Treatment of
Metastatic
Renal Cell Carcinoma

林協霆1; 陳建廷2

  1. Presenter, 專研醫師，和信治癌中心醫院腫瘤內科部

  2. Moderator, 主治醫師，和信治癌中心醫院腫瘤內科部

Case

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.

05128236

Case

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.

Figure:

Figure:

Case

Lab Findings

  1.        2023/08/02
  2. HGB    15.6
  3. PLT    212.0
  4. W.B.C  5.81
  6.             2023/08/02
  7. Creatinine  1.22
  8. Ca          9.8

IMDC Risk Score

Figure:

Case

Facts About Renal cell carcinoma

  • most common type of kidney tumor. 90%
  • classic triad: 1️⃣ hematuria, 2️⃣ abdominal pain, and a 3️⃣ 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
Case

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

Figure:

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)
Pathology and molecular pathogenesis

Genomic Alterations in Inherited and Sporadic Renal Tumors

Figure:

  • 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
Pathology and molecular pathogenesis

VHL pathways for oncogenes activation

Figure

Figure:

  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
Pathology and molecular pathogenesis

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

Figure:

Figure:

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

Work up

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')
Work up

Diagnostic and treatment approaches to the patient with a kidney mass

Figure:

Work up

Stages of kidney cancer and treatments

Figure:

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

Work up

Prognosis

Figure:

Work up

Risk Factor Stratification for Metastatic RCC

Figure:

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

Treatment of
mRCC

nephrectomy

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

before 2019... 🈹 🥔

Figure:

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

SURTIME badge badge badge badge

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

  • predominantly MSKCC intermediate risk

🈚PFS 6.8 v.s. 7.1

Figure:

🔮 OS 23.7 v.s. 15.0 HR 0.71 p=0.225

Figure:

JAMA Oncol 2019 Feb 1; 5: 164-170

CARMENA

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Sunitinib Alone or after Nephrectomy in mRCC

  • MSKCC intermediate or poor

Figure:

Figure:

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

Systemic Therapeutic evolution of metastatic clear cell renal cell carcinoma

Figure:

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

Figure:

Figure:

CYTOKINES

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

SINGLE-AGENT TYROSINE KINASE INHIBITORS

Figure:

Sunitinib

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SU011248 vs Interferon-Alfa As 1L For mRCC

🈚PFS: 11 vs 5 mos
HR: 0.42 (0.32-0.54)

Figure:

🔮OS 26.4 vs 21.8 months
HR: 0.82 (0.67-1.001) p=.051

Figure:

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

COMPARZ

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

🈚PFS: 8.3 v.s. 9.5
Figure:

🔮OS: 28.4 v.s. 29.3

Figure:

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

COMPARZ

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

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Cabozantinib or Sunitinib in Untreated Locally Advanced or Metastatic RCC

🈚PFS: 8.6 v.s. 5.3

Figure:

🔮OS: 43 v.s. 47

Figure:

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

CABOSUN

mTOR inhibitor

1L Temsirolimus

2L Everolimus

  • mTOR protein: increased production of HIF-1a and HIF- 2a.
  • temsirolimus improved OS compared with IFN (10.9 vs. 7.3 months)
  • In treatment-naϊve patients with poor-risk meta- static renal cell carcinoma.

Figure:

ARCC

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Temsirolimus, interferon alfa, or both for advanced RCC

Figure:
Figure:

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

IMMUNE CHECKPOINT INHIBITOR COMBINATION

Morden Warefare 🪖

ICI

Figure:

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

ICI

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

Figure:

Scientist in 2007:
PD-1+ immune cells are more likely to exhibit adverse pathologic features including increased tumor size, higher nuclear grade, and advanced tumor-node-metastasis stage

Figure:

CheckMate-214

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

Figure:

CheckMate-214

CheckMate-214 Result

🈚 PFS 11.6 vs 8.4 months HR: 0.82 (0.64-1.05)
⚠️ P=0.03 prespecified threshold (p<0.009)

Figure:

🔮 OS: 55.7 vs 38.4 months HR: 0.72 (0.62-0.85) p <.0001

Figure:

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

Figure:

CheckMate-214 Subgroup Analysis of 🔮OS

IMDC score high: favor Nivo+IPI

CheckMate-214

VEGF TYROSINE KINASE INHIBITOR
AND
IMMUNOTHERAPY COMBINATIONS

KEYNOTE-426

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Pembrolizumab + Axitinib vs Sunitinib in RCC

title: KEYNOTE-426

  • Stratified by IMDC risk group (favorable vs intermediate vs poor),
  • region (N. America vs W. Europe vs ROW)
  • End of Pembrolizumab Treatment at month 24th

KEYNOTE-426 Ⓒ Hsieh-Ting Lin

Eur Urol Oncol 2022 Apr; 5: 225-234

KEYNOTE-426

KEYNOTE-426 Result PFS

🈚 PFS 15.7 vs 11.1

Figure:

Figure:

👀IMDC risk category

N Engl J Med 2019; 380:1116-1127

KEYNOTE-426

KEYNOTE-426 Result 🔮OS

Figure:

Indicator Pembro-axitinib Sunitinib
median PFS 15.7 months 11.1 months
median OS 45.7 months 40.1 months

Figure:

Lancet Oncol. 2020;21:1563.

