxorubicin (0.1 µM) was added. Cell growth was continuously monitored using the RTCA MP Instrument. Cell Index (CI) values were normalized to the CI value at the time point of compound addition indicated by the black solid line. The CI profiles of treated cells reflect the initial cell attachment, logarithmic growth phase and response to the respective treatments. Error bars show the standard deviation of the mean of triplicates.

Pre-Clinical studies and Phase I clinical study supplementary methods.

A translational study was designed to analyze the expression of nucleotide excision repair (NER) and homologous recombination (HR) genes as potential predictive biomarkers for trabectedin in soft-tissue sarcoma (STS). This study is part of a randomized phase II trial comparing trabectedin plus doxorubicin versus doxorubicin in advanced STS. Gene expression levels were evaluated by qRT-PCR, while CUL4A protein levels were quantified by immunohistochemistry. Expression levels were correlated with patients' progression-free survival (PFS) and overall survival (OS). Gene expression was also evaluated in cell lines and correlated with trabectedin sensitivity. In doxorubicin arm and in the whole series, which includes samples from both arms, no significant differences in terms of PFS were observed amongst the analyzed genes. In the group treated with trabectedin plus doxorubicin, the median of PFS was significantly longer in cases with CUL4A, ERCC1, or ERCC5 overexpression, while BRCA1 expression did not correlated with PFS. Gene expression had no prognostic influence in OS. CUL4A protein levels correlated with worse PFS in doxorubicin arm and in the whole series. In cell lines, only overexpression of ERCC1 was significantly correlated with trabectedin sensitivity. In conclusion, CUL4A, ERCC5, and mainly ERCC1 acted as predictive factors for trabectedin efficacy in advanced STS.

OBJECTIVESCastration resistant prostate cancer (CRPC) is an heterogeneous disease the molecular basis of which we are starting to know in depth. Currently, there are various pathways and targets under study, and probably many others to be characterized. In this paper, we review the most recent knowledge concerning the molecular biology of CRPC with a special focus on the therapeutic application of this knowledge.METHODSWe performed a bibliographic review using PUBMED as the search engine, including the following terms: "Castration resistant prostate cancer", "genomics", "molecular biology", "AR", "WNT", "mTOR", "PTEN", "cell-cycle", "DNA damage repair gene"and "chromatin modifier genes".RESULTSCRPC has a high load of genetic alterations, probably derived from therapeutic pressure. The most frequent alterations involve the androgen receptor (RA) [60-70%] and the PI3K- AKT-mTOR [40-60%], even though other relevant pathways alterations have been identified such as those relative to cellular cycle [25%], DNA lesion repair genes [20%] and other pathway like WNT-βcatenin [15-22%]. The knowledge of these pathways is helping as a base for development of new therapeutic targets with promising results and multiple ongoing studies.CONCLUSIONSOver the last decade, the progress in the knowledge of the molecular bases of CRPC has been very relevant. Even though AR alterations are the most frequent and best characterized, anomalies in other pathways have been also identified as important in the biology of CRPC and derived a notable therapeutic development.

BACKGROUND:A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.METHODS:In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.FINDINGS:From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).INTERPRETATION:To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.FUNDING:Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

Abstract Purpose: Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as coadjuvant of doxorubicin by inhibiting MRP-1/P-gp efflux activity. The phase I part of the study is presented here. Patients and Methods: Nilotinib 400 mg/12 hours was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose escalation levels for doxorubicin at 60, 65, and 75 mg/m2 were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma, leiomyosarcoma, and unresectable/metastatic high-grade chondrosarcoma. Results: Thirteen patients were enrolled: 7 chondrosarcoma, 4 liposarcoma, and 2 leiomyosarcoma. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one dose-limiting toxicity (febrile neutropenia) was reported in the third dose level. With regard to efficacy, 1 partial response (1 liposarcoma), 9 stable diseases (5 chondrosarcoma, 2 liposarcoma, 1 leiomyosarcoma), and 3 progressive diseases (2 chondrosarcoma and 1 leiomyosarcoma) were present. ABCB1 and ABCC1 RNA expression levels decreased by 58.47-fold and 1.47-fold, respectively, on day 5 of the cycle. Conclusions: Combination of MRP-1/P-gp inhibitor, nilotinib, as coadjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared with doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m2. Clin Cancer Res; 24(21); 5239–49. ©2018 AACR.

