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EGFR mutant non-small cell lung cancer patients' disease demonstrates remarkable responses to EGFR-targeted therapy, but inevitably they succumb to acquired resistance, which can be complex and difficult to treat. Analyzing acquired resistance through broad molecular testing is crucial to understanding the resistance mechanisms and developing new treatment options. We performed diverse clinical testing on a patient with successive stages of acquired resistance, first to an EGFR inhibitor with MET gene amplification and then subsequently to a combination EGFR and MET targeted therapies. A patient-derived cell line obtained at the time of disease progression was used to identify NRAS gene amplification as an additional driver of drug resistance to combination EGFR/MET therapies. Analysis of downstream signaling revealed extracellular signal-related kinase activation that could only be eliminated by trametinib treatment, while Akt activation could be modulated by various combinations of MET, EGFR, and PI3K inhibitors. The combination of an EGFR inhibitor with a MEK inhibitor was identified as a possible treatment option to overcome drug resistance related to NRAS gene amplification.

Background: Neoantigens arising from somatic mutations are attractive targets for cancer immunotherapy as they may be recognized as foreign by the immune system. RO7198457, a systemically administered RNA-Lipoplex iNeST was designed to stimulate T cell responses against neoantigens. A first-in-human Phase Ib study of RO7198457, in combination with the aPD-L1 antibody atezolizumab is being conducted in patients with locally advanced or metastatic solid tumors. Methods: RO7198457 is manufactured on a per-patient basis and contains up to 20 tumor-specific neoepitopes. Nine doses of RO7198457 were administered i.v. in weekly and bi-weekly intervals during the 12-week induction stage and every 24 weeks during the maintenance stage. Atezolizumab 1200 mg was administered on Day 1 of each 21-day cycle. Results: In total, 132 patients enrolled in cohorts with doses ranging from 15-50 μg RO7198457 in combination with atezolizumab. Most common tumor types were NSCLC, TNBC, melanoma and CRC. The median number of prior therapies was 3 (range 1-11). 39% of patients received prior immunotherapy. Most patients had low levels of PD-L1 expression (93% patients with Citation Format: Juanita S. Lopez, Ross Camidge, Marco Iafolla, Sylvie Rottey, Martin Schuler, Matthew Hellmann, Ani Balmanoukian, Luc Dirix, Michael Gordon, Ryan Sullivan, Brian S. Henick, Charles Drake, Kit Wong, Patricia LoRusso, Patrick Ott, Lawrence Fong, Aglaia Schiza, Jeffery Yachnin, Christian Ottensmeier, Fadi Braiteh, Johanna Bendell, Rom Leidner, George Fisher, Guy Jerusalem, Laura Molenaar-Kuijsten, Marcus Schmidt, Scott A. Laurie, Raid Aljumaily, Achim Rittmeyer, Eelke Gort, Ignacio Melero, Lars Mueller, Rachel Sabado, Patrick Twomey, Jack Huang, Manesh Yadav, Jingbin Zhang, Felicitas Mueller, Evelyna Derhovanessian, Ugur Sahin, Özlem Türeci, Thomas Powles. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT301.

