Georg A Bjarnason1, Jennifer J Knox2, Christian K Kollmannsberger3, Denis Soulieres4, D Scott Ernst5, Pawel Zalewski6, Christina M Canil7, Eric Winquist5, Sebastien J Hotte8, Scott A North9, Daniel Yick Chin Heng10, Robyn Jane Macfarlane11, Peter M Venner9, Anil Kapoor8, Aaron R Hansen2, Bernhard J Eigl3, Piotr Czaykowski12, Ben Boyd13, Lisa Wang2, Naveen S Basappa9. 1. Sunnybrook Odette Cancer Centre, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada. Electronic address: georg.bjarnason@sunnybrook.ca. 2. Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada. 3. BC Cancer Agency, Vancouver Cancer Centre, Vancouver, British Columbia, V5Z 4E6, Canada. 4. Centre Hospitalier de L'Universite de Montreal, 1560 Sherbrooke Est, Montreal, Québec, H2L 4M1, Canada. 5. London Health Sciences Centre, 790 Commissioners Rd East, London, Ontario, N6A 4L6, Canada. 6. R.S. McLaughlin Durham Regional Cancer Centre, 1 Hospital Court, Oshawa, Ontario, L1G 2B9. 7. The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ontario, K1H 8L6, Canada. 8. Juravinski Cancer Centre, 699 Concession Street, Hamilton, Ontario, L8V 5C2, Canada. 9. Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada. 10. Tom Baker Cancer Center, 1331, 29th Avenue NW, Calgary, Alberta, Canada. 11. Queen Elizabeth II Health Sciences Centre, 1276 South Park Street, Halifax, Nova Scotia, B3H 2Y9 Canada. 12. Cancer Care Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, R3E 0V9, Canada. 13. Ozmosis Research Inc, 65 Queen St W, Toronto, Ontario, M5H 2M5, Canada.
Abstract
BACKGROUND: Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. MATERIALS AND METHODS: In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. RESULTS: The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration. CONCLUSIONS: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS. GOV IDENTIFIER: NCT01499121.
BACKGROUND:Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. MATERIALS AND METHODS: In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. RESULTS: The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration. CONCLUSIONS: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS. GOV IDENTIFIER: NCT01499121.
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