A Roadmap for Modern RCC Care: Navigating Personalized Treatment Selection and Sequencing

Chair and Presenters, Sumanta Kumar Pal, MD, FASCO, Nizar M. Tannir, MD, FACP, and Tian Zhang, MD, MHS, prepared useful Practice Aids pertaining to renal cell carcinoma for this CME/MOC/NCPD/AAPA/IPCE activity titled “A Roadmap for Modern RCC Care: Navigating Personalized Treatment Selection and Sequencing.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3xgpDpY. CME/MOC/NCPD/AAPA/IPCE credit will be available until July 2, 2025.

1. Patient Education:
Understanding Renal Cell Carcinoma
Full abbreviations, accreditation, and disclosure information available at PeerView.com/GXM40
Receiving a diagnosis of renal cell carcinoma (RCC) can be
overwhelming for patients and their care partners. Please use the
following one-page, printable resource to help your patients and
their care partners understand RCC treatment options and where
they can turn for more support.
Printable Resource

2. Understanding Kidney Cancer: A Quick Reference for Patients
If you or someone you love has been diagnosed with the most common form of kidney cancer—
renal cell carcinoma or RCC—you may have a lot of questions about treatment options and where you can turn for help.
What are the different kinds of RCC?
There are a variety of kidney cancers; the most common is renal cell carcinoma (RCC), which accounts for
85% of kidney tumors. Within RCC, there are different subtypes, the most common of which is clear cell.
Non–clear cell RCC includes papillary and chromophobe subtypes.
What do staging and grading refer to, and what do they mean for treatment?
• Kidney cancer is staged—or classified—by the size of the tumor and whether it has spread beyond
the original tumor; stage 1 tumors are small and localized, while stage 4 tumors have spread to nearby
and possibly distant organs and lymph nodes.
• Cancer grading refers to how aggressive the cells look under a microscope and also uses a 1 to 4 scale,
with 1 being the least and 4 the most aggressive.
Staging and grading provide the treatment team with information on how
quickly a cancer is expected to grow and how likely it is to recur. The patient and
cancer care team will consider these factors when choosing a treatment plan.
What treatments are available?
Patients with small tumors that have not spread to other parts of the body may be treated with surgery or,
in some cases, radiation. Patients with more advanced kidney cancer that has spread beyond the kidney
may require immunotherapy, which is a treatment that uses a person’s own immune system to fight
cancer; targeted therapies, which target specific changes in a cancer cell to block its growth and spread;
or combinations of immunotherapy and/or targeted agents.
Your team will let you know what to expect from each treatment, including
how the medicine is given, which side effects are common, and how the medication
may affect your lifestyle, so you and your team can choose a treatment
plan that best fits your needs.
What side effects are associated with kidney cancer treatments?
Side effects vary by treatment, and not all patients have the same experience with each agent. Patients
receiving immunotherapy or targeted therapies may experience diarrhea, rashes, fatigue, and other
issues, depending on the particular treatment.
If you think you may be experiencing a side effect, it is important to let your cancer
care team know right away. Your provider may adjust or change your treatment, as
the goal is for you to receive treatment as long as possible to achieve optimal
results while maintaining your quality of life.
Spotlight on Clinical Trials
Your cancer care team may offer you the option of enrolling
in a clinical trial. These studies provide important information
on whether a treatment is safe and effective and give you
access to new strategies that could be better than the
options currently used.
Clinical trial enrollment is voluntary. Each trial has
specific enrollment criteria (eg, age, type of cancer,
stage, prior treatments). Talk to your cancer care team
about whether clinical trial enrollment
is right for you.
Where Can You Get More Support?
Online and in-person advocacy foundations for patients and
their care partners provide a variety of services, including
support groups, counseling, financial assistance, information
on treatments and clinical trials, opportunities to support and
participate in research, and educational workshops.
 Action to Cure Kidney Cancer: ackc.org
 American Cancer Society: cancer.org
 CancerCare: cancercare.org/support_groups/137-
kidney_cancer_patient_support_group
 International Kidney Cancer Coalition: ikcc.org
 KCCure: kccure.org
 Kidney Cancer Association: kidneycancer.org
 KidneyCAN: kidneycan.org
Visit the websites below to learn more about the
resources each organization offers.
What You Need to Know About Kidney Cancer Treatment

3. Understanding the Importance of
Patient Perspectives and Their Role
in Kidney Cancer Therapy Decisions
1-3
Full abbreviations, accreditation, and disclosure information available at PeerView.com/GXM40 KCCure conducts its own
patient-centered research aimed
at improving the quality of life of all
patients with kidney cancer by better
identifying and defining patients’
needs and concerns.
KCCure’s Research Helps Inform
Providers of the Patient Voice
The Kidney Cancer Research Alliance
(KCCure) provides answers to
questions that patients and care partners
are asking.
Wherever they are in their diagnosis,
patients can visit
kccure.org
to find updated information on the
different types of kidney cancer, new
treatment options, and more.

