Efficacy, safety and pharmacokinetics of axitinib in nasopharyngeal carcinoma: a preclinical and phase 2 correlative study

Purpose:We hypothesized that axitinib is active with improved safety profile in nasopharyngeal carcinoma (NPC). Experimental Design: We evaluated axitinib in preclinical models of NPC, and studied its efficacy in a phase 2 clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice-daily in continuous 4-weeks cycles. Primary endpoint was clinical benefit rate (CBR), defined as percent of patients achieving complete response (CR), partial response (PR) or stable disease (SD) by RECIST criteria for more than 3 months. Results:We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) received ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI: 65.6-91.2%) at 3 months and 43.2% (30.4-56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%) and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during first 3 months of axitinib treatment was significantly associated with improved overall survival (HR=0.29, 95% C.I 0.13-0.64, P=0.0012). Patient reported fatigue symptom was associated with hypothyroidism (p=0.039). Axitinib PK parameters (C max and AUC(0-t)) were significantly correlated with tumor response, toxicity and serum thyroid-stimulating hormone (TSH) changes. Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients.

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