Clinical Responses to EGFr-TKI’s characterized by drug-induced cell death in human NSCLC primary cultures

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18184 Background: Small molecule inhibitors of the EGFr have proven effective in advanced NSCLC but response rates in unselected populations remain low. Certain subsets of patients appear favored including females, non-smokers and Asians. Molecular profiles suggest that gene amplification or EGFr mutations (codons 19–21) may underlie responses. Our prior observations (Proc. AACR 2002, Abs.3902) indicated that gefitinib and erlotinib induced cell-death in human tumor microspheroids isolated from surgical specimens of some NSCLC patients, suggesting programmed cell death to be an important mechanism of action for these molecules. As part of an IRB-approved clinical trial, patients whose tumors were found sensitive to the EGFr-TKI’s by laboratory analysis, received 1st line single agent oral erlotinib at 150 mg/day. Methods: Following informed consent, NSCLC patients participating in the trial provided tissue for analysis as previously described (J Clin Oncol, 2000 18: 2245–2249). Dose response curves provided LC50 values by interpolation. Modified Z-score analysis identified patients sensitive to the EGFr-TKI’s by comparison with a database of over 900 EGFr-TKI analyses. Results: Three female caucasian patients were found more sensitive to EGFr-TKI’s than cytotoxic chemotherapy (2 non- & 1 former smoker). All 3 responded to erlotinib, 2 near-CR by PET, 1 lasting 19 months, the 2nd continuing at 10 months, with a 3rd patient in continuous PR at month 6. Toxicities have been moderate. One near-CR had virtually no skin rash. The molecular profile of 1 near-CR revealed no known gain of function mutation but instead a novel mutation in the EGFr domain. Conclusions: Exposure of human NSCLC microspheroids to EGFr-TKI’s in short term culture results in cell death events associated with clinical response, suggesting that programmed cell death is an important determinant of clinical response to these agents. This is consistent with the concept of oncogene addiction, in tumors driven by EGFr upregulation. Accrual to this trial continues. Supported by the Memorial Medical Center Foundation. [Table: see text]