An independent data monitoring committee recommended that the phase III METLung study be stopped due to a lack of clinically meaningful efficacy, following an interim analysis.
The study evaluated MetMab (onartuzumab) in combination with Tarceva (erlotinib) in previously treated, advanced non-small cell lung cancer with tumors were identified as MET-positive, compared to Tarceva alone. Overall adverse event rates were generally similar between the two groups. Data will be submitted for presentation at an upcoming medical meeting.
Genentech, onartuzumab’s sponsor, is evaluating the implications of the METLung study results across the ongoing clinical program.
METLung was a double-blind study that randomized 499 patients to receive 150 mg of Tarceva taken daily plus either intravenous 15 mg/kg of onartuzumab every three weeks or intravenous placebo every three weeks. The study also included a companion diagnostic immunohistochemistry test, which was co-developed with Ventana Medical Systems Inc., a member of the Roche Group.
The primary endpoint of the study was overall survival. Secondary endpoints included progression-free survival, objective response rate and safety profile.
Onartuzumab, a monovalent, monoclonal antibody designed to specifically target the MET receptor, is being studied in various cancers. MET is a protein found on the surface of cells and acts as a receptor that binds to Hepatocyte Growth Factor, also known as “Scatter Factor.” When HGF binds to MET, it causes MET proteins to form pairs, which triggers a signaling cascade that tells cells to grow, divide and spread to other parts of the body.
Phase IIb Trial of Vintafolide- Docetaxel Combination Meets Primary Endpoint of Progression-Free Survival
A phase IIb trial of a combination of vintafolide and docetaxel in folate receptor positive recurrent non-small cell lung cancer met its primary endpoint of improved progression-free survival.
The study data showed that risk of disease worsening or death was reduced by 25 percent for patients treated with the vintafolide/docetaxel combination versus docetaxel alone (HR 0.75; p=0.0696, one-sided test). Detailed trial results, including data regarding overall survival, will be presented at an upcoming medical conference.
The trial, named TARGET, was conducted in 199 patients, randomized to one of three arms: vintafolide (EC145/MK-8109) alone, vintafolide/docetaxel combination, or docetaxel alone. Secondary endpoints, including overall response rate and OS, also showed trends in favor of the combination arm. Median OS has been reached for the vintafolide and docetaxel single-agent arms but has not yet been reached in the combination arm. In addition, the investigational combination regimen showed better activity in patients with adenocarcinoma, a subset analysis pre-specified in the trial design.
TARGET is an international, open-label study designed to evaluate vintafolide in patients with stage IIIb or IV NSCLC with all lesions positive for the folate receptor as determined by the investigational companion imaging agent etarfolatide and who have failed one prior chemotherapy.
Secondary endpoints included the comparison of overall response rate, disease control rate, duration of response, duration of disease control, overall survival of the participants between treatment arms, and the incidence of adverse and serious adverse events.
The safety profile of the combination arm was consistent with those observed with docetaxel alone and vintafolide alone, though a higher rate of hematologic and peripheral neuropathy adverse events were observed in the combination arm. There were no drug-related deaths in the combination arm. Single-agent vintafolide at the schedule evaluated in this study demonstrated less activity than single-agent docetaxel.
Vintafolide is an investigational conjugate of folic acid (vitamin B9) linked to an anti-cancer agent, the potent vinca alkaloid desacetylvinblastine hydrazide (DAVLBH). Since cancer cells generally consume higher levels of folate than normal cells to fuel their growth, some cancer cell types–including ovarian and NSCLC–have high concentrations of the folate receptor on their surface.
Vintafolide is designed to selectively target the folate receptor to deliver the anti-cancer agent to the cancerous tissue. Tumors that have high concentrations of the folate receptor are identified by etarfolatide, a non-invasive imaging diagnostic agent. Intravenous folic acid is used with 99mTc-etarfolatideetarfolatide for the enhancement of image quality.
Vintafolide, etarfolatide and IV folic acid have been granted orphan drug status by the EMA. FDA has also granted orphan drug status to vintafolide and etarfolatide. Further evaluation is ongoing in the global PROCEED phase III clinical trial in folate receptor-positive platinum-resistant ovarian cancer. Vintafolide is sponsored by Endocyte Inc.
Ceritinib Demonstrates 58% ORR, 7-month PFS in ALK+ NSCLC
Investigational compound LDK378 (ceritinib) achieved an overall response rate of 58 percent and a median progression-free survival of 7 months in adults with advanced anaplastic lymphoma kinase positive non-small cell lung cancer who received 400 mg or higher of LDK378 per day in a phase I single-arm study.
The study evaluated 114 ALK+ NSCLC patients treated with LDK378, including patients who had progressed during or following treatment with commonly prescribed ALK inhibitor crizotinib, and those who had not received prior treatment with an ALK inhibitor.
The study results, published in the New England Journal of Medicine, demonstrated a median PFS of 7.0 months (95% CI; 5.6-9.5 months) in patients with ALK+ NSCLC treated with LDK378 at doses of 400 mg to the maximum tolerated dose of 750 mg per day.
The study also reported an ORR of 59 percent (95% CI; 47-70%) in patients taking LDK378 at 750 mg per day. The responses observed demonstrated LDK378 is active in patients with advanced ALK+ NSCLC, including those who were previously treated with crizotinib, with or without new mutations in the ALK gene.
The most frequent adverse events were nausea, diarrhea, vomiting, fatigue and increased alanine aminotransferase levels. Preliminary data from this publication were first presented at the 2013 American Society of Clinical Oncology annual meeting. The study is ongoing with more data to become available, according to Novartis, the drug’s sponsor. The data served as the basis for regulatory application to FDA, with action expected this year.
FDA designated LDK378 a Breakthrough Therapy, which is intended to expedite the development and review of drugs that treat serious or life-threatening conditions.
Several major studies evaluating treatment with LDK378 are being conducted in more than 300 study centers across more than 30 countries. Currently, two phase II trials are fully enrolled and ongoing. In addition, two phase III trials are actively recruiting patients to further evaluate LDK378 in patients with ALK+ NSCLC.
