For these various histologies, option 1 according to Dr. Pal is the mixed bag approach. However, the problem with this approach is that we don’t always get a clear answer for specific histologies. For example, in the ESPN trial, it is hard to assess whether everolimus or sunitinib is the best approach for patients with chromophobe or unclassified disease, as there are less than 10 patients in each cohort. The approach that Dr. Pal has been a proponent of for the last several years is the histologic bag approach. This is where clinical trials are tailored to an individual subtype of disease, for example, the SWOG S1500 PAPMET trial that randomized patients with type I papillary RCC to either sunitinib, cabozantinib, crizotinib, or savolitinib. The problem with the histologic bag approach is a practical one in that given the relative rarity of these subtypes, these studies are slow to accrue patients. For example, in the SWOG S1500 PAPMET trial, they accrued an average of 3.6 patients/month with many centers accruing three or fewer patients. A second problem with the histologic bag approach is that there is a lot of diversity amongst histologies. For patients with papillary RCC, you see a fair number of patients, particularly in type I disease, that are met-driven, but there are also patients with alterations around cell cycle pathways and TOR pathways. As Dr. Pal points out, this is also true for chromophobe and collecting duct RCC.
The third approach, which the three abstracts Dr. Pal is discussing have taken, is the biologically driven bag approach. The first study is the SAVOIR study presented by Dr. Choueiri and colleagues that randomized patients with met-driven papillary RCC 1:1 to savolitinib versus sunitinib. The trial design for SAVOIR is as follows:
This study aimed to enroll 180 patients, but ultimately only 60 patients were enrolled. According to Dr. Pal, this study should have continued given that in a retrospective study of patients with papillary RCC, time to treatment failure was similar to whether you had met-driven or met-independent disease; overall survival was also similar. Indeed, this trial did not suffer from poor accrual, with 4 patients accrued per month, a similar accrual rate to SWOG S1500 PAPMET trial. Regarding efficacy, patients receiving savolitinib had a 27% ORR compared to 7% for sunitinib, as well as a median OS of not reached for savolitinib vs 13.2 months for sunitinib (HR 0.51, 95% CI 0.21-1.17). Dr. Pal notes that this is compelling early data with encouraging trends in both response and survival. When assessing these responses of savolitinib to other met-driven therapeutics, savolitinib stands up well and is on par with savolitinib + durvalumab:
Dr. Pal notes that what may have saved the SAVIOR trial is perhaps more widespread genomic testing for patients with non-clear cell kidney cancer, which may have linked more patients to this clinical trial.
The second abstract Dr. Pal discussed was presented by Dr. Srinivasan and colleagues assessing HLRCC treated with bevacizumab and erlotinib in a phase 2 trial. From an overview perspective, Dr. Pal notes that the response rate for HLRCC was 72.1% compared to 35% in sporadic papillary RCC. This data is further supplemented by a real-world corroboration of bevacizumab + erlotinib showing PFS of 13.3 months and a response rate of 50% in 10 patients with HLRCC from South Korea.4 Whether bevacizumab + erlotinib should be standard of care for HLRCC remains to be seen. Those that think that it should point to the PFS/RR data that is incredibly compelling, as well as the fact that no standard currently exists in this population, thus a randomized trial is hard to envision. Those that do not think bevacizumab + erlotinib should be standard of care would suggest that this is a single-center study requiring travel to a specialty center, with a slow pace of accrual (0.4 patients/month), with the possibility of selection bias. Furthermore, it was a non-randomized trial, without a control arm.
The final study that Dr. Pal discussed was a phase 2 study of the oral HIF-2alpha inhibitor MK-6482 for patients with von Hippel-Lindau (VHL) disease-associated RCC. This study of 61 patients had a confirmed response rate (partial response) of 27.9% in RCC lesions, with 86.9% of patients having a decrease in the size of the target lesions. This data for MK-6482 aligns favorably with previous studies looking at sunitinib (33.0% partial response) and pazopanib (49.0% partial response) for patients with VHL-associated RCC. Dr. Pal highlights that the best way to get trials done for rare subtypes of RCC is to utilize a multi-center approach, in addition to engaging investigators, patients, advocates, and industry.
He concluded with the following take-home messages for these three abstracts:
- Savolitinib appears encouraging in MET-driven RCC, but we need to amplify efforts to genomically profile patients
- Bevacizumab + erlotinib data appears very promising in HLRCC-associated RCC, but we need to consider multicenter studies
- MK-6482 has activity in VHL disease-associated RCC and now is probably the time to consider randomized studies to establish standard therapy
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.
- Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in Metastatic Non-clear cell renal cell carcinoma (ESPN): A Randomized Multicenter phase 2 trial. Eur Urol 2016;69(5):866-874.
- Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): A multicentre, open-label, randomized phase 2 trial. Lancet Oncol 2016 Mar;17(3):378-388.
- Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32(25):2765-2772.
- Choi Y, Keam B, Kim M, et al. Bevacizumab plus Erlotinib combination therapy for advanced hereditary leiomyomatosis and renal cell carcinoma-Associated hereditary renal cell carcinoma: A multicenter retrospective analysis in Korean patients. Cancer Res Treat 2019 Oct;51(4):1549-1556.