5513 Background: C225 plus RT improved survival vs. RT alone (Bonner, 2009). E2303 evaluated C225 with induction CT plus C225 and RT (CRT) in stage III/IV head and neck SCC with focus on event free survival, pathologic complete response (pCR) and toxicity. Restaging biopsy showed high pCR after C225/CRT 50 Gy w/ low toxicity. We now report 2-yr disease control and organ preservation rates. Methods: IRB consented resectable stage III/IV (21/42) patients (pts) sites- (oropharynx, 61%, larynx 22% other 16%) had triple endoscopy, gastrostomy, CT/MRI. Induction CT was C225 (400mg/m2 wk1, then 250mg/m2), P 90mg/m2, C (AUC=2)/ wk × 6. Restaging primary site (PS) biopsy (bx) was done wk 8, if the pt had a clinical CR and at wk 14 if disease persisted after CRT (C225 250mg/m2, P 30mg/m2, C (AUC=1) wkly × 6, 50 Gy). If PS bx was negative wk 14 pts completed CRT (68-72 Gy); If positive, the pt had surgery. Results: Of 74 enrolled pts, 70 had induction and 68 pts CRT. (13% < 70 Gy, 87% ≥70Gy ): 63 pts were eligible for analysis. Of 41 pts (59%) with clinical CR after induction, PS bx was neg. in 24 (59% pCR); Re-bx at wk 14 after chemo-RT (50Gy) in 34 pts (15 previous bx'd and 19 initial non-responders) was neg in 33 pts (97%). Thus 57 of 60 (95%) re biopsied pts and 91% of all eligible 63 pts had pCR. Neck dissection (n=34) was positive in 11 pts (32%). Pattern of failure was noted as: Local recurrence 11 (17.5%), regional 5 (8%), distant 5 (8%). Primary disease control at 2yr was 83%. Overall survival (OS): 1yr 97%, 2yr 82%; progression free survival (PFS) was 1yr 82%, 2 yr 66%. 2 yr PFS in stage III was 62%; in stage IV it was 68%. Conclusions: Induction C225 and CT followed by C225 plus CRT induces a 95% primary site path CR in biopsied pts and 91% response in eligible pts with a 2 yr OS of 82%, and PFS of 66%. This therapy and management approach produced promising local control, organ site preservation, and 2-yr survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, GenMab AACR, ASCO, IMER, NCCN, Pfizer Amgen, Bristol-Myers Squibb