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Phase 2 Trial Shows XL647 Has Antitumour Activity in All Lung Cancer Patients With EGFR Mutations: Presented at AACR-NCI-EORTC

By Crina Frincu-Mallos, PhD

SAN FRANCISCO, CA -- November 2, 2007 -- A novel chemotherapeutic, part of the tyrosine kinase inhibitors class, XL647, is clinically active in non-small cell lung cancer (NSCLC) patients presenting epidermal growth factor receptor (EGFR) mutations in tumour tissue, researchers reported here at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

EGFR is one of the current targets in cancer research and development, being involved in tumour growth and metastasis. In patients with NSCLC, sensitivity to EGFR inhibitors has been associated with the presence of EGFR-activating mutations.

Naiyer A. Rizvi, MD, Medical Oncologist, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer, New York, New York, United States, presented the results here on October 24.

Dr. Rizvi and colleagues from Memorial Sloan-Kettering Cancer, Case Western Reserve University, Carle Cancer Center, Exelixis, Inc, and Karmanos Cancer Institute sought to elucidate the activity of XL647 in previously untreated patients with advanced NSCLC.

Patients were selected based on demographic markers predicting sensitivity to EGFR inhibitors, such as Asian and/or female, minimal smoking history, or EGFR mutations in the tumour, said Dr. Rizvi in his poster presentation.

The mutational status in tumour DNA was assessed either by direct sequencing or by sequencing of cloned amplification products.

This ongoing, nonrandomised, open-label study uses a Simon stage-2 design, and is designed to accrue a total of 42 patients.

This interim analysis includes data available as of September 28, 2007, according to the researchers. To date, 11 men and 26 women were enrolled in the study, median age 65 years (range, 44-86 years).

Seventeen of the patients never smoked, and 12 had a minimal smoking history, Dr. Rizvi said.

The investigational drug -- XL647 -- is administered orally, at a 350 mg dose, during days 1 to 5 of a 14-days cycle. Patients are allowed to receive treatment with XL647 for up to 1 year if their disease does not progress on the drug and that the drug-related toxicities are minimal.

Currently, 16 patients are still on treatment out of the 37 initial patients, said Dr. Rizvi and colleagues. A relatively high number of patients (n=21) had to withdraw due to progressive disease (n=19), drug-related duodenal ulcer/GI hemorrhage (n=1) and elevated QTc value (n=1).

The best response observed was partial response (PR). Over the whole evaluation period, there were a total of 10 PRs. Seven patients still have PRs, with duration between 2 and 11 months.

Out of 34 evaluable patients, seven have EGFR-activating mutations. Interestingly, five patients with exon 19 deletions and one patient with L858 point mutation had PRs.

However, out of the patients with 10 PRs, three patients did not exhibit EGFR mutations, including the patient with the longest response (11+ months).

The researchers used positron emission tomography scans and computed tomography imaging to assess tumour response to treatment with XL647.

Toxicity data is available for 32 of 37 patients. A total of 16 serious adverse events were reported in 8. Five that occurred in four patients were considered possibly or probably related to the investigational drug: a grade 4 pulmonary embolism; a grade 3 hemorrhage and duodenal ulcer (both in one patient); a grade 3 pneumonia; and a grade 2 haemoptysis.

The most frequent grade 1 adverse events attributed to XL647 were diarrhoea (n=15), rash (n=10), fatigue (n=9), and nausea (n=8). There were also two cases of grade 2 diarrhoea (n=2) and fatigue (n=2).

Even though patients with and without EGFR mutation responded to the investigational drug therapy, all seven patients with EGFR-activating mutations had clinical benefit from XL647, concluded the researchers.

XL647 is in the developmental pipeline at Exelixis, Inc., South San Francisco, California. Funding for this study was provided by Exelixis.


[Presentation title: A Phase II Study of XL647 in Patients With Non-Small Cell Lung Cancer (NSCLC) Enriched for Presence of EGFR Mutations. Abstract B124]

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