Background We report mature PFS, updated OS and safety data from the global phase III ALEX study (NCT02075840) of ALC vs CRZ in patients (pts) with untreated ALK+ NSCLC after a further 12 months (m) of follow-up (cutoff date: 30 Nov 2018). Methods Eligible pts had stage IIIB/IV ALK+ NSCLC (by central IHC), ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Asymptomatic CNS metastases (mets) were allowed. Pts were randomised 1:1 to twice-daily ALC 600mg (n = 152) or CRZ 250mg (n = 151). Primary endpoint: investigator (INV)-assessed PFS (RECIST v1.1), with q8w CNS imaging in all pts. Results Mature, median INV-assessed PFS: 34.8 m (95% CI 17.7–NR) ALC vs 10.9 m (95% CI 9.1–12.9) CRZ (ITT stratified HR 0.43, 95% CI 0.32–0.58; p Conclusions This final updated PFS analysis confirms the superior efficacy and favourable tolerability of ALC compared with CRZ in pts with untreated ALK+ NSCLC. OS data remain immature (stratified HR 0.69, 95% CI 0.47–1.02), with a 4-year OS rate of 64.5% (95% CI 55.6–73.4) with ALC. Table . 1484PD PFS event-free rate, % (95% CI) OS event-free rate, % (95% CI) ALC (n = 152) CRZ (n = 151) ALC (n = 152) CRZ (n = 151) Duration (years) Overall Baseline CNS mets Overall Baseline CNS mets Overall Overall Yes No Yes No 1 67.8 (60.3–75.3) 58.5 74.5 48.0 (39.7–56.2) 32.5 57.2 84.3 (78.4–90.2) 82.5 (76.1–88.9) 2 56.6 (48.6–64.6) 52.0 59.8 24.8 (17.6–32.1) 6.3 35.7 72.5 (65.1–79.9) 65.1 (56.7–73.4) 3 46.4 (38.2–54.5) 40.5 50.6 13.5 (7.7–19.3) 2.1 20.2 66.9 (59.0–74.8) 56.7 (47.8–65.6) 4 43.7 (35.4–51.9) 38.0 47.6 NE (NE–NE) NE NE 64.5 (55.6–73.4) 52.2 (42.6–61.8) NE, not estimable Clinical trial identification NCT02075840. Editorial acknowledgement Nicola Griffin of Gardiner-Caldwell Communications; funded by F. Hoffmann-La Roche. Legal entity responsible for the study F. Hoffmann-La Roche Ltd. Funding F. Hoffmann-La Roche Ltd. Disclosure T.S.K. Mok: Leadership role: Sanonics Ltd.; Honoraria (self), Advisory / Consultancy: ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chimed, Cirina, Fishawack Facilitate, Ignyta, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, SFJ Pharm; Research grant / Funding (self): AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, SFJ Pharmaceutical and XCovery. A.T. Shaw: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche Ltd, Genentech, Pfizer, Novartis, Ariad, Ignyta, Daiichi-Sankyo, Taiho, Blueprint medicines, LOXO, EMD Serono and Foundation medicine. R.D. Camidge: Honoraria (self), Advisory / Consultancy: AbbVie, Ariad, Array, Celgene, Clovis Oncology, Eli Lilly, Genoptix, G1 Therapeutics, Novartis, Orion, and F. Hoffmann-La Roche Ltd/Genentech. S.M. Gadgeel: Honoraria (self), Advisory / Consultancy: Ariad, AstraZeneca, Bristol-Myers Squibb, Pfizer and F. Hoffmann-La Roche Ltd/Genentech. R. Dziadziuszko: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche Ltd, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca and Tesaro. D. Kim: Travel / Accommodation / Expenses: F. Hoffmann-La Roche Ltd, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca and Tesaro; Travel / Accommodation / Expenses: Novartis Oncology; Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery and Yuhan. M. Perol: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche Ltd/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Sharp & Dohme, Chugai, Bristol-Myers Squibb, Amgen, Novartis, Pierre Fabre, AstraZeneca, Takeda ; Research grant / Funding (institution): F. Hoffmann-La Roche Ltd, AstraZeneca, Chugai and Takeda. S. Ou: Honoraria (self): ARIAD, AstraZeneca, Pfizer, F. Hoffmann-La Roche Ltd/Genentech and TP Therapeutics; Speaker Bureau / Expert testimony: ARIAD, AstraZeneca and F. Hoffmann-La Roche Ltd/Genentech; Research grant / Funding (self): ARIAD, AstraZeneca, Daiichi Sankyo, Pfizer and F. Hoffmann-La Roche Ltd/Genentech; Shareholder / Stockholder / Stock options: TP Therapeutics. W. Bordogna: Full / Part-time employment: F. Hoffmann-La Roche Ltd. V. Smoljanovic: Full / Part-time employment: F. Hoffmann-La Roche Ltd. M. Hilton: Full / Part-time employment: F. Hoffmann-La Roche Ltd. S. Peters: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche Ltd, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Nova. All other authors have declared no conflicts of interest.

