Cabometyx Quickipedia

CABOMETYX® expands TKI targets beyond VEGFR1-4


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TKI: tyrosine kinase inhibitors;
VEGFR: vascular endothelial growth factor receptor;
PDGFR: platelet derived growth factor receptor;
MET: hepatocyte growth factor receptor;
AXL: growth arrest-specifi c protein 6 receptor; mTOR: mammalian target of rapamycin;
PD-1: programmed cell death protein 1;
PDL-1: programmed death-ligand 1.
Figure adapted from Greef B and Eisen T. Br J Cancer 2016; Yu SS et al. OncoTargets and Therapy 2016 and Zhou L et al. Oncogene 2016

1. Greef B and Eisen T. Br J Cancer. 2016; 115: 505–516.
2. CABOMETYX® Summary of Product Characteristics.
3. Zhou L et al. Oncogene 2016; 35: 2687–2697.
4. Yu SS et al. OncoTargets and Therapy 2016; 9: 5825–5837

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CABOMETYX® licensing in previously treated advanced RCC was based on the METEOR trial1-3

A randomised, open-label, multicentre phase 3 trial that compared the effi cacy of CABOMETYX® with that of everolimus in patients with advanced RCC who had previously received at least one prior VEGFR TKI1,2


Lancet Oncology, New England Journal of Medicine



71% of patients in the METEOR trial received CABOMETYX® in the second line1

  • Dose reductions were allowed in both arms2
  • Patients received treatment until disease progression or experiencing unacceptable toxicity.2
    Patients in both arms who had disease progression could continue at the discretion of the investigator2,3

*The primary PFS analysis was conducted in the fi rst 375 patients randomised to treatment.
The intention-to-treat (ITT) population included all 658 patients.1,2


Key inclusion/exclusion criteria2,3

  • Age ≥ 18 years
  • Advanced or metastatic RCC with a clear-cell component
  • Measurable disease as defi ned by RECIST version 1.1
  • Prior treatment with at least one VEGFR TKI
  • Radiographic progression during treatment or within 6 months after the most recent dose of VEGFR TKI and within 6 months before randomisation
  • Brain metastases allowed if adequately treated, stable and asymptomatic
  • No limit to the number of prior therapies
  • Karnofsky performance score of at least 70%
  • No prior therapy with an mTOR inhibitor or cabozantinib
  • Adequate organ and marrow function

Prespecified stratification2,3

  • Number of prior VEGFR TKIs (1 or ≥2)
  • Prognostic risk category according to the MSKCC criteria (favourable, intermediate or poor for previously treated patients)

Statistical design3

Primary endpoint: PFS by independent radiology review committee (IRC):

  • Assessed in the first 375 patients randomly assigned (PFS population)
  • 259 events were estimated to achieve 90% power

Secondary endpoints: OS and ORR by IRC3

OS: 408 deaths in the intention-to-treat (ITT) population of 650 planned patients were estimated to provide 80% power to detect a HR of 0.75:

  • First interim analysis for OS: planned at the time of primary PFS analysis
  • Unplanned second interim analysis of OS: undertaken upon the results of the first and after consultation with the FDA and EMA

 


RECIST: Response Evaluation Criteria in Solid Tumours.

1. CABOMETYX® Summary of Product Characteristics.
2. Choueiri TK et al. N Engl J Med. 2015; 373: 1814–1823.
3. Choueiri TK et al. Lancet Oncol. 2016; 17: 917–927.

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CABOMETYX® MEETS ALL 3 OF ITS ENDPOINTS IN THE METEOR TRIAL1,2

CABOMETYX® extended median OS by almost 5 months vs everolimus in the overall population (n=658)1,2

CABOMETYX® resulted in a survival rate of 73% vs 63% for everolimus at 12 months, and 48% vs 31% at 24 months3


a. ITT population; b. Partial responses only.

