2022 - Medical Therapy for Renal Cell

Question 1

What were the key results and FDA approval date for CheckMate 214?

Answer 1

Nivolumab + Ipilimumab vs. Sunitinib. ORR: 42.1% vs 26.3%, CR: 10% vs 1%, OS: 47 vs 26.6 months. FDA approval: April 2018.

Question 2

What were the key results and FDA approval date for Keynote-426?

Answer 2

Axitinib + Pembrolizumab vs. Sunitinib. ORR: 60% vs 40%, CR: 9% vs 3%, PFS: 15.4 vs 11.1 months, OS: not reached vs 35.7 months. FDA approval: April 2019.

Question 3

What were the key results and FDA approval date for JAVELIN Renal 101?

Answer 3

Axitinib + Avelumab vs. Sunitinib. ORR in PD-L1+: 55% vs 25.5%, CR: 4.4% vs 2.1%, PFS PD-L1+: 13.8 vs 7.2 months. FDA approval: May 2019.

Question 4

What were the key results and FDA approval date for CheckMate 9ER?

Answer 4

Nivolumab + Cabozantinib vs. Sunitinib. ORR: 55.7% vs 27.1%, CR: 8.0% vs 4.6%, PFS: 16.3 vs 8.3 months. FDA approval: January 2021.

Question 5

What were the key results and FDA approval date for CLEAR?

Answer 5

Lenvatinib + Everolimus or Lenvatinib + Pembrolizumab vs. Sunitinib. ORR: 70.1% vs 36.1%, CR: 16.1% vs 4.2%, PFS: 23.9 vs 9.2 months. FDA approval: August 2021.

Question 6

What were the key results for Immotion 151, and was it submitted to the FDA?

Answer 6

Atezolizumab + Bevacizumab vs. Sunitinib. ORR in PD-L1+: 43% vs 35%, PFS in PD-L1+: 12.2 vs 7.7 months. Not submitted to the FDA.

Question 7

What are the preferred regimens for favorable and poor/intermediate risk clear cell kidney cancer?

Answer 7

Favorable risk: Axitinib + Pembrolizumab, Pazopanib, Sunitinib.
Poor/Intermediate risk: Ipilimumab + Nivolumab, Axitinib + Pembrolizumab, Cabozantinib.

Question 8

What are the other recommended regimens for favorable and poor/intermediate risk clear cell kidney cancer?

Answer 8

Favorable risk: Ipilimumab + Nivolumab, Axitinib + Avelumab, Cabozantinib (category 2B), Pazopanib, Sunitinib.
Poor/Intermediate risk: Axitinib + Avelumab.

Question 9

What regimens are considered useful in certain circumstances for favorable and poor/intermediate risk clear cell kidney cancer?

Answer 9

Favorable risk: Active surveillance, High dose IL-2, Axitinib.
Poor/Intermediate risk: Temsirolimus, Axitinib (category 2B), High dose IL-2.

Question 10

What updates are expected in the NCCN regimens with later 2021 versions?

Answer 10

Expect updates with CheckMate 9ER and CLEAR trials based on data from table 1.

Question 11

What are the preferred regimens for subsequent therapy for clear cell kidney cancer?

Answer 11

Cabozantinib (category 1), Nivolimab (category 1), Ipilimumab + Nivolumab (category 1).

Question 12

What are the other recommended regimens for subsequent therapy for clear cell kidney cancer?

Answer 12

Axitinib (category 1), Lenvatinib + Everolimus (category 1), Axitinib + Pembrolizumab, Everolimus, Pazopanib, Sunitinib, Axitinib + Avelumab (category 3).

Question 13

What is the annual estimate of new cases and deaths from kidney and renal pelvis cancer in the U.S.?

Answer 13

74,000 new cases and 15,000 deaths.

Question 14

What percentage of kidney cancer cases is represented by RCC?

Answer 14

Over 90%.

Question 15

According to the SEER data, what percentage of RCC patients present with metastatic disease, and what is the 5-year survival rate?

Answer 15

16% present with metastatic disease, and the 5-year survival rate is 12%.

Question 16

Why is it essential for the urology community to be aware of the rapid advancements in kidney cancer treatment?

Answer 16

Because 30%-40% of high-risk stage 2 and 3 cases may recur and require systemic treatment, and many patients ultimately need systemic treatment.

Question 17

What classic symptoms can still present with advanced RCC?

Answer 17

Flank pain, hematuria, and palpable abdominal renal mass.

Question 18

Why is a detailed family history important in RCC diagnosis, and what percentage may have a hereditary component?

