64-year-old woman

Initial Diagnosis and Treatment

• 2013-05: Right RCC s/p laparoscopic right radical nephrectomy. pT1bNx

Subsequent Diagnosis

• 2023-08: Left RCC, discovered incidentally during a sonogram.
• A 54x74-mm mass in the left kidney, tumor thrombus in the left renal vein.
• metastatic lymph nodes in the para-aortic region.
• an enlarged nodule in the left adrenal gland.
• subcentimeter pulmonary nodules of undetermined nature, which have increased in number.

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Additional Imaging and Biopsy

• CT of Chest:
  • Metastatic LN in both pulmonary hila and retrocaval space.
  • Subcentimeter pulmonary nodules.
• Biopsy: CT-guided biopsy of the tumor confirmed renal cell carcinoma, clear cell type.
• Clinical Stage: cT2aN1M1, Stage IV.

Lab Findings

Facts About Renal cell carcinoma

• most common type of kidney tumor. 90%
• classic triad: hematuria, abdominal pain, and a palpable mass is rarely seen in modern practice.
• Incidental diagnoses are increasing.
• Risk factors include
  • smoking
  • obesity
  • hypertension
  • environmental exposures
  • hereditary kidney cancer syndromes
  • acquired cystic kidney disease leading to end-stage renal disease

Internist's tumor

• paraneoplaastic syndromes

1. anemia: can have the picture of anemia of chronic disease and precede the diagnosis of RCC.
2. hepatic dysfunction / STAUFFER's Syndrome: nephrogenic hepatic dysfunction syndrome without jaundice
3. Fever: in up to 20% of people with additional constitutional symptoms
4. hypercalcemia: from bony mets, increased prostaglandins or PtHRP
5. erythrocytosis thrombocytosis
6. AA amyloidosis
7. other hormonal overproduction....gonadotropins, human chorionic somatomammotropin, an ACTH-like substance, renin, insulin, glucagon

Toronto. The internist’s tumor..... Blogspot.com. Published 2020. Accessed January 17, 2024. https://morningreporttwh.blogspot.com/2009/05/internists-tumor.html

Distinct subtypes of renal cell carcinoma

• 75% of renal cell carcinomas (RCCs) are clear cell RCC.(a)
• 15% of kidney cancers are Papillary RCCs,
  • classified as type 1 basophilic (b) and 2 eosinophilic (c)
• Chromophobe RCCs comprise 5% of kidney tumors. (d)
• Collecting duct RCCs. (f)

Genomic Alterations in Inherited and Sporadic Renal Tumors

• Somatic mutations of VHL were also identified in as many as 90% of sporadic, non-familial ccRCC cases
• Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall

VHL pathways for oncogenes activation

1. Fig. 10.1. Organs affected by von Hippel-Lindau disease. ResearchGate. Published 2015. Accessed January 17, 2024. https://www.researchgate.net/figure/Organs-affected-by-von-Hippel-Lindau-disease_fig1_299451768

VHL inactivation in clear cell renal cell carcinoma and its implication in targeted therapy

Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nature Reviews Disease Primers. 2017;3(1). doi:https://doi.org/10.1038/nrdp.2017.9

Diagnostic work-up

RCC suspected

• Whole-Abd CT (contrast-enhanced) or MRI
• Chest X-ray
• Bone scan (if clinically indicated)

Who needs a biopsy?

• If surgery anyway, No

But you need a biopsy

• To assess small renal masses
• To select most suitable therapy strategy ('Treat or not to treat')

Diagnostic and treatment approaches to the patient with a kidney mass

Stages of kidney cancer and treatments

HSIEH, James J., et al. Renal cell carcinoma. Nature reviews Disease primers, 2017, 3.1: 1-19.

Prognosis

Risk Factor Stratification for Metastatic RCC

MSKCC: for IL-2 era, IMDC: for VEGFRi/VEGFi era

Heng, D. Y., Xie, W., Regan, M. M., Harshman, L. C., Bjarnason, G. A., Vaishampayan, U. N., ... & Choueiri, T. K. (2013). External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. The lancet oncology, 14(2), 141-148.

Treatment of
mRCC

What is the role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma?

before 2019...

