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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SUMMARY REPORT

Your score: [score] questions

Here are the answers and additional info:

Easy Level

Question 1.

Which criteria is NOT used to determine the metastatic RCC IMDC risk category?

a) corrected serum calcium levels above normal limits

b) LDH levels 1.5 the upper level limits

c) hemoglobin below lower level limits

d) platelet counts above normal limits

e) neutrophil counts levels above normal limits

You Answered: [answer]

Answer Rationale

The IMDC criteria for metastatic renal carcinoma takes into account the following : time from initial diagnosis to treatment, Karnofsky performance score, low hemoglobin, high calcium, high platelet counts and high neutrophil counts. It does not take into account LDH levels.

Reference:

Ko JJ, Xie W, Kroeger N, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol 2015; 16(3):293–300.

Question 2.

Which drug is NOT a VEGF/VEGFR inhibitor?

a) sunitinib

b) axitinib

c) everolimus

d) bevacizumab

e) pazopanib

You Answered: [answer]

Answer Rationale

Sunitinib, axitinib, bevacizumab and pazopanib target the HIF/VEGF axis but everolimus, is an inhibitor of the mammalian target of rapamycin (mTOR) pathway.

Reference:

Escudier B, Porta C, Schmidinger M, et al. Renal Cell Carcinoma: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up.  Ann Oncol. 2019;30(5):706-720.

Question 3.

Which statement matches the design or conclusions of the CARMENA study?

a) CARMENA is a phase-II study comparing upfront to delayed cytoreductive nephrectomy for newly diagnosed metastatic clear cell renal cell carcinoma.

b) CARMENA concluded that delayed cytoreductive nephrectomy after 2 cycles of sunitinib improved overall survival compared to upfront nephrectomy

c) CARMENA is a phase-III randomized trial comparing pazopanib alone to pazopanib and cytoreductive nephrectomy for the treatment of newly diagnosed metastatic clear cell renal cell carcinoma

d) CARMENA concluded that sunitinib alone was not inferior to cytoreductive nephrectomy followed by sunitinib in patients with metastatic clear cell renal cell carcinoma at diagnosis

e) CARMENA included both non-clear cell and clear cell renal carcinoma.

You Answered: [answer]

Answer Rationale

The CARMENA phase 3 trial assessed the role of nephrectomy in patients with metastatic renal cell carcinoma who were receiving targeted therapies. This study concluded that sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease.

Reference:

Méjean A, Ravaud A, Thezenas S, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med 2018;379(5):417-427.

Question 4.

Which drug is NOT recommended by the ESMO guidelines for the treatment of ANY subtype of metastatic non-clear cell renal carcinoma?

a) sunitinib

b) everolimus

c) pazopanib

d) cisplatin-based regimen

e) high-dose IL-2

You Answered: [answer]

Answer Rationale

According to the ESMO guidelines, the treatments above (targeted therapies: sunitinib, pazopanib, everolimus and cisplatin-based therapy) except for high-dose IL-2 are recommended for any subtype of metastatic non-clear cell RCC (e.g. papillary, chromophobe, collecting duct/medullary and sarcomatoid).

Reference:

Escudier B, Porta C, Schmidinger M, et al. Renal Cell Carcinoma: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up.  Ann Oncol. 2019;30(5):706-720.

Question 5.

Which gene and renal cell carcinoma subtype association is wrong?

a) MET and hereditary papillary RCC

b) VHL and Von Hippel Lindau Syndrome

c) FLCN and BHD Syndrome

d) FH and Hereditary Leiomyomatosis and RCC

e) None of these options

You Answered: [answer]

Answer Rationale

All of the above genes and their associated syndromes have been shown to have an increased risk of all types of renal cancer. Clear cell renal cancer is associated with von Hippel Lindau disease, chromosome 3 translocations, PTEN hamartoma tumor syndrome and mutations in BAP1, as well as several of the genes encoding the proteins comprising the succinate dehydrogenase complex (SDHB/C/D). Type 1 papillary renal cancers arise in conjunction with germline mutations in MET and type 2 as part of Hereditary Leiomyomatosis and Renal Cell Cancer (FH mutations). Chromophobe and oncocytic renal cancers are predominantly associated with Birt Hogg Dubé (BHD) syndrome.

Reference:

Carlo MI, Hakimi AA, Stewart GD, et al. Familial Kidney Cancer: Implications of New Syndromes and Molecular Insights. Eur Urol. 2019;76(6):754–764.

Intermediate Level

Question 6.