1. CABOMETYX® SmPC
2. Choueiri TK, et al. Lancet Oncol 2016;17:917-27 
3. Cabometyx® CHMP assessment report. July 2016. EMA/664123/2016

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CABOMETYX® significantly delays disease progression
or death vs everolimus1,2

PFS Population

CABOMETYX® significantly extended median progression-free survival (PFS) to 7.4 months vs 3.8 months for everolimus1


Independent radiology review committee data (n=375). ITT = intention-to-treat.
The data cutoff point was 22 May 2015, and the minimum follow up period was 11 months.1
Figure adapted from Choueiri TK et al. N Engl J Med. 2015


ITT Population

PFS advantage vs everolimus maintained in larger ITT population2


Disease progression was assessed by an independent radiology review committee in all 658 randomly assigned patients.
The data cutoff point was 22 May 2015, and the median follow-up period was 11.4 months in the CABOMETYX® group and 11.5 months in the everolimus group.2
Figure adapted from Choueiri TK et al. Lancet Oncol. 2016.


Progression-free survival (PFS) and intention-to-treat (ITT) populations

Efficacy was evaluated in two populations according to the ITT principle.1
To evaluate the secondary endpoint of overall survival, 650 patients were planned (the overall survival population).1
However, only 375 patients were required to achieve appropriate statistical power for the primary endpoint of PFS.1
Therefore, the study was designed to evaluate the primary endpoint in the first 375 patients who underwent randomisation (the PFS population) to allow longer follow-up of PFS.1


1. Choueiri TK et al. N Engl J Med. 2015; 373: 1814-1823.
2. Choueiri TK et al. Lancet Oncol. 2016; 17: 917-927

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CABOMETYX® significantly extends overall survival (OS) vs everolimus1

Overall survival

CABOMETYX® showed an OS advantage of 4.9 months over everolimus1


Independent radiology review committee data (n=658). The data cutoff point was 31 December 2015, and the median follow-up period was 18.7 months in the CABOMETYX® group and 18.8 months in the everolimus group.
Figure adapted from Choueiri TK et al. Lancet Oncol. 2016.

The above results are at 320 events. Comparable results for OS were observed with a follow-up analysis (descriptive) at 430 events.2


Survival rates

CABOMETYX® Survival rates with CABOMETYX® vs everolimus3


CABOMETYX®, n=330 (at 12 months 95% CI, 68%, 79%; at 24 months 95% CI, 39%, 55%); everolimus, n=328 (at 12 months, 95% CI, 58%, 78%; at 24 months 95% CI, 23%, 39%).1,3
Figure adapted from Choueiri TK et al. Lancet Oncol. 2016 (supplementary appendix).

 



1. Choueiri TK et al. Lancet Oncol. 2016; 17: 917-927.
2. CABOMETYX® Summary of Product Characteristics.
3. Choueiri TK et al. Lancet Oncol. 2016; 17: 917-927 (supplementary appendix)

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CABOMETYX® data has shown to produce a faster response than, and offers a significantly improved tumour response vs, everolimus1,2

The median time to first response with CABOMETYX® is less than 2 months (1.91 months with CABOMETYX® vs 2.14 months with everolimus by IRC; p<0.0001).1
Over 8 out of 10 patients achieved a partial response or stable disease with CABOMETYX® (p<0.0001).1-3


Confirmed complete response in both arms = 0%. IRC: independent review committee. IR: investigator review
Table adapted from CABOMETYX® Summary of Product Characteristic


1. CABOMETYX® Summary of Product Characteristics.
2. Choueiri TK et al. Lancet Oncol. 2016; 17: 917-927 (supplementary appendix).
3. CABOMETYX® CHMP assessment report, July 2016. EMA/664123/2016.

