Pemetrexed (P) and bevacizumab (B) in patients (pts) with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Final results and correlation with TS, MTHFR, and VEGF gene polymorphisms.

Abstract

5533 Background: We hypothesized that B, a monoclonal antibody against VEGF, will potentiate the activity of P, a multi- targeted antifolate, in R/M SCCHN. Methods: Eligible pts had R/M SCCHN with measurable disease, good performance status (PS), no history of gross hemoptysis, and no prior systemic therapy for R/M SCCHN. Treatment consisted of P 500 mg/m2 and B 15 mg/Kg, given intravenously every 21 days, with folic acid and B12, until progression. Primary endpoint was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and VEGF. Results: 40 pts were enrolled. Median age 59 (36-85); male/female, 32/8; PS 0/1, 16/24; prior chemotherapy as part of curative treatment: 29; primary site: oropharynx (21), oral cavity (7), larynx (4). Median number of cycles 5.5 (1-15). In 37 evaluable pts, the overall response rate was 30% (95% CI, 19-51%) (CR: 2; PR:11; SD: 21) and disease control rate 86%. Median TTP was 4.9 months (mo) (95% CI, 2.9-6.9) and median overall survival (OS) 11.5 mo (8.8-14.2). Bleeding events >grade 2 occurred in 6 pts (15%), 4 were grade 3 and 2 fatal (1 tracheal bleeding in a pt with history of tracheal bleeding that had responded to re-irradiation; 1 recurrent tumor-related bleeding after re-challenging with B); 8 other grade 1-2 bleeding events occurred. Other serious toxicities (all grade 3): anemia (2), neutropenia (4), AST elevation (1), stomatitis (1), anorexia (1), edema (1), hyponatremia (2), hypokalemia (1), fatigue (2), infection (3); 1 pt died of sepsis after receiving 8 cycles. 28 pts were genotyped. For the MTHFR A1298C SNP, median TTP for homozygote pts with AA was 4.2 and for pts with AC or CC 7 mo (p=0.069); median OS for AA was 11 mo and for AC or CC 32.8 mo (p=0.006). The associations with other SNPs were not significant. Conclusions: P and B is a novel, efficacious non-platinum regimen in R/M SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Genentech, Lilly Genentech, Lilly