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Dear [nickname],
Thank you for playing the RCC Quest. The objective of this game is to identify the learning gaps and needs of urologists on the topic of systemic therapy in RCC.
Below outlines a summary report of your performance. Each question is followed by the correct answer as well as an explanation of the rationale for the correct answer, and the corresponding reference, for your information.
We hope you will find this information helpful to you.
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Your score: [score] questions
Here are the answers and additional info:
Easy LevelWhich of the following drugs is a programmed death-1 (PD-1) inhibitor?
a) Avelumab
b) Tremelimumab
c) Nivolumab
d) Atezolizumab
e) Durvalumab
You Answered: [answer]Of the answers, only nivolumab is a monoclonal antibody against PD-1. Avelumab, atezolizumab and durvalumab are monoclonal antibodies against the ligand of PD-1 (PD-L1 inhibitors) and tremelimumab is a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
Reference: Ljungberg B, Albiges L, Abu-Ghanem Y, Bedke J, Capitanio U, Dabestani S, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: the 2022 update. Eur Urol. 2022;82(4):399-410. doi:10.1016/j.eururo.2022.03.006.
Several immune checkpoint inhibitor adjuvant trials have recently been performed in kidney cancer. Which of the following drugs is approved for adjuvant use following resection of renal cancer with a high risk of recurrence?
a) Nivolumab
b) Pembrolizumab
c) Atezolizumab
d) Nivolumab plus ipilimumab
e) Durvalumab plus tremelimumab
You Answered: [answer]Only the KEYNOTE-564 trial was positive for disease-free survival and led to approval of pembrolizumab; all other trials were negative or did not fully recruit.
Reference: Kuusk T, Bex A. Adjuvant and neoadjuvant therapy in renal cell carcinoma. Hematol Oncol Clin North Am. 2023;25:S0889-8588(23)00075-8. doi:10.1016/j.hoc.2023.05.020.
Which of the following statements regarding cytoreductive nephrectomy (CN) in the era of immune checkpoint inhibitor combination therapy is TRUE?
a) Deferred CN following immune checkpoint inhibitor therapy is supported by randomized controlled trials.
b) Retrospective data suggest that patients with complete response at metastatic sites can gain durable complete remission by deferred CN
c) To improve response to immunotherapy, CN should be offered upfront.
d) Patients with oligometastatic disease do not benefit from CN.
e) Inflammatory reactions following immune checkpoint inhibitor therapy facilitate surgical resection.
You Answered: [answer]Currently randomized controlled trials (PROBE, NORDICSUN) investigate the role of deferred CN versus no CN in patients who do not progress with immune checkpoint inhibitor therapy but data are not yet available. Meanwhile retrospective data reveal that approximately 10% of patients treated with their primary tumour in place achieve complete responses at metastatic sites. Deferred CN in those patients can lead to durable complete remission but surgery may be difficult due to inflammatory reactions.
Reference: Meerveld-Eggink A, Graafland N, Wilgenhof S, Van Thienen JV, Lalezari F, Grant M, Szabados B, et al. Primary renal tumour response in patients treated with nivolumab and ipilimumab for metastatic renal cell carcinoma: real-world data assessment. Eur Urol Open Sci. 2022;35:54-58. doi:10.1016/j.euros.2021.11.003.
Which statement about adverse events reported in adjuvant renal cancer trials with immune checkpoint inhibitors is TRUE?
a) The most common adverse event with adjuvant pembrolizumab was hand-foot syndrome.
b) Adjuvant atezolizumab had the highest frequency of treatment-related adverse events compared to other adjuvant immune checkpoint inhibitors.
c) All-cause adverse events of any grade led to discontinuation of adjuvant nivolumab plus ipilimumab in 32% of treated patients.
d) There were no deaths attributed to treatment with adjuvant nivolumab plus ipilimumab.
e) Serious adverse events were not observed with adjuvant atezolizumab.
You Answered: [answer]Hand-foot syndrome is a typical adverse event of VEGFR-TKI but not immune checkpoint inhibitors. Adjuvant atezolizumab was well tolerated with only few grade 3-4 adverse events and 18% serious adverse events. On the contrary, all-cause adverse events of any grade led to discontinuation of adjuvant nivolumab plus ipilimumab in 32% of treated patients and 4 deaths (1%) were attributed to treatment.
References:
Motzer RJ, Russo P, Grünwald V, Tomita Y, Zurawski B, Parikh O, et al. Lancet. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet. 2023;401(10379):821-832. doi:10.1016/S0140-6736(22)02574-0.
