A phase 1 dose escalation study and signs of anti-metastatic activity of ARQ 197, a selective c-Met inhibitor

B91 ARQ 197 is a selective, non-ATP competitive inhibitor of the c-Met receptor tyrosine kinase, a high-affinity receptor for hepatocyte growth factor (HGF). c-Met is dysregulated in a broad spectrum of human cancers and may contribute to cancer cell proliferation, apoptosis, angiogenesis, invasive growth, dissemination, and metastasis. A phase 1 dose escalation study of ARQ 197 was initiated in adult patients with metastatic solid tumor in 2006, from which a recommended phase 2 dose (RP2D) of 120 mg bid was established based on pharmacokinetic data. Doses of up to 180 mg bid were administered orally with one of two dosing schedules, bid for 2 weeks following by 1 week of rest (schedule A) or bid continuously (schedule B). Maximum tolerated dose (MTD) was not reached, and dose escalation was terminated based on pharmacokinetic data. Fifty-five patients (37 schedule A, 18 schedule B) have been treated with no dose-limiting toxicity observed. The safety profiles are similar between the two dosing schedules. The most commonly reported drug-related adverse events were fatigue and nausea. Tumor types in the patient population included colon/colorectal (16.4%), renal (7.3%), thyroid (7.3%), ovarian (7.3%), pancreatic (7.3%), prostate (5.5%), non-small cell lung cancer (NSCLC, 3.6%), nasopharyngeal (3.6%), neuroendocrine (3.6%), breast (3.6%) and others (34.5%). Of 47 patients evaluable per the study protocol, 3 (6.4%) had partial responses. Twenty-eight (59.6%) had stable disease (SD) for more than 2 months, 19 (40.4%) had prolonged SD for more than 4 months (range from 4 to 17 months). Consistent with preclinical data, signs of anti-metastatic activity were observed. Based on Investigators’ evaluations, 33 (94.3%) of 35 patients who had received more than two cycles (6 weeks) of treatment showed no evidence of new metastatic lesions developing during their treatment with ARQ 197. Two patients (5.7%), one with renal cell carcinoma and the other with paraspinal sacral sarcoma, developed new lesions after approximately 10 and 12 months of treatment, respectively. Seven (35.0%) of other 20 patients who had received 2 or fewer cycles of treatment with ARQ 197 developed new lesions. The tumor types of these 7 patients were colon cancer (3) with new lesion(s) developed in lung, peritoneal and lung respectively, colorectal (1) with new liver lesions, NSCLC (1) with a new liver lesion, breast (1) with a new liver lesion, and spindle cell sarcoma (1) with new lung lesions. New lesions occurred only in organs with documented preexisting metastatic disease, except in one colon cancer patient with new peritoneal metastases who had lung and liver metastases at study enrollment. All patients’ original images are under review by an independent reviewer to assess the anti-metastatic activity of ARQ 197. Updated data will be presented. In summary, ARQ 197 is well tolerated with an acceptable safety profile, and MTD was not reached. RP2D was established based on pharmacokinetics data. Early signs of anti-tumor and anti-metastatic activities of ARQ 197 have been observed.