IASLC: IGF Receptor Inhibitor Shows Early Promise in NSCLC

SEOUL, South Korea, Sept. 6 -- An inhibitor of insulin-like growth factor receptors demonstrated activity in advanced non-small-cell lung cancer, suggesting potential as a new targeted strategy.

When added to chemotherapy, the IGF-1R antagonist, currently known as CP-751,871, was associated with an overall response rate of 46%, almost 50% better than with chemotherapy alone, Daniel D. Karp, M.D., of the M.D. Anderson Cancer Center in Houston, told attendees at an industry symposium held during the International Association for the Study of Lung Cancer's world conference here.

Adding the receptor antagonist to chemotherapy boosted the response rate for all histologies, age groups, disease stages, and smoking histories, although the numbers were small.

"The response rate satisfies the criterion for continuing the study," said Dr. Karp. "The high overall response rate in patients with nonadenomatous carcinoma warrants further investigation. Toward that end we hope to add 80 additional patients, including 50 with nonadenomatous histology, to confirm these initial observations."

The IGF-1R family of tyrosine kinase receptors have a major role in signal transduction pathways, said Dr. Karp. The receptors work through various pathways to induce signals involved in regulating cell growth, division, differentiation, survival, angiogenesis, and tumor metastasis.

Altered signaling mediated by IGF-1R kinases occurs in lung cancer. IGF-1R is involved in both growth stimulation and inhibition of apoptosis. Inhibition of the molecules represents a rational approach to targeted therapy for lung cancer, he continued.

Dr. Karp headed a randomized phase II multicenter clinical evaluation of CP-751,871 (a monoclonal antibody directed against IGF-1R) in patients with untreated advanced non-small-cell lung cancer. Patients were randomized 2:1 to receive paclitaxel 200 mg/m² plus carboplatin AUC 6 plus CP-P751,871 10 mg/kg or to chemotherapy alone. Treatment was administered every three weeks for a maximum of six cycles.

Investigators enrolled 73 patients, 80% of whom had stage IV disease. Dr. Karp said 40% to 45% of the patients had adenocarcinoma. He noted that a substantial proportion of the patients -- 28% in the experimental arm and 16% in the control arm -- had non-small-cell or not-otherwise-specified histology. Patients with unclassified histology represent a growing proportion of lung cancer patients, he added.

At a planned interim analysis, 22 of 48 patients (45.8%) in the experimental arm had major responses compared with 8 of 25 (32%) in the control group.

Examination of responses by histology showed that eight of 21 (38%) with adenocarcinoma responded to the experimental therapy compared with three of 10 (30%) in the control group.

Response rates in patients with nonadenocarcinoma were 52% (14 of 27) in the experimental arm and 33% (five of 15) in the control group. The experimental therapy resulted in a 71% response rate in patients with squamous histology.

Patients had the option to cross over to the experimental arm or to receive single-agent CP-751,871. One patient who stopped chemotherapy and crossed over to receptor antagonist temporarily regained response, suggesting potential single-agent activity, said Dr. Karp. Data on other crossover patients are not yet available.

The principal side effects attributable to CP-751,871 were several cases of grade 3 - 4 dehydration and hyperglycemia, which was managed with standard diabetic therapy.

"The results show that specific inhibitors of IGF-1R are active in non-small cell lung cancer," Dr. Karp concluded. "The higher response rate in nonadenocarcinomas warrants further investigation."