BC Cancer Protocol Summary for the Treatment of Metastatic or

Advanced Renal Cell Carcinoma using Nivolumab and Cabozantinib

Protocol Code GUAVNIVC

Tumour Group Genitourinary

Contact Physician Dr. Krista Noonan

ELIGIBILITY:
Patients must have:
 Advanced or metastatic or renal cell carcinoma (RCC),
 No prior treatment in the metastatic setting,
 Any histology and IMDC risk group,
 No option for curative surgery or radiation, and
 Access to a treatment centre with expertise to manage immune-mediated adverse
reactions of nivolumab

Patients should have:

 Good performance status,
 Adequately controlled blood pressure, and
 Adequate hepatic and renal function

Notes:
 Patients with stable CNS metastases are eligible
 PD-L1 status and CPS score not required
 Patients may receive GUAVNIVC if relapse occurs more than 6 months following
completion of GUAJPEM or GUAJPEM6, if all other eligibility criteria are met
 Patients are eligible to receive one of the following, but not sequential use of these
agents except for intolerance:
o Nivolumab with cabozantinib (GUAVNIVC or GUAVNIC4),
o Nivolumab with ipilimumab (GUAVIPNI),
o Pembrolizumab with lenvatinib (GUAVPEML or GUAVPEML6), or
o Pembrolizumab with aXitinib (GUAVPEMAX)
 At time of subsequent disease progression, retreatment with nivolumab is allowed
with or without cabozantinib for an additional one year of therapy (26 cycles of
nivolumab at 2-weekly dosing or 13 cycles at 4-weekly dosing, or a combination of
both) if:
o Patients have completed 2 years of therapy without progression
o Disease progression occurred during a treatment break
 BC Cancer Compassionate Access Program (CAP) approval is not required to
switch between 2-weekly and 4-weekly dosing of nivolumab

BC Cancer Protocol Summary GUAVNIVC Page 1 of 8

Activated: 1 Apr 2025 Revised:
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
EXCLUSIONS:
Patients must not have:
 Prior tyrosine kinase inhibitor therapy,
 Recurrence within 6 months of adjuvant pembrolizumab,
 Uncontrolled hypertension, and
 Pre-existing significant QTc prolongation or unable to discontinue medications that
can prolong QTc

CAUTIONS:
 Active autoimmune disease, and
 Long term immunosuppressive therapy or systemic corticosteroids (Requiring more
than 10 mg predniSONE/day or equivalent)

TESTS:
 Baseline: CBC & Diff, creatinine, alkaline phosphatase, ALT, total bilirubin, LDH,
sodium, potassium, TSH, morning serum cortisol, total protein, albumin, dipstick or
laboratory urinalysis for protein, uric acid, calcium, magnesium, blood pressure,
heart rate, chest x-ray or CT chest if not previously done, ECG
 Baseline if clinically indicated: lipase, random glucose, serum or urine HCG (required
for women of childbearing potential if pregnancy suspected), free T3 and free T4,
serum ACTH levels, testosterone, estradiol, FSH, LH, MUGA scan or
echocardiogram
 Cycles with nivolumab and cabozantinib:
o Prior to each cycle: CBC & Diff, creatinine, alkaline phosphatase, ALT, total bilirubin,
LDH, sodium, potassium, TSH, dipstick or laboratory urinalysis for protein, uric acid,
blood pressure, heart rate
o If clinically indicated: chest x-ray, morning serum cortisol, lipase, random glucose,
serum or urine HCG (required for women of childbearing potential if pregnancy
suspected), free T3 and free T4, serum ACTH levels, testosterone, estradiol, FSH,
LH, total protein, albumin, GGT, calcium, magnesium, phosphate, troponin, INR,
ECG, MUGA scan or echocardiogram
 Cycles with cabozantinib monotherapy:
o Prior to each cycle: CBC & Diff, creatinine, ALT, total bilirubin, uric acid, dipstick or
laboratory urinalysis for protein, blood pressure, heart rate
o If clinically indicated: total protein, albumin, GGT, alkaline phosphatase, LDH,
sodium, potassium, calcium, magnesium, phosphate, TSH, ECG, MUGA scan or
echocardiogram
 24-hour urine for protein if laboratory urinalysis for protein is greater than or equal to
1 g/L or dipstick urinalysis shows 2+ or 3+ proteinuria
 For patients on warfarin: regular INR monitoring
 Blood pressure monitoring at home: See Precautions
 Weekly telephone nursing assessment for signs and symptoms of side effects while
on nivolumab and cabozantinib combination treatment (Optional)