Answer 18

It’s important to identify potential hereditary syndromes, especially in those diagnosed at a young age. Approximately 5%-8% of RCC may have a hereditary component.

Question 19

What are the preferred imaging techniques for detecting and staging RCC?

Answer 19

Multiphased abdominal CT or MRI, chest CT for high-risk patients, bone scan for specific cases, and brain MRI if neurological symptoms are present.

Question 20

What are the two major risk models for stratifying patients with advanced RCC?

Answer 20

The Memorial Sloan Kettering Cancer Center Prognostic Model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Criteria.

Question 21

What recent trials suggest that operating on poor surgical candidates with RCC may lead to worse outcomes?

Answer 21

The CARMENA and SURTIME trials.

Question 22

What are some of the options for managing both symptomatic and asymptomatic oligometastatic RCC disease?

Answer 22

Resection or metastasectomy, complete surgical resection of metastases, percutaneous ablation, and stereotactic radiation.

Question 23

What classic signs may indicate advanced RCC, and what specific signs could signify concerns for an obstructive tumor thrombus?

Answer 23

Classic signs include flank pain, hematuria, and palpable abdominal renal mass. Varicoceles, ascites, caput medusae, and lower extremity edema can signify concerns for an obstructive tumor thrombus.

Question 24

What considerations are necessary when evaluating RCC in younger patients (age ≤46 years), and what percentage of RCC may have a hereditary component?

Answer 24

Considerations include suspicion for hereditary syndromes like hereditary leiomyomatosis and RCC or Birt-Hogg-Dubé, and a detailed family history. Approximately 5%-8% of RCC may have a hereditary component.

Question 25

What imaging techniques are preferred for new renal tumors, and what are the considerations for chest imaging and high-risk patients?

Answer 25

Multiphased abdominal CT or MRI is preferred. Chest CT is more accurate for high-risk patients with a large renal mass. Second-generation macrocyclic MRI contrast agents are safer for moderate and severe renal dysfunction.

Question 26

What are the two major risk models for stratifying advanced RCC, and what era were the IMDC criteria developed in?

Answer 26

The two major risk models are the Memorial Sloan Kettering Cancer Center Prognostic Model and the IMDC Criteria, developed in the post-cytokine, targeted therapy era.

Question 27

What recent trials suggest caution in operating on poor surgical candidates with RCC, and what factors have led to diminished enthusiasm for cytoreductive nephrectomy?

Answer 27

The CARMENA and SURTIME trials caution against operating on poor surgical candidates or those with poor risk disease. Diminished enthusiasm stems from outstanding systemic agents and concerns for delay of therapy.

Question 28

What are the options for managing asymptomatic, low-volume RCC disease, and what has been observed in a phase II prospective trial regarding the initiation of systemic treatment?

Answer 28

Options include active surveillance, which can spare unnecessary toxicity. In a phase II trial with 52 asymptomatic RCC patients, the median time to initiation of systemic treatment of symptomatic disease was 14.9 months.

Question 29

What strategies are emerging for managing both symptomatic and asymptomatic oligometastatic RCC disease, and what benefits are associated with complete metastasectomy?

Answer 29

Strategies include resection or metastasectomy, percutaneous ablation, and stereotactic radiation. Complete metastasectomy is associated with a significantly reduced likelihood of death in the era of targeted and checkpoint inhibitor therapy.

Question 30

What were the limitations of cytotoxic chemotherapy prior to the 1990s, and how did the use of IL-2 and IFN-α evolve in the treatment of RCC?

Answer 30

Cytotoxic chemotherapy failed to provide meaningful responses. IL-2 and IFN-α were used during the cytokine era, with IL-2 showing a 15%-20% response rate but significant side effects. FDA approved IL-2 in 1992 and IFN-α in Europe in 1990 (U.S. in 2009).

Question 31

What groundbreaking discovery led to the 2019 Nobel Prize in Medicine concerning RCC treatment, and how did it influence the development of anti-angiogenic agents?

Answer 31

The discovery of VHL mutations in clear cell RCC, which affects angiogenesis through HIFa and VEGF, led to the development of targeted agents like bevacizumab, sorafenib, and sunitinib. The discovery won the 2019 Nobel Prize in Medicine.

Question 32

Describe the success of sunitinib in RCC treatment, and what side effects are commonly associated with VEGF-TKI agents?

Answer 32

Sunitinib showed higher response rates (31% vs 6%), improved PFS (11 vs 5 months), and greater OS (26.4 vs 21.8 months) compared to IFN-α. Side effects include hypertension, hand-foot syndrome, diarrhea, and vomiting.

Question 33

How has cabozantinib contributed to the treatment landscape of RCC, and what pathways does it affect?

