Intermittent Erlotinib With Docetaxel Shows Promise in NSCLC

SACRAMENTO, California- Tyrosine kinase (TK) inhibitors such as gefitinib(Drug information on gefitinib) (Iressa) and erlotinib (Tarceva) have proven effective in advanced non-small-cell lung cancer (NSCLC) as single agents but not, paradoxically, when used concurrently with cytotoxic chemotherapy. Now, a small pilot study suggests that intermittent use of erlotinib in combination with docetaxel(Drug information on docetaxel) (Taxotere) may improve outcomes when continuous administration of the two drugs has failed. Angela M. Davies, MD, and colleagues at the University of California, Davis, Cancer Center in Sacramento tested intermittent erlotinib with docetaxel in patients who had previously treated, advanced solid tumors. A total of 42 patients took part in the study, and about half had NSCLC. "The efficacy was very promising for this population," said Dr. Davies, an assistant professor of medicine in the department of internal medicine at UC Davis (abstract 7038). Among the 20 evaluable patients with NSCLC, there were four partial responses, one complete response, five minor responses, and two patients with stable disease. Ordinarily one would expect a lower response rate to second-line therapy in advanced disease, Dr. Davies said. Charles Rudin, MD, PhD, director of the lung cancer therapeutics program at Sidney Kimmel Comprehensive Cancer Center, agreed that the number of responses in this study was encouraging. "The responses are certainly intriguing in this phase I context," he said. Different Erlotinib Doses, Schedules The study included two simultaneous phase I trials, or arms, to test different doses and schedules of erlotinib. Docetaxel was given every 21 days in both arms. Erlotinib was given weekly in one arm, on days 2, 9, and 16; in the other arm, it was given daily, at lower doses, on days 2 to 16. On the weekly schedule, the maximum tolerated dose (MTD) of erlotinib was 600 mg/m². On the daily schedule, theMTD was 200 mg/m². In both trials, the MTD of docetaxel was 70 mg/m². Among patients receiving the daily doses of erlotinib, there were fewer toxicities and more responses than among those who received the higher weekly doses. Dose-limiting toxicities on both arms included febrile neutropenia, mucositis, and diarrhea. Cell Cycle Effect The efficacy of intermittent dosing may be related to the effect of erlotinib on the cell cycle, Dr. Davies said. In a model developed by coinvestigator Paul H. Gumerlock, PhD, also at UCDavis, erlotinib induces arrest at the G1 phase of the cell cycle, thus blocking the M-phase where docetaxel is active. When docetaxel is given first, it induces M-phase arrest and apoptosis, which is then enhanced by erlotinib's activity at the G1 phase, according to this model. The daily erlotinib regimen is now being tested as second-line therapy in advanced NSCLC in a phase II trial at UC Davis. In addition, phase I trials are testing both schedules with pemetrexed(Drug information on pemetrexed) (Alimta) rather than docetaxel, Dr. Davies said. Exploring Schedules, EGFR Mutational Status In his discussion, Dr. Rudin noted that other studies are exploring different schedules for possible combinations of TK inhibitors and chemotherapy. For example, researchers at Memorial Sloan-Kettering Cancer Center in New York, he said, have found that erlotinib given immediately before, rather than after, docetaxel shows promise. "Many schedules can be rationalized," he said. "Several are supported by preclinical data. What is going to be the optimal schedule? I think time will tell." Dr. Rudin also stressed the importance of determining whether patients have the mutations in epidermal growth factor receptors that have been shown to be targets of gefitinib and erlotinib: "I want to emphasize that mutational status may dictate the optimal combination and particularly the optimal schedule of these agents," Dr. Rudin said.