Impact of neuroendocrine morphology on cancer outcomes and stage at diagnosis: a UK nationwide cohort study 2013-2015.

BACKGROUND: The diagnosis of neuroendocrine neoplasms (NENs) is often delayed. This first UK population-based epidemiological study of NENs compares outcomes with non-NENs to identify any inequalities. METHODS: Age-standardised incidence rate (ASR), 1-year overall survival, hazard ratios and standardised mortality rates (SMRs) were calculated for all malignant NENs diagnosed 2013-2015 from UK national Public Health records. Comparison with non-NENs assessed 1-year overall survival (1YS) and association between diagnosis at stage IV and morphology. RESULTS: A total of 15,222 NENs were identified, with an ASR (2013-2015 combined) of 8.6 per 100,000 (95% CI 8.5-8.7); 4.6 per 100 000 (95% CI, 4.5-4.7) for gastro-entero-pancreatic (GEP) NENs. The 1YS was 75% (95% CI, 73.9-75.4) varying significantly by sex. Site and morphology were prognostic. NENs (predominantly small cell carcinomas) in the oesophagus, bladder, prostate, and female reproductive organs had a poorer outcome and were three times more likely to be diagnosed at stage IV than non-NENs. CONCLUSION: Advanced stage at diagnosis with significantly poorer outcomes of some NENs compared with non-NENs at the same anatomical site, highlight the need for improved access to specialist services and targeted service improvement.

ABOUND.2L+: A randomized phase 2 study of nanoparticle albumin-bound paclitaxel with or without CC-486 as second-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC).

BACKGROUND: This randomized phase 2 trial compared the efficacy and safety of second-line nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without the addition of CC-486 (an oral formulation of 5-azacytidine) in patients with advanced-stage, nonsquamous non-small cell lung cancer. METHODS: Patients were randomized to receive either nab-paclitaxel 100 mg/m2 on days 8 and 15 plus CC-486 200 mg daily on days 1 to 14 or single-agent nab-paclitaxel 100 mg/m2 on days 1 and 8, with both regimens administered every 21 days until tumor progression or unacceptable toxicity. The primary endpoint was progression-free survival. Secondary endpoints included the overall response rate, the disease control rate, and overall survival. RESULTS: Between January 2015 and August 2016, 161 patients were randomized (81 to the combination arm and 80 to the single-agent nab-paclitaxel arm). There was no benefit from the addition of CC-486 to nab-paclitaxel. The median progression-free survival was 3.2 months for the combination and 4.2 months for single-agent nab-paclitaxel (hazard ratio, 1.3; 95% confidence interval, 0.9-1.9). The median overall survival was 8.1 months in the combination arm and 17 months in the single-agent nab-paclitaxel arms (hazard ratio, 1.7; 95% confidence interval, 1.08-2.57). Grade 3 or greater treatment-related, emergent adverse events were reported by 40.5% of patients in the combination arm and by 31.6% of those in the single-agent nab-paclitaxel arm. CONCLUSIONS: Single-agent nab-paclitaxel was associated with promising outcomes and a tolerable safety profile as second-line treatment for patients with advanced-stage, nonsquamous non-small cell lung cancer. There was no benefit from the addition of CC-486 to nab-paclitaxel.

Survivin in solid tumors: rationale for development of inhibitors.

Survivin is a 16.5 kDa protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. Absent in most adult tissues, survivin is selectively upregulated in many human tumors, where its overexpression correlates with poor outcome and treatment resistance. Consequently, survivin is a promising target for cancer therapy. Preclinical data demonstrate that survivin inhibition reduces cell proliferation, increases apoptosis, and sensitises cells to cytotoxic agents and radiotherapy. The pharmacological survivin inhibitors LY2181308 and YM155 have demonstrated acceptable toxicity and evidence of therapeutic efficacy as single agents in early-phase clinical trials. Current efforts seek to define the optimum use of survivin inhibitors in combination with cytotoxic therapies, where it is hoped that preclinical evidence of treatment synergy will translate into improved therapeutic efficacy. Results from these ongoing studies are keenly awaited.