BC Cancer Protocol Summary GUAVNIVC Page 2 of 8

Activated: 1 Apr 2025 Revised:
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
PREMEDICATIONS:
 For nivolumab: Antiemetics are not usually required
 For cabozantinib: Antiemetic protocol for moderate emetogenic chemotherapy
protocols (see SCNAUSEA)
 If prior infusion reactions to nivolumab: diphenhydrAMINE 50 mg PO, acetaminophen
325 to 975 mg PO and hydrocortisone 25 mg IV 30 minutes prior to treatment

TREATMENT:
Drug Dose BC Cancer Administration Guideline
3 mg/kg on Day 1 IV in 50 to 100 mL NS over 30 minutes
nivolumab
(maximum 240 mg) using a 0.2 micron in-line filter
40 mg once daily
cabozantinib PO
continuously

 Duration of treatment:
o cabozantinib: Continuous treatment, until disease progression or unacceptable
toxicity (may continue nivolumab if cabozantinib omitted due to toxicity).
o nivolumab: Repeat every 2 weeks until disease progression or unacceptable
toxicity (may continue cabozantinib if nivolumab omitted due to toxicity) to a
maximum of 52 cycles or 2 years of treatment (including doses given 4-weekly)
o Retreatment may be permitted (see eligibility)

DOSE MODIFICATIONS:
 Toxicity profiles of nivolumab and cabozantinib may overlap. Consider interruption of
cabozantinib to determine causative agent when appropriate.
 No specific dose modifications for nivolumab. Toxicity managed by treatment delay
and other measures (see SCIMMUNE protocol for management of immune-
mediated adverse reactions to checkpoint inhibitors immunotherapy.

cabozantinib dose levels:

Starting Dose Dose Level -1 Dose Level -2
40 mg PO once daily 20 mg PO once daily 20 mg PO every other day

BC Cancer Protocol Summary GUAVNIVC Page 3 of 8

Activated: 1 Apr 2025 Revised:
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
1. Hepatotoxicity during treatment:
ALT or
total bilirubin cabozantinib nivolumab
AST
Less than or equal to
and 100% 100%
1.5 x ULN
Hold until
Less than
• Total bilirubin less than
or equal to
and Greater than 1.5 x ULN or equal to 1.5 x ULN,
3 x ULN
then restart at next lower
dose
and Greater than 3 x ULN Discontinue
Hold until
• ALT/AST less than or
equal to 3 x ULN, and
Greater *See
and Less than 2 x ULN • Total bilirubin less than SCIMMUNE
than 3 to or equal to 1.5 x ULN,
less than then restart at next lower
10 x ULN dose
Greater than or equal to
and Discontinue
2 x ULN
Greater
than or
or Greater than 3 x ULN Discontinue
equal to 10
x ULN

*No specific dose modifications. Toxicity managed by treatment delay and other
measures (see SCIMMUNE protocol for management of immune-mediated adverse
reactions to checkpoint inhibitors immunotherapy.

BC Cancer Protocol Summary GUAVNIVC Page 4 of 8

Activated: 1 Apr 2025 Revised:
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
2. Diarrhea:
Nivolumab
Grade Description Cabozantinib dose
dose
Increase of less than 4
1 stools per day over Continue same dose
baseline
Increase of 4 to 6 stools
2 per day over baseline;
limiting instrumental ADL
Increase of 7 or more *See
3 despite stools per day over Hold until Grade 1 or SCIMMUNE
antidiarrheal baseline; limiting self care less, then restart at next
treatment ADL; hospitalization lower dose
indicated
4 despite Life-threatening
antidiarrheal consequences; urgent
treatment intervention indicated

*No specific dose modifications. Toxicity managed by treatment delay and other
measures (see SCIMMUNE protocol for management of immune-mediated adverse
reactions to checkpoint inhibitors immunotherapy).