Despite major advances in the knowledge of the molecular basis of renal cell carcinoma, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. With these premises, we aimed to analyse the expression and to determine the prognostic and predictive value of 64 key single nucleotide polymorphisms in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of patients with localized and advanced renal cell cancer treated at our institution. The presence of the selected single nucleotide polymorphisms was correlated with clinical features, disease free survival, overall survival and response rate. In patients with localized renal cell cancer, 5 of these polymorphisms in 3 genes involved in angiogenesis predicted for worse disease free survival (VEGFR2: rs10013228; PDGFRA: rs2228230) or shorter overall survival (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) (p < 0.05). Rs2071559 in VEGFR2 showed a protective effect (p = 0.01). In the advanced setting, 5 SNPs determined inferior overall survival (IL8: rs2227543, PRKAR1B: rs9800958, PDGFRB: rs2302273; p = 0.05) or worse response rate (VEGFA: rs699947, rs3025010 p ≤ 0.01)). Additionally 1 single nucleotide polymorphism in VEGFB predicted for better response rate rs594942 (p = 0.03). Genetic analysis of renal cell carcinoma patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics drugs seem to determine post-surgical outcomes and treatment response in our series.

Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmacogenetic advances in colorectal cancer. This review is based on the lectures presented by the speakers of the symposium "Pharmacogenetics and Pharmacogenomics as Tools in Cancer Therapy" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF), held in Madrid (Spain) on April 21, 2015.

BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model.

Introduction The risk for lung cancer is incremented in high degree dysplasia (HGD) and in subjects with hypermethylation of multiple genes. We sought to establish the association between them, as well as to analyze the DNA aberrant methylation in sputum and in bronchial washings (BW). Methods Cross sectional study of high risk patients for lung cancer in whom induced sputum and autofluorescence bronchoscopy were performed. The molecular analysis was determined on DAPK1, RASSF1A and p16 genes using Methylation-specific PCR. Results A total of 128 patients were enrolled in the study. Dysplasia lesions were found in 79 patients (61.7%) and high grade dysplasia in 20 (15.6%). Ninety eight patients out of 128 underwent molecular analysis. Methylation was observed in bronchial secretions (sputum or BW) in 60 patients (61.2%), 51 of them (52%) for DAPK1, in 20 (20.4%) for p16 and in three (3.1%) for RASSF1A. Methylated genes only found in sputum accounted for 38.3% and only in BW in 41.7%, and in both 20.0%. In the 11.2% of the patients studied, HGD and a hypermethylated gene were present, while for the 55.1% of the sample only one of both was detected and for the rest of the subjects (33.6%), none of the risk factors were observed. Conclusions Our data determines DNA aberrant methylation panel in bronchial secretions is present in a 61.2% and HGD is found in 15.6%. Although both parameters have previously been identified as risk factors for lung cancer, the current study does not find a significative association between them. The study also highlights the importance of BW as a complementary sample to induced sputum when analyzing gene aberrant methylation.