Background Repotrectinib is a next-generation ROS1/TRK/ALK TKI with >90-fold potency versus crizotinib against ROS1 and >100-fold potency versus larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. Preclinical studies demonstrate robust activity against all known ROS1/TRK resistance mutations, including the most common solvent-front mutations (SFM) ROS1 G2032R, TRKA G595R, and TRKC G623R/E. Methods In the ongoing phase 1 study (NCT03093116), TKI-naive and TKI-pretreated (≥1 TKI) pts with advanced ROS1, TRK, or ALK fusion+ solid tumors received repotrectinib. Endpoints include safety, PK, and confirmed overall response (cORR). Results As of 4-March-2019, 83 pts were treated with repotrectinib (dose levels from 40 mg QD to 200 mg BID under fasted/fed conditions). Most AEs were manageable and grade (gr) 1-2. The most common treatment-emergent AEs (found in > 30% of pts) were dizziness (57%), dysgeusia (51%), dyspnea (30%), and fatigue (30%). Four DLTs occurred and were manageable with dose modifications: gr3 dyspnea/hypoxia (n = 1); gr2 (n = 1) and gr3 (n = 1) dizziness at 160 mg BID, and gr3 dizziness (n = 1) at 240 mg QD. In ROS1+ NSCLC, the median number of prior TKIs was 1 (0-3); all TKI-naive and 77% of TKI-pretreated pts received prior chemotherapy. In 11 evaluable TKI-naive ROS1+ NSCLC pts, cORR by Blinded Central Review (BCR) was 82% (95% CI 48 - 98); median duration of response was not reached ((range 5.6 - 17.7+ months (mos)). In 18 ROS1+ NSCLC pts pretreated with 1 prior TKI, cORR by BCR was 39% (95% CI 17 – 64), and in 11 pts with 1 prior TKI at doses of 160 mg QD or above cORR was 55% (95% CI 23 - 83). All pts with ROS1 G2032R had tumor regression [cORR of 40% (n = 2/5)]. In 1 TKI-pretreated pt with ETV6-NTRK3+ and an acquired TRKC G623E-mutant salivary gland tumor, a cPR of 9.8 mos was achieved; the patient was treated for 17.9 mos. Enrollment continues. Updated data in ∼10 additional ROS1+ NSCLC and TRK+ solid tumor pts will be presented. Conclusions Repotrectinib was well tolerated and demonstrated encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors. Clinical trial identification NCT03093116. Legal entity responsible for the study Turning Point Therapeutics Inc, San Diego, CA, USA. Funding Turning Point Therapeutics Inc, San Diego, CA, USA. Disclosure A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche; Honoraria (self), Advisory / Consultancy: Loxo Oncology/Bayer/Lilly; Honoraria (self), Advisory / Consultancy: TP Therapeutics Inc; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (institution), Advisory / Consultancy: Takeda/Ariad/Milenium; Honoraria (self), Advisory / Consultancy: Helsinn; Honoraria (institution), Advisory / Consultancy: Beigene; Honoraria (self), Advisory / Consultancy: BergenBio; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy: Tyra Biosciences; Research grant / Funding (institution): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: MORE Health; Honoraria (self), Advisory / Consultancy: Verastem; Travel / Accommodation / Expenses: Puma; Research grant / Funding (institution): Teva; Research grant / Funding (institution): GlaxoSmithKlein. B.C. Cho: Shareholder / Stockholder / Stock options: heraCanVac Inc; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Research grant / Funding (institution): AtraZeneca; Honoraria (self), Research grant / Funding (institution): MOGAM Institute; Honoraria (self): Dong-A ST; Licensing / Royalties: Champions Oncology. J.J. Lin: Speaker Bureau / Expert testimony: TP Therapeutics Inc; Honoraria (institution): Chugai; Honoraria (institution): Boehringer-Ingelheim. V. Zhu: Shareholder / Stockholder / Stock options: TP Therapeutics Inc; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astra Zeneka; Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Honoraria (self): Biocept; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech. R.D. Camidge: Research grant / Funding (self): Takeda. S. Stopatschinskaja: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: TP Therapeutics Inc. J..J. Cui: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: TP Therapeutics Inc. D.M. Hyman: Advisory / Consultancy, Travel / Accommodation / Expenses: Chugai; Advisory / Consultancy: CytomX Therapeutics; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Research grant / Funding (self): Puma Biotechnology; Research grant / Funding (self): Loxo. S. Ou: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: TP Therapeutics Inc; Shareholder / Stockholder / Stock options: Ignyta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ariad; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech/Roche; Honoraria (self), Research grant / Funding (institution): Ignyta; Honoraria (self): Novartis; Research grant / Funding (institution): Blueprint Medicine. A.T. Shaw: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Ariad; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Blueprint Medicine; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EDM Serono; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: KSQ Therapeutics; Advisory / Consultancy: Natera; Advisory / Consultancy: Loxo; Advisory / Consultancy: Takeda; Advisory / Consultancy: Bayer; Advisory / Consultancy: Chugai Pharm; Research grant / Funding (institution): TP Therapeutics. R.C. Doebele: Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Licensing / Royalties: Ignyta; Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Genentech; Shareholder / Stockholder / Stock options: Roche; Research grant / Funding (institution), Licensing / Royalties: Rain Therapeutics; Licensing / Royalties: Abbott Molecular. All other authors have declared no conflicts of interest.