3. Palmar-Plantar Erythrodysesthesia (PPE):

Description Nivolumab
Grade Cabozantinib dose
dose
Minimal skin changes or
dermatitis (e.g., erythema,
1 Continue same dose
edema, or hyperkeratosis)
without pain
Skin changes (e.g.,
peeling, blisters, bleeding,
2 fissures, edema, or
hyperkeratosis) with pain; 100%
limiting instrumental ADL Hold until Grade 1 or
Severe skin changes less, then restart at
(e.g., peeling, blisters, next lower dose
bleeding, fissures, edema,
3
or hyperkeratosis) with
pain; limiting self care
ADL

BC Cancer Protocol Summary GUAVNIVC Page 5 of 8

Activated: 1 Apr 2025 Revised:
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
4. Hypertension:
 Initiate antihypertensive therapy if clinically indicated
 If cabozantinib is discontinued, a drop in blood pressure should be anticipated.
 Antihypertensive dose adjustment or interruption may be required
Blood Pressure Elevation Cabozantinib Dose
 Hold until systolic less than 160
mmHg and diastolic less than 100
160 mmHg systolic or greater, or 100
mmHg
mmHg diastolic or greater
 Once controlled, restart at next lower
dose level
Elevated blood pressure with life-
threatening consequences
(e.g., malignant hypertension, Discontinue
transient or permanent neurologic
deficit, hypertensive crisis)

5. Proteinuria:

Proteinuria Cabozantinib Dose

Negative or 1+ Dipstick, or less than 1
Maintain dose
g/L lab urine protein
 Obtain 24-hour urine, hold treatment
for greater than or equal to 1 g/24 h

2+ Dipstick or greater, or greater than  Repeat 24-hour urine prior to next

or equal to 1 g/L lab urine protein treatment

 When proteinuria less than 1 g/24h;

resume at reduced dose level

24-hour urine protein: greater than or

Discontinue
equal to 3.5 g/24h

PRECAUTIONS:

1. Serious immune-mediated reactions to nivolumab: Can be severe to fatal and

usually occur during the treatment course but may develop months after
discontinuation of therapy. They may include enterocolitis, intestinal perforation or
hemorrhage, hepatitis, dermatitis, neuropathy, endocrinopathy, pneumonitis, as well
as toxicities in other organ systems. Early diagnosis and appropriate management
are essential to minimize life-threatening complications (see SCIMMUNE protocol for
management of immune-mediated adverse reactions to checkpoint inhibitors
immunotherapy).
BC Cancer Protocol Summary GUAVNIVC Page 6 of 8
Activated: 1 Apr 2025 Revised:
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
2. Infusion-related reactions: Isolated cases of severe infusion reactions have been
reported. Discontinue nivolumab with Grade 3 or 4 reactions. Patients with mild or
moderate infusion reactions may receive nivolumab with close monitoring and use of
premedication.
3. Diarrhea: Both nivolumab and cabozantinib can cause diarrhea. Early diagnosis and
appropriate management are essential to minimize life-threatening complications.
See Dose Modifications.
4. Hypertension: The onset of hypertension usually occurs early in treatment. Blood
pressure should be controlled prior to initiation of treatment with cabozantinib.
Temporary suspension of cabozantinib is recommended for patients with severe
hypertension (greater than 160 mmHg systolic or greater than 100 mmHg diastolic).
See Dose Modifications. Discontinue cabozantinib for severe and persistent
hypertension despite anti-hypertensive therapy.
It is recommended that for at least the first 2 months of treatment, patients monitor
their blood pressure daily (home measurements, GP’s office, etc.) and regularly
thereafter. Patients should keep a journal of their blood pressure measurements that
can be submitted to the physician at the next appointment.
5. Cardiac Toxicity: cabozantinib can cause prolongation of the QTc interval, decreased
heart rate and PR interval prolongation. Correct electrolyte disturbances prior to
initiation. Use with caution in patients with baseline heart rate less than 60 beats per
minute or history of conduction abnormalities, arrhythmia, ischemic heart disease, or
congestive heart failure. Discontinue for arterial or venous thromboembolic events
that require medical intervention (e.g., myocardial infarction, cerebral infarction).
Monitor electrolytes and follow ECGs during treatment as indicated. Caution when
combining with medications that cause bradycardia or drugs that can decrease
electrolytes. See BC Cancer Drug Manual.
6. Renal dysfunction: Use cabozantinib with caution in patients with mild to moderate
impairment. Cabozantinib has not been studied in severe renal impairment.
7. Hemorrhagic events: Severe and fatal hemorrhagic events have been reported
with cabozantinib. Arterial aneurysm and artery dissection, including rupture, have
been reported in patients with and without hypertension. Avoid cabozantinib in
patients with recent hemorrhage. Discontinue cabozantinib in patients who
experience severe hemorrhage.
8. Hepatotoxicity: Hepatitis, fatal hepatic failure and hepatic encephalopathy have
been reported with cabozantinib treatment. Cabozantinib in combination with
nivolumab has not been studied in patients with mild or moderate hepatic
impairment. No dosing recommendation can be provided. Avoid in severe hepatic
impairment.
9. Wound healing complications: cabozantinib may suppress wound healing. Hold
treatment at least 4 weeks prior to scheduled surgery, including dental surgery.
Treatment resumption is based on clinical judgement. Discontinue treatment in
patients with wound dehiscence.
10. Reversible posterior leukoencephalopathy syndrome (RPLS) (rare): Symptoms
may include seizures, headache, altered mental status, visual disturbance, or
cortical blindness, with or without associated hypertension. Brain imaging is
necessary to confirm diagnosis. Discontinue cabozantinib when signs/symptoms or

BC Cancer Protocol Summary GUAVNIVC Page 7 of 8

Activated: 1 Apr 2025 Revised:
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.
 RPLS are present and provide supportive management of symptoms. The safety of
reinitiating treatment is not known.
11. Drug interactions: cabozantinib is predominantly metabolized by cytochrome P450
3A4. Potential drug interactions with cytochrome P450 3A4 interacting agents must
be considered if combination cannot be avoided and cabozantinib dose
modifications may be necessary. Avoid use with concomitant medications known to
prolong the QT interval. See BC Cancer Drug Manual.
12. Venous and arterial thromboembolic events: Are reported during cabozantinib
treatment. Monitor and treat as clinically indicated.
13. Gastrointestinal (GI) perforation and fistulas: Have been reported during
treatment with cabozantinib. Use caution in patients with a history of inflammatory
bowel disease, prior GI surgery and/or metastases to the GI tract.
14. Palmar-Plantar Erythrodysesthesia (PPE): Is reported in patients taking
cabozantinib. See Dose Modifications, above.

Call Dr. Krista Noonan or tumour group delegate at (604) 930-2098 or 1-800-523-
2885 with any problems or questions regarding this treatment program.

References:
1. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus
Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar
4;384(9):829-841.
2. Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-
line treatment of advanced renal cell carcinoma: extended follow-up from the phase III
randomised CheckMate 9ER trial. ESMO Open. 2024 May;9(5):102994.
3. Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus
cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in
CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022
Feb;23(2):292-303.
4. Cabozantinib (Cabometyx) Canada’s Drug Agency (CDA-AMC) Reimbursement
Recommendation. Canadian Journal of Health Technologies Nov 2023; 3(11): 1-20.
5. Canada’s Drug Agency (CDA-AMC) Reimbursement Review. Provisional Funding Algorithm.
Renal Cell Carcinoma. Feb 2024.

BC Cancer Protocol Summary GUAVNIVC Page 8 of 8

Activated: 1 Apr 2025 Revised:
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use.