Viktor Grünwald, Bex A. The role of nephrectomy in metastatic renal cell carcinoma. Nature Reviews Nephrology. 2018;14(10):601-602. doi:https://doi.org/10.1038/s41581-018-0041-3

SURTIME

Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer

• predominantly MSKCC intermediate risk

JAMA Oncol 2019 Feb 1; 5: 164-170

CARMENA

Sunitinib Alone or after Nephrectomy in mRCC

• MSKCC intermediate or poor

N Engl J Med 2018 Aug 2; 379: 417-427

Systemic Therapeutic evolution of metastatic clear cell renal cell carcinoma

HSIEH, James J., et al. Renal cell carcinoma. Nature reviews Disease primers, 2017, 3.1: 1-19.

PRINCIPLES OF SYSTEMIC THERAPY FOR RELAPSE OR STAGE IV DISEASE

Once Upon a Time...

CYTOKINES

• Until 2006, had represented the primary treatment
• low but reproducible response rates of 10%-20%, with occasional durable responses.
• Response rates greater than 30% have been reported for patients with small-volume disease primarily limited to the lung.
• A dose response to IFN-a is suggested, because few responses are associated with a dose less than 3 million units per day, with maximal benefit seen in the dose range of 5 million to 20 million units per day.
• IL-2 linked to treatment-related deaths (4%)
• IL-2 good for young, good-risk patients
• No role for cytokine therapy in adjuvant setting

SINGLE-AGENT TYROSINE KINASE INHIBITORS

Sunitinib

SU011248 vs Interferon-Alfa As 1L For mRCC

N Engl J Med. 2007 Jan 11;356(2):115-24.; J Clin Oncol. 2009 Aug 1;27(22):3584-90.

COMPARZ

Pazopanib is non-inferior than Sunitinib in the Locally Advanced and/or Metastatic RCC

N Engl J Med. 2013 Aug 22;369(8):722-31. | BMC Cancer 2020 Mar 14; 20: 219 | Clin Genitourin Cancer 2019 Dec; 17: 425-435.e4

Safety and QoL profiles favor pazopanib

• Sunitinib with a higher incidence of
  • fatigue (63% vs 55%)
  • hand-foot syndrome (50% vs 29%)
  • thrombocytopenia (78% vs 41%)
• The mean change from baseline in 11 of 14 health-related Qol domains during the first 6 months of treatment favored pazopanib (p<0.05 for all 11 comparisons)

CABOSUN

Cabozantinib or Sunitinib in Untreated Locally Advanced or Metastatic RCC

Oncologist 2019 Nov; 24: 1497-1501 | Clin Cancer Res 2019 Oct 15; 25: 6080-6088

mTOR inhibitor

ARCC

Temsirolimus, interferon alfa, or both for advanced RCC

• Rx-naϊve, poor-risk mRCC
• now rarely used as a front-line single agent.

IMMUNE CHECKPOINT INHIBITOR COMBINATION

Morden Warefare

Xu, W., Atkins, M. B., & McDermott, D. F. (2020). Checkpoint inhibitor immunotherapy in kidney cancer. Nature Reviews Urology. doi:10.1038/s41585-020-0282-3

ccRCC is also considered an immunogenic tumour with high numbers of immune cells such as tumour-infiltrating lymphocytes

CheckMate-214

Nivolumab + Ipilimumab vs Sunitinib in Previously Untreated Advanced or Metastatic RCC

CheckMate-214 Result

N Engl J Med 2018; 378:1277-1290 | Cancer 2022 Jun 1; 128: 2085-2097

CheckMate-214 Subgroup Analysis of OS

IMDC score high: favor Nivo+IPI

VEGF TYROSINE KINASE INHIBITOR
AND
IMMUNOTHERAPY COMBINATIONS

KEYNOTE-426

Pembrolizumab + Axitinib vs Sunitinib in RCC

KEYNOTE-426 Ⓒ Hsieh-Ting Lin

Eur Urol Oncol 2022 Apr; 5: 225-234

KEYNOTE-426 Result PFS

N Engl J Med 2019; 380:1116-1127

KEYNOTE-426 Result OS

Lancet Oncol. 2020;21:1563.

KEYNOTE-426 Final Analysis: Efficacy by IMDC Risk

ORR 60%

Rini. ASCO 2021. Abstr 4500.

CheckMate 9ER

Nivolumab + Cabozantinib vs Sunitinib in Previously Untreated Advanced or Metastatic RCC

Citation not found

CheckMate-9ER Result

Metric	Nivolumab + Cabozantinib	Sunitinib
PFS	16.6 months	8.3 months
PFS HR	0.51	-
OS	49.5	35.5
OS HR	0.60	-
ORR	55.7%	27.1%
Median Duration of Response	20.2 months	11.5 months
Complete Response Rate	8.0%	4.6%

N Engl J Med [[2021.md|2021]]; 384:829-841

CheckMate-9ER Overall Survival Subgroup Analysis

3-Yr Update: PFS and OS in ITT Population and by IMDC Risk Subgroup

CLEAR

Lancet Oncol 2022 Jun; 23: 768-780

PFS Lenvatinib+Pembrolizumab 23.4 vs Sunitinib 9.2

CHOUEIRI, Toni K., et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. The Lancet Oncology, 2023, 24.3: 228-238.

