| General information |
| Database: | DB00843 |
| Objective: | Although patients with non small cell lung cancer (non small cell lung cancer) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, they studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, human epidermal growth factor receptor 2, and EphB4, in non small cell lung cancer patients known or suspected of having tumors harboring T790M. |
| Authors: | Pietanza MC, et al |
| Title: | XL647a multitargeted tyrosine kinase inhibitor: results of a phase II study in subjects with non small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib. |
| Journal: | J Thorac Oncol. |
| Year: | 2012 |
| PMID: | 22011666 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | XL647
|
| Target: | endothelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2, human epidermal growth factor receptor 2 and Ephrin typeB receptor 4 (EphB4)
|
| Cancer Type: | non small cell lung cancer |
| Cancer Subtype: | non small cell lung cancer |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a phase II study |
| Key Patients Feature: | Eligible patients included those with relapsed or recurrent advanced non small cell lung cancer who progressed after more than and equal to 12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. |
| Biomarker: | Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA. |
| Biomark Analysis: | Of patients whose tumors harbored T790M, 67% (8/12) had progression of disease as best response compared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35%) of which were found to have EGFR mutations. |
| Control Group Info: | single arm |
| Treatment Info: | XL647 300 mg was administered once daily |
| Primary End Point: | objective response rate. |
| Secondary End Point: | NA |
| Patients Number: | 41 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | 3% |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 3.5 months (range, 0.5-17.3 months; 90% CI, 2.8 to 5.5) |
| Median OS A vs. C: | 16.1 months (90% CI, 9.8 to not reached, as not enough events have been observed) |
| Adverse Event(agent arm): | Eleven patients (28%) required a dose reduction for toxicity, most commonly for diarrhea (27%) and rash (18%). Eight serious adverse events that occurred in four patients were thought to be related to XL647. One patient experienced five events of grade 3 severity: diarrhea (two events), abdominal pain, nausea, and vomiting; XL647 was discontinued. One patient each had grade 4 bilateral pulmonary emboli (XL647 discontinued); grade 3 ventricular arrhythmia (XL647 discontinued); and grade 3 QTc prolongation (patient asymptomatic). In addition to the three patients described in whom XL647 was discontinued, the drug was stopped in three other patients for an adverse event related to the study agent and in one patient for a serious adverse event not related to XL647, totaling 7 (17%). There were no treatmentrelated deaths. |
| Conclusions: | Although patients with non small cell lung cancer (non small cell lung cancer) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, they studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, human epidermal growth factor receptor 2, and EphB4, in non small cell lung cancer patients known or suspected of having tumors harboring T790M. |