Durable disease stabilization and antitumor activity with OSI-774 in renal cell carcinoma: A phase II, pharmacokinetic (PK) and biological correlative study with FDG-PET imaging

Abstract

3050 Background: EGFR is over-expressed in >80% of renal neoplasms and is implicated in tumor initiation and progression. Antitumor activity against RCC in the phase I study of OSI-774, a selective oral quinazoline inhibitor of EGFR tyrosine kinase (EGFR-TK) activity, has lead to a 2-stage Phase II evaluation in patients (pts) with advanced RCC. Methods: OSI-774 (150mg) was administered daily using 28-day courses, until disease progression. A single dose reduction to 100 mg daily was allowed for ≥ grade-3 toxicity. Primary end point was objective response rate (CR+PR+SD). Secondary endpoints were progression free survival (PFS), overall survival, toxicity and response correlation with post-receptor effects of EGFR-TK inhibition. Results: One patient in the initial 19 patients had a partial response necessitating expanded accrual to stage 2. A total of thirty pts; 23♂/ 7♀; median age -57 (range 38–73); ECOG PS- 0(8)/ 1(18)/ 2(4); received 152 courses (median-3; range 1–15). Tumor histology was: clear cell (77 %) and granular (13 %). Median number of prior therapies was 2 (range 0–4): nephrectomy (90%), immunotherapy (83%), radiation (37%) and chemotherapy (20%). Prolonged stable disease (SD) lasting more than 6 months was noted in 7 pts (23 %) including 3 patients who remained on treatment for 14, 14, and 15 months. Four pts underwent dose reduction for reversible grade 3 toxicities: skin rash (2), hand-foot syndrome (1) and PT prolongation (1). No other grade 3–4 toxicities have occurred. Minimum plasma steady state concentration of OSI-774 and biological correlatives such as pERK, pAkt and p27 are being assessed in all pts. Serial FDG-PET scans have been performed prior to dosing and day 28 on all patients entered into stage 2 to prospectively determine if this imaging modality can identify and prospectively predict patients most likely to obtain clinical benefit (responders and stable disease) from OSI-774. Conclusion: OSI-774 induces prolonged stable disease (≥ 6 months) and antitumor response in a significant subset of patients with metastatic renal cell carcinoma. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech; OSI Pharmaceuticals Genentech Genentech; OSI Pharmaceuticals; Pfizer Novartis Pharmaceuticals