6039 Background: To assess the efficacy and identify a biomarker of response, a phase II trial of pemetrexed (PT) and oxaliplatin (OX) as an induction regimen in locally advanced head and neck squamous cell carcinoma (HNSCC) was conducted. We hypothesized that the tumors with increased DNA repair and folate biosynthesis capacities would have resistance to the regimen. Methods: Patients (pts) were given PT 500 mg/m2 and OX 85 mg/m2 Q 2 weeks for 4 cycles. Response was assessed at the end of treatment by CT scan. Frozen and formalin-fixed paraffin-embedded tumors were collected for DNA microarray analysis. The gene expression data were queried using significance analysis of microarrays (SAM) for comparison of stable disease (SD) versus partial response (PR). Results: 15 pts have been enrolled (Male/female: 14/1, Median age: 57.3). ECOG PS: 0 (6), 1 (8) and 2 (1). Primary sites: oropharynx (5), oral cavity (6), larynx (2), hypopharynx (1) and unknown primary (1). Fourteen of the 15 pts were evaluable for response: 0 CR, 10 PR, 4 SD and 0 PD. Toxicity was minimal with grade (G) 3 toxicities in 2 pts for diarrhea and elevated AST. The most common toxicity was nausea (G1–2). Eight tumors (5 PR and 3 SD) and 3 adjacent normal mucosal epithelia were collected and evaluated using DNA microarray. SAM yielded 77 differentially expressed genes between PR vs. SD. The genes most significantly associated with PR were higher expression of TS, DHFR, CDKN2C and CDKN2A, and lower expression of GSTA1 and GSTA4. Because of the association of upregulated CDKN2A, DHFR and HPV infection, the data were queried with the 91-gene HPV signature and presence of the signature was associated with response. The HPV status was also confirmed with HPV E6 and E7 PCR. Conclusions: The combination of PT/OX is active in locally advanced HNSCC patients. Higher expression of genes involving folate biosynthesis and HPV infection may associate with better response to this regimen while no known DNA repair gene expressions were found to associate with the response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology