Advanced NSCLC

CHICAGO—A novel antibody against insulin-like growth factor 1 receptor (IGF-1R) improved the relative response rates in patients with advanced non-small-cell lung cancer (NSCLC) by approximately 40% when combined with a standard paclitaxel-carboplatin regimen, compared with patients who received the two-drug regimen. Interim analysis of the randomized Phase II trial of the agent, CP-751871, along with paclitaxel and carboplatin, showed a 46% overall response rate in previously untreated patients compared with 32% for patients receiving paclitaxel and carboplatin alone, according to the data presented in an oral session here at the ASCO Annual Meeting. And the reported 52% overall response rate in non-adenocarcinoma patients is “tantalizing,” said the lead researcher, Daniel D. Karp, MD, Professor in the Department of Thoracic/Head and Neck Medical Oncology and Director of the Clinical Translational Research Center at the University of Texas M. D. Anderson Cancer Center.Figure: The interim analysis of the Phase II study reported by Daniel D. Karp, MD, found that CP-751871, along with paclitaxel and carboplatin, produced a 46% overall response rate in previously untreated patients with NSCLC compared with 32% for patients receiving paclitaxel and carboplatin alone. And the reported 52% overall response rate in non-adenocarcinoma patients is “tantalizing,” he said.The combination was found to be safe and well tolerated and warrants further study, he said, noting that his team expects to be able to present survival data by the end of the year. IGF Strongly Upregulated in NSCLC Dr. Karp noted that insulin-like growth factor is an attractive anticancer target because it is strongly upregulated in NSCLC, and to a lesser extent in breast, prostate, and colorectal cancers. IGF enhances proliferative and “prosurvival” signaling, he said, and inhibition of IGF-1R activation in tumor models suppresses tumor growth and increases tumor sensitivity to chemotherapy. CP-751871, a fully human IgG2 monoclonal antibody to IGF-1R, inhibits autophosphorylation and induces receptor internalization. The study, sponsored by Pfizer Oncology and conducted in 10 centers in the United States, Canada, and Spain, included previously untreated patients with recurrent Stages IIIb and IV NSCLC who had a good performance status. In the 2:1 randomization schema, 48 patients in the three-drug study arm received paclitaxel at 200 mg/m2, carboplatin to an area under the curve of 6, and CP-751871 at 10 mg/kg every three weeks to a maximum of six cycles, with maintenance of the study drug up to a maximum of 17 doses of the antibody. The 25 patients in the second study arm received only paclitaxel and carboplatin, at the same dosages. If these patients showed no response or progressive disease after two courses, the physician had the discretion to add CP-751871 or give it as a single agent. Among patients taking three drugs, 44% had adenocarcinoma, as did 40% of those in the two-drug arm. As of yet, there is no significant difference in progression-free survival between the two study arms, but follow-up will continue, Dr. Karp said. The most common adverse events with CP-751871 were Grade 3 and 4 dehydration and hyperglycemia. Blood sugars did go quite high in five patients (10%) in the CP-751871 arm but these were easily managed with insulin and hydration, he noted. The mechanism of hyperglycemia, he speculated, seems to be due to increased growth hormone. Response Rates by Cancer Type In an interview after his presentation, Dr. Karp said the overall response rate of 46% in advanced lung cancer, in a multi-institution study, is very encouraging. Even more encouraging, he said, was the 71% response rate for patients with squamous histology. And the response rates for study-drug patients with non-adenocarcinoma also were impressive—52% vs 33% for the non-adenocarcinoma controls.Figure: Paul Bunn, Jr., MD: “Several companies are producing both small molecule tyrosine kinase inhibitors and specific monoclonal antibodies, with most in preclinical development.” The two now in advanced clinical studies are CP-751871 and axitinib (AG-013736). “The higher response rates in the CP-751871 arm [of the study reported by Dr. Karp] are encouraging, and the differences in histology are interesting.”For adenocarcinomas the response rates were 38% and 30%, respectively. In this noncomparative study, Dr. Karp said he did not expect to see differences yet in progression-free survival, but that the data might be ready for presentation in September at the International Association for the Study of Lung Cancer World Conference. Discussant The Discussant for the study, Paul A. Bunn, Jr., MD, Director of the University of Colorado Cancer Center and Professor of Medicine at the University of Colorado Health Sciences Center, noted that the IGF signal pathway is very complicated, with several ligands and receptors, as well as a variety of IGF-binding proteins, any of which might dampen the IGF effect. “Because of the importance of this signal pathway, several companies are producing both small molecule tyrosine kinase inhibitors and specific monoclonal antibodies, with most in preclinical development,” he said. The two now in advanced clinical studies are CP-751871 and axitinib (AG-013736). “The higher response rates in the CP-751871 arm are encouraging, and the differences in histology are interesting,” Dr. Bunn said. Dr. Bunn, a member of OT's Editorial Board, said that similar Phase II trials combining a novel agent with paclitaxel and carboplatin have reported response rates varying from 31% (with bevacizumab) to 50% (with AZD2171). The most provocative Phase II results have been with high-dose bevacizumab, paclitaxel, and carboplatin, he noted, with 7.4 months of progression-free survival and 14 months of overall survival. But while the study design from this trial was excellent and has proceeded to the second stage, Dr. Bunn said, it is quite difficult to make a final interpretation without having data on progression-free survival or overall survival. “The remaining issues, while we wait, are to evaluate the central biomarkers, since only a minority of patients still benefit,” he said. “Remember, the response rate was only 14 percent higher [46% vs 32%].” Dr. Bunn said he hoped that biomarkers such as IGF-1R and IGF2 will provide clues to those most likely to benefit from CP-751871, and that he looked forward to studies combining it with other novel agents such as erlotinib or an angiogenesis inhibitor. Coming in Future Issues ▪ Inflammation & Cancer: Research Roundup ▪ Integrative Cancer Therapies: What You & Your Patients Need to Know ▪ Institute of Medicine Forum on Drug Discovery, Development, & Translation ▪ Survival of NSCLC Patients Treated with Gefitinib Found Similar to that for Patients Receiving IV Docetaxel, with Better Quality of Life ▪ New Melanoma Drug with Novel Mechanism of Action Shows Good Activity & Increased Survival in Phase II Trial. ▪ Axitinib Has Efficacy in Renal Cell Cancer Patients Whose Disease Has Progressed on Sorafenib or Sunitinib. ▪ Cancer Prevention: Research Update

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