Carcinosarcomas (CS) are biphasic tumors with malignant epithelial and mesenchymal elements. The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or liposarcoma. CS of the upper urinary tract are extremely rare but are associated with a poor prognosis. We report a case of a 44-year-old man with a localized right renal pelvis mass treated with a right nephroureterectomy. The pathological examination showed a high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0). A few days later, he developed lower back pain, hematuria, cough with hemoptoic sputum and progressive dyspnea. Radiological explorations showed multiple bilateral lung nodules and a retroperitoneal mass. A CT-guided biopsy of the retroperitoneal mass revealed a high-grade angiosarcoma. A review of the nephrectomy specimen showed a microscopic focus of angiosarcoma in the urothelial carcinoma. Therefore, the initial diagnosis was changed to CS of the renal pelvis with an angiosarcoma component. The patient developed progressive respiratory failure and died 8 weeks after surgery. An autopsy revealed a large retroperitoneal mass with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. All lesions were angiosarcoma, with no evidence of urothelial carcinoma. This is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component with a very aggressive course that caused the immediate appearance of multiple angiosarcoma metastases. We also describe the clinical and molecular characteristics of CS, which will help to contribute to a better understanding of this type of tumor.

Personalized medicine involves the selection of the safest and most effective pharmacological treatment based on the molecular characteristics of the patient. In the case of anticancer drugs, tumour cell alterations can have a great impact on drug activity and, in fact, most biomarkers predicting response originate from these cells. On the other hand, the risk of developing severe toxicity may be related to the genetic background of the patient. Thus, understanding the molecular characteristics of both the tumour and the patient, and establishing their relation with drug outcomes will be critical for the identification of predictive biomarkers and to provide the basis for individualized treatments. This is a complex scenario where multiple genes as well as pathophysiological and environmental factors are important; in addition, tumours exhibit large inter- and intraindividual variability in space and time. Against this background, the huge amounts of biological and genetic data generated by the high-throughput technologies will facilitate pharmacogenomic progress, suggest novel druggable molecules and support the design of future strategies aimed at disease control. Here, we will review the current challenges and opportunities for pharmacogenomic studies in oncology, as well as the clinically established biomarkers. Lung and renal cancer, two areas in which huge progress has been made in the last decade, will be used to illustrate advances in personalized cancer treatment; we will review EGFR mutation as the paradigm of targeted therapies in lung cancer, and discuss the dissection of lung cancer into clinically relevant molecular subsets and novel advances that suggest an important role of single nucleotide polymorphisms in the response to antiangiogenic agents, as well as the challenges that remain in these fields. Finally, we will present new approaches and future prospects for personalizing medicine in oncology.

The EURTAC trial demonstrated that the tyrosine kinase inhibitor (TKI) erlotinib was superior to chemotherapy as first-line therapy for advanced non-small cell lung cancers (NSCLC) that harbor EGFR activating mutations in a predominantly Caucasian population. Based on EURTAC and several Asian trials, anti-EGFR TKIs are standard of care for EGFR mutation-positive NSCLC. We sought to validate a rapid multiplex EGFR mutation assay as a companion diagnostic assay to select patients for this therapy. Samples from the EURTAC trial were prospectively screened for EGFR mutations using a combination of laboratory-developed tests (LDTs), and tested retrospectively with the cobas EGFR mutation test (EGFR PCR test). The EGFR PCR test results were compared to the original LDT results and to Sanger sequencing, using a subset of specimens from patients screened for the trial. Residual tissue was available from 487 (47%) of the 1044 patients screened for the trial. The EGFR PCR test showed high concordance with LDT results with a 96.3% overall agreement. The clinical outcome of patients who were EGFR-mutation detected by the EGFR PCR test was very similar to the entire EURTAC cohort. The concordance between the EGFR PCR test and Sanger sequencing was 90.6%. In 78.9% of the discordant samples, the EGFR PCR test result was confirmed by a sensitive deep sequencing assay. This retrospective study demonstrates the clinical utility of the EGFR PCR test in the accurate selection of patients for anti-EGFR TKI therapy. The EGFR PCR test demonstrated improved performance relative to Sanger sequencing.