Association of long-term administration of the survivin mRNA-targeted antisense oligonucleotide LY2181308 with reversible kidney injury in a patient with metastatic melanoma.

A 57-year-old man with metastatic melanoma was treated with the survivin inhibitor and antisense oligonucleotide LY2181308 as part of a First-in-Human Dose trial. After 18 months of treatment, he developed kidney injury and the treatment was discontinued. At 9 months and before the development of kidney injury, LY2181308 concentrations were 8- to 10-fold higher relative to median predicted values, but within the targeted exposure considered to be safe. However, at 17 months, 28 days after stopping LY2181308 therapy, LY2181308 concentration exceeded the predicted range by 38-fold. His decreased kidney function was slow to improve after stopping treatment. A kidney biopsy showed signs of acute tubular injury with regeneration. Complete recovery of kidney function occurred 6 months after treatment was stopped. The relationship between high exposures and slow LY2181308 clearance with the gradual improvement in kidney function after stopping the antisense treatment suggests that the oligonucleotide was related to the kidney injury. Based on this case report, kidney function should be monitored frequently in patients receiving long-term treatment with antisense oligonucleotides that specifically target survivin, particularly when they receive concomitant angiotensin-converting enzyme inhibitors or nonsteroidal anti-inflammatory drugs.

A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer.

PURPOSE: The primary aim of this study was to measure the objective tumor response rate following treatment with indisulam [E7070; N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] as second-line therapy in patients with advanced non-small cell lung cancer. The secondary aims were to determine progression-free survival, to assess the safety and tolerability of indisulam, and to study its pharmacokinetic and pharmacodynamic profile. EXPERIMENTAL DESIGN: Patients were randomized to receive indisulam every 3 weeks either as a single i.v. dose of 700 mg/m(2) on day one (dx1) or 130 mg/m(2) given on days 1 to 5 inclusive as a daily infusion (dx5). All patients had previously received platinum-based chemotherapy. RESULTS: Forty-four patients were randomized. Only minor responses were seen. Myelosuppression, gastrointestinal symptoms, and lethargy were the most common toxicities and were more frequent in the dx1 arm. The pharmacokinetics of indisulam in each treatment schedule were adequately described using a previously developed population pharmacokinetic model and were mostly consistent with the results of the phase I program. Flow cytometric analysis of endobronchial and metastatic disease revealed a reduction in the fraction of cycling cells and an increase in apoptosis following indisulam compared with pretreatment levels. CONCLUSIONS: We conclude that, despite evidence of tumor-specific indisulam-induced apoptosis, neither of these treatment schedules has single-agent activity as second-line treatment of non-small cell lung cancer.

Isolation of a small molecule inhibitor of DNA base excision repair.

The base excision repair (BER) pathway is essential for the removal of DNA bases damaged by alkylation or oxidation. A key step in BER is the processing of an apurinic/apyrimidinic (AP) site intermediate by an AP endonuclease. The major AP endonuclease in human cells (APE1, also termed HAP1 and Ref-1) accounts for >95% of the total AP endonuclease activity, and is essential for the protection of cells against the toxic effects of several classes of DNA damaging agents. Moreover, APE1 overexpression has been linked to radio- and chemo-resistance in human tumors. Using a newly developed high-throughput screen, several chemical inhibitors of APE1 have been isolated. Amongst these, CRT0044876 was identified as a potent and selective APE1 inhibitor. CRT0044876 inhibits the AP endonuclease, 3'-phosphodiesterase and 3'-phosphatase activities of APE1 at low micromolar concentrations, and is a specific inhibitor of the exonuclease III family of enzymes to which APE1 belongs. At non-cytotoxic concentrations, CRT0044876 potentiates the cytotoxicity of several DNA base-targeting compounds. This enhancement of cytotoxicity is associated with an accumulation of unrepaired AP sites. In silico modeling studies suggest that CRT0044876 binds to the active site of APE1. These studies provide both a novel reagent for probing APE1 function in human cells, and a rational basis for the development of APE1-targeting drugs for antitumor therapy.

Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma.

PURPOSE: MetXia-P450 is a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2B6 gene (CYP2B6), Escherichia coli lacZ, and neomycin resistance marker genes. Cytochrome P450 enzymes are primarily expressed in the liver and convert the prodrug cyclophosphamide to an active phosphoramide mustard and acrolein. Gene-based delivery of CYP2B6 to the tumor site leads to local prodrug activation and higher concentrations of the active metabolites at the target site. EXPERIMENTAL DESIGN: MetXia-P450 was directly injected into metastatic cutaneous tumor nodules on days 1 and 2 and nodules biopsied on day 7. Oral cyclophosphamide (100 mg/m(2)) was administered between days 8 and 22. Subsequent cycles of oral cyclophosphamide were repeated for 2 of 4 weeks. Gene transfer levels in biopsy samples were measured by histologic and quantitative PCR analyses. Safety assessments were made using PCR for vector dissemination to the blood after injection and using PCR and serologic analyses to detect replicating virus. Secondary end points included clinical response, toxicity, and evaluation of antitumor immune responses by measurement of carcinoembryonic antigen and 5T4 antibodies. RESULTS: Twelve patients with breast cancer (n = 9) and melanoma (n = 3) received three dose levels of MetXia-P450 ( approximately 8 x 10(5), approximately 8 x 10(6), and approximately 8 x 10(7) lacZ transferring units/mL). The product was safe and well tolerated. The lacZ transgene was detected in biopsy material by immunohistochemistry in 10 of 12 patients and integrated viral sequences by PCR in 3 of 6 patients. One (8%) patient with breast cancer had a partial response and received 7 months of oral cyclophosphamide. Four (33%) patients had stable disease for > or =3 months and the rest had progressive disease. Preliminary immunologic analyses were suggestive of an antitumor response in two patients (partial response in one patient and stable disease in one patient). CONCLUSION: MetXia was safe and well tolerated. Gene transfer was detected at all dose levels, and the initial suggestion of an antitumor response indicates that MetXia-P450 should undergo further clinical assessment.

Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment.

Malignant pleural mesothelioma is an aggressive malignancy of the pleural surface, predominantly caused by prior asbestos exposure. There is a global epidemic of malignant pleural mesothelioma underway, and incidence rates are predicted to peak in the next few years.This article summarises the epidemiology and pathogenesis of malignant pleural mesothelioma, before describing some key factors in the patient experience and outlining common symptoms. Diagnostic approaches are reviewed, including imaging techniques and the role of various biomarkers. Treatment options are summarised, including the importance of palliative care and methods of controlling pleural effusions. The evidence for chemotherapy, radiotherapy and surgery is reviewed, both in the palliative setting and in the context of trimodality treatment. An algorithm for managing malignant pleural effusion in malignant pleural mesothelioma patients is presented. Finally new treatment developments and novel therapeutic approaches are summarised.

Targeted Next-Generation Sequencing of Plasma DNA from Cancer Patients: Factors Influencing Consistency with Tumour DNA and Prospective Investigation of Its Utility for Diagnosis.

Use of circulating tumour DNA (ctDNA) as a liquid biopsy has been proposed for potential identification and monitoring of solid tumours. We investigate a next-generation sequencing approach for mutation detection in ctDNA in two related studies using a targeted panel. The first study was retrospective, using blood samples taken from melanoma patients at diverse timepoints before or after treatment, aiming to evaluate correlation between mutations identified in biopsy and ctDNA, and to acquire a first impression of influencing factors. We found good concordance between ctDNA and tumour mutations of melanoma patients when blood samples were collected within one year of biopsy or before treatment. In contrast, when ctDNA was sequenced after targeted treatment in melanoma, mutations were no longer found in 9 out of 10 patients, suggesting the method might be useful for detecting treatment response. Building on these findings, we focused the second study on ctDNA obtained before biopsy in lung patients, i.e. when a tentative diagnosis of lung cancer had been made, but no treatment had started. The main objective of this prospective study was to evaluate use of ctDNA in diagnosis, investigating the concordance of biopsy and ctDNA-derived mutation detection. Here we also found positive correlation between diagnostic lung biopsy results and pre-biopsy ctDNA sequencing, providing support for using ctDNA as a cost-effective, non-invasive solution when the tumour is inaccessible or when biopsy poses significant risk to the patient.

