ASCO 2017: Can Subgroup Analyses Identify Enrichment Strategies for Adjuvant RCC Studies?
Dr. Heng started by highlighting the three reported TKI adjuvant trials: (i) ASSURE, which found no disease-free survival (DFS) or overall survival (OS) benefit for either sunitinib or sorafenib among clear cell and non-clear cell RCC ≥T2Gr3/4 patients [3]; (ii) S-TRACT, which found a DFS benefit (1-2 years, HR 0.75), but no OS benefit with the immature data (and underpowered) among patients with clear cell RCC ≥T3 disease [4]; and (iii) PROTECT, which found no DFS or OS for adjuvant pazopanib among patients with clear cell RCC ≥T2Gr3/4 patients [1]. Indeed, adjuvant therapy for resected localized RCC remains controversial, with low uptake. It is difficult to know if high risk subgroups may benefit more from adjuvant TKI therapy.
Dr. Heng feels that the optimal adjuvant therapy population has the following characteristics: high recurrence score, clear cell histology, and high stage. Adequate dosing for these patients is also crucial. As highlighted in the PROTECT Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 survey, tolerability of pazopanib, similarly to the ASSURE and S-TRAC studies, was poor. Furthermore, as was highlighted in a recent study, even when broken down by quartiles of different dose intensities, there was no difference in DFS in the ASSURE trial [5]. Despite these underwhelming initial trial results, we are awaiting reporting of three ongoing trials: (i) ATLAS – axitinib vs placebo among patients with ≥T2 or N+ disease with >50% clear cell histology; (ii) SORCE – sorafenib (1 vs 3 years) vs placebo among patients with Leibovich stage 3-11 disease with both clear and non-clear cell histology; and (iii) EVEREST – everolimus vs placebo among patients with T1b-4 or N+ disease with both clear and non-clear cell histology.
The concept of RCC histology is important. S-TRAC enrolled only patients with clear cell RCC, which Dr. Heng suggests may partially explain the DFS improvement and may be a necessary strategy to enrich for patients that benefit from therapy. However, as he cautions, limiting enrollment to clear cell histology marginalized papillary and other histologies.
The concept of the Recurrence Score was previously developed by Dr. Escudier’s group and published in 2015 [6]. This was developed retrospectively for patients with localized clear cell RCC stages I-III, using gene expression assay using tumor FFPE. The developmental cohort was performed at the Cleveland Clinic and subsequently validated in the French cohort, followed by comparison against the Leibovich Score. In this study, the Leibovich Score had a c-index for predicting recurrence of 0.74, the 16-gene Recurrence score gene assay c-index was 0.79, and the Leibovitch + 16 gene assay Recurrence score together had a c-index was 0.81. However, as Dr. Heng notes, the recurrence scores are only helpful if there is appropriate adjuvant therapy, which to date is marginal. With Dr. Escuider’s presentation to day [2], the 16-gene recurrence score is now externally validated, raising a number of considerations: (i) these are subgroup analysis, not prospective randomization by stratification, (ii) only 34% of S-TRAC patients were included in the analysis since not everyone had tissue available, (iii) we need to determine additional information the Recurrence Score provides beyond other criteria (ie. Leibovich) which already exist, and (iv) there was not enough power to detect significant interaction between Recurrence Score and sunitinib, suggesting there could be effect modification not detectable due to the small sample size. Prospective studies assessing Recurrence Score, particularly with PD1 trials should be strongly considered.
Dr. Heng concluded by stating once again that adjuvant pazopanib should not be used. The 16-gene Recurrence Score is now externally validated, but should not be used solely for now to determine if patients will benefit from adjuvant sunitinib, since it is not predictive. The optimal adjuvant patient is still controversial however we have hints based on subgroup analysis that these patients are likely clear cell histology, receive higher dose medication, higher stage, and higher Recurrence Score. Patient participation and tissue collection is critical in advancing predictive biomarkers for adjuvant therapy.
Presented By: Daniel Yick Chin Heng, Tom Baker Cancer Centre, Calgary, AB, Canada
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @zklaassen_md
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA
References:
1. Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol 2017;35(suppl; abstr 4507).
2. Escudier BJ, Rini BI, Martini JF, et al. Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: Validation of the 16-gene Recurrence Score in stage III patients. J Clin Oncol 2017;35(suppl; abstr 4508).
3. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomized, phase 3 trial. Lancet 2016 May 14;387(10032):2008-2016.
4. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 2016 Dec 8;375(23):2246-2254.
5. Haas NB, Manola J, Dutcher JP, et al. Adjuvant Treatment for High-Risk Clear Cell Renal Cancer: Updated Results of a High-Risk Subset of the ASSURE Randomized Trial. JAMA Oncol 2017 Mar 9 [Epub ahead of print].
6. Rini B, Goddard A, Knezevic D, et al. A 16-gene assay to predict recurrence after surgery in localized renal cell carcinoma: development and validation studies. Lancet Oncol 2015 Jun;16(6):676-685.