4. Understanding the Importance of
Patient Perspectives and Their Role
in Kidney Cancer Therapy Decisions
1-3
Full abbreviations, accreditation, and disclosure information available at PeerView.com/GXM40 Results From a Recent Patient Survey Focusing on the Use of Combination Treatment Regimens
a
Patient Views Related to Oral Dose Reduction (While on Combination Therapy)
Was the dose
reduction helpful?
It helped a lot
76%
It did not make
a difference
6%
It helped
a little
18%
No
60%
Yes
40%
Felt Relieved
Have you ever not taken your oral
therapy to reduce side effects
(without telling your doctor)?
No
82%
Yes
18%
No
58%
Yes
42%
Worried About Reducing Efficacy
By encouraging patients to report any AEs right away, providers may be able to suggest AE management strategies, including dose
adjustments, that allow patients to keep receiving an effective treatment as long as possible while maintaining quality of life
No
84%
Yes
16%
Asked for a Dose Reduction
Yes
66%
No
34%
Due to side effects, did your doctor
reduce the dose of your oral therapy
(while on combination tx)?
Patient and Provider Perceptions of Benefits and Risks of Adjuvant Therapy in RCC
Combination Treatments and Dose Reduction: Understanding the Patient’s Viewpoint
• Of 1,062 participants, 639 patients (median age, 57 y) self-identified with localized RCC and 223 had stage 3 RCC at initial diagnosis
• 113 patients were offered adjuvant therapy by their physician, and 74 patients reported being treated with or having received treatment
with adjuvant therapy (TKIs, 18%; immune checkpoint inhibitor, 82%)
Stage 1
13%
28%
Stage 2
23%
37%
Stage 3
37%
47%
Physician
Patient
0 10 20
Estimation of Risk, %
30 40 50
Recurrence Risk Assessment Estimation According to Stage
Patients with high-risk localized disease estimated their recurrence risk to be higher than their physicians; these findings highlight
the importance of effective communication between patients and providers regarding the risks and benefits of adjuvant therapy
to promote an informed and shared decision
a
Patient survey data; June to September 2022; US and global participation; N = 119.
1. kccure.org. 2. Battle D et al. ASCO GU 2023. Abstract 663. 3. Battle D et al. AUA 2023. Abstract MP28-19.

5. Managing Immune-Related
Adverse Events
1-6
Full abbreviations, accreditation, and disclosure information
available at PeerView.com/GXM40

Monitor closely for potential
irAEs by evaluating blood
work, including liver
enzymes, creatinine, and
thyroid function
Ask patients about
symptoms such as cough,
shortness of breath, and
diarrhea, which may be
signs of pneumonitis
or colitis
Stay in communication with
patients to help mitigate and
treat more common AEs
such as fatigue, nausea,
and anemia
Pancreatitis, 
autoimmune diabetes
Colitis
Enteritis
Encephalitis, aseptic meningitis
Thyroiditis, hypothyroidism,
hyperthyroidism
Dry mouth, mucositis
Hypophysitis
Uveitis 
Pneumonitis
Thrombocytopenia,
anemia 
Hepatitis 
Adrenal insufciency
Nephritis
Vasculitis
Arthralgia
Neuropathy 
Rash, vitiligo
Myocarditis
Any organ system can be afected; commonly occurring irAEs are 
pulmonary (pneumonitis), dermatologic (rash, pruritus, blisters, ulcers, 
vitiligo), gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, 
pancreatitis), and endocrine (thyroiditis, hypophysitis, 
adrenal insufciency)
What Is the Spectrum of Potential irAEs?
• In general, checkpoint inhibitor therapy should be continued
with close monitoring, with the exception of some neurologic,
hematologic, and cardiac toxicities
Minimal or no symptoms; diagnostic changes only
Grade 1
• Hold checkpoint inhibitor therapy for most grade 2 toxicities
• Consider resuming immunotherapy when symptoms and/or
laboratory values revert to grade 1 or lower
• Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or
equivalent) may be administered
Grade 3 toxicities
• Hold checkpoint inhibitor therapy
• Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d or
methylprednisolone IV 1-2 mg/kg/d)
• If symptoms do not improve with 48-72 hours of high-dose
corticosteroids, infliximab may be offered for some toxicities
• Taper corticosteroids over the course of at least 4-6 weeks
• When symptoms and/or laboratory values revert to grade 1 or lower,
rechallenging with immunotherapy may be offered; however, caution
is advised, especially in those patients with early-onset irAEs; dose
adjustments are not recommended
Grade 4 toxicities
• In general, permanent discontinuation of checkpoint inhibitor
therapy is warranted with the exception of endocrinopathies that
have been controlled by hormone replacement
Grade 2
Mild to moderate symptoms
Severe or life-threatening symptoms
Grades 3/4
irAE Grading and Management
Safety Considerations
for Immunotherapies

