“The results of the SORCE trial will end the debate about adjuvant tyrosine kinase inhibitors in renal cell carcinoma for most investigators,” Tim Eisen, MBBChir, PhD, of Cambridge (England) University Hospitals NHS Foundation Trust, said in an interview.
Dr. Eisen and colleagues reported results from SORCE in the Journal of Clinical Oncology.
Patients with intermediate- or high-risk RCC after surgical resection have 5-year relapse rates of 30%-40% and 5-year survival of 74.8% that declines steeply to 16% with metastatic disease, Dr. Eisen and colleagues wrote.
While adjuvant strategies – including cytokines, radiotherapy, and hormone therapy – have not yielded success, oral tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor have shown efficacy in metastatic RCC.
With inconsistent results in randomized trials of TKIs in the adjuvant RCC setting, however, active surveillance after nephrectomy has remained the international standard of care. SORCE was conducted “to settle the question of adjuvant TKI therapy” in RCC, according to Dr. Eisen and colleagues.
The investigators enrolled 1,711 patients with completely resected, clear cell or non–clear cell RCC at intermediate or high risk of relapse. The patients’ mean age was 58 years, 71% of patients were men, and 84% had clear cell histology.
Patients were randomized (2:3:3) to 3 years of placebo, 1 year of sorafenib followed by 2 years of placebo, or 3 years of sorafenib.
The initial sorafenib dose was 400 mg twice per day orally, but it was amended to 400 mg daily.
The primary outcome was investigator-reported disease-free survival comparing 3 years of sorafenib with placebo.
No survival benefit, more adverse events
Survival outcomes were similar across the study arms. The median disease-free survival was not reached for 3 years of sorafenib or for 3 years of placebo (hazard ratio, 1.01; 95% confidence interval, 0.82-1.23; P = .946).
The restricted mean survival time over 10 years was 6.81 years for 3 years of sorafenib and 6.82 years for 3 years of placebo (P = .988).
As for overall survival, the hazard ratio for 3 years of sorafenib versus 3 years of placebo was 1.06 (95% CI, 0.82-1.38; P = .638), and the hazard ratio for 1 year of sorafenib versus 3 years of placebo was 0.92 (95% CI, 0.71-1.20; P = .541).
Adverse events of grade 3 or higher were reported by 58.6% of patients receiving 1 year of sorafenib, 63.9% of patients receiving 3 years of sorafenib, and 29.2% of patients receiving placebo. Serious adverse events were reported at rates of 19.1% for placebo, 21.6% for 1 year of sorafenib, and 24% for 3 years of sorafenib.
Despite being offered treatment adaptations, more than half of participants had stopped treatment by 12 months because of toxicity.
Results undermine TKI use
“The significant toxicity observed with TKI monotherapy, despite pragmatic dose reductions, together with lack of evidence of a survival benefit, fundamentally undermines the use of TKIs in the adjuvant treatment of RCC,” Dr. Eisen and colleagues concluded.
In an interview, Dr. Eisen noted: “We are now asking whether adjuvant PD-1/PD-L1, with or without CTLA4 checkpoint inhibitors, are of benefit for patients who have had a high- or intermediate-risk RCC resected. A more challenging question is whether neoadjuvant checkpoint inhibitors may add further benefit. There are many such studies, which will report over the next few years and have the potential to change the treatment landscape enormously.”
“Interest in the field in general has shifted to immunotherapy and immunotherapy/TKI combinations,” observed Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute in Bethesda, Md., who was not involved in this study.
“The majority in the field probably had a fairly good idea that sorafenib was unlikely to show any benefit, whether given over 1 or 3 years. SORCE results were not unexpected. They do cement our belief that TKIs such as sorafenib do not have a real role in managing patients with kidney cancer in the adjuvant setting,” Dr. Srinivasan said.
The SORCE trial was supported by Bayer, Cancer Research UK, the Medical Research Council, University College London, Cancer Australia, and the Australian National Health and Medical Research Council. Dr. Eisen disclosed relationships with AstraZeneca, Roche, EUSA, Bayer, Pfizer, Macmillan Cancer Support, and Kidney Cancer UK. His coauthors disclosed relationships with many companies. Dr. Srinivasan disclosed that the National Cancer Institute has received funds from Calithera Biosciences and Peloton/Merck for clinical trials on which he was the principal investigator.
SOURCE: Eisen T et al. J Clin Oncol. 2020 Oct 14. J Clin Oncol. 2020 Oct 14. doi: 10.1200/JCO.20.01800.