Xenograft response to combination therapy with the ErbB1-ErbB2 tyrosine kinase inhibitor GW572016.

3823 In the current clinical oncology environment few anti-cancer agents are employed as stand alone therapies. With this in mind the compatibility and efficacy of GW572016, an ErbB1 (EGFR)-ErbB2 tyrosine kinase inhibitor, in combination with established anti-cancer therapies has been examined. The response to GW572016 combination therapy with paclitaxel, carboplatin, doxorubicin, and vinorelbine was followed in three xenograft models: BT474, an ErbB2 overexpressing human breast carcinoma; HN5, an ErbB1 overexpressing head and neck carcinoma; and NCI-H322, a ErbB1 and ErbB2 expressing non-small cell lung carcinoma. These studies were designed to examine combinations at or near the maximum tolerated dose as well as combinations at reduced dosages. The latter scheme is an attempt to detect strong combinatorial responses. All three xenograft models are sensitive to GW572016 and the outgrowth portion of the study was often used to detect significant improvement over the GW572016 response. GW572016 combinations were generally well tolerated; weight loss was observed with vinorelbine — GW572016 combinations, similar to that reported with gefitinib, and was controlled via dose reduction of either agent. The antitumor response to GW572016 in combination with additional agents was favorable with significant responses seen relative to the response of either agent alone. The response to GW572016 in combination with any of the chemotherapeutic agents evaluated was rarely consistent across the tumor panel examined here. This response pattern is reflective of the complexity of combination therapy and the heterogeneity of the models themselves and points to the lack of probability of any one preclinical model being predictive of clinical therapeutic outcome. The response to combination therapy with paclitaxel - GW572016 was the most encouraging with the combination resulting in a significantly improved response relative to either agent alone in both the BT474 breast and NCI-H322 non-small cell lung carcinoma xenograft models. Following dose reduction, the vinorelbine -GW572016 response, in the BT474 breast carcinoma xenograft model, was also favorable relative to either agent as mono-therapy.