Pharmacokinetic study of cisplatin and infusional etoposide phosphate in advanced breast cancer with correlation of response to topoisomerase IIalpha expression.

PURPOSE: There is substantial interpatient variability in etoposide pharmacokinetics. Pharmacokinetic adjustment to specific plasma concentrations may make it possible to define a therapeutic plasma concentration and relate drug target expression in the tumor to response. This study evaluated the combination of cisplatin with a prolonged infusion of etoposide phosphate (EP) in advanced breast cancer and correlated response to topoisomerase II expression. EXPERIMENTAL DESIGN: Eligible patients, previously treated with an anthracycline, received 60 mg/m(2) cisplatin, followed by a 5-day infusion of EP. Plasma etoposide levels were measured on days 2 and 4 of each cycle with adjustment of the infusion rate to achieve an initial target etoposide concentration of 2 micro g/ml or 1.5 micro g/ml. Primary tumor blocks were stained by immunohistochemistry for topoisomerase IIalpha and beta. RESULTS: Thirty-six patients, treated in three consecutive cohorts, received 145 cycles of chemotherapy. Targeting plasma etoposide concentration reduced interpatient pharmacokinetic variability (32% and 62% of patients, respectively, within 10% of target concentration on days 2 and 4; cycle 1). Significant hematological toxicity (89% of patients with at least one episode of grade III/IV neutropenia, 64% of patients with at least one episode of grade III/IV thrombocytopenia) was observed. Thirty-nine percent of patients achieved a partial response, and 19% had stable disease for at least 3 months. The median time to tumor progression was 4 months, with a median survival of 11 months. Topoisomerase IIalpha expression was significantly higher (P < 0.001) in responding patients compared with those with stable or progressive disease. There was no difference in topoisomerase IIbeta expression between groups. CONCLUSION: Cisplatin and infusional EP is an active, but intensive, schedule in heavily pretreated patients with breast cancer. Clinical response correlates with tumor topoisomerase IIalpha expression.

A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer.

PURPOSE: Tumor necrosis factor (TNF) alpha is a key player in the tumor microenvironment and is involved in the pathogenesis of breast cancer. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biological activity, and therapeutic efficacy of Etanercept in metastatic breast cancer. EXPERIMENTAL DESIGN: We initiated a Phase II, nonrandomized, open-labeled study in patients with progressive metastatic breast cancer refractory to conventional therapy (Phase I toxicity data were available in patients with rheumatoid arthritis). Etanercept was administered subcutaneously at a dose of 25 mg twice weekly until disease progression. RESULTS: Sixteen patients were recruited [median age 53 years (range, 34 to 74)]. A total of 141.6 weeks of therapy was administered (median of 8.1 weeks). Seven patients received > or =12 weeks of therapy. The most common side effects were injection site reactions (6), fatigue (5), loss of appetite (2), nausea (1), headache (1), and dizziness (1). Brief period of disease stabilization was seen in 1 patient lasting for 16.4 weeks. Immunoreactive TNF-alpha was elevated within 24 hours of therapy and persisted until the end of treatment (days 7, 28, 56, and 84). Phytohemagglutinin stimulates the production of interleukin-6 and CCL2 in peripheral blood cells, and the ability of Etanercept to modulate this response was assessed in a cytokine release assay. A consistent decrease in interleukin-6 and CCL2 level was seen compared with pretreatment values in serial blood samples (days 1, 7, 28, 56, and 84). CONCLUSIONS: Our study shows the safety and biological activity of Etanercept in breast cancer and provides data to assess pharmacodynamic endpoints of different schedules of Etanercept and combinations with chemotherapy or other biological therapies.