Final OS analyses in IMDC risk subgroups

• For intermediate and poor: Lenvatinib + Pembrolizumab 47.9 vs Sunitinib 34.3

CHOUEIRI, Toni K., et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. The Lancet Oncology, 2023, 24.3: 228-238.

IMmotion151

A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma (RCC)

PFS: 11.2 months vs. 8.4 months

JAMA Oncol 2022 Feb 1; 8: 275-280

JAVELIN Renal 101

A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101)

PFS: 13.3 months v.s. 8.0 months

J Clin Oncol 2022 Jun 10; 40: 1929-1938

COSMIC-313

Cabozantinib + Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic RCC

• 1L CheckMate-214 +/- Cabozantinib

ASCO 2020: COSMIC-313 Phase III Study of Cabozantinib in Combination with Nivolumab and Ipilimumab in Patients with Previously Untreated Advanced Renal Cell Carcinoma of Intermediate or Poor-Risk. Urotoday.com. Published 2020. Accessed January 16, 2024.

PFS NR v.s. 11.3

Choueiri TK, Powles T, Albigès L, et al. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. The New England Journal of Medicine. 2023;388(19):1767-1778. doi:https://doi.org/10.1056/nejmoa2212851

• The triplet arm was also notable for significantly higher rates toxicities, and only 58% of patients received all doses of ipilimumab versus 73% in the doublet arm.

Comparisons of Current First line treatment option with Sunitinib in mRCC ITT poupulation

Cross-Trial Comparison of Response in ITT Population

Second Line Settings

AXIS

Axitinib (AG 013736) As Second Line Therapy For Metastatic Renal Cell Cancer

• PFS 8.3 vs 5.7

Future Oncol 2020 Jun; 16: 1199-1210

PFS patients previously treated with sunitinib-based regimen

Rini, B. I., Escudier, B., Tomczak, P., Kaprin, A., Szczylik, C., Hutson, T. E., ... & Motzer, R. J. (2011). Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. The Lancet, 378(9807), 1931-1939.

METEOR

A Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma

Clin Cancer Res 2022 Feb 15; 28: 748-755

CABOSEQ

Sankey diagram outlining treatment patterns for patients receiving second line(2L) cabozantinib

Clinical Genitourinary Cancer. 2023;21(1):106.e1-106.e8.

HOPE 205

Lenvatinib +/- Everolimus in 2L for unresectable advanced or Metastatic RCC

Br J Cancer 2021 Jan; 124: 237-246

PFS

CheckMate 025

Study of Nivolumab (BMS-936558) vs. Everolimus in Pre-Treated Advanced or Metastatic Clear-cell Renal Cell Carcinoma (CheckMate 025)

PFS 4.2 months v.s. 4.5 months; OS 25.8 months v.s. 19.7

Pharmacoeconomics 2021 Mar; 39: 345-356

Motzer RJ, Escudier B, McDermott R, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. The New England Journal of Medicine. 2015;373(19):1803-1813. doi:https://doi.org/10.1056/nejmoa1510665

BMC Cancer. 2022;22(1).

Summary

10 pages left

Trials Outcomes of mRCC Systemic Treatment, ITT group

Ⓒ Hsieh-Ting Lin
Immuno-Oncology Advances in Genitourinary Cancers. American Society of Clinical Oncology Educational Book. Published 2024. Accessed January 17, 2024. https://ascopubs.org/doi/pdf/10.1200/EDBK_430428

PFS

OS

Back To Our Patient: 64-year-old woman

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Take Home Message

• IO and IO/TKI has now become the defacto standard of care for ND mRCC
  • CheckMate-214,
  • KEYNOTE-426,
  • CLEAR,
  • CheckMate-9ER
• Questions still remain regarding the optimal initial approach including the identification of biomarkers to predict response
• Make every effort to ensure that the patient can receive all treatments, including second-line VEGFRi.

mRCC_NHI Ⓒ Hsieh-Ting Lin M.D.

Thank you for your time and attention

Have a nice day

Addendum