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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.

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.

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.

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.

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.

Background Chromosomal rearrangements of anaplastic lymphoma kinase (ALK) are associated with marked clinical responses to crizotinib, an orally available tyrosine kinase inhibitor targeting ALK. This global randomized phase III study compared the efficacy and safety of crizotinib (C) with standard chemotherapy (pemetrexed or docetaxel [P/D]) as 2nd-line therapy for patients (pts) with advanced ALK+ NSCLC. Methods Between Feb 2010 and Feb 2012, 347 pts with stage IIIB/IV ALK+ NSCLC previously treated with 1 prior platinum-based regimen were randomized to receive C 250 mg PO BID (n = 173) or either P 500 mg/m2 or D 75 mg/m2 IV q3w (n = 174; 58% P, 42% D). ALK was detected by FISH in a central lab. Pts with progressive disease on P/D were offered C on PROFILE 1005. The primary endpoint was progression-free survival (PFS) per independent radiologic review; secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. Results The study met its primary objective by demonstrating the superiority of C over P/D in prolonging PFS (median 7.7 vs 3.0 mo; HR 0.49; 95% CI 0.37–0.64; P Conclusions C showed significant improvement in PFS and ORR compared with P/D and had an acceptable safety profile. These findings establish C as the standard of care for pts with previously treated advanced ALK+ NSCLC. Disclosure A.T. Shaw: Advisory relationship with Pfizer, Ariad, Chugai, Novartis and Daiichi-Sankyo. Research funding from AstraZeneca and Novartis. D.W. Kim: Advisory relationship with Pfizer. Honoraria from Pfizer. K. Nakagawa: Honoraria from Pfizer and Eli Lilly. B. Besse: Research funding from Pfizer. B. Solomon: Advisory relationship with Pfizer. Research funding from Pfizer. F.H. Blackhall: Advisory relationship with Pfizer. Honoraria from Pfizer. Research funding from Pfizer. Expert testimony for UK NICE scoping for crizotinib. Y. Wu: Honoraria from Pfizer, Roche, AstraZeneca, Eli Lilly, and Sanof-Aventis. Research funding from Pfizer, Roche, and AstraZeneca. M. Thomas: Advisory relationship with Pfizer. K.J. O'Byrne: Adivsory relationships with and honoraria, research funding, travel-cost remuneration from Pfizer and Eli Lilly. D. Moro-Sibilot: Honoraria from Pfizer. R. Camidge: Advisory relationship with Pfizer. Honoraria from Pfizer. V. Hirsh: Advisory relationship with Pfizer. Honoraria from Pfizer. T.S.K. Mok: Advisory relationships with and honoraria from Pfizer, AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Taiho, GSK, and Boehringer Ingelheim. Research funding from AstraZeneca. V. Tassell: Employed by Pfizer. Holds Pfizer stock. A. Polli: Employed by Pfizer. Holds Pfizer stock. P. Janne: Advisory relationships with Pfizer, Boehringer Ingelheim, Roche, Genentech, Abbott, AstraZeneca, Sanofi, and Teva. Renumeration from LabCorp. All other authors have declared no conflicts of interest.

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.

The family of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) plays a critical role in cell proliferation and survival. A variety of genetic alterations (e.g. amplifications, mutations, and translocations) of these receptors and ligands have been found in diverse types of tumors. NVP-BGJ398 is a potent, selective, and orally bioavailable inhibitor of the FGFR tyrosine kinases. It inhibits the proliferation of various FGFR-dependent cell lines at nano-molar concentrations including breast and lung cancers harboring FGFR1 amplification, FGFR2-amplified gastric cancer cell lines and FGFR3-mutated bladder cancers. Objectives of the study: The purpose of this phase I-First In Human dose-escalation study is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD) of NVP-BGJ398 when administered orally to adult patients with advanced solid tumors. Secondary objectives include safety, tolerability, pharmacokinetics and preliminary anti-tumor activity in FGFR-dependent cancer. Methods: Patients received BGJ398 daily in a 28-day cycle in escalating dose cohorts starting from 5mg once daily. After cohort 3, patients had to have FGFR1 or FGFR2 amplification or FGFR3 mutation. Dose limiting toxicities (DLTs) were pre-defined and included both severe events and those resulting in significant dosing delays. Preliminary data: 26 patients have been treated, including 10 patients with FGFR1-amplified breast and 3 patients with FGFR1-amplified squamous cell lung cancer. The dose was escalated from 5 mg to 150 mg over 7 dose cohorts. One DLT of delayed dose occurred following a grade 3 AST/ALT event at 100 mg. Adverse events (AE) were generally grade 1-2. The most frequently observed AEs were diarrhea (37%) fatigue (37%) and nausea (32%) Hyperphosphatemia was observed, with increasing frequency at higher doses of NVP-BGJ398, and could be managed with phosphate binders and diuretics. One lung cancer patient with an FGFR1/CEP8 ratio of 2.6 by FISH analysis responded to 100 mg of NVP-BGJ398 with a 33% reduction in target lesions by CT scan at 8 weeks, confirmed at 12 weeks, and a substantial SUV decrease on PET. These observations provide early evidence that inhibition of the FGFR pathway is effective in patients with FGFR dependent cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-122. doi:1538-7445.AM2012-LB-122