KEYNOTE-426

KEYNOTE-426 Final Analysis: Efficacy by IMDC Risk

Figure:

ORR 60%

Rini. ASCO 2021. Abstr 4500.

CheckMate 9ER

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

Figure:

Citation not found

CheckMate 9ER

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%

Figure:

Figure:

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

CheckMate 9ER

CheckMate-9ER 🔮Overall Survival Subgroup Analysis

Figure:

CheckMate 9ER

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

Figure:

CLEAR

CLEAR badge badge badge badge

Figure:

Lancet Oncol 2022 Jun; 23: 768-780

CLEAR

🈚PFS Lenvatinib+Pembrolizumab 23.4 vs Sunitinib 9.2

Figure:

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.

CLEAR

Final OS analyses in IMDC risk subgroups

Figure:

  • 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

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

HEADER
Figure:

PFS: 11.2 months vs. 8.4 months

JAMA Oncol 2022 Feb 1; 8: 275-280

JAVELIN Renal 101

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

Figure:

PFS: 13.3 months v.s. 8.0 months

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

COSMIC-313

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

Figure:

  • 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.

COSMIC-313

🈚PFS NR v.s. 11.3

Figure:

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.
Cross-Trial Comparison

Figure:

Cross-Trial Comparison

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

Figure:

Cross-Trial Comparison

Cross-Trial Comparison of Response in ITT Population

Figure:

Cross-Trial Comparison

Second Line Settings

Figure:

AXIS

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

Figure:

  • PFS 8.3 vs 5.7

Future Oncol 2020 Jun; 16: 1199-1210

AXIS

🈚PFS patients previously treated with sunitinib-based regimen

Figure:

Figure:

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

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

Primary Outcomes

  • Progression-free Survival (🈚PFS)

Figure:

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

METEOR

🈚PFS 7.4 vs 2.7

Figure:

🔮OS 20.1 vs 12.1

Figure:

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

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

Figure:

Br J Cancer 2021 Jan; 124: 237-246

HOPE 205

🈚PFS

Figure:

Figure:

CheckMate 025

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

Figure:
Figure:

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

Pharmacoeconomics 2021 Mar; 39: 345-356

CheckMate 025

🈚PFS 4.6 vs 4.4

Figure:

🔮OS 25 v.s. 19.6

Figure:

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

CheckMate 025

Figure:

BMC Cancer. 2022;22(1).

Summary

Summary

10 pages left 📃

Summary

Trials Outcomes of mRCC Systemic Treatment, ITT group

Figure:

Ⓒ 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

Summary

Figure:

Figure:

Summary

Figure:

Summary

PFS

Figure:

Summary

OS

Figure:

Summary

Back To Our Patient: 64-year-old woman

  • right renal cell carcinoma,
    • s/p laparoscopic right radical nephrectomy in 2013.
  • recurrent left RCC stage IV with metastasis to left adrenal gland, left renal vein, para-aortic lymph nodes, pulmonary hila, and retrocaval space
  • post chemotherapy includes three cycles Nivlumab(3mg/kg) plus Ipilimumab(1mg/kg), SD ~2023/10/06
  • followed by Sunitinib
  • The disease was stable as per the CT scan of December 14, 2023.

Figure:

05128236

Figure:

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

Adjuvant ALK Inhibitor

Addendum

### The renal cell carcinoma-specific cancer–immunity cycle

Targets of Drugs

![bg right:60% height:630px](https://i.imgur.com/zd2dWm6.png)

> BRAUN, David A., et al. Beyond conventional immune-checkpoint inhibition—novel immunotherapies for renal cell carcinoma. Nature reviews Clinical oncology, 2021, 18.4: 199-214.

:::free

In the COMPARZ trial, the median OS was 28.4 months in the PZ group (95% CI 26.2–35.6) and 29.3 months in the SU group (95% CI 25.3–32.5). The median PFS was 8.4 months with PZ (95% CI 8.3–10.9) and 9.5 months with SU (95% CI 8.3–11.1).

> Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. The New England Journal of Medicine. 2017;376(4):354-366. doi:<https://doi.org/10.1056/nejmra1601333>

![Figure: height:450px](https://i.imgur.com/V1M62Yf.png)

#### Sankey diagram depicting treatment pathways

![Figure: width:1150px](https://i.imgur.com/eihQcX5.png)