Phase I trial of neoadjuvant and postoperative paclitaxel (P), carboplatin (C) and erlotinib with concurrent accelerated hyperfractionation radiation (AHFR) followed by erlotinib maintenance therapy in stage III non-small cell lung cancer (NSCLC)

Abstract

2091 Background: Erlotinib (E), a potent reversible Her1/EGFR tyrosine kinase inhibitor is a radiosensitizer in preclinical studies. Our study was conducted to determine the recommended dose of E when given with P, C and AHFR before/after surgery in patients (pts) with potentially resectable stage III NSCLC. Methods: Pts had biopsy-proven Stage III NSCLC, and ECOG performance status of 0/1. Treatment Plan was: 1) Induction AHFR (30 Gy/1.5 Gy BID), with concurrent P [50 mg/m2] C (AUC 2), weekly x 3, and E at 3 dose levels (DL); I: 50, II: 100, and III: 150 mg, orally once daily (qd) for 4 weeks (wks); 2) Surgery after 4 wks; 3) a second identical course of chemoradiotherapy (CRT) 4–6 wks postoperatively; 4) 2-year maintenance of a fixed dose of E (150 mg qd). 3 to 6 pts were treated at each DL of E. A dose level was deemed intolerable if greater than or equal to 2 of 6 pts develop a dose-limiting toxicity (DLT). Results: Between 8/03 and 11/04, 6 male and 3 female pts were enrolled, 4 at DL I, 3 at DL II, 2 at DL III. Median age was: 61(range 33–68) years. All pts completed induction treatment. 7 pts had surgery (3 lobectomy; 4 pneumonectomy). One patient (pt) progressed; 1 pt was deemed unresectable. 6 of 9 pts received postoperative CRT + E. No DLT was observed at DL I or DL II. One pt at DL 3 had prolonged postoperative recovery from respiratory failure (grade IV toxicity). Common grade I-II toxicities were, rash (6 pts), diarrhea (3 pts), and esophagitis (3 pts). One pt at DL I had reversible posterior leucoencephalopathy, thought to be unrelated to treatment. There were no unexpected surgical complications, and no treatment-related mortality. 4 pts were downstaged at surgery; to stage I: 1 pt, stage II: 2, and 1 pt had complete pathologic response. Maintenance E was started in 6 pts. 7 of 9 pts are progression free at a mean follow-up of 9.1 months (range: 5–15). Additional pts are being treated at DL III to further characterize toxicity. Conclusion: Erlotinib in combination with concurrent weekly P/C/AHFR is well tolerated. The recommended dose of E has not yet been determined. A phase II study is planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Genentech, Lilly Oncology, Pfizer, Bayer, Antigenics Amgen, Pfizer, Eyetech, Genentech, Genentech Genentech, Pfizer, Celgene, Antigenics, Amgen, Wyeth