FGFR Inhibitor Dovitinib Shows Modest Efficacy in Squamous NSCLC


“The FGFR inhibitor dovitinib showed modest efficacy in a phase II trial of patients with pretreated, advanced squamous cell carcinoma (SCC) of the lung with FGFR1 amplification. Further work on the drug, in particular to find biomarkers of efficacy, was deemed warranted.

“ ‘The majority of new cytotoxic chemotherapies for the treatment of non–small-cell lung cancer (NSCLC) such as pemetrexed or targeted agents such as gefitinib or erlotinib are not indicated for the SCC subtype because of a lack of efficacy or because activity is limited to tumors with specific genetic alterations that are rarely found in patients with squamous cell NSCLC,’ wrote study authors led by Myung-Ju Ahn, MD, PhD, of Samsung Medical Center in Seoul, South Korea. SCC accounts for about 30% of all NSCLC cases.”

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Clovis Oncology Announces First Patient Enrolled in Lucitanib Phase 2 Study in Squamous Non-small Cell Lung Cancer

The gist: The first patient has now enrolled in a new clinical trial to test a new lung cancer drug. The drug is called lucitanib. It is meant to treat patients with advanced squamous non-small cell lung cancer (NSCLC) whose tumors have tested positive for a genetic mutation called FGFR1-amplification. The drug has already shown promise for people with breast cancer who have similar tumor mutations. Patients who wish to enroll in the clinical trial must have had at least one prior treatment that failed to keep their tumor(s) from growing.

“Clovis Oncology, Inc. (NASDAQ: CLVS) announced today that its global Phase 2 study of lucitanib in patients with FGFR1-amplified squamous non-small cell lung cancer (NSCLC) has commenced and the first patient has been dosed at a U.S. study site. Lucitanib is the Company’s oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 through 3 (FGFR1-3), vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFR α-ß).

“ ‘The lucitanib data presented to date in patients with FGF-aberrant breast cancer are very encouraging, and we know that FGFR1 amplification occurs in approximately 15 percent of patients with squamous non-small cell lung cancer,’ said Dr. Benjamin Besse, Head of Thoracic Oncology, Institut Gustave Roussy, and the lead investigator of the study in squamous NSCLC. ‘Accordingly, we are very enthusiastic to explore lucitanib in this selected population of patients with lung cancer, for whom there is significant need for novel therapies.’

“ ‘Less than a year after acquiring lucitanib, we are commencing a broad clinical development program, which includes this study in FGFR1-amplified squamous NSCLC, as well as our ongoing study currently underway in FGF-aberrant breast cancer,’ said Patrick J. Mahaffy, President and CEO of Clovis Oncology. ‘We are enthusiastic about the opportunity to explore lucitanib in these indications, and potentially in other solid tumors exhibiting FGFR pathway activation.’

“The Phase 2 study will enroll FGFR1-amplified squamous NSCLC patients with advanced disease who have progressed on at least one prior line of therapy. The global study will assess objective response rate, progression-free survival, and duration of response, as well as the safety, tolerability, and pharmacokinetics of lucitanib.”

Clovis Oncology Announces First Patient Enrolled in Lucitanib Phase 2 Study in FGF-aberrant Advanced Breast Cancer

The gist: The first patient has been enrolled in a new clinical trial—a research study with volunteer patients. The trial is testing whether a drug called lucitanib can be used to treat people with advanced breast cancer. Specifically, the drug will be tested in patients whose tumors have certain mutations in “FGF pathway” genes. By testing different amounts of the drug in different patients, the researchers hope to be able to determine the best dosage of lucitanib for patients.

“Clovis Oncology (CLVS) today announced that its Phase 2 study of lucitanib in patients with FGF-aberrant, advanced breast cancer has commenced and the first patient dosed at a U.S. study site. Lucitanib is the Company’s oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 and 2 (FGFR1-2), vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFR α-ß).

“ ‘Early lucitanib data are encouraging, and suggest that determination of genetic alterations in the FGF pathway may be important to identify the patients most likely to benefit from lucitanib treatment,’ said Professor Carlos L. Arteaga, MD, Associate Director for Clinical Research, Director of the Center for Cancer Targeted Therapies, and Director of the Breast Cancer Program at the Vanderbilt-Ingram Cancer Center of Vanderbilt University. ‘This study will further explore two doses of lucitanib in patients with FGF-aberrant breast cancer, a population which possesses these genetic alterations, and for whom new treatment options are needed.’ ”

Online Screening for Rare Lung Cancer Subtypes Opens Door to New Kind of Clinical Trial

Editor’s note: This article discusses a new clinical trial—a research study that is enrolling volunteer patients. The goal of the trial is to enroll lung cancer patients whose tumors have mutations in the FGFR1 gene, and to see how well the FGFR1-targeted drug ponatinib works for them. The FGFR1 mutation is rare, so the researchers behind the trial are spreading the word to patients through the internet, with the help of participating organizations.