Which of the following immune checkpoint inhibitor combination therapies are recommended in treatment-naive patients with metastatic clear-cell renal cell carcinoma with IMDC favourable risk based on overall survival benefit?

a) Nivolumab plus ipilimumab

b) Pembrolizumab plus axitinib

c) Atezolizumab plus bevacizumab

d) Avelumab plus axitinib

You Answered: [answer]

Answer Rationale

Correct answer is b based on the results of the Keynote trial published in NEJM. Nivo plus Ipi is not recommended in favourable risk and c and d have no OS advantage (yet).

References:

1: ESMO Guidelines eUpdate: RCC algorithm.

2: Rini BI, Plimack ER, Stus V et al; Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019; 380(12): 1116–1127.

Question 7.

Which of the following VEGFR-TKIs should be preferred after treatment failure of first-line dual immune checkpoint inhibition:

a) Sunitinib

b) Cabozantinib

c) Tivozanib

d) None of these options

You Answered: [answer]

Answer Rationale

The latest ESMO RCC guideline update (electronic version from 07.02.20) does recommend a VEGFR-TKIs without a preference due to the absence of data from randomized controlled trials in this setting.

Reference:

https://www.esmo.org/guidelines/genitourinary-cancers/renal-cell-carcinoma/eupdate-renal-cell-carcinoma-treatment-recommendations

Question 8.

The complete response (CR) rate achieved with nivolumab and ipilimumab in a population unselected for PD-L1 expression in the original publication was:

a) 16%

b) 5.8%

c) 9%

d) 2.5%

You Answered: [answer]

Answer Rationale

The CR rate in the NEJM publication by Motzer et al. is 9%.

Reference:

Motzer RJ, Tannir NM, McDermotte DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21.

Question 9.

In which setting does the EAU renal cancer guidelines advise upfront cytoreductive nephrectomy?

a) In all MSKCC risk groups, because MSKCC risk was never designed to decide about cytoreductive nephrectomy

b) Only in intermediate MSKCC risk when systemic therapy is required

c) In patients with good performance or oligometastatic disease which can be rendered disease free or observed before starting systemic therapy

d) In the many patients presenting with MSKCC favourable risk group

You Answered: [answer]

Answer Rationale

Regarding answer d: very few patients are favourable risk.

Reference:

Bex, A. Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma Eur Urol. 2018 Dec;74(6):805-809. Epub 2018 Aug 31.

Question 10.

Which of the following statements regarding follow-up after surgical resection of non-metastatic renal cell carcinoma is FALSE:

a) Post-recurrence survival is better in patients if they were followed with high-intensity imaging protocols

b) Follow-up frequency and intervals should be tailored by risk-of-recurrence

c) Follow-up regimens for renal cancer have never been compared prospectively

d) AUA, EAU and NCCN guidelines make use of risk-adapted recommendations

You Answered: [answer]

Answer Rationale

RECUR database analysis demonstrated that metastasectomy or other focal therapies in patients with resectable oligometastatic recurrence in high-risk disease had the shortest disease-free survival compared to intermediate or low-risk RCC.

Reference:

Dabestani S, Beisland C, Stewart GD, et al.  Intensive Imaging-based Follow-up of Surgically Treated Localised Renal Cell Carcinoma Does Not Improve Post-recurrence Survival: Results from a European Multicentre Database (RECUR). Eur Urol. 2019 Feb;75(2):261-264. Epub 2018 Oct 11

Difficult Level

Question 11.

Which TKI improved disease-free survival in the adjuvant setting for high-risk localized clear cell RCC?

a) Pazopanib

b) Sunitinib

c) Axitinib

d) Sorafenib

e) Sunitinib and Pazopanib

You Answered: [answer]

Answer Rationale

Four trials examining the role of adjuvant targeted therapy have been reported, the PROTECT trial (pazopanib vs placebo), the ATLAS trial (axitinib vs placebo), the ASSURE trial (sunitinib or sorafenib vs placebo) and the S-TRAC study (sunitinib vs placebo). None of these trials demonstrated an overall survival benefit. Only the S-TRAC trial showed a statistically significant benefit for disease-free survival, making sunitinib an option after carefully weighing the pros and cons. However, due to the lack of an overall survival benefit adjuvant therapy with targeted agents is generally not considered standard of care.

References:

1: Gross-Goupil M, Kwon TG, Eto M, Ye D, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol. 2018 Dec 1;29(12):2371-2378.

2: Motzer RJ, Haas NB, Donskov F, et al; PROTECT investigators. Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol. 2017 Dec 10;35(35):3916-3923.

3: Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med. 2016 Dec 8;375(23):2246-2254.

4: 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, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16.

Question 12.

