A non-interventional biomarker study in patients with adenocarcinoma of the lung treated with nintedanib plus docetaxel following progression on chemotherapy and/or immunotherapy: LUME-BioNIS.

Background: Anti-angiogenic agents, such as nintedanib and ramucirumab, when combined with docetaxel, are subsequent treatment options in patients with non-small cell lung cancer (NSCLC) who have failed on first-line chemotherapy or immunochemotherapy. However, to date, there are no validated predictive biomarkers for efficacy of anti-angiogenic therapies in this setting. The aim of this study was to explore whether genetic or genomic markers, alone or combined with clinical covariates, could be used to predict overall survival (OS) in patients with NSCLC who are eligible for treatment with nintedanib plus docetaxel.

Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1).

Background: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations.

Methods: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B).

Safety and tolerability of weekly docetaxel plus nintedanib: A phase I trial after first-line chemotherapy failure in NSCLC.

Introduction: Studies have shown improved tolerability with once-weekly versus three-weekly docetaxel in the second-line treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the tolerability of nintedanib plus weekly docetaxel in patients with NSCLC.

Methods: This phase I, open-label, dose-escalation study (NCT02668393) enrolled patients with locally advanced/metastatic adenocarcinoma NSCLC that had progressed on first-line platinum chemotherapy.

Afatinib in paediatric patients with recurrent/refractory ErbB-dysregulated tumours: Results of a phase I/expansion trial.

Aim: This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer.

Methods: The dose-finding part enroled patients (2-<18 years) with recurrent/refractory tumours. Patients received 18 or 23 mg/m/d afatinib orally (tablet or solution) in 28-d cycles.

Phase II study of afatinib plus pembrolizumab in patients with squamous cell carcinoma of the lung following progression during or after first-line chemotherapy (LUX-Lung-IO).

Introduction: Afatinib and pembrolizumab have separately shown survival benefit in patients with squamous cell carcinoma (SqCC) of the lung, and there is biological rationale for concurrent inhibition of the programmed death ligand-1 and epidermal growth factor receptor (EGFR) pathways in this patient population.

Materials And Methods: This open-label, single-arm study enrolled patients with SqCC of the lung who had progressed during/after first-line chemotherapy and comprised two parts: a safety run-in to establish the recommended phase II dose (RP2D; afatinib 40 mg or 30 mg once daily with pembrolizumab 200 mg every 3 weeks); and the main part assessing efficacy and safety of the RP2D. The primary endpoint was objective response rate (ORR); secondary endpoints included the RP2D, progression-free survival (PFS) and overall survival (OS).

Experience from Asian centers in a named-patient-use program for afatinib in patients with advanced non-small-cell lung cancer who had progressed following prior therapies, including patients with uncommon EGFR mutations.

Background: This study evaluated outcomes among patients with advanced/metastatic non-small-cell lung cancer (NSCLC) treated at Asian centers participating in the global named-patient-use (NPU) program for afatinib.

Methods: Patients had progressed after initial benefit with erlotinib or gefitinib, and/or had an EGFR or HER2 mutation, had no other treatment options, and were ineligible for afatinib trials. The recommended starting dose of afatinib was 50 mg/day.

Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation-Positive Advanced NSCLC: Findings From a Global Named Patient Use Program.

Introduction: Approximately 1% to 4% of NSCLC tumors harbor erb-b2 receptor tyrosine kinase 2 (ERBB2) mutation; there is no approved targeted treatment for this subgroup.

Methods: Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments, and were ineligible for afatinib trials were enrolled in a named patient use program, receiving afatinib 30 to 50 mg/d on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with ERBB2 mutation-positive NSCLC.

Global named patient use program of afatinib in advanced non-small-cell lung carcinoma patients who progressed following prior therapies.

Aim: A global afatinib named patient use program in non-small-cell lung carcinoma (NSCLC) commenced in 2010.

Materials & Methods: Eligible NSCLC patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had activating EGFR/HER2 mutations, exhausted all other treatments, and were ineligible for afatinib trials.

Results: Data, as of January 2016, were reported on 3966 heavily pretreated NSCLC patients (41 countries; six continents).