Abstract Purpose: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations. Experimental Design: We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations, and Bcl-2 interacting mediator of cell death (BCL2L11, also known as BIM) mRNA expression in 95 patients with EGFR-mutant non–small-cell lung cancer (NSCLC) included in the EURTAC trial (trial registration: NCT00446225). Results: T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and peptide-nucleic acid-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5,000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, whereas among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P < 0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BCL2L11 expression levels, whereas among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P = 0.0003). Overall survival was 28.6 months for patients with high BCL2L11 expression and 22.1 months for those with low/intermediate BCL2L11 expression (P = 0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (HR = 0.35; P = 0.0003), whereas high BCL2L11 expression was a marker of longer PFS (HR = 0.49; P = 0.0122) and overall survival (HR = 0.53; P = 0.0323). Conclusions: Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BCL2L11 mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies. Clin Cancer Res; 20(7); 2001–10. ©2014 AACR.

Background: AEG1 is highly expressed in most solid tumors conferring multidrug resistance, increased proliferation, angiogenesis, metastatic potential and poor outcome. AEG1 activates multiple signal transduction pathways such as PIK3/AKT, NFKB, MAPK, WNT and is a rational target for therapeutic intervention in cancer. Our previous data in advanced EGFR mutated and EGFR wild type lung cancer patients confirmed that AEG1 overexpression is indicative of poor outcome to targeted and pleiotropic therapy. In addition, AEG1 functionality is instrumental in the natural history of brain tumors. Material and Methods: We designed an in silico model based on inhibition of the NFkB (p65) binding domain of AEG1, identifying a possible interacting interface between the two proteins that could be modeled as a 3-dimensional structure. This interface was reduced and transformed into a 3-point pharmacophore for virtual screeningcomparing both molecular interaction fields and the pharmacophore. A total of 217,000 chemical entities (CEs) were tested in this model. Each CE was scored using the Hercules affinity ranking. The top sixty CEs amongst the high scores were selected, and thus 4 compounds were proposed for in vitro screening. Twenty analogs were then synthesized, and PB03, a small molecular weight polyheterocyclic compound, was selected as the CE lead. Results: PB03 displays antitumor activity at low mM and nM concentrations. PB03-induced growth inhibition appears to be independent of EGFR, KRAS, BRAF, PIK3CA and p53 mutational status, Her2 amplification, and BRCA1 and AEG1 mRNA expression. PB03 clusters in vitro molar potency (MP) of Glial (Gliobastoma, GBM) and Neural Crest (Neuroblastoma (NBM) and Melanoma) -derived tumors as compared with PB03 profile in other solid tumors and in non-tumoral cells (p < 0.0001). A lack of impact of MGMT methylation status on PB03 (MP) sensitivity has been observed. PB03 is between 500 and 1000 fold more potent than temozolomide and MTIC in GBM and NBM (p < 0.0001). The mean PB03 IC50s in human non-tumoral cell lines is 2.08mM versus 1.22mM in the solid tumor panel vs 0.40mM in the Glial and Neural Crest-derived panel vs 0.11mM in GBM+NBM. Preliminary data in PC9 shows downregulation of AEG1 mRNA expression upon exposure to PB03. Expansion of the Glial and Neural Crest-derived tumor panel, cell kinetics, drug-induced cell death and in vivo/PK-PD studies in in vivo models is ongoing. PB03 has a negative score when screened in the SCIfinder chemical data base confirming PB03 as a first-in-class CE. Conclusions: This is the first successful attempt at the pharmacological intervention against the AEG1 pathway. The observed clustering of Glial and Neural Crest-derived malignancies is unique and a tool for rational development.

Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs.Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation.Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC. (C) 2014 Elsevier Ltd. All rights reserved.

ObjectivesVorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors.Patients and methodsWe conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR12w). Pre-treatment plasma samples were required to assess T790M resistant mutation.ResultsA total of 33 patients were enrolled in the phase I–II trial. The maximum tolerated dose was erlotinib 150mg p.o., QD, and 400mg p.o., QD, on days 1–7 and 15–21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR12w was 28% (IC95%: 18.0–37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43–8.45) and overall survival (OS) 10.3 months (95% CI: 2.4–18.1).ConclusionFull dose of continuous erlotinib with vorinostat 400mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression.