Cabometyx + Opdivo Clinical Presentation

Cabometyx (cabozatinib):
● Cabometyx: kinase inhibitor indicated for tx of patients with:
○ RCC
○ First line tx in combo with nivolumab
○ HCC pts who have previously been treated with sorafenib
○ Off label: does not recommend for use; not approved by FDA
○ Approved for RCC in Dec 2017
● MOA:
○ Multi kinase TKI
○ Synergism with PD-1 and PDL-1 inhibitors
○ Increased angiogenesis and immune suppression
● RCC:
○ Determining risk groups: MSKCC & IMDC
○ Advanced RCC treatment targeted agents:
■ Cabozantinib, bevacizumab, axitinib, lenvatinib, pazopanib, sorafenib, sunitinib
○ Approval in 1/2021: Nivolumab + cabozantinib

CheckMate 9ER Trial

● Phase 3 Study Design
○ Randomized 1:1
○ Primary endpoint: PFS
○ Secondary: overall survival, objective response rate, safety, tolerability
○ 651 patients
● Inclusion criteria: clear cell component, including patients who may have sarcomatoid features
● Exclusion criteria: prior systemic therapy, autoimmune disease or other medical conditions
requiring systemic immunosuppression
● Evaluated:
○ Cabozantinib at 40mg PO Qday (+) Nivolumab 240mg IV Q2wk
○ Sunitinib 50mg QD (4 weeks on/ 2 weeks off)
● Efficacy
○ PFS improved with both agents
■ Complete response
● 8% in Cabozantinib + Nivolumab
● 4.6% in Sunitinib group
■ Partial response
● 48% in Cabozantinib + Nivolumab
● 23% in Sunitinib group
○ Follow-up: 1.5 years (+) 6 months (~2 year follow up median)
● Adverse Reactions in patients receiving cabozantinib + nivolumab
○ ADRs: Diarrhea, fatigue, hepatotoxicity, PPE, UTI, hypertension, hypothyroidism,
musculoskeletal pain, decreased appetite
● Most frequent adverse reactions leading to dose delay
 ○ Diarrhea
○ PPE
○ HTN
○ ALT increase
● Summary:
○ Cabozantinib median PFS is much longer
○ PFS median of 16.6 months for combination vs 8.3 months for sunitinib (statistically
significant)
○ Cabozantinib + Sunitinib demonstrates superiority over sunitinib by doubling PFS time,
doubling overall response rate, and significantly improving overall survival
○ Safety (grade 3/4 AEs >5%): HTN, hepatotoxicity, fatigue, PPE, diarrhea
○ Important to manage AE’s more closely so patient can stay on the medication therapy for
longer amount of time
● AEs that occurred more frequently when administered in combo
○ Diarrhea
○ HTN
○ Hypothyroidism
○ ALT increase
○ Fatigue
○ Rash
● Dose delay
○ Toxicity related to ONLY nivolumab - delay nivolumab
○ Toxicity related to ONLY cabozantinib - delay cabozantinib
○ Toxicity related to BOTH, or if unable to determine which drug caused AE - delay both
● Corticosteroids - primary therapy for IO drug-related AEs
● Immune-mediated AEs:
○ Thyroiditis/hypothyroidism, rash, hepatitis, diarrhea/colitis
■ Diarrhea more extended compared to just TKI-related therapy diarrhea
○ In CABOMETYX + nivolumab arm:
■ AE in diarrhea 64% All Grades, 7% Grade 3-4
● Median time to onset: 12.4 weeks
● Dose delay or reduction 24.4% all grade
■ IMAE category diarrhea/colitis: 5.3% any grade, 1.6% grade 3-4
● Median time to onset: 29.3 weeks
● Dose delay or reduction 3.4%
■ Diarrhea and colitis may be treated with dose reduction/delays or OTC
antidiarrheal products depending on amount of loose stools per day
● AST/ALT increase
○ Median time to onset 2.3 months
○ Monitor LFTs before initiation and periodically throughout treatment
○ Consider corticosteroid therapy
○ If >3x ULN but ≥10xULN w/ total bilirubin <2x ULN, withhold both Cabometyx and nivolumab
until recovery
● Hypertension
 ○ AEs 36% all grade
○ Median time to onset: 4.1 weeks
○ Do not initiate in pts with uncontrolled HTN
○ Monitor BP regularly during treatment
○ Withhold for HTN that is not controlled with medical management and when controlled
then resume at a reduced dose
○ D/c Cabometyx for severe HTN that can’t be controlled with anti-hypertensive therapy or
hypertensive crisis
● PPE
○ AE 40% all grade
○ Median time to onset 7.4 weeks
○ Dose delay or reduction 19.1% all grade
● Rash
○ IMAEs 10% any grade
○ Median time to onset 12.4 weeks
○ Dose delay or reduction 3.4%