Purpose In addition to prospective trials for non–small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data—clinical, pathologic, and molecular features—were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

Cancer clinical trials enable the development of novel agents for the potential benefit of cancer patients. Enrolment in a trial offers patients the chance of superior efficacy coupled to the risk of unanticipated toxicity. For trial results to be generalisable, the data need to be collected in patients' representative of the general cancer population. Socioeconomic deprivation is associated with poor cancer outcomes. In the developed world, the gap between the most and least deprived is widening. This mini-review explores the evidence regarding socioeconomics and access to cancer trials, highlighting the underrepresentation of deprived patients, and exploring reasons for this disparity.

Background Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC). Patients and methods An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR). Results Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873–1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835–1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698–1.33; P = 0.8336]. The safety profiles were comparable between arms. Conclusions There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL-based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance, and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL-based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL DRs in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.

Background This phase I study evaluated the safety, tolerability and preliminary efficacy of sorafenib combined with vorinostat in patients with solid tumors. Patients and methods Patients were treated with sorafenib 400 mg po bid daily and vorinostat 200–400 mg po days 1–14 of a 21 day cycle to establish the recommended phase II dose (RP2D). The tolerability and efficacy of the RP2D was further tested in two cohorts of 6–12 patients each with advanced RCC and NSCLC. Results 17 patients were treated in the dose escalation phase that established the RP2D at sorafenib 400 mg po bid daily, vorinostat 300 mg po days 1–14. Dose limiting toxicities (DLT) included intolerable grade 2 hand-foot syndrome and multiple grade 1 toxicities causing dose interruption for more than 14 days. Despite good tolerance in the all-comers population, the RP2D was poorly tolerated in the RCC and NSCLC cohorts with the majority being unable to finish 2 full cycles of therapy. Although there were no confirmed responses, 1 patient each with NSCLC adenocarcinoma and renal sarcoma had unconfirmed partial responses and 5 of 8 patients with RCC having durable minor responses (11–26 %), including 2 who were on treatment for nearly a year. Conclusions Although tolerable in other tumor types, sorafenib 400 mg po bid with vorinostat 300 mg po daily days 1–14 of a 21-day cycle is not tolerable without dose reductions/delays in RCC and NSCLC patients. These patients may require lower doses than the RP2D explored within this study. No confirmed responses were seen but minor responses particularly in RCC were observed.