Answer 33

Cabozantinib blocks VEGF, MET, and other pathways relevant to kidney cancer. It has shown improvement in PFS, OS, and response rate compared to everolimus and has become the standard approach in certain situations.

Question 34

What is the role of mTOR inhibition in RCC, and how have drugs like temsirolimus and everolimus impacted treatment?

Answer 34

mTOR inhibitors regulate cell growth and are approved for RCC. Temsirolimus showed an OS benefit, and everolimus improved PFS. They have limited activity but are combined with other drugs like Lenvatinib.

Question 35

How has immune CPI therapy changed the RCC treatment paradigm, and what are the results from significant trials like CheckMate 214 and KEYNOTE-426?

Answer 35

Immune CPI therapy enhances the immune system against RCC. Trials like CheckMate 214 showed improved PFS and ORR with ipilimumab plus nivolumab. KEYNOTE-426 showed benefits with pembrolizumab plus axitinib.

Question 36

What are the recent developments in combination therapies involving CPI and VEGF-TKI, and how have they shown efficacy in different trials?

Answer 36

Combination therapies like nivolumab plus cabozantinib, and avelumab with axitinib, have shown superior results in PFS, OS, and response rate. These results support the use of combination CPI-based therapy across various risk groups.

Question 37

What are the current goals in treating metastatic clear cell RCC?

Answer 37

Cure, if achievable, or long-term disease control and survival using immune checkpoint therapy combinations.

Question 38

What are the preferred first-line therapy options for metastatic clear cell RCC according to the NCCN® guidelines?

Answer 38

Axitinib/pembrolizumab for favorable and intermediate/poor risk groups, and ipilimumab/nivolumab for intermediate/poor risk group.

Question 39

What treatment options are available for patients considered ineligible or high risk for immunotherapy?

Answer 39

VEGF-TKI monotherapy options such as sunitinib, pazopanib, and cabozantinib.

Question 40

What are the challenges in managing patients after CPI treatment, and what are the available second-line therapies?

Answer 40

Limited data guide optimal management post-CPI, but single-agent CPI nivolumab has been approved as a second-line therapy.

Question 41

What are the primary treatment options for advanced nccRCC, and what challenges exist in treating this type?

Answer 41

Options include CPIs, VEGF-TKIs, and mTOR inhibitors, but evidence is limited, and responses vary by histological subtype.

Question 42

What success has been found in targeting the MET pathway in nccRCC?

Answer 42

Cabozantinib has shown improvement in PFS and response rate, making it the current standard of care for papillary kidney cancer.

Question 43

What are the findings of immunotherapy-based regimens in nccRCC?

Answer 43

Studies like CheckMate 374 and KEYNOTE-427 showed response rates with nivolumab and pembrolizumab. Immunotherapy-based regimens have also shown promising activity in sarcomatoid transformed RCC.

Question 44

What are the treatment approaches for less common nccRCC variants like collecting duct and medullary RCC?

Answer 44

Treatment usually starts with conventional chemotherapy, with some reported efficacy in immunotherapy.

Question 45

What were the findings of the ASSURE and S-TRAC trials evaluating adjuvant sunitinib?

Answer 45

ASSURE failed to meet its endpoint, showing no improvement. S-TRAC showed improved DFS (6.8 vs 5.6 years), leading to FDA approval of sunitinib, but with poor utilization.

Question 46

How did trials with other TKIs, such as SOURCE, PROTECT, and ATLAS, perform in adjuvant therapy for high-risk RCC?

Answer 46

These trials with sorafenib, pazopanib, and axitinib did not improve DFS or OS, and the ATLAS study closed due to futility.

Question 47

What are the main challenges in adjuvant therapy for high-risk RCC?

Answer 47

Challenges include high toxicity leading to dose reduction and treatment discontinuation, discordance in outcome in different trials, and the lack of improvement in OS.

Question 48

What is the ongoing EVEREST trial, and what is its focus?

Answer 48

EVEREST is evaluating the mTOR inhibitor everolimus for 1 year in the adjuvant setting in 1,545 patients. The final analysis is anticipated in March 2022.

Question 49

What were the key lessons learned from modern adjuvant trials in kidney cancer?

Answer 49

The lessons include the need for meaningful clinical endpoints like OS, and the need to consider dose levels to improve tolerability in largely asymptomatic patients.

Question 50

How have immune CPIs changed the treatment of kidney cancer, and what is the focus of ongoing trials?

Answer 50

Immune CPIs have become standard first-line therapy in kidney cancer. Ongoing trials are evaluating CPIs for high-risk RCC in the adjuvant setting, including combination therapy and monotherapy with PD-1/PD-L1 inhibitors.