LBA7501 Background: Mapatumumab, a fully human agonist monoclonal antibody, targets and activates the death receptor TRAIL-R1. We conducted this randomized, controlled phase II trial to evaluate mapatumumab in combination with carboplatin and paclitaxel as first-line therapy in advanced non-small call lung cancer (NSCLC). Methods: Patients were required to have histologically or cytologically confirmed Stage IIIB or IV advanced primary NSCLC with measurable disease by RECIST. Patients were randomly assigned to Arm A, paclitaxel 200 mg/m2 + carboplatin AUC 6.0 (PC); Arm B, PC + mapatumumab 10 mg/kg; or Arm C, PC + mapatumumab 30 mg/kg. Cycles were repeated every 21 days; patients completed up to 6 cycles in the absence of evidence of disease progression or unacceptable toxicity. Patients in Arms B and C could receive additional cycles of mapatumumab in the absence of disease progression. The co-primary endpoints were response rate (RR; complete response + partial response) and progression-free survival (PFS). Images were read by independent radiologists blinded to treatment group assignment, as well as locally. Results: 111 patients were enrolled at 22 sites in 4 countries. Addition of mapatumumab to PC did not improve RR or PFS. RR and PFS, based on the independent read, and overall survival results are summarized below. The results based on local reading also showed no benefit from the addition of mapatumumab to PC. Adverse events were generally balanced across treatment groups; there was no evidence that mapatumumab exacerbated toxicities associated with PC. Conclusions: The results do not support further evaluation of mapatumumab in combination with PC in patients with advanced NSCLC. Additional trials of mapatumumab in other indications are ongoing. [Table: see text] [Table: see text]

Background: Belinostat (B) is a low molecular weight, synthetic hydroxamic acid derivative that inhibits class I and II histone deacetylases. Bortezomib (Bz) is a potent, selective inhibitor of the 26S proteasome. In preclinical studies, synergistic antiproliferative and pro-apoptotic effects were observed with the combination, providing the rationale for this study. Methods: This phase 1 study is designed to determine the maximum tolerated dose (MTD) and to evaluate the safety and pharmacokinetic (PK) behavior of the combination of B and Bz. Each 21-day treatment cycle consists of B (600–1000 mg/m2) IV daily over 30 minutes on days 1–5 and Bz (0.7–1.5 mg/m2) IVP over 3–5 seconds on days 1, 4, 8, and 11 (days 2, 5, 8 and 11, cycle 1 only). Results: To date, 26 patients have been enrolled (median age 59 [range 27–72]; median PS 1 [range 0–1]). Twenty-two patients were evaluable for toxicity and received a total of 58 treatment cycles (median 2 [range 1–6]). Four patients, 2 at dose level (DL) 3 (B: 600 mg/m2)/Bz: 1.3 mg/m2) and 2 at DL 5 (B: 1000 mg/m2)/Bz: 1.5 mg/m2) experienced a dose limiting toxicity (DLT). At DL 3, the DLTs were grade (gr) 3 dehydration and gr 4 thrombocytopenia. The exact relationship of the gr 3 dehydration and study combination is unclear as the patient had uncontrolled constipation and decreased oral intake as a result of a change in pain medications on cycle 1 day 1. This cohort was expanded to 9 pts to further determine tolerability of the study combination. No other DLTs were identified and dose escalation continued. At DL 5, DLTs included gr 4 thrombocytopenia and gr 4 fatigue. Most adverse events (AEs) have been mild to moderate. Gr 1–2 AEs (number of cycles) include anorexia (8), acute infusion reaction (5), fatigue (14), nausea (19), neutropenia (1), pain (12), phlebitis (6), thrombocyctopenia (11), and vomiting (12). Gr 3 AEs (occurring after course 1) include anorexia, dehydration, fatigue, nausea, vomiting, hypoalbuminemia, and elevation of alkaline phosphatase. Analysis of B PK demonstrates no statistical differences in the parameters between days 1 (B only) and 2 (B + Bz) for AUC, Cmax, clearance, or t1/2. Likewise, increasing Bz doses have no effect on B PK, whereas doses of B from 600 to 1000 mg/m2 result in dose-proportional increases in drug exposure. Four patients have maintained stable disease for 4–6 cycles of therapy. Conclusions: Belinostat and bortezomib is a reasonable combination with a tolerable toxicity profile and no evidence of pharmacological interactions. Accrual is ongoing at the MTD, DL 4 (B: 1000 mg/m2)/Bz: 1.3 mg/m2). Additional biological assessments are planned in an expanded cohort of patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B238.