Cell lines generated from human tumors have been an invaluable tool in dissecting the underlying molecular mechanisms of cancer biology and for cancer drug development. The large library of original human lung cancer cell lines established by Minna and Gazdar, though instrumental in investigating various aspect of lung cancer biology, lacks examples of some of the diverse mutations responsible for this cancer. The CUTO (Colorado University Thoracic Oncology) cell line series, initiated in 2011, had the goal of curating a new panel of cells derived from NSCLC patients with distinct oncogenic drivers. By generating multiple, unique cell lines representing each oncogene driver subset, we believe that these lines would allow study of interpatient variability that underlie differential patient responses and duration of response to targeted therapies. The current CUTO panel consist of 33 cell lines with either 1) gene rearrangements in ALK, RET, ROS1 or NTRK1; 2) activating mutations in the ERBB gene family including exon 20 insertions in EGFR and ERBB2 (HER2) as well as rare mutations in EGFR; and 3) inactivation of the NF1 gene either as a concurrent mutation with other oncogenic alterations or as the sole driver mutation. For cells harboring gene rearrangements we have amassed four EML4-ALK lines, two KIF5B-RET cell lines, five ROS1 fusion lines (3 CD74-ROS1, 1 SDC4-ROS1, and 1 TPM3-ROS1), and one MPRIP-NTRK1 cell line. Our ERBB mutant lines include one cell line with HER2 exon 20 insertion, three lines with different exon 20 insertions in EGFR, and two EGFR mutant cell lines with compound mutations. We present our characterization of these cell lines in terms of their proliferation profiles and molecular signaling pathways in the presence of targeted inhibition. The derivation and characterization of these cell lines have facilitated the study of cell signaling in oncogene-driven cancer, have helped identify new resistance mechanisms, and have facilitated drug development for rare oncogenes such as NTRK1 gene fusions and EGFR exon 20 insertions. We expect that this growing library of cell lines will continue to further our understanding of oncogenic-driven tumor biology and provide mechanistic insight towards the development of novel therapeutics and drug combinations. Citation Format: Anh Tuan Le, Adriana Estrada-Bernal, Laura Schubert, Andrea Doak, Nan Chen, Kurtis Davies, Aria Vaishnavi, Mary Jackson, Vignesh Narayana, Kimi Kondo, John Mitchell, Michael Weyant, Tom Purcell, Paul Bunn, Ross Camidge, Janet Freeman-Daly, Robert Doebele. The CUTO panel of patient-derived NSCLC cell lines reveals unique molecular characteristics and responses to targeted therapies [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A29.

Lung cancer is the leading cause of cancer-related death in the United States. Outcomes for patients with lung cancer have reached a plateau with cytotoxic chemotherapy. Lung cancer remains very much at the vanguard of the new revolution in cancer therapy using molecular targets. Although striking improvements in survival have been observed in the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors, and in a subset of breast cancer using this approach, the impact of targeted therapies in lung cancer is quite modest. Along with advances in imaging and cancer genomics, there is now considerable optimism that the pace of progress in the treatment of lung cancer will accelerate in the next 10 years. As has been the custom for the past 8 years, leading experts in the biology, diagnosis and treatment of lung cancer met for three days to discuss current areas of research and future directions. This summary provides a brief snapshot of the discussions held at the 8th Annual Meeting on Targeted Therapies for Lung Cancer sponsored by the International Association for the Study of Lung Cancer in Santa Monica in early February 2008.

