Novel ALK Inhibitor Shows High Response Rate in Patients with Advanced Non-Small Cell Lung Cancer with Specific ALK Gene Alteration
Novel ALK Inhibitor Shows High Response Rate in Patients with Advanced Non-Small Cell Lung Cancer with Specific ALK Gene Alteration
An expanded Phase I clinical trial finds that the large majority (approximately 90 percent) of patients with advanced non-small cell lung cancer (NSCLC) with a specific form of the ALK responded to treatment with the investigational ALK inhibitor, crizotinib (PF-02341066), and more than half of these patients experienced tumor shrinkage.
“Many of these patients had received three or more prior treatments, and we would expect only about 10 percent to respond,” said lead author Yung-Jue Bang, MD, PhD, professor in the Department of Internal Medicine at Seoul National University College of Medicine in Seoul, Korea. “These results are quite dramatic, and represent an important improvement over what we would see with standard chemotherapy for patients with metastatic disease.”
When the ALK gene fuses with another gene, it promotes lung cancer cell growth by encoding the production of a tumor-specific protein called anaplastic lymphoma kinase, or ALK – an enzyme that is critical for the growth and development of cancer cells. Crizotinib, which is taken orally, works by inhibiting the ALK enzyme. About one in 20 lung cancer patients in the United States are estimated each year to be diagnosed with ALK-positive NSCLC.
The study assessed crizotinib in patients with NSCLC, most of whom had adenocarcinoma and were nonsmokers or former smokers. All of the patients had the ALK gene fusion. Nearly all patients (87 percent at 8 weeks) who received crizotinib to date responded to this treatment and experienced tumor shrinkage or disease stabilization. Among those, 57 percent had tumor shrinkage.
The median duration of treatment was approximately six months. A randomized, Phase III trial (PROFILE-1007) has begun, comparing crizotinib to standard second-line chemotherapy.
Abstract 3
Clinical activity of the oral ALK inhibitor, PF-02341066, in ALK positive patients with non-small cell lung cancer (NSCLC).
Y. Bang, E. L. Kwak, A. T. Shaw, D. R. Camidge, A. J. Iafrate, R. G. Maki, B. J. Solomon, S. I. Ou, R. Salgia, J. W. Clark
Background: PF-02341066 (PF-1066) is a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases. EML4-ALK fusion oncogenes have been reported in approximately 4% of NSCLC. Patients with NSCLC harboring an ALK fusion were recruited into an expanded cohort at the recommended Phase 2 dose within the first-in-patient monotherapy trial of PF-1066.
Methods: Patients with ALK fusions, as determined by FISH using a break-apart probe to ALK, were enrolled into the expanded cohort irrespective of prior therapy. Treated brain metastases were allowed. PF-1066 was given orally at a dose of 250 mg BID. Responses were determined using RECIST with radiographic studies repeated every 8 weeks. The disease control rate (DCR) was determined based on the frequency of patients with RECIST CR, PR and stable disease at 8 weeks.
Results: To date, 76 ALK+ NSCLC patients have been treated. The median number of prior treatments was 3 (range, 0-7). Most patients had adenocarcinoma histology and were never or former smokers. Mean plasma Ctrough was 292 ng/ml, which was above the predicted efficacious concentration from preclinical models (120 ng/ml). The median t1/2 was ~53 hours. To date, 50 patients are evaluable for response; ORR is 64% and DCR 90%. The median progression-free survival is not yet mature. The median duration of treatment is 25.5+ weeks. Radiological responses typically were observed at the first or second restaging CT scan. Gastrointestinal toxicities, including nausea (55%) and vomiting (39%), were the most frequent adverse events.
Conclusions: The oral ALK inhibitor, PF-1066, demonstrated a high response rate in patients selected for ALK fusions and was associated with a good safety profile. A Phase 3 study has been initiated. This study supports the concept of molecular selection of NSCLC patients for appropriately designed treatment.
Disclosures: Yung-Jue Bang, Consultant or Advisory Role, Pfizer, Honoraria, Pfizer, Research Funding, Pfizer; Eunice Kwak, Research Funding, Pfizer; Alice Shaw, Honoraria, Pfizer, Research Funding, Pfizer; D. Camidge, Research Funding, Pfizer; A. Iafrate, Honoraria, Pfizer, Research Funding, Pfizer; Robert Maki, Research Funding, Pfizer; Benjamin Solomon, Research Funding, Peter MacCallum Cancer Center, Pfizer; Sai-Hong Ou, Research Funding, Pfizer; Ravi Salgia, Research Funding, Pfizer.