The annual meeting of the European Society of Medical Oncology (ESMO) held in Copenhagen, Denmark on 7-11 October 2016 shed light on how renal cell carcinoma could be treated in the future, but uncertainty and questions were also raised. As things stand, resectable disease is treated by surgery, with curative intent, and adjuvant drug treatment is only prescribed in the context of clinical trials. Current treatment for locally advanced or metastatic disease consists of targeted therapies (angiogenesis and mTOR inhibitors) and immunotherapies (predominantly an immune checkpoint inhibitor; Opdivo). Positive data announced were:
- In the Phase III S-TRAC study, Pfizer’s Sutent was evaluated in the adjuvant setting versus placebo, for the treatment of high-risk, locoregional, clear-cell renal cell carcinoma following nephrectomy1. The primary end point was met, with Sutent achieving a DFS of 6.8 years compared to 5.6 years for placebo (HR = 0.76; P = 0.03). At the time of data cut-off, MOS had not been reached in either group. Sutent was associated with increased grade 3/4 toxicities (62%) compared to placebo (21%)–notably, hand-foot syndrome, hypertension, and neutropenia–however, no deaths occurred due to treatment-related toxicity.
- Cabometyx (Exelixis/Ipsen) was compared to Sutent as a first-line treatment for poor- and intermediate-risk, locally advanced or metastatic renal cell carcinoma in the Phase II CABOSUN study2. Cabometyx achieved a significantly greater median PFS compared to Sutent (8.2 months vs. 5.6 months, respectively; HR = 0.69; P = 0.012), corresponding to a 31% reduction in the risk of disease progression or death, and a numerical improvement in ORR (46% vs. 18%, respectively). Incidence of adverse events (grade ≥3) reported were similar in the Cabometyx and Sutent treatment groups. Data for OS (which was initially a primary end point, but demoted to a secondary end point3) were immature.
The positive data for Sutent as an adjuvant treatment has the potential to address a significant unmet need in this disease (i.e., to reduce or delay distant metastatic disease recurrence). The results from S-TRAC are impressive, particularly given the failed attempts of a multitude of therapies including immunotherapies and radiotherapy in the adjuvant setting. However, data from S-TRAC is contradictory to another Phase III trial in the adjuvant setting (ASSURE), which showed that neither Sutent nor Nexavar improved DFS and OS compared with placebo4. The different outcomes of the S-TRAC and ASSURE trials can be explained through nuances in patient recruitment. The former recruited only patients at high-risk of disease progression whereas the latter included both intermediate- and high-risk patients, hence, the benefits provided by Sutent in high-risk patients (ASSURE trial) could have been diluted by the participants residing in the intermediate-risk group. Although Sutent may be approved in the adjuvant setting based on the S-TRAC trial, only high-risk patients will be eligible for this treatment (accounting for approximately 20-25% of the resectable market), which will significantly hamper potential sales of the agent in this setting. In addition, physicians will weigh potential benefits very carefully before prescribing a therapy with high toxicities in the adjuvant setting. As such, they are likely to only reserve adjuvant Sutent for their highest-risk patients with good health status.
In the CABOSUN trial, Cabometyx demonstrated strong PFS and ORR benefit compared with the current first-line standard of care, Sutent, for the treatment of locally advanced or metastatic, clear-cell renal cell carcinoma. Experts interviewed by DRG previously expressed concern regarding Cabometyx’s toxicity; however, it transpired that the safety profile was comparable between the Cabometyx and Sutent arms. It is noteworthy that CABOSUN is a Phase II study (N = 157), and while Eisai’s Lenvima/Kisplyx in combination with Afinitor was granted approval in the United States and Europe for previously-treated advanced renal cell carcinoma based on a Phase II registration study recruiting a similar number of patients (N = 153)5,6, DRG does not expect data from the CABOSUN to be solely sufficient. Rather, we expect that a confirmatory Phase III trial will be required to secure a label expansion to the first-line setting to support the positive data acquired from the CABOSUN study.
The positive data from S-TRAC and CABOSUN could pave the way for significant advancements in the management of renal cell carcinoma. S-TRAC and CABOSUN could lead to valuable new treatment options in the adjuvant and locally advanced and metastatic settings, and alter the treatment algorithm. These trials could potentially translate to a significant benefit from a patient perspective, including a prolongation in life-expectancy. However, they also reveal unanswered questions, and further data will be needed to elucidate optimal medical practice.
Further insights on Sutent and Cabometyx in renal cell carcinoma, including their positioning in current and future treatment algorithms and market dynamics, can be found in our 2016 offerings (Disease Landscape & Forecast; Current Treatment; Unmet Need).
- Ravaud A et al. Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC). ESMO 2016; LBA11_PR.
- Choueiri TK et al. CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial. ESMO 2016; LBA30_PR.
- Exelixis, Press Release, May 23, 2016
- Haas NB et al. Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol 33, 2015 (suppl 7; abstr 403).
- FDA, Press Release, May 13, 2016.
- Eisai, Press Release, September 15, 2016.