Dose escalation of sunitinib after progression of metastatic renal cell carcinoma (mRCC) may be beneficial, with added progression-free survival, a delay in the change of systemic therapy, and an acceptable toxicity, researchers concluded in a poster presented at the 2017 Genitourinary Cancers Symposium in Orlando, Florida.
Jacques Raphael, MD, and colleagues at Sunnybrook Health Sciences Centre in Toronto studied 25 mRCC patients who experienced disease progression while on the standard 50 mg dose of sunitinib. At progression, physicians escalated the dose to 62.5 and 75 mg on an individual schedule if toxicity permitted.
At the 50 mg dose, 60% and 16% of patients had a partial response and stable disease, respectively, as per RECIST 1.1 criteria, for a median duration of 11.4 months, Dr Raphael’s group reported. After progression, 36% and 28% had a partial response and stable disease, respectively, for a median duration of 7.8 months. Three patients who had progressive disease as the best response on 50 mg doses achieved either partial response (1 patient) or stable disease (2 patients) after dose escalation.
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The overall survival for the 25 patients was 63.6 months (95%CI 25.9-NR). The patients had a median progression-free survival of 6.1 months (95%CI 2.3-19.4) on the 50 mg dose and 6.7 months (95%CI 2.6-8.4) when on dose-escalated sunitinib, according to the investigators.
Patients experienced grade 1–2 toxicities (CTCAE vs 4.0), most commonly fatigue and diarrhea.
The cohort had a mean age of 54 years, and 22 patients (88%) were male. The median follow-up was 40.3 months. Eighteen patients had clear cell RCC, 6 had papillary RCC, and 1 had other RCC histology.
Twenty-one patients (84%) were dose escalated to 62.5 mg. The dose escalation schedule was 14 days on/7 days off for 19 patients, 7 days on/7 days off for 1 patient, and 16 days on/7 days off for 1 patient. Ten patients (40%) were dose escalated to 75 mg. The dose escalation schedule was 14 days on/7 days off for 5 patients, 9 days on/5 days off for 1 patient, 21 days on/7 days off for 2 patients, and 7 days on/7 days off for 2 patients.
The rationale behind the study is supported by preclinical data suggesting that dose escalation may overcome resistance to standard doses. The study was limited by its retrospective design, small number of patients and events, and heterogeneous treatments (dose/schedule), the researchers acknowledged. The individualized sunitinib strategy to optimize tumor response and overcome resistance is currently being tested in the prospective NCT01499 trial.
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References
1. Raphael J, Thawer A, Bjarnason GA. Sunitinib dose escalation after disease progression in metastatic renal cell carcinoma. Results presented in poster format at the 2017 Genitourinary Cancers Symposium in Orlando, Florida. Poster Session C, Board D21. Abstract 458.
2. Adelaiye R, Ciamporcero E, Miles KM, et al. Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications. Mol Cancer Ther 2015;14:513-522.
3. Ornstein MC, Wood L, Elson P, et al. Clinical effect of dose escalation after disease progression in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 2016 Aug 18 S1558-7673(16)30248-8.
4. Bjarnason GA, Knox JJ, Kollmannsberger CK, et al. Phase II study of individualized sunitinib as first-line therapy for metastatic renal cell cancer (mRCC). ASCO Meeting Abstracts 2015; 33:abstract 4555.