A 62-year old male patient with primary metastatic clear-cell renal cell carcinoma, 2 metastatic sites (liver and multiple lung) and low hemoglobin count, with a WHO performance of 1 and rheumatoid arthritis as comorbidity is best treated with:

a) Nivolumab and ipilimumab only

b) Upfront cytoreductive nephrectomy with observation of metastases

c) Sunitinib only

d) Sunitinib with the option to perform a cytoreductive nephrectomy after response at metastatic sites

You Answered: [answer]

Answer Rationale

Due to the rheumatoid arthritis, the patient is not a candidate for dual ICI. He has two metastatic sites, intermediate MSKCC risk (2 factors low hemoglobin and time from diagnosis to treatment) and a performance of 1 indicating he should start with systemic therapy. The sunitinib-only arm allowed secondary nephrectomies in CARMENA and good OS was achieved with a deferred CN strategy in SURTIME.

Reference:

Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma. Eur Urol. 2018 Dec;74(6):805-809. Epub 2018 Aug 31.

Question 13.

Patients with sarcomatoid or partially sarcomatoid RCC represent a particular therapeutic challenge. High complete response rates (> 10%) and significant overall survival benefit have been shown for which therapies?

a) Sunitinib

b) Pembrolizumab + Axitinib

c) Nivolumab

d) Nivolumab + Ipilimumab

e) Pembrolizumab + Axitinib + Nivolumab + Ipilimumab

You Answered: [answer]

Answer Rationale

Sarcomatoid RCC is an aggressive form of RCC carrying very poor prognosis. Results with targeted agents have been very disappointing. Recent studies have shown significantly improved results with immunotherapy as compared to targeted agents including a high number of complete responses. Therefore, immunotherapy or immunotherapy combinations are recommended for the treatment of sarcomatoid RCC or RCC with sarcomatoid components.

References:

Rini B, Plimack E, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study. J Clin Oncol 2019;37(15): 4500-4500.

McDermott DF, Choueiri TK, Motzer RJ, et al. CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features. J Clin Oncol 2019;37(15):4513-4513.

Question 14.

How many patients on Nivolumab/Ipilimumab (n=550) in Checkmate-214 required high-dose steroids (≥ 40 mg prednisone or prednisone equivalent) at some point in their treatment and how many required high-dose steroids (≥ 40 mg prednisone or prednisone equivalent) for more than 4 weeks?

a) 10% and 5%

b) 18% and 10%

c) 29% and 12%

d) 45% and 25%

e) 65% and 40%

You Answered: [answer]

Answer Rationale

Immune mediated side effects occur in a significant number of patients treated with Nivolumab/ipilimumab. Early recognition and treatment are key to safely manage these adverse events. 29% of all patients treated with nivolumab/ipilimumab required high dose steroids defined as ≥ 40 mg prednisone or prednisone equivalent in order to manage their immune mediated toxicity. 12% of all patients required high dose steroids for more than 4 weeks. Timely and competent management is a critical component of immunotherapy in metastatic RCC.

Reference:

Tannir NM, Motzer RJ, Plimack ER, et al. Outcomes in patients (pts) with advanced renal cell carcinoma (aRCC) who discontinued (DC) first-line nivolumab + ipilimumab (N+I) or sunitinib (S) due to treatment-related adverse events (TRAEs) in CheckMate 214. J Clin Oncol 2019;37(7):581-581

Question 15.

Based on results from phase II studies or real-world data, which of the following agents are treatment options for non-clear cell RCC:

a) Pembrolizumab

b) Sunitinib

c) Nivolumab

d) Cabozantinib

e) All of these agents

You Answered: [answer]

Answer Rationale

Non-clear cell RCC comprises about 15% of all RCC patients and includes a large variety of different RCC subtypes with papillary RCC being the most common one. Only very few prospective and/or randomized trials have been conducted in non-clear cell RCC. The optimal systemic treatment remains unclear but a number of targeted agents and more recently immunotherapies have shown activity in non-clear cell RCC. Most guidelines recommend the same treatment algorithm for non-clear cell RCC as for clear cell RCC.

References:

McDermott DF, Lee J-L, Ziobro M, et al. First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): Results from KEYNOTE-427 cohort B. J Clin Oncol. 2019;37(7): 546

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, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88.

Chahoud J, Msaouel P, Campbell MT, et al. Nivolumab for the Treatment of Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma (nccRCC): A Single-Institutional Experience and Literature Meta-Analysis. Oncologist. 2019 Sep 9. pii: theoncologist.2019-0372. [Epub ahead of print]

Martínez Chanzá N, Xie W, Asim Bilen M, et al. Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. Lancet Oncol. 2019;20(4):581-590.