DISCUSSION
PD‐L1, RCC, renal cell carcinoma, kidney cancer, Cancer
RENAL CELL CARCINOMA, KIDNEY CANCER, RCC, CANCER
To our knowledge, this is the first study which evaluated whether alternating sunitinib and temsirolimus therapies could potentially increase the PFS in patients with mRCC and be reasonably well tolerated. The choice of sunitinib and temsirolimus here is important because there has not been any data published on this specific alternating regimen. In vitro studies of temsirolimus in renal cell carcinoma cell lines showed reduction of hypoxia‐inducible factors HIF‐1 and HIF‐2 alpha, and the vascular endothelial growth factor (VEGF). By reducing VEGF, temsirolimus reduces target competition for sunitinib which binds the VEGF receptor and could potentially therefore increase efficacy of combining sunitinib with temsirolimus in this treatment regimen. VEGF and mTOR converge at HIF and VEGFR inhibitors are more effective in clear cell RCC (75%–80% of RCC are clear cellAlthough our study did not evaluate immunological parameters, the underlying rationale for potential synergistic immunological effects of sunitinib and temsirolimus has been subsequently supported by a study comparing the immunological impact of sunitinib, everolimus, and temsirolimus which indicated that temsirolimus was expected to offer the best outcome with immunomodulators in RCC.Since the onset of this trial, other studies have been conducted that tested the efficacy and safety of alternating TKIs and mTOR inhibitors with similar results. Two phase II trials have studied alternating sunitinib and everolimus, an mTOR inhibitor, as first‐line therapy for metastatic RCC. A single‐arm phase II trial in advanced RCC (EVERSUN) investigated a 12‐week alternating regimen cycle consisting of sunitinib 4 weeks on, 2 weeks off, followed by everolimus 5 weeks on, 1 week off schedule.There have also been studies of alternating TKIs with bevacizumab, a monoclonal antibody that targets VEGF. A phase I/II trial of patients with advanced clear cell RCC tested the standard 4 weeks on, 2 weeks off sunitinib regimen with the addition of bevacizumab on Day 29 of each sunitinib cycle.A Phase III trial in untreated advanced RCC (KEYNOTE‐426) revealed pembrolizumab (anti‐PD‐1) plus axitinib (anti‐VEGFR) with PFS of 15.1 months and ORR 59.3% was more effective than sunitinib with PFS of 11.1 months and ORR 35.7%. This benefit was seen across all risk groups regardless of PD‐L1 expression.A phase III trial in untreated advanced RCC (CheckMate 9ER) demonstrated nivolumab (anti‐PD1) plus cabozantinib (anti‐VEGFR) was safe and effective with a median PFS of 16.6 months and 85.7% overall survival (OS) at 12 months compared to PFS of 8.3 months and OS at 12 months of 75.6% for sunitinib.The results of these landmark trials have confirmed that immune checkpoint inhibitor combined with VEGFR‐TKI therapy is the standard of care in treating patients with advanced mRCC. National Comprehensive Cancer Network (NCCN) clinical practice guidelines for kidney cancer state preferred regimens for first‐line treatment in patients with clear cell RCC as axitinib with pembrolizumab, cabozantinib with nivolumab, and lenvatinib with pembrolizumab for all risk groups.Our study was terminated prior to completion of enrollment due to a slow rate of accrual impacted by the emergence of the aforementioned therapies as well as the previously described interim analysis that showed no improvement in PFS over historical data even if the study enrolled the total projected population of In conclusion, although the alternating schedule of sunitinib and temsirolimus can be given to patients relatively safely, the regimen did not improve the median PFS in patients with mRCC. The standard of care for mRCC has changed considerably since we first started enrolling patients into the study in 2011 with improvements in PFS and overall survival. With the current widespread use of additional therapeutic options particularly immune checkpoint inhibitors and the futility analysis performed on our study data for prolonging PFS, the alternating regimen of sunitinib–temsirolimus is not recommended for further study in larger clinical trials. This recommendation is based not only on the results of our study and but other clinical trials, where the treatment approach of alternating TKIs and mTOR inhibitors has not shown an improvement in clinical outcomes for patients with mRCC and therefore does not warrant additional investigation. Nevertheless, the observations of two patients with PFS of 36.9 and 59.4 months in this study support the evaluation of exceptional responders to better appreciate the mechanistic heterogeneity of therapeutic pathways.