We would like to highlight a serious complication of a nonprescription medication take in accordance with the manufacturer's instructions, illustrated by the following case. A 27 year-old man presented with a 3 month history of increasing clumsiness, vomiting, dizziness and confusion. For the preceding 5 years he had suffered from persistent epigastric discomfort. An oesophago-gastro-duodenoscopy arranged by his general practitioner had been normal. His discomfort was eased by omeprazole 20 mg once a day. In addition, for many years he had also consumed 10 Tums (SmithKline Beecham) or 6 Rennie (Roche) antacid tablets a day. He drank little milk and had no recent sun exposure. His admission blood results revealed urea 22.4 mmol l−1, creatinine 489 µmol l−1, calcium 4.1 mmol l−1, phosphate 0.95 mmol l−1, albumin 41 g l−1, alkaline phosphatase 104 IU l−1, bicarbonate 63 mmol l−1 and parathyroid hormone (PTH) 10 ng l−1 (normal range 10–65). Immunoglobulins, 24 h urinary calcium, serum angiotensin converting enzyme and parathyroid hormone-related protein levels were all normal. A repeat oesophago-gastro-duodenoscopy and a whole body CT scan were normal. He was vigorously rehydrated using intravenous 0.9% saline with potassium supplements. Within 12 h his symptoms ceased and his renal function began to improve. After 3 days of hydration, because his calcium remained elevated at 3.02 mm l−1, 60 mg of disodium pamidronate was given intravenously. The following day the patient revealed that he had continued to take Rennie in the hospital without informing the medical or nursing staff, having not considered antacids as ‘medication’. His antacids were discontinued at that point. A week later he developed symptomatic hypocalcaemia (calcium 0.87 mmol l−1) requiring calcium supplementation before normalizing. On discharge he was advised to avoid antacids containing calcium carbonate. When reviewed 6 months later he was asymptomatic, with normal blood results and requiring no medication. The milk–alkali syndrome is a triad of hypercalcaemia, alkalosis and renal impairment resulting from the ingestion of calcium and absorbable alkali [1]. Calcium carbonate, present in the majority of nonprescription antacids, acts as a common source of both. A self-perpetuating environment is thought to develop within the kidney whereby the calcium and alkali limit the excretion of each other [1]. Renal impairment, secondary to hypercalcaemia and dehydration, exacerbates the situation. The amount of calcium carbonate required to provoke the milk–alkali syndrome is controversial. The antacid regimens used before the development of H2-receptor antagonists and proton-pump inhibitors employed 20–60 g calcium carbonate per day and up to 35% patients developed toxic symptoms [1]. Such high levels of calcium carbonate are no longer used therapeutically and the syndrome has become correspondingly rare. Only seven patients presented with the milk–alkali syndrome during an 8 year period in one American teaching hospital. In these patients calcium carbonate was implicated at doses as low as 4–12 g day−1 [2]. Similarly, our patient only took 4–5 g calcium carbonate a day, which was within the maximum recommended by the antacid's manufacturer. The recommended dosages for nonprescription antacids available in the UK allow for daily calcium carbonate loads ranging from 7.2 g (Andrew's Antacid, SmithKline Beecham) to 10.8 g (Rennie's, Roche). Indeed, one antacid product, Bisodol Indigestion Relief (Whitehall Laboratories) states no recommended maximum dosage, but only that one or two tablets (each containing 522 mg calcium carbonate) be ‘taken as required’. We feel that certain individuals are clearly susceptible to developing the milk–alkali syndrome at doses of calcium carbonate less than many antacid manufacturer's recommended daily limits. Individual variations in the fraction of any calcium carbonate load absorbed, or in its metabolism may be responsible. Our case exemplifies the importance of nonprescription medications in a full drug history, and raises concerns about the printed advice given to users of calcium carbonate containing antacids. If dyspeptic symptoms are controlled, antacid packaging that only states ‘consult your doctor if symptoms persist', may not deter chronic ingestion. Such advice inevitably increases the risk of severe hypercalcaemia from nonprescription antacids even when taken at or below the recommended daily dose.