Question 51

What were the initial results of Keynote-564, and what is the significance of these results?

Answer 51

Keynote-564 showed a DFS of 77.3% vs 68.1% favoring pembrolizumab with a hazard ratio of 0.68 (p=0.001) after 24 months. Though OS data is not yet mature, this may be a future option for high-risk clear cell RCC patients.

Question 52

What are the current challenges and focus areas in the management of advanced kidney cancer?

Answer 52

Challenges include defining clinically relevant predictive biomarkers for personalized therapy, exploring novel approaches beyond VEGF-TKI and CPI, and preventing distant disease in the adjuvant setting. Collaboration and engagement of urologists in surgical and medical management are essential.

Question 53

Which combination therapy is listed as a preferred first-line option for metastatic clear cell RCC in both favorable and intermediate/poor risk groups?
a. axitinib/ipilimumab
b. axitinib/pembrolizumab
c. sunitinib/ipilimumab
d. sunitinib/pazopanib

Answer 53

b. axitinib/pembrolizumab
Explanation: The NCCN® guidelines list axitinib/pembrolizumab as a preferred first-line therapy option for patients in both the favorable and intermediate/poor risk groups.

Question 54

Which agent has been approved as second-line therapy based on data from the CheckMate 025 study?
a. pembrolizumab
b. cabozantinib
c. nivolumab
d. axitinib

Answer 54

c. nivolumab
Explanation: Single-agent CPI nivolumab has been approved as second-line therapy, based on data from the CheckMate 025 study.

Question 55

What is the current standard of care for metastatic papillary RCC?
a. savolitinib
b. sunitinib
c. cabozantinib
d. pazopanib

Answer 55

c. cabozantinib
Explanation: Cabozantinib has been established as the current standard of care for metastatic papillary RCC.

Question 56

For patients considered ineligible or high risk for immunotherapy, what type of monotherapy is an option?
a. CPI
b. VEGFR-TKI
c. mTOR
d. IFN-a

Answer 56

b. VEGFR-TKI
Explanation: For high-risk patients unable to receive immunotherapy, VEGFR-TKI monotherapy is an option.

Question 57

Which of the following agents showed modest activity and a median PFS of 9 months in a small cohort with papillary kidney cancer?
a. cabozantinib
b. foretinib
c. savolitinib
d. everolimus

Answer 57

b. foretinib
Explanation: Foretinib, a VEGF-TKI with MET inhibition, showed modest activity and a median PFS of 9 months in papillary kidney cancer.

Question 58

Which trial evaluating adjuvant sunitinib showed significant improvement in disease-free survival (DFS) in very high-risk clear cell patients?
a. EVEREST
b. PROTECT
c. S-TRAC
d. ASSURE

Answer 58

c. S-TRAC
Explanation: The S-TRAC trial showed significant improvement in DFS with sunitinib, the only survival benefit observed in any modern adjuvant RCC trial.

Question 59

What is the focus of ongoing trials in the prevention of distant disease in the adjuvant setting for RCC?
a. Immunotherapy
b. VEGF-TKI and CPI
c. Targeted therapy
d. Chemotherapy

Answer 59

b. VEGF-TKI and CPI
Explanation: The conclusion section emphasizes the need for novel approaches beyond VEGF-TKI and CPI for refractory cases of clear cell RCC and other rare variants.

Question 60

Which trial recently presented the initial results at ASCO 2021, favoring pembrolizumab in DFS?
a. Keynote-564
b. RAMPART
c. PROSPER RCC
d. CheckMate 914

Answer 60

a. Keynote-564
Explanation: Keynote-564 recently presented results favoring pembrolizumab in DFS at ASCO 2021.

Question 61

Which trial evaluates a single dose of nivolumab within a month of surgery, followed by 9 months of therapy after recovery, without a placebo group?
a. RAMPART
b. IMMOTION-010
c. Keynote-564
d. PROSPER RCC

Answer 61

d. PROSPER RCC
Explanation: The PROSPER RCC trial evaluates a single dose of nivolumab within a month of surgery, followed by 9 months of therapy, and uniquely does not have a placebo group.

Question 62

Which agent was studied in a phase 2 study and shown to be superior to sunitinib in intermediate and poor risk disease for frontline therapy?
a. everolimus
b. pazopanib
c. axitinib
d. cabozantinib

Answer 62

d. cabozantinib
Explanation: Cabozantinib was shown to be superior to sunitinib in a phase 2 study with intermediate and poor risk disease, and it may also be an option for frontline therapy.