Pal SK, Uzzo R, Karam JA, Master VA, Donskov F, Suarez C, Albiges L, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2022;400(10358):1103-1116. doi:10.1016/S0140-6736(22)01658-0.
Which of the following is not a subtype entity in kidney cancer?
a) Papillary
b) Chromophobe
c) Collecting duct carcinoma
d) Sarcomatoid
e) Clear cell
You Answered: [answer]Sarcomatoid is a differentiation and can occur in conjunction with several subtypes of clear cell and non-clear cell renal cell carcinoma.
Reference: Albiges L, Flippot R, Rioux-Leclercq N, Choueiri TK. Non-clear cell renal cell carcinomas: from shadow to light. J Clin Oncol. 2018;36(36):3624-3631. doi:10.1200/JCO.2018.79.2531.
Which of the following small molecule inhibitors is matched correctly with its target(s)?
a) Belzutifan – HIF1b
b) Cabozantinib – MET, Axl, VEGFRs
c) Tivozanib – FGFR, VEGFRs
d) Lenvatinib – mTOR
e) Everolimus – PDGFR
You Answered: [answer]Belzutifan inhibits HIF2a, tivozanib is more selective for VEGFRs than FGFR, lenvatinib has activity against VEGFRs and FGFR, and everolimus is an mTOR inhibitor. Only cabozantinib is matched appropriately with its targets MET, Axl and VEGFRs.
Reference: Grülich C. Cabozantinib: Multi-kinase inhibitor of MET, AXL, RET, and VEGFR2. Recent Results Cancer Res. 2018;211:67-75. doi:10.1007/978-3-319-91442-8_5.
Which patient subset had the highest benefit in disease-free survival (DFS) from KEYNOTE-564 of adjuvant pembrolizumab versus placebo?
a) T2 N0 M0, grade 4 or sarcomatoid
b) Tx N+ M0
c) T3/T4 N0 M0, any grade
d) M1 NED
e) None of these options
You Answered: [answer]30-month follow-up of KEYNOTE-564 continued to show highest DFS benefit in M1 NED population.
Reference: Powles T, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23(9):1133-1144. doi:10.1016/S1470-2045(22)00487-9.
For immunotherapy refractory metastatic clear cell renal cell carcinoma, which of the following remains the preferred treatment based on randomized phase 3 data?
a) Lenvatinib-pembrolizumab
b) Cabozantinib
c) Cabozantinib-nivolumab
d) Cabozantinib-atezolizumab
e) Axitinib-pembrolizumab
You Answered: [answer]Patients with IO-refractory metastatic clear cell RCC were enrolled on the phase 3 CONTACT-03 trial, comparing cabozantinib with cabozantinib-atezolizumab. Cabozantinib-atezolizumab did not show an additive response. Lenvatinib-pembrolizumab has only shown randomized benefit in upfront mRCC and single cohort benefit for non-clear cell RCC. Similarly, cabozantinib-nivolumab and axitinib-pembrolizumab have shown randomized benefit in upfront mRCC and have not been tested in refractory clear cell RCC.
Reference: Pal SK, Albiges L, Tomczak P, Suárez C, Voss MH, de Velasco G, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. The Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4.
A patient with metastatic renal cell carcinoma is being treated with axitinib and pembrolizumab. He calls with new onset diarrhea 5-6 times over the past 24h. What is the usual first step in management?
a) Stop axitinib
b) Start oral prednisone 1mg/kg
c) Start IV solumedrol 1mg/kg
d) Start loperamide
e) Start diphenoxylate and atropine
You Answered: [answer]Diarrhea is an overlapping toxicity of both axitinib and pembrolizumab. Axitinib has a short half-life (4 hours) and is the easiest to hold first, for side effect attribution. If diarrhea does not improve after holding axitinib, then treating with steroids for immune mediated colitis is warranted.
Reference: Zakharia Y, Huynh L, Du S, Chang R, Pi S, Sundaresan S, et al. Impact of therapy management on axitinib-related adverse events in patients with advanced renal cell carcinoma receiving first-line axitinib + checkpoint inhibitor. Clin Genitourin Cancer. Published online April 2023. doi:10.1016/j.clgc.2023.03.017.
