A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib.

Background: This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health-related quality of life of dacomitinib (PF-00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild-type non-small cell lung cancer (NSCLC).

Methods: Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild-type or known EGFR-sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21-day cycles.

Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib.

Purpose: To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) patients.

Methods And Materials: Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤ 4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered.

A phase Ib dose-escalation study of everolimus combined with cisplatin and etoposide as first-line therapy in patients with extensive-stage small-cell lung cancer.

Background: This phase Ib study aimed to establish the feasible everolimus dose given with standard-dose etoposide plus cisplatin (EP) for extensive-stage small-cell lung cancer (SCLC).

Patients And Methods: An adaptive Bayesian dose-escalation model and investigator opinion were used to identify feasible daily or weekly everolimus doses given with EP in adults with treatment-naive extensive-stage SCLC. A protocol amendment mandated prophylactic granulocyte colony-stimulating factor (G-CSF).

Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer.

The targeting of oncogenic 'driver' kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy.

Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib.

Background: To the best of the authors' knowledge, the renal side effects of crizotinib have not been investigated previously.

Methods: The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based prediction equation during the first 12 weeks of crizotinib therapy and after crizotinib but before the introduction of any further systemic therapy.

Results: A total of 38 patients with stage IV anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer who were treated with crizotinib were identified.

Native and rearranged ALK copy number and rearranged cell count in non-small cell lung cancer: implications for ALK inhibitor therapy.

Background: Patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) respond to ALK inhibitors. Clinically, the presence of ≥15% cells with rearrangements identified on break-apart fluorescence in situ hybridization (FISH) classifies tumors as positive. Increases in native and rearranged ALK copy number also occur.

Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group.

Neurocognitive function, neurological symptoms, functional independence, and health-related quality of life are major concerns for patients with brain metastases. The inclusion of these endpoints in trials of brain metastases and the methods by which these measures are assessed vary substantially. If functional independence or health-related quality of life are planned as key study outcomes, then the reliability and validity of these endpoints can be crucial because methodological issues might affect the interpretation and acceptance of findings.

Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group.

Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed.

Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies--results of a phase I dose-escalation study.

Objectives: The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies.

Methods: In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.

Clinical benefit from pemetrexed before and after crizotinib exposure and from crizotinib before and after pemetrexed exposure in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer.

Background: Crizotinib produces high response rates and prolonged PFS in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib naive ALK+ NSCLC. Cross-resistance between crizotinib and pemetrexed has not been previously investigated.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.

Background: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown.

Methods: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen.

Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients.

Background: Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported.

Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer.

Unlabelled: EML4-ALK gene rearrangements define a unique subset of patients with non-small cell lung carcinoma (NSCLC), and the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy. Here, we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, leading to greater in vitro potency, superior antitumor efficacy, and prolonged animal survival compared with results obtained with crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo.

Characteristics of lung cancers harboring NRAS mutations.

Purpose: We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells.

Experimental Design: We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations.

First-in-human phase I trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies.

Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors.

Experimental Design: OSI-930 was administered once or twice a day using a modified accelerated titration design.

Diagnostic assays for identification of anaplastic lymphoma kinase-positive non-small cell lung cancer.

In series dominated by adenocarcinoma histology, approximately 5% of non-small cell lung cancers (NSCLCs) harbor an anaplastic lymphoma kinase (ALK) gene rearrangement. Crizotinib, a tyrosine kinase inhibitor with significant activity against ALK, has demonstrated high response rates and prolonged progression-free survival in ALK-positive patients enrolled in phase 1/2 clinical trials. In 2011, crizotinib received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of proven ALK-positive NSCLC using an FDA-approved diagnostic test.

Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.

Introduction: Many patients with oncogene-driven non-small-cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to central nervous system (CNS) and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively.

Methods: Patients with metastatic ALK+ NSCLC treated with crizotinib (n = 38) and EGFR-MT NSCLC treated with erlotinib (n = 27) were identified at a single institution.

Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma.

Purpose: To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies.

Methods: Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m(2) IV) and cisplatin (75 mg/m(2) IV) q3w up to 6 cycles.