Vaccine & New TKI in Early-Stage Lung Cancer Trials

OAK BROOK, Illinois—While pharmaceutical companies are actively engaged in the development of new drug treatments for cancer, the number of drugs eventually approved by the US Food and Drug Administration for oncology has declined. One of the principal reasons is that investigators often end up studying late-stage disease in patients who have a large tumor burden and have undergone several rounds of treatment.

Drug treatments in this population can be expected to produce minimal effects, Lone H. Ottesen, PhD, research and development director, GlaxoSmithKline, United Kingdom, said at the Lung Cancer Workshop IV: Application of High Resolution CT Imaging Data to Lung Cancer Drug Development.

Pharmaceutical companies such as GlaxoSmithKline consequently are focusing new drug development efforts on early-stage disease. Dr. Ottesen reported on two of the pharmaceutical approaches GlaxoSmithKline is investigating for early-stage lung cancer, one involving the MAGE-A3 antigen as a lung cancer vaccine and one involving the angiogenesis inhibitor pazopanib.

The MAGE-A3 antigen is tumor specific; it is not expressed on normal cells, and it is expressed by various tumor types, including lung and bladder malignancies. MAGE-A3 also is associated with a poor prognosis for lung cancer. The protein is more commonly expressed as disease progresses. GlaxoSmithKline has conducted a phase II study of MAGE-A3 as adjuvant therapy for lung cancer. In the study, 82 patients were randomized in a 2:1 fashion to receive MAGE-A3 vaccine as induction and maintenance for 27 months or placebo. A total of 29 serious adverse events were reported, but only 3 were related to treatment.

The hazard ratio for disease-free interval was 0.73, which did not reach statistical significance (

P

= .107). However, this study was the first to show an improvement in the time to recurrence of lung cancer with a vaccine, Dr. Ottesen reported. As a result of this finding, a phase III study will be conducted in patients with early-stage, resectable lung cancer. The study will include 2,270 patients who are MAGE-A3 positive, and the primary endpoint will be disease-free survival.

Pazopanib

Pazopanib is a multi-targeted tyrosine kinase inhibitor (TKI). In a "first-time in man" study that used contrast-enhanced MRI to measure tumor perfusion, pazopanib produced changes in lesion activity. After 8 days of treatment, the ratio of activity in an active lesion in the liver decreased from 1.6 to 0.3, compared to adjacent tissue. In collaboration with the International Early Lung Cancer Action Program (I-ELCAP) group, GlaxoSmithKline is planning a phase II study of pazopanib in presurgical patients with stage I or II resectable lung cancer.

After a biopsy-confirmed diagnosis, RNA, DNA, and immunohistochemistry analysis, and PET/CT perfusion studies at baseline, patients will be given pazopanib for at least 2 weeks and for as long as 6 weeks. Patients will undergo additional imaging after treatment plus a washout period to clear the angiogenesis inhibitor before surgery. The endpoint of the study will be tumor volume reduction as shown by high-resolution CT.

Investigators are actively recruiting patients for the study: 11 patients have been screened, and 8 are in treatment. "This is an important trial for our lung cancer strategy for this drug, because it is designed to provide a proof of concept," Dr. Ottesen said. "We are following opportunities in early lung cancer by combining pazopanib with existing treatment. I want to highlight the importance of this study as one pointing to the future of how to develop drugs in this disease setting."