“In the previous few years, several breakthrough treatments have become available for key subtypes of lung cancer. Patients who may benefit from these treatments can be pre-identified by looking for defined genetic abnormalities in their cancer. For example, patients whose lung cancer is driven by rearrangement of the gene ALK derive significant benefit from the drug crizotinib, which targets this abnormality. Many ongoing clinical trials are now attempting to replicate this success by matching different drugs with specific subtypes of the disease based on the presence of such “predictive biomarkers.” However, testing these new drugs in clinical trials requires finding and enrolling patients with what may be very rare molecular subtypes of a disease – one of the challenges is discovering enough needles in enough haystacks to prove the effectiveness of each biomarker-drug pairing.

“The University of Colorado Cancer Center is now taking a novel approach to this problem, reaching out via the internet to expand the pool of patients potentially eligible for just such a biomarker-preselected clinical trial. After completing the interactive online screening questions, eligible patients with advanced lung cancer will be consented via the phone to permit a pre-existing biopsy sample of their lung cancer tissue to be shipped to the CU Cancer Center for trial-specific molecular testing. The testing is designed to identify patients who may have lung cancers driven by alterations in the gene FGFR1. Patients whose tumors turn out to be FGFR1-positive and meet the other trial screening criteria will then be offered treatment for their cancer within a clinical trial at CU Cancer Center using the experimental FGFR1 inhibitor drug ponatinib. Ponatinib is already licensed for treating certain blood cancers, but work by CU scientists in laboratory models suggest it may also be a potent agent in some specific molecular subtypes of lung cancer driven by, among other things, changes in the FGFR1 gene.”

A Molecular Signature Predictive of Indolent Prostate Cancer

“Many newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished as indolent and aggressive subgroups on the basis of their expression of genes associated with aging and senescence. Using gene set enrichment analysis, we identified a 19-gene signature enriched in indolent prostate tumors. We then further classified this signature with a decision tree learning model to identify three genes—FGFR1PMP22, and CDKN1A—that together accurately predicted outcome of low Gleason score tumors. Validation of this three-gene panel on independent cohorts confirmed its independent prognostic value as well as its ability to improve prognosis with currently used clinical nomograms. Furthermore, protein expression of this three-gene panel in biopsy samples distinguished Gleason 6 patients who failed surveillance over a 10-year period. We propose that this signature may be incorporated into prognostic assays for monitoring patients on active surveillance to facilitate appropriate courses of treatment.”

FGFR1 is Essential for Prostate Cancer Progression and Metastasis

The fibroblast growth factor receptor FGFR1 is ectopically expressed in prostate carcinoma cells, but its functional contributions are undefined. In this study, we report the evalulation of a tissue-specific conditional deletion mutant generated in an ARR2PBi(Pbsn)-Cre/TRAMP/fgfr1loxP/loxP transgenic mouse model of prostate cancer…”

Avastin-Containing Chemotherapy May Be Safe in Lung Cancer Patients with Brain Metastases

Bevacizumab (Avastin), which is approved for treatment of a number of advanced-stage cancer types, is commonly avoided in patients with brain metastases (cancer that has spread to the brain) because of fear of brain hemorrhages (bleeding in the brain). A retrospective study of 52 patients with advanced non-small cell lung cancer (NSCLC) who had received chemotherapy containing Avastin found no cases of serious bleeding events and no significant differences in survival or treatment side effects between patients with or without brain metastases. Avastin may therefore be a safe treatment option in NSCLC with brain metastases.

Research paper: https://www.jstage.jst.go.jp/article/acrt/20/2/20_47/_pdf

Overexpression of IGF1R and EGFR Genes May Worsen Lung Cancer Prognosis

The roles of the genes IGF1R and EGFR in lung cancer were examined in patients with non-small cell lung cancer (NSCLC) who had their primary tumor surgically removed. Patients whose tumors had increased expression of both IGFR1R and EGFR were more likely to experience recurrence of the cancer after a shorter amount of time and had shorter survival times after surgery. This finding suggests that concurrent overexpression of IGF1R and EGFR is a negative prognosis factor in NSCLC and may indicate patients who are more likely to benefit from novel treatments with IGF1R inhibitors.

Research paper: http://link.springer.com/article/10.1007/s00280-012-2056-y/fulltext.html

Study Suggests Iressa Effective for Elderly Patients with EGFR-Mutant Lung Cancer

A retrospective study in Japan examined 55 patients aged 75 years or over with inoperable non-small cell lung cancer (NSCLC) who had a mutation in the EGFR gene and received gefitinib (Iressa) as first-line therapy. The treatment was generally well tolerated and patients experienced longer periods without cancer progression (median: 13.8 months) and longer overall survival (median: 29.1 months) than commonly reported for similar patients. While studies using control groups will need to confirm that Iressa is indeed more effective than standard chemotherapy or a placebo, these findings suggest that Iressa may be a preferable first-line treatment in elderly patients with advanced EGFR-mutant NSCLC.

Research paper: http://link.springer.com/article/10.1007/s12032-012-0450-2/fulltext.html