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Oblimersen sodium (G3139, Genasense®) is a BCL2-targeted investigational compound currently in a Phase 3 clinical trial in combination with docetaxel (Taxotere®) against late-stage NSCLC. However, new EGFR-targeted agents such as gefitinib (Iressa®) and erlotinib (Tarceva™), and the folate pathway inhibitor pemetrexed (Alimta®), are emerging as important agents against NSCLC. Resistance to NSCLC therapies, whether de novo or acquired after repeated therapy, is inevitable in disseminated disease. Thus, we have evaluated the potential of G3139 to improve the initial response to these newly approved therapeutic agents and to abrogate acquired resistance. Several NSCLC xenograft models have been characterized for EGFR status and responsiveness to treatment with gefitinib and erlotinib. Specific mutations in EGFR correlate with responsiveness to gefitinib, but responsive models that do not contain detectable mutations have been reported, suggesting that gefitinib might have non-EGFR-mediated effects. NSCLC models MV522 and A549 do not harbor gefitinib-sensitizing EGFR mutations and demonstrate de novo resistance to MTD levels of gefitinib. When treated with a combination of G3139 (10 mg/kg/day) and gefitinib, both MV522 and A549 tumors in severe combined immune deficient (scid) mice are sensitive to gefitinib, suggesting that the de novo resistance is reduced significantly by G3139. While gefitinib alone at 175 mg/kg/day reduces tumor growth by approximately 50%, G3139 + gefitinib treatment produces significant suppression of A549 tumor growth, analogous to the results reported in gefitinib-responsive models, at gefitinib doses as low as 75 mg/kg/day. G3139 + erlotinib is being compared to G3139 + gefitinib in the same panel of xenograft models because both compounds target EGFR, but no sensitizing mutation has been observed for erlotinib and the clinical response rate is low, similar to gefitinib. Pemetrexed combined with G3139 is also being evaluated in NSCLC models. A459 growth is unaffected by treatment with MTD levels of pemetrexed (100 mg/kg/day), even when administered with folic acid supplementation. In sharp contrast to pemetrexed treatment alone, A549 exhibits a clear dose response to pemetrexed, over a range of 50 to 100 mg/kg/day, when co-administered with a constant dose of G3139 (10 mg/kg/day). Tumor growth is completely suppressed at the highest levels of G3139 + pemetrexed. We are extending these investigations to other gefitinib- and pemetrexed-resistant models. These results could have important implications to the majority of NSCLC patients, who do not harbor gefitinib-sensitizing mutations and who do not respond to pemetrexed.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]