6. Managing Immune-Related
Adverse Events
1-6
Full abbreviations, accreditation, and disclosure information
available at PeerView.com/GXM40
1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Schneider BJ et al. J Clin Oncol. 2021;39:4073-4126. 3. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related
Toxicities. Version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 4. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.
5. Naidoo J et al. J Immunother Cancer. 2023;11:e006398. 6. Haanen J et al. Ann Oncol. 2022;33:1217-1238 .
Consult irAE management guidelines
(eg, ASCO, NCCN, SITC, ESMO)
IO
Pruritus
Pneumoni tis
Myocarditis
Adrenal crisis
TKI
Hypertension
Taste changes
Stomatitis
Dyspepsi a
Cytopenia
HFSR
Overlapping
Rash
Diarrhea
Hepatitis
Hypothyroid
AMS
IO + TKI Combination Toxicities
Determine which therapy is causing the AE
in order to plan a management strategy
Hold TKI (shorter half-life than checkpoint inhibitor)
In certain cases, use appropriate suppor tive care
If symptoms resolve in a few days, TKI was likely the cause
Two mechanisms of action result in two sets of
AE profiles that are not mutually exclusive
PRESEncephalitis

7. Contemporary Treatment Regimens
for Kidney Cancer
1-3
Full abbreviations, accreditation, and disclosure information
available at PeerView.com/GXM40
Approaches Under Investigation
Select FDA-Approved Regimens
for the Refractory Setting
Case example: 68-year-old patient with mRCC and lung 
metastases
 Started on initial therapy with an IO + TKI regimen
 Progression in the liver… 
 Scenario #1: symptomatic and rapid tumor kinetics
 • Two sets of scans 6 weeks apart 
  –  Liver lesion grew from 2 to 6 cm
  –  Lung metastases grew from 1 to 4 cm
  – Treatment choice: tivozanib (VEGFR TKI)
      based on phase 3 TIVO-3 (phase 3 TiNivo-2  
      underway: tivozanib + nivolumab) 
 Scenario #2: asymptomatic progression
 • Two sets of scans 8 weeks apart
  –  Liver lesion grew from 1 to 2 cm
  –  Three pulmonary nodules grew from 1 to 1.5 cm
  – Treatment choice: belzutifan (HIF-2α inhibition) 
      based on phase 3 LITESPARK-005
Potential for Improving Daily Management:
Subcutaneous IO
• SC administration provides an alternative with 
  potential benefts for both patients and providers
• SC dosing may:
 –  Alleviate the need for IV vein ports
 –  Lower the risk of dosing errors
 –  Allow more patient fexibility
 –  Reduce dose preparation and administration times
 –  Optimize occupancy in infusion centers
• SC nivolumab is under FDA review across indications  
  based on positive results in refractory mRCC
  (phase 3 CheckMate -67T)
Multi-Targeted TKI: Zanzalintinib
• TKI of VEGFR2, MET, AXL, and MER
• Similar target profle to cabozantinib 
 –  Shorter clinical half-life 
 –  PK properties for once-daily oral dosing
• Phase 1 STELLAR-001: refractory ccRCC cohort
• Phase 1 STELLAR-002: 1L ccRCC, 2L ccRCC, 1L non-ccRCC
• Phase 1b/2 STELLAR-009: zanzalintinib + HIF-2⍺
inhibitor AB521 in ccRCC
• Phase 3 STELLAR-304: 1L non-ccRCC
Impact of the Microbiome and Other Targets
• The gut microbiome may predict outcome with ICIs
 –  CBM588, a live bacterial product containing 
Clostridium butyricum is under investigation in 
    combination with multiple IO-based therapies
• CD70 is expressed in up to 80% of RCC cells
 –  CD70 CAR-T cell therapy; CD70 ADC therapy
•Improved OS
•Longest follow-up
•Durable responses
•Potential to stop
therapy
•QOL
•Potential for 
higher initial
irAE
•Lower PFS/
response rates
How to Choose Among the Bounty of
First-Line Therapy Regimens in mRCC
•Improved OS
•High ORR, low PD
•Longer PFS
•Lower irAE rate
•Overlapping
toxicity
•Potential for 
chronic TKI 
toxicity
Dual IO IO + TKI
Pros Pros
Cons Cons
Ipilimumab + nivolumab
(CheckMate -214)
Pembrolizumab + axitinib
(KEYNOTE-426)
Nivolumab + cabozantinib
(CheckMate -9ER)
Pembrolizumab +
lenvatinib (CLEAR)
Patient
convenience
Administration
time
Level of
invasiveness
Infusion
center
availability
1. NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. 2. clinicaltrials.gov. 3. Lonardi S et al. ESMO 2022. Abstract 739P.