The risk of suicide in cancer patients has been reported as elevated in several countries. These patients are exposed to many medicines that may confuse or provide a means for harm, potentially also increasing their risk from accidents. Ratios of observed/expected numbers of hospital admission and death events relating to deliberate self-harm (DSH) and accidents were calculated in the 5 years from a cancer diagnosis in Scotland 1981–1995, compared to the matched general population. The relative risk (RR) of suicide was 1.51 (95% confidence interval (CI): 1.29–1.76). The RR of hospital admissions for DSH was not significantly increased, suggesting a strong suicidal intent in DSH acts in cancer patients. Accidental poisonings and all other accidents were both increased (RR death=3.69, 95% CI: 2.10–6.00; and 1.58, 95% CI: 1.48–1.69, respectively) (RR hospital admissions=1.32, 95% CI: 1.19–1.47; and 1.55, 95% CI: 1.53–1.57, respectively). The association of only certain tumour types (e.g. respiratory) with suicide and accidental poisoning, and a broad range of tumour types with an elevated risk of all other accidents, suggests accidental poisoning categories may be a common destination for code shifting of some DSH events. A previous history of DSH or accidents, significantly increased the RR of suicide or fatal accidents, respectively (RR suicide=14.86 (95% CI: 4.69–34.97) vs 1.16 (95% CI: 0.84–1.55)) (RR accidental death=3.37 (95% CI: 2.53–4.41) vs 1.29 (95% CI: 1.12–1.49)). Within 5 years of a cancer diagnosis, Scottish patients are at increased RR of suicide and fatal accidents, and increased RR of hospital admissions for accidents. Some of these accidents, particularly accidental poisonings, may contain hidden deliberate acts. Previous DSH or accidents are potential markers for those most at risk, in whom to target interventional techniques.

ICD-9 code 163 (malignant neoplasm of pleura) listed as underlying cause of death detected only 40% of Scottish mesothelioma cases (all body sites) from the cancer registry in 1981–1999. This is lower than both the previously published 55% figure, derived from UK mesothelioma register data 1986–1991, which is based on any mention of mesothelioma on death certificates, cross-referenced to cancer registry data, and the 44% figure derived from Scottish mortality data 1981–1999, which captured any mention of mesothelioma on the death certificate. Detection from cancer registry data increased to 75% under ICD-10 in Scotland, confirming earlier predictions of the benefit of ICD-10's more specific mesothelioma codes. Including the accidental poisoning codes E866.4 (ICD-9) and X49 (ICD-10), covering poisoning by ‘unspecified' and ‘other' causes, which appear to have been used as coding surrogates for mesothelioma when asbestos exposure was explicitly mentioned in deaths suggestive of a mesothelioma, and which are recorded as the underlying cause of death in 4–7% of mesotheliomas, may improve the mesothelioma detection rate in future epidemiological studies.

Easily accessible normal tissues expressing the same molecular site(s) of drug action as malignant tissue offer an enhanced potential for early proof of anticancer drug mechanism and estimation of the biologically effective dose. Studies were undertaken in healthy male volunteers to assess the tolerability of single and multiple (four in 24 h) 3 mm punch biopsies of the buccal mucosa, and to determine the feasibility of detecting and quantifying a range of proliferation, cell-cycle arrest and apoptosis markers by immunohistochemistry (IHC) for use as potential pharmacodynamic (PD) end points. The biopsy procedure was well tolerated with 100% of volunteers stating that they would undergo single (n = 10) and multiple (n = 12) biopsies again. Total retinoblastoma protein (pRb), phosphorylated pRb (phospho-pRb), total p27, phosphorylated p27 (phospho-p27), phosphorylated-histone H3 (phospho-HH3), p21, p53, Cyclin A, Cyclin E, Ki67 all produced good signal detection, but M30, cleaved caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling did not. Total pRb, phospho-pRb, total p27 and phospho-p27 were quantified further in a multiple biopsy study to allow components of variability to be addressed to inform future sizing decisions on intervention studies. Neither site of biopsy within the oral cavity, nor the nominal time of biopsy had any significant impact on any of the four markers expression levels. Inter- and intrasubject coefficients of variation (CVs) that could be used to size future intervention studies for pRb, phospho-pRb, total p27 and phospho-p27 were 14, 19, 18 and 16%; and 18, 29, 25 and 19%, respectively. In conclusion, quantitation of such markers in 3 mm buccal punch biopsies would be suitable to explore as PD end points within intervention studies of drugs acting on these pathways.

