“The genetic mutations underlying treatment resistance in non-small cell lung cancer (NSCLC) are more complex and dynamic than previously thought. Analysis of 355 biopsied tumors from patients who acquired resistance to EGFR inhibitors, the most common form of targeted therapy for NSCLC, found that mutations frequently varied between biopsies and that nearly one in five patients harbored more than one type of genetic resistance to treatment. Findings will be presented today at the 2017 Multidisciplinary Thoracic Cancers Symposium.”
“Clovis has stopped clinical development of rociletinib, its once promising EGFR inhibitor for the treatment of patients with EGFR T790M–mutated non–small cell lung cancer (NSCLC).
“In a statement, the company reported that it had been notified by the FDA that it would receive a complete response letter on or before the scheduled PDUFA date of June 28, 2016. Receiving such correspondence means that the FDA is not approving a new drug application based on the available data.
“Clovis has terminated enrollment in all ongoing rociletinib studies, including the phase III TIGER-3 trial, and has withdrawn its application for regulatory approval in the European Union. Rociletinib will continue to be provided to patients whose clinicians recommend continuing therapy, according to Clovis.”
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“Afatinib (Giotrif, EU; Gilotrif, US) has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) as a treatment for patients with advanced squamous cell non–small cell lung cancer (NSCLC) following progression on platinum-based chemotherapy, according to Boehringer Ingelheim, the manufacturer of the irreversible EGFR inhibitor.
“The CHMP opinion, which recommends that the treatment should gain approval from the European Medicines Agency in this setting, is based on data from the phase III LUX-Lung 8 trial. In the study, second-line afatinib reduced the risk of both disease progression and death by 19%, compared with erlotinib (Tarceva) in patients with advanced squamous cell carcinoma of the lung.”
“Clovis Oncology, Inc. (NASDAQ: CLVS) announced today that the U.S. Food and Drug Administration (FDA) has scheduled the New Drug Application (NDA) for rociletinib for discussion by the Oncologic Drugs Advisory Committee (ODAC) on April 12, 2016. Rociletinib is an investigational therapy for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) who have been previously treated with an EGFR-targeted therapy and have the EGFR T790M mutation.
“The ODAC reviews and evaluates data concerning the safety and effectiveness of marketed and investigational human drug products for use in the treatment of cancer and makes recommendations to the FDA.
“ ‘We are actively preparing for this advisory committee meeting and look forward to the discussion about rociletinib,’ said Patrick J. Mahaffy, President and CEO of Clovis Oncology. ‘New treatments are needed for this hard-to-treat patient population, and we believe that rociletinib represents an important new option for patients with mutant EGFR T790M-positive lung cancer.’ “
“Adding the EGFR inhibitor cetuximab (Erbitux) to chemotherapy failed to improve survival in patients with advanced non-small cell lung cancer, a multicenter randomized trial showed.
“The primary analysis showed a median overall survival of 10.9 months compared with 9.4 months, a difference that did not achieve statistical significance (HR 0.94, 95% CI 0.84-1.06). The trial also failed to demonstrate improvement in progression-free survival for patients with EGFR-positive disease, the co-primary endpoint.
“However, cetuximab led to a 25% reduction in hazard ratio among patients who had EGFR-positive tumors by fluorescence in situ hybridization (FISH) and were not candidates for bevacizumab (Avastin), a prespecified secondary endpoint. An exploratory analysis analysis showed that patients with EGFR-positive, squamous-cell tumors lived almost twice as long with cetuximab as with chemotherapy alone (11.8 vs 6.4 months, P=0.006), as reported here at the World Conference on Lung Cancer.”
“In a meta-analysis reported in the Journal of Clinical Oncology, Lee et al found that increased progression-free survival benefit of EGFR tyrosine kinase inhibitor treatment vs chemotherapy was exhibited in patients with exon 19 deletion, never-smokers, and women.
“The meta-analysis included seven trials (N = 1,649) comparing EGFR tyrosine kinase inhibitors with chemotherapy in patients with newly diagnosed advanced EGFR-mutant disease. Overall, tyrosine kinase inhibitor therapy was associated with significantly prolonged progression-free survival (hazard ratio [HR] = 0.37, 95% confidence interval [CI] = 0.32–0.42)…
“The investigators concluded: ‘Although EGFR [tyrosine kinase inhibitors] significantly prolonged [progression-free survival] overall and in all subgroups, compared with chemotherapy, greater benefits were observed in those with exon 19 deletions, never-smokers, and women. These findings should enhance drug development and economic analyses, as well as the design and interpretation of clinical trials.’ “
“A clinical trial of the EGFR inhibitor AZD9291 in patients with advanced non–small cell lung cancer (NSCLC) who had disease progression after previous treatment with EGFR tyrosine kinase inhibitors has found that the drug was highly active—achieving a 95% disease control rate—in patients with the EGFR T790M mutation. The median progression-free survival was 9.6 months in the EGFR T790M–positive patients, and 2.8 months in EGFR–negative patients. Why the drug is less effective in patients whose cancers lacked the T790M mutation is unclear. The study by Jänne et al is published in The New England Journal of Medicine.
“A total of 253 patients were enrolled in the study. The researchers administered AZD9291 at doses of 20 mg to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors.
“The study included dose-escalation cohorts and dose-expansion cohorts; prestudy tumor biopsies were required for central determination of EGFR T790M status in the expansion cohorts. Patients were assessed for safety, pharmacokinetics, and efficacy.”
“Two new drugs for a specific lung cancer scenario are approaching the market –― AZD9291 (AstraZeneca Pharmaceuticals LP) and rociletinib (Clovis Oncology), and both companies are preparing to file for approval.
“Both drugs are third-generation EGFR inhibitors destined for use in patients who have non–small cell lung cancer (NSCLC) that is EGFR-mutation-positive and has responded to treatment with first-line EGFR inhibitors, but is now progressing.
“In about 60% of these cases, the disease is progressing because the tumor has developed a new mutation, known as EGFR T790M. This mutation confers resistance to treatment with first- generation EGFR inhibitors, such as erlotinib (Tarceva, Osi Pharmaceuticals, Inc) and gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) or the second-generation EGFR inhibitor afatinib (Gilotrif, Boehringer Ingelheim Pharmaceuticals, Inc).”
“Almost one in four patients (24%) with advanced lung cancer in Europe, Asia and the US are not receiving EGFR test results before being started on treatment, researchers report at the European Lung Cancer Conference.
“Medical Oncologist James Spicer from King’s College London at Guy’s Hospital, London, and colleagues studied how widely hospitals had implemented testing for mutations in the epidermal growth factor receptor gene among lung cancer patients.
“Targeted therapies can more effectively treat cancers that are known to carry such mutations, Dr Spicer said. However anecdotal evidence had suggested the tests required to clarify a patient’s status were not always been conducted, Dr Spicer said.
” ‘The arrival of a new group of targeted EGFR inhibitors for the treatment of lung cancer driven by mutations in the EGFR gene has brought with it a new requirement for diagnostic laboratories to implement genetic testing,’ he explained. ‘For many institutions this has represented a significant departure from traditional pathology, which had previously focused only on microscopic examinations of tumour tissue.’ “