The present invention relates to the treatment of EGFR-mediated disease, particularly cancer, which is resistant to tyrosine kinase inhibitor therapies. Methods for treatment of cancer and reduction of tumor growth in individuals with secondary EGFR mutations, particularly tyrosine kinase domain mutations, resistant to standard therapy are provided. The invention provides methods for the treatment of tyrosine kinase inhibitor resistant cancers with anti-EGFR antibodies. Methods for treatment of recurrent lung cancer, including non-small cell lung carcinoma which is resistant to tyrosine kinase inhibitors, with the antibody anti-EGFR mAb806 are described.