We have demonstrated the feasibility of detecting and quantifying six cell-cycle-related nuclear markers (Ki67, pRb, p27, phospho-p27 (phosphorylated p27), phospho-pRb (phosphorylated pRb), phospho-HH3 (phosphorylated histone H3)) in plucked human scalp and eyebrow hair. Estimates of the proportion of plucked hairs that are lost or damaged during processing plus the intra- and intersubject variability of each nuclear marker with these techniques are provided to inform sizing decisions for intervention studies with drugs potentially impacting on these markers in the future.

Self-poisoning by ingestion or inhalation is common, and it is important to study its various epidemiological manifestations with clear definitions. Data on fatal self-poisonings are recorded nationally within the UK and are codified according to the International Classification of Diseases (ICD) revision relevant at the time. Most fatal self-poisonings are codified as suicides, accidental deaths or undetermined deaths (‘open verdicts’). Non-fatal self-poisoning data, whether accidental or as a manifestation of deliberate self-harm, are recorded through hospital discharge information nationally but are not routinely published in the same way as mortality data. The bulk of the UK's published epidemiological information on nonfatal self-poisoning episodes is largely based on individual hospitals' admission or discharge records (‘special studies’). After establishing definitions for different self-poisoning categories we discuss the published data on self-poisoning as they relate to suicide, accidental self-poisoning and deliberate self-harm in the UK.

Dysphagia occurs in only a small percentage of patients with lung cancer, but the frequency of this cancer means that large numbers are affected. Non-quantitative analysis of a large Scottish series of lung cancer cases indicates the following eight broad categories of dysphagia according to underlying mechanisms: mediastinal disease; cervical lymphadenopathy; brainstem lesions; gastrointestinal tract metastases; associated systemic disorders; second primaries; oropharyngeal and oesophageal infections; and radiation-induced oesophageal toxicity.

Background: New oncology drugs are being developed in conjunction with companion diagnostics with approval restricting their use to certain biomarker-positive subgroups. We examined the impact of different predictive biomarker screening techniques and population enrichment criteria on the cost-effectiveness of targeted drugs in lung cancer, using ALK and crizotinib to build the initial model. Methods: Health economic modeling of cost per Quality Adjusted Life Year was based on literature review and expert opinion. The modeled population represented advanced non-small cell lung cancer (NSCLC), eligible for predictive biomarker screening with prescribing restricted to biomarker-positive patients. Results: For assays costing $1400 per person, cost per quality-adjusted life year (QALY) gained for ALK screening all advanced NSCLC, excluding treatment cost, is $106 707. This falls to $4756 when only a highly enriched population is screened (increasing biomarker frequency from 1.6 to 35.9%). However, the same enrichment involves missing 56% patients who segregate within the unscreened group. Cheaper screening tests that miss some true positives can be more cost-effective if proportional reductions in cost exceed proportion of subjects missed. Generic modeling of idealised screening assays, including treatment cost, reveals a dominant effect of screening cost per person at low biomarker frequencies. Cost-effectiveness of

Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of pound 301 359. This equated to pound 6500 per life years gained and pound 7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of pound 430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer.