Which of the following is the preferred first-line treatment for metastatic papillary renal cell carcinoma?
a) Cabozantinib with atezolizumab
b) Cabozantinib
c) Lenvatinib with pembrolizumab
d) Sunitinib
e) Lenvatinib with everolimus
You Answered: [answer]Based on the SWOG PAPMET trial, cabozantinib was shown to be superior to sunitinib, crizotinib, and savolitinib for metastatic papillary RCC.
Reference: Pal SK, Tangen C, Thompson IM, Balzer-Haas N, George DJ, Heng DYC, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703. doi:10.1016/S0140-6736(21)00152-5.
Which of the following drugs is a HIF-2α inhibitor?
a) Sunitinib
b) Avelumab
c) Belzutifan
d) Savolitinib
e) Lenvatinib
You Answered: [answer]Belzutifan is a novel HIF-2α inhibitor. Sunitinib and Lenvatinib are VEGFR-TKIs. Avelumab is a PD-L1 inhibitor. Savolitinib is a c-MET inhibitor.
Reference: Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805. doi:10.1038/s41591-021-01324-7.
The triplet combination of cabozantinib/nivolumab/ipilimumab is statistically significant superior to ipilimumab/nivolumab with regards to:
a) Progression-free survival
b) Progression-free survival and response rate
c) Overall survival and response rate
d) Response rate and duration of response
e) None of these options
You Answered: [answer]Based on the COSMIC 313 study, only PFS was statistically significant improved.
Reference: Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851.
Which treatment regimen provides an overall survival benefit for the following patient:
62-year-old male, nephrectomy January 2022, lung and lymph node metastases March 2023, ECOG performance of 1, and neutrophils 5.9 (normal range 2.0-8.0), hemoglobin 137 (normal range 135-170), platelets 307 (normal range 150-400), sodium 132 (normal range 135-145), creatinine 125 (normal range 60-115), calcium 2.41 (normal range 2.18-2.58), albumin 37 (normal range 35-45), LDH 510 (normal range 90-225).
a) Pembrolizumab/axitinib
b) Nivolumab/ipilimumab
c) Pembrolizumab/lenvatinib
d) Pembrolizumab/axitinib + Pembrolizumab/lenvatinib
e) None of these options
You Answered: [answer]Patient is favorable risk according to the IMDC classification: good performance status, time from diagnosis to systemic treatment >1 year, normal neutrophils, platelets, calcium and hemoglobin. No regimen has demonstrated an overall survival benefit for IMDC favorable risk patients.
References:
Plimack ER, Powles T, Stus V, Gafanov R, Nosov D, Waddell T, et al. Pembrolizumab plus axitinib versus sunitinib as first-line treatment of advanced renal cell carcinoma: 43-month follow-up of the phase 3 KEYNOTE-426 study. Eur Urol. 2023;S0302-2838(23)02901-9. doi:10.1016/j.eururo.2023.06.006.
Grünwald V, Powles T, Kopyltsov E, Kozlov V, Alonso-Gordoa T, Eto M, et al. Survival by depth of response and efficacy by international metastatic renal cell carcinoma database consortium subgroup with lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma: analysis of the phase 3 randomized CLEAR study. Eur Urol Oncol. 2023;6(4):437-446. doi:10.1016/j.euo.2023.01.010.
Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851.
Motzer RJ, McDermott DF, Escudier B, Burotto M, Choueiri TK, Hammers HJ, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097. doi:10.1002/cncr.34180.
How many patients in the cabozantinib/nivolumab/ipilimumab arm of COSMIC-313 discontinued any component of their treatment regimen and how many required high-dose steroids (≥40 mg prednisone or prednisone equivalent for any duration) at some point in their treatment?
a) 20% and 5%
b) 67% and 30%
c) 29% and 34%
d) 45% and 58%
e) 31% and 78%
You Answered: [answer]Based on the COSMIC-313 analysis: 45% of patients in the triplet arm discontinued any component of their treatment regimen due to toxicity and 58% required high-dose steroids of any duration during treatment.
Reference: Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023; 388 (19):1767-1778. doi:10.1056/NEJMoa2212851.
Which of the following RCC subtypes may be caused by fumarate hydratase mutations?
a) Papillary type 1
b) Chromophobe
c) Collecting duct carcinoma
d) Papillary type 2
e) Renal medullary RCC
You Answered: [answer]Hereditary leiomyomatosis/fumarate hydratase mutation is associated with aggressive papillary type II RCCs.
Reference: Maher E. Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management. World J Urol. 2018;36(12):1891-1898. doi:10.1007/s00345-018-2288-5.
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