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Drug-resistant lung tumors respond to new precision therapy in early-stage trial

  • Pasi A. Jänne, MD, PhD

    In a phase I clinical trial, about half of non-small cell lung cancer (NSCLC) patients whose tumors no longer responded to conventional targeted drugs had their tumors shrink after receiving a new, more precisely targeted agent. Dana-Farber Cancer Institute researchers will report these findings at the annual meeting of the American Society of Clinical Oncology (ASCO) on Saturday, May 31, 2014

    The drug, known as AZD9291, not only showed encouraging signs of effectiveness but also produced markedly fewer side effects than did earlier targeted therapies for this type of lung cancer, the researchers found.

    “The vast majority of patients with this type of NSCLC, which is characterized by an abnormality in the epidermal growth factor receptor (EGFR) protein, benefit from agents such as erlotinib,” said the study’s lead author, Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber. “Unfortunately, the tumors often become resistant to these drugs in 10 to 14 months and begin to grow again. AZD9291 is one of several agents being developed for such drug-resistant tumors.”

    The study involved 199 patients whose NSCLC cells carried an abnormality in EGFR. All the patients had originally benefited from EGFR-targeting drugs such as erlotinib (Tarceva®) but no longer responded to them. The trial — a dose-escalation study in which successive groups of patients received incrementally higher doses of AZD9291 — was designed to assess the safety, optimal dosage, and effectiveness of the drug.

    Overall, 51 percent of patients in the study had some degree of tumor shrinkage after taking AZD9291. Such shrinkage occurred at each of the five different levels of dosage tested, even in patients whose cancer had spread to the brain.

    AZD9291 targets an EGFR abnormality known as a T790M mutation, which often arises as a resistance mechanism after treatment with erlotinib. Unlike erlotinib and similar drugs, AZD9291 targets only the altered version of EGFR in tumor cells, not the normal version in the skin and other organs. The result, developers hypothesized, would be a decrease in side effects associated with the treatment.

    Investigators determined that 67 percent of the patients in the clinical trial had the T790M mutation in their tumor cells. In 64 percent of these patients, treatment with AZD9291 caused tumors to shrink or stop growing, a result that occurred in only 23 percent of patients who lacked the mutation. Even the highest dose levels tested did not produce severe side effects in most patients.

    About 10 to 15 percent of Caucasian patients with NSCLC, and 40 percent of Asian patients with the disease, have mutations involving EGFR. In the United States, that equals 18,000 patients a year.

    “The effectiveness of targeted therapies for this form of lung cancer was first demonstrated 10 years ago,” remarked Jänne, who is also the scientific director of the Belfer Institute for Applied Cancer Science at Dana-Farber. “This study points to promise of a new generation of targeted therapies that can be used when the initial drugs lose their effectiveness.”

    The study was funded by Astra Zeneca.

Posted on May 29, 2014

  • Pasi A. Jänne, MD, PhD
  • Research
  • Non-small Cell Lung Cancer
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