Low-dose IFN-gamma induces tumor MHC expression in metastatic malignant melanoma.

Specific antitumor immune responses require expression of MHC class I or II molecules on tumor cells, and MHC antigen down-regulation is a presumed tumor growth promoting mechanism. Because IFN-gamma up-regulates tumor MHC antigen expression in vitro, in this Phase II trial of an immunologically active dose and schedule we evaluated whether this was the case in vivo. Twenty-three patients with metastatic melanoma were treated with IFN-gamma 100 microg/m(2) s.c. once weekly for a maximum of 6 months. There were three complete responses, now maintained for 53, 36, and 25 months. The remainder had progressive disease. The treatment was well tolerated, with no toxicity exceeding National Cancer Institute Common Toxicity Criteria grade II. Immunohistochemical analysis of tumor biopsies during treatment was performed using monoclonal antibodies to HLA class I (W/632) and class II (CR3/43) monomorphic determinants. HLA class I was down-regulated in 2 of 19 patients pretreatment and up-regulated by IFN-gamma in both. HLA class II was down-regulated pretreatment in 14 of 18 patients and up-regulated by IFN-gamma in 6 (43%). The HLA up-regulation persisted throughout the study. IFN-gamma induced significant but short-lived up-regulation of surrogate markers of monocyte activation (serum neopterin) and class I up-regulation (serum beta-2-microglobulin) in most patients. There was no consistent relationship between surrogate marker up-regulation, tumor antigen up-regulation, and responses. The study shows that the significant immune modulation induced by IFN-gamma does not correlate with tumor responses and that the serum surrogate marker changes do not reflect tumor events. The durable and long-lived responses, clear demonstration of tumor MHC up-regulation, and low toxicity suggest that weekly IFN-gamma 100 microg/m(2) would be a useful addition to chemoimmunotherapeutic regimens.

Capecitabine and streptozocin ± cisplatin in advanced gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: Cytotoxic chemotherapy is widely used for advanced, unresectable pancreatic and other gastrointestinal foregut neuroendocrine tumours (NETs) and the most commonly used regimen combines 5-fluorouracil with streptozocin. The NET01 trial was designed to investigate whether capecitabine combined with streptozocin was an acceptable regimen with or without adding cisplatin. METHODS: Patients with advanced, unresectable NETs of pancreatic, gastrointestinal foregut or unknown primary site were randomised to receive three-weekly capecitabine (Cap) 625 mg/m(2) twice daily orally, streptozocin (Strep) 1.0 g/m(2) intravenously on day 1, with or without cisplatin (Cis) 70 mg/m(2) intravenously on day 1. The primary outcome measure was objective response. Secondary outcome measures included progression-free and overall survival, quality of life, toxicity and biochemical response. RESULTS: 86 (44 CapStrep, 42 CapStrepCis) patients were randomised. Best objective response rate was 12% (95% confidence interval (CI)=2-22%) with CapStrep and 16% (95% CI=4-27.4%) with CapStrepCis. Disease-control rate was 80% with CapStrep and 74% with CapStrepCis. The estimated median progression-free and overall survival were 10.2 and 26.7 months for CapStrep and 9.7 and 27.5 months for CapStrepCis. 44% of CapStrep and 68% of CapStrepCis patients experienced grade ≥3 adverse events. INTERPRETATION: The efficacies of the novel CapStrep±Cis regimens were very similar. CapStrep was better tolerated than CapStrepCis. The trial was registered as EudraCT: 2004-005202-71 and ISRCTN: 35124268.

