Alan Sandler, MD

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State-of-the-Art Treatment for Advanced NonSMQ-8211-SMQSmall-Cell Lung Cancer

December 1st 2003

Patients with locally advanced or metastatic nonSMQ-8211-SMQsmall-cell lungcancer (stage III and IV) who are not candidates for surgery and exhibitgood performance status are typically treated with concurrent radiationand platinum-based chemotherapy for disease palliation. Platinum-based chemotherapies, used alone or with radiation therapy, offera small but significant survival benefit compared with supportivecare. The incorporation of first-line agents such as gemcitabine(Gemzar), vinorelbine (Navelbine), and paclitaxel, as well as secondlineagents such as docetaxel (Taxotere), in doublet and triplet combinationshas had a further significant therapeutic impact. Randomizedtrials have shown that cisplatin-based therapy in combination with newagents results in improved 1- and 2-year survival rates in patients withadequate performance status. The 1-year survival benefit has significantlyimproved, with greater symptom relief and improved quality oflife in these patients. Thus, delaying disease progression with combinationchemotherapy appears both beneficial and cost-effective in patientswith advanced nonSMQ-8211-SMQsmall-cell lung cancer. Newer approachesSMQ-8212-SMQincluding targeting critical signaling pathways, such as tyrosine kinasereceptors, angiogenesis, and downstream signal transductionmechanismsSMQ-8212-SMQmay provide novel agents with an improved toxicity profileand the potential for better disease management.

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Clinical Experience With the HER1/EGFR Tyrosine Kinase Inhibitor Erlotinib

November 2nd 2003

In phase I trials in healthy volunteers and patients with refractorycancers, erlotinib (Tarceva) was well tolerated and showed activityagainst non–small-cell lung cancer and other tumors. The dose identifiedfor further clinical development was 150 mg/d; at this dose, erlotinibachieves high exposure, with maximum concentrations greater than2,000 ng/mL and 24-hour area under the concentration-time curvegreater than 35,000 ng • h/L. In a phase II trial in 57 patients withpreviously treated advanced non–small-cell lung cancer, erlotinib treatmentproduced an objective response rate of 12.3% and a stable diseaserate of 38.6%, with median duration of response of 19.6 weeks;median overall survival was 8.4 months and 1-year survival was 40%,with 9 patients remaining alive over follow-up of greater than 18 months.No grade 4 toxicity was observed, and grade 3 toxicity was minimal. Inan ongoing phase II trial in bronchioloalveolar carcinoma, erlotinibtreatment has produced objective response in 26% of 50 evaluable patients,with median duration of response not yet having been reached.An ongoing phase II trial is examining the combination of erlotinibwith the angiogenesis inhibitor bevacizumab (Avastin) in previouslytreated non–small-cell lung cancer; phase I evaluation revealed no doselimitingtoxicities at tested doses and provided evidence of antitumoractivity. Two phase III trials are examining erlotinib in combinationwith carboplatin (Paraplatin)/paclitaxel (the TRIBUTE trial) orcisplatin/gemcitabine (Gemzar) (the TALENT trial) as first-line treatmentin advanced non–small-cell lung cancer. The phase III BR.21trial is assessing erlotinib monotherapy in advanced refractory non–small-cell lung cancer. Results of these phase II trials will soon beavailable.