Cardiac safety of afatinib: a review of data from clinical trials.

Background: Afatinib is an oral irreversible ErbB family blocker that targets epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and HER4 (ErbB4) and is approved for the first-line treatment of advanced non-small cell lung cancer (NSCLC) with certain sensitizing EGFR mutations. As anti-HER2 therapies have been associated with cardiac dysfunction, we report cardiac safety data for afatinib.

Methods: Cardiac data were analyzed from phase III trials of afatinib 40 mg in treatment-naive patients with EGFR mutation-positive NSCLC (LUX-Lung 3 [LL3]; n = 229 afatinib, n = 111 chemotherapy) and afatinib 50 mg in EGFR tyrosine kinase inhibitor-pretreated NSCLC patients (LUX-Lung 1 [LL1]; n = 390 afatinib, n = 195 placebo).

Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1).

Background: Patient-reported symptom and health-related quality of life (HRQoL) benefit of afatinib, a novel, irreversible, ErbB Family Blocker, was investigated in a double-blind, randomized, phase IIb/III trial (LUX-Lung 1).

Methods: Five hundred and eighty-five patients with lung adenocarcinoma (stage IIIb/IV), who had progressed after chemotherapy (1-2 lines) and at least 12 weeks of erlotinib or gefitinib, were randomized (2:1) to receive either afatinib plus best supportive care (BSC) or placebo plus BSC. Symptom and HRQoL benefit were measured using the lung cancer-specific European Organisation for Research and Treatment of Cancer (QLQ-C30/LC13) and EuroQol (EQ-5D) questionnaires.

Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.

Background: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors.

Methods: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib.

Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial.

Background: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations.

Methods: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors.

Phase 1 clinical experience using intravenous administration of PV701, an oncolytic Newcastle disease virus.

PV701 is a naturally-attenuated, non-recombinant, oncolytic strain of Newcastle disease virus that displays preclinical intravenous (IV) efficacy. PV701 is selective at killing human cancer cells versus normal human cells based on tumor specific defects in the interferon (IFN)-mediated antiviral response. This oncolytic virus displays a broad spectrum of antitumor activity in vitro and in vivo.

An optimized clinical regimen for the oncolytic virus PV701.

Purpose: Previous phase 1 trials of i.v.-administered PV701 have shown this virus to be well-tolerated with toxicity primarily associated with the first dose.

Naturally occurring viruses for the treatment of cancer.

The use of naturally occurring viruses in the treatment of cancer is not new, and reports describing the administration of viruses to cancer patients date back more than fifty years. The advent of molecular biology and the arrival of biologics to the cancer therapy arena have now set the stage for a fresh look at the potential of these agents. These viruses have the potential to specifically target tumor cells, and insights into the molecular mechanisms of this selectivity are beginning to emerge.

Naturally oncolytic viruses.

Naturally oncolytic viruses are replication-competent viruses that have an innate ability to selectively infect and kill tumor cells. Despite being used in the original attempts to treat cancer with live viruses five decades ago, interest in naturally oncolytic viruses has lagged behind the support for engineered adenoviruses and herpesviruses as cancer therapeutics. Recently, however, there has been renewed interest in the high potency and selectivity of these naturally occurring agents.

A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization.

Purpose: In a previous phase 1 study, adverse events, especially flu-like symptoms, were observed mainly following the first i.v. bolus dose of PV701, an oncolytic Newcastle disease virus.

Overview of phase I studies of intravenous administration of PV701, an oncolytic virus.

PV701 is an attenuated, non-recombinant, oncolytic strain of Newcastle disease virus that displays preclinical intravenous (i.v.) efficacy.

Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers.

Purpose: PV701, a replication-competent strain of Newcastle disease virus, causes regression of tumor xenografts after intravenous administration. This phase I study was designed to define the maximum-tolerated dose (MTD) and safety of single and multiple intravenous doses of PV701 as a single agent in patients with cancer.

Patients And Methods: Seventy-nine patients with advanced solid cancers that were unresponsive to standard therapy were enrolled.