The association between Lambert-Eaton myasthenic syndrome and small cell lung carcinoma.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder mediated by autoantibodies to voltage-gated calcium channels. The disorder is diagnosed clinically on the basis of a triad of symptoms (proximal muscle weakness, hyporeflexia, and autonomic disturbance), supported by electrophysiological findings and the presence of autoantibodies. Between 40% and 62% of patients diagnosed with LEMS are found to have small-cell lung cancer (SCLC), almost all of whom develop neurological symptoms before their cancer is diagnosed. Prompt identification of LEMS and appropriate screening for SCLC is key to improving the outcome of both conditions. Here we review the pathophysiology and clinical management of LEMS, focusing particularly on the relationship with SCLC.

Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052).

BACKGROUND: This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18 weeks (PFSR-18)(1) as primary end-point. METHODS: Chemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75 mg/m(2) on day 1 and bortezomib 1.3mg/m(2) on days 1, 4, 8, 11 every 3 weeks. The primary end-point validation utilised the landmark method. RESULTS: Between 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42-64%). The overall survival (OS) was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The median PFS was 5.1months (95% CI 3.3-6.5) and the response rate was 28.4% (95% CI 18.9-39.5%). The most frequent grade 3-4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest. End-point validation showed that patients with no progression/progression at 18 weeks had median OS of 16.9/11.9 months, respectively. Hazard ratio was 0.46 (CI 0.32-0.67), logrank test and C-index were 0.007 and 0.60. CONCLUSION: The 50% PFSR-18 for CB was contained within the 80% CI for (42-64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.

Quantitative analysis of survivin protein expression and its therapeutic depletion by an antisense oligonucleotide in human lung tumors.

RNA-directed antisense and interference therapeutics are a promising treatment option for cancer. The demonstration of depletion of target proteins within human tumors in vivo using validated methodology will be a key to the application of this technology. Here, we present a flow cytometric-based approach to quantitatively determine protein levels in solid tumor material derived by fiber optic brushing (FOB) of non-small cell lung cancer (NSCLC) patients. Focusing upon the survivin protein, and its depletion by an antisense oligonucleotide (ASO) (LY2181308), we show that we can robustly identify a subpopulation of survivin positive tumor cells in FOB samples, and, moreover, detect survivin depletion in tumor samples from a patient treated with LY2181308. Survivin depletion appears to be a result of treatment with this ASO, because a tumor treated with conventional cytotoxic chemotherapy did not exhibit a decreased percentage of survivin positive cells. Our approach is likely to be broadly applicable to, and useful for, the quantification of protein levels in tumor samples obtained as part of clinical trials and studies, facilitating the proof-of-principle testing of novel targeted therapies.

Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer.

PURPOSE: This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily. RESULTS: One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib. CONCLUSION: Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.

What oncologists believe they said and what patients believe they heard: an analysis of phase I trial discussions.

UNLABELLED: PURPOSE; Evaluation of the communication and informed consent process in phase I clinical trial interviews to provide authentic, practice-based content for inclusion in a communication skills training intervention for health care professionals. PATIENTS AND METHODS: Seventeen oncologists and 52 patients from five United Kingdom cancer centers consented to recording of phase I trial discussions. Following each consultation, clinicians completed questionnaires indicating areas they felt they had discussed, and researchers conducted semistructured interviews with patients examining their recall and understanding. Patients and oncologists also completed the Life Orientation Test-Revised questionnaire, measuring predisposition toward optimism. Independent researchers coded the consultations identifying discussion of key information areas and how well this was done. Observed levels of agreement were analyzed for each consultation between oncologist-coder, oncologist-patient, and patient-coder pairs. RESULTS: In several key areas, information was either missing or had been explained but was interpreted incorrectly by patients. Discussion of prognosis was a frequent omission, with patients and coders significantly more likely to agree that oncologists had not discussed it (odds, 4.8; P < .001). In contrast, coders and oncologists were more likely to agree that alternate care plans to phase I trial entry had been explained (odds, 2.5; P = .023). CONCLUSION: These data indicate that fundamental components of communication and information sharing about phase I trial participation are often missing from interviews. Important omissions included discussion of prognosis and ensuring patient understanding about supportive care. These findings will inform educational initiatives to assist communication about phase I trials.