Regulatory Decision Summary for Sutent

The indication sought by this SNDS was based on the results derived from the S-TRAC study. S-TRAC was a double blinded, randomized, multicenter, placebo-controlled phase 3 study. Patients included in S-TRAC had been diagnosed with non-metastatic renal cell carcinoma (nmRCC) and were at high risk of recurrence following partial or radical nephrectomy, as determined by the University of California, Los Angeles Integrated Staging System (UISS) criteria. The primary end point was disease free survival (DFS) as evaluated by a blinded independent third-party central reviewer (BICR) and the investigators. Secondary end-points included overall survival (OS), safety/toxicity of Sutent, and quality of life

In response to the NON issued for this submission on July 19, 2018, the sponsor has further restricted the proposed indication to those patients at the highest risk of recurrence. These are patients with T3 and Fuhrmans Grade >2, or T4 or node positive with any T tumours. This subgroup represents approximately 10% of the overall population of surgically resected patients in Canada and approximately 65% of the ITT population of the S-TRAC study.

Post Hoc analysis of the patients at the highest risk (by the BICR) of recurrence showed that 81 (40.7%) patients had a DFS event (recurrence) in the sunitinib arm versus 105 (52.8%) in the placebo arm. The HR was 0.727 (95% CI: 0.544, 0.972) with a 2-sided p-value of 0.031 in favor of sunitinib. The median DFS was 6.0 years (95% CI: 4.1, not reached [NR]) in the sunitinib arm and 3.9 years (95% CI: 2.5, 5.8) in the placebo arm. AEs were consistent with those observed in patients with mRCC treated with sunitinib.

Several concerns in regard to the statistical robustness of the S-TRAC study were raised in the initial review of this SNDS and these concerns remained in the R-NON review. For instance, the secondary analysis of efficacy (by Investigators) does not support the primary analysis by the BICR whether the ITT population or the Highest Risk population is used to perform the analysis. Sensitivity analysis of DFS applying EU-preferred censoring rules (i.e. not censoring for start of a new anticancer therapy or 2 or more missed assessments) did not reach statistical significance for both the BICR- and Investigator-based assessment in the ITT population. Together, these results point to the lack of robustness of the findings and raise the question as to whether or not the efficacy of sunitinib as determined by BICR-based assessment is reflective of the real clinical setting.

While OS data was not mature, no trend in favor of placebo or sunitinib could be observed from the Kaplan-Meier curves. The gain in DFS attributable to sunitinib is counterbalanced by the absence of OS improvement.

The impact of sunitinib toxicity on patients was substantiated by a high rate of permanent discontinuation in the sunitinib arm (28.1%) compared to the placebo arm (5.9%). In this regard, at least two published studies showed that other anti-angiogenic agents, used as adjuvant therapy for patients with nmRCC at high-risk of recurrence following nephrectomy, were not well tolerated at the dose recommended for metastatic RCC. In these studies, patients needed a dose reduction in order for the study to proceed. The above suggest that this population of patients is particularly sensitive to the toxicity of these anti-angiogenic agents.

The proof of concept for the use of anti-angiogenics as adjuvant therapy for patients at risk of recurrence following nephrectomy due to nmRCC has not been established.

In summary, the gain in DFS attributable to sunitinib is counterbalanced by the absence of OS improvement, the questions around the robustness of the study, and the substantial toxicity of sunitinib on patients. The use of sunitinib as adjuvant therapy for patients with non-metastatic RCC at high risk of recurrence following nephrectomy is not recommended by the European Association of Urology and the Kidney Cancer Research Network of Canada. Experts contacted by Health Canada unanimously agreed that the benefit of sunitinib as adjuvant therapy does not outweigh the risk of treatment, especially in the absence of OS improvement.