There are potential advantages to detecting pharmacodynamic (PD) and pharmacokinetic (PK) endpoints in a tissue-based compartment such as the skin during the development of molecularly targeted drugs. We explored regional differences between inner arm, inner thigh, lower back and buttocks in 12 healthy male Caucasian volunteers in the tolerability of skin biopsy procedures; the Ki67 proliferation index; the frequency of detecting hair follicles and sweat glands; and the percentage of melanocytes. We also explored the amounts of tissue and protein obtained, and two separate methods of splitting biopsies for processing in mutually exclusive media. Biopsies from all body sites were well tolerated. The subjective ranking order was inner armbuttocks = backthigh. There were no statistically significant differences in the Ki67 labelling index (P0.05). The frequency of detecting sweat glands was the same in all body sites, but the frequency of detecting hair follicles was higher in back and buttock, compared to arm and thigh. The percentage of melanocytes was significantly lower in the buttocks compared to the back and thigh (P0.05), but not compared to the arm (P = 0.07). A 4-mm punch biopsy yielded a mean of 16.8 mg of tissue (range: 9-28 mg) and 160 microg of protein (range: 80-270 microg). In vivo sample splitting, by following a 2-mm punch with a 4-mm overpunch, had a shorter time from devascularisation to immersion into processing medium than ex vivo dissection of a 4-mm sample, which may be of importance to the assessment of labile endpoints. We conclude that multiple punch biopsies of the skin are feasible, with the buttocks representing the studied body site with the optimal balance between tolerability, hair follicle density and melanocyte density for obtaining tissue in which to assess PD and PK endpoints during drug development studies.

Aim: AP26113 is an investigational orally-active tyrosine kinase inhibitor with preclinical activity against ALK and all 9 clinically-identified crizotinib-resistant mutants tested. Methods: The Phase (Ph) 2 portion of a Ph1/2 single arm, multicenter study in patients (pts) with advanced malignancies is underway. We report updated safety for all treated pts and efficacy data for ALK+ NSCLC pts previously treated with crizotinib. NCT01449461. Results: As of 17 March 2014, 125 pts were enrolled: 66 in Ph1 (30-300 mg) and 59 in Ph2 (90 or 180 mg). Baseline characteristics: 58% female, median age 57 yr; diagnoses: NSCLC n = 117, other n = 8. 62 pts remain on study; median follow-up for all pts is 3.1 mo (max= 24.4 mo, ongoing). The most common treatment-emergent adverse events (≥20%) were nausea (40%), fatigue (34%), diarrhea (34%), cough (26%), headache (25%), and vomiting (21%), which were generally Grade 1/2 in severity. Early onset pulmonary symptoms (dyspnea with hypoxia and/or new findings on chest imaging) were observed in 12/125 (10%) pts: 6/44 (14%) at 180 mg qd and 1/38 (3%) at 90 mg qd. Symptoms occurred within 7 days following initiation of AP26113, required medical attention, and occurred at lower rates with lower doses. Pts continue to be enrolled at 90 mg qd. Among 51 evaluable ALK+ NSCLC pts with prior crizotinib, 35 (69%) responded. Duration of response was 1.6– 14.7+ mo. 23 had confirmed responses and 7 await confirmation. Among 55 evaluable pts with ALK+ NSCLC, median progression free survival is 10.9 mo. Independent radiological review conducted on 10 pts enrolled with untreated or progressing brain metastases showed 6/10 pts with regression in brain, including 4 with undetectable brain metastases following AP26113; 2 had stable disease, 2 progressed; 7/10 remain on study (range 2.7-19.5 mo). Updated data will be presented. Conclusions: AP26113 has promising anti-tumor activity in pts with crizotinib-resistant ALK+ NSCLC, including pts with brain metastases. A randomized Ph2 trial evaluating either 90 mg qd or 90mg qd escalated to 180 mg qd in crizotinib-resistant ALK+ NSCLC has been initiated. Disclosure: S. Gettinger: research funding (ARIAD); consultancy (ARIAD); honoraria (ARIAD); C. Langer: research funding (ARIAD); A. Shaw: consultancy (ARIAD); G.J. Weiss: consultancy (Genentech, Pfizer, Celgene, Quintiles, Medscape); N.I. Narasimhan: employment and equity ownership (ARIAD); D.J. Dorer: employment and equity ownership (ARIAD); V.M. Rivera: employment and equity ownership (ARIAD); T. Clackson: employment and equity ownership (ARIAD); F.G. Haluska: employment and equity ownership (ARIAD); R. Camidge: research funding (ARIAD); honoraria (ARIAD). All other authors have declared no conflicts of interest.