Phase 1 Clinical Trial of Re-irradiation With Pemetrexed and Erlotinib Followed by Maintenance Erlotinib for Patients With Recurrent and Second Primary Squamous Cell Carcinoma of the Head and Neck: Management of Recurrent Head-and-Neck Squamous Cell Carcinoma

Abstract

Re-irradiation with concurrent chemotherapy has emerged as a treatment option for patients with recurrent or second primary Squamous Cell Carcinoma of the Head and Neck (SCCHN) who have received prior radiation therapy. The combination of pemetrexed and EGFR inhibitors has recently demonstrated synergistic effect as well as radiosensitizing properties in vitro and in clinical studies. Our phase 1 clinical study incorporates the oral tyrosine kinase inhibitor erlotinib into a re-irradiation strategy, both as a radiosensitizer in combination with pemetrexed as well as in a maintenance post-re-irradiation phase. Patients with unresectable loco-regional recurrent or second primary SCCHN received re-irradiation with pemetrexed and erlotinib beginning with the first day of radiation therapy. Patients qualified for the study if they received prior head and neck radiation therapy to no more than 72 Gy. 75% of the tumor volume had to be in areas previously irradiated to > 45 Gy. The total cumulative spinal cord dose was limited to 54Gy. The RT total dose delivered was 60 Gy in 30 daily fractions to gross tumor, with additional 6 Gy allowed to a small area of gross residual disease. Erlotinib dose was escalated from 100 mg to 125 mg and 150 mg daily with a standard 3+3 design. Maintenance erlotinib with dose-adjustment per smoking status was continued until disease progression, unacceptable toxicity or to a maximum of 2 years. 15 patients were enrolled in the study. All patients treated at the first and second erlotinib dose level tolerated treatment very well with no significant toxicities. At the third dose level, two out of three treated patients presented Dose Limiting Toxicity: one patient had increased LFTs grade III for more than 5 days and another patient developed mesenteric ischemia, sepsis and death. No patient discontinued the maintenance treatment with erlotinib because of toxicity and two patients received it for up to the maximum of two years. Detailed results are currently under analysis and further details will be presented at the time of the meeting. Maximum tolerated dose of erlotinib in combination with pemetrexed and re-irradiation was determined to be 100 mg po daily, dose recommended for the phase 2 clinical trial that is ongoing. The maintenance treatment with erlotinib was well tolerated.