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CABOMETYX® tolerability in the METEOR trial1,2

Adverse events reported as Grade 1–2 in ≥10% of patients in either treatment arm (tolerability population)2

CABOMETYX® (n=331) everolimus (n=322)
Adverse event Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4
Number of patients with an event (%)
Any adverse event 70 (21) 210 (63) 25 (8) 103 (32) 167 (52) 26 (8)
Diarrhoea 206 (62) 43 (13) 0 85 (26) 7 (2) 0
Fatigue 159 (48) 36 (11) 0 130 (40) 24 (7) 0
Nausea 158 (48) 15 (5) 0 92 (29) 1 (<1) 0
Decreased appetite 146 (44) 10 (3) 0 111 (35) 3 (1) 0
Palmar-plantar erythrodysaesthesia syndrome 115 (35) 27 (8) 0 16 (5) 3 (1) 0
Vomiting 106 (32) 7 (2) 0 44 (14) 3 (1) 0
Weight decreased 105 (32) 9 (3) 0 42 (13) 0 0
Constipation 89 (27) 1 (<1) 0 64 (20) 1 (<1) 0
Dysgeusia 80 (24) 0 0 30 (9) 0 0
Hypothyroidism 76 (23) 0 0 1 (<1) 1 (<1) 0
Hypertension 73 (22) 49 (15) 0 14 (4) 12 (4) 0
Dysphonia 68 (21) 2 (1) 0 16 (5) 0 0
Cough 67 (20) 1 (<1) 0 107 (33) 3 (1) 0
Stomatitis 65 (20) 8 (2) 0 71 (22) 7 (2) 0
Mucosal inflammation 60 (18) 5 (2) 0 64 (20) 10 (3) 1 (<1)
Dyspnoea 56 (17) 10 (3) 0 82 (26) 11 (3) 3 (1)
Back pain 54 (16) 8 (2) 0 41 (13) 7 (2) 0
Rash 52 (16) 2 (1) 0 92 (29) 2 (1) 0
Asthenia 49 (15) 15 (5) 0 46 (14) 8 (2) 0
Abdominal pain 48 (15) 12 (4) 0 27 (8) 5 (2) 0
Pain in extremity 46 (14) 5 (2) 0 31 (10) 1 (<1) 0
Muscle spasms 45 (14) 0 0 17 (5) 0 0
Arthralgia 43 (13) 1 (<1) 0 46 (14) 4 (1) 0
Headache 43 (13) 1 (<1) 0 42 (13) 1 (<1) 0
Dizziness 41 (12) 1 (<1) 0 21 (7) 0 0
Dyspepsia 40 (12) 1 (<1) 0 15 (5) 0 0
Oedema peripheral 39 (12) 0 0 70 (22) 6 (2) 0
Dry skin 37 (11) 0 0 35 (11) 0 0
Flatulence 33 (10) 0 0 7 (2) 0 0
Insomnia 32 (10) 0 0 33 (10) 1 (<1) 0
Pyrexia 31 (9) 3 (1) 0 57 (18) 2 (1) 0
Pruritus 27 (8) 0 0 48 (15) 1 (<1) 0
Epistaxis 14 (4) 0 0 46 (14) 0 0
* All adverse events, irrespective of whether the event was considered by the investigator to be related to the study treatment

The most frequent adverse events of any grade with CABOMETYX® (experienced by ≥25% of patients) were diarrhoea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysaesthesia, hypertension, vomiting, weight loss and constipation1

  • CABOMETYX® dose reduction was used to manage adverse events in 62% of patients vs 25% everolimus2
  • Treatment discontinuations due to adverse events were similar for CABOMETYX® and everolimus (12% vs 11%)2

Treatment emergent laboratory abnormalities reported as Grade 1–2 in ≥10% of patients in either treatment arm (tolerability population)2

CABOMETYX® (n=331) everolimus (n=322)
Adverse event Laboratory abnormalities Grade 1-2 Grade 3 Grade 4 Grade1-2 Grade 3 Grade 4
Number of patients with an event (%)
Aspartate aminotransferase increased 55 (17) 5 (2) 0 19 (6) 1 (<1) 0
Alanine aminotransferase increased 47 (14) 7 (2) 1 (<1) 20 (6) 1 (<1) 0
Anaemia 42 (13) 19 (6) 0 73 (23) 53 (17) 0
Hypomagnesaemia 38 (12) 6 (2) 10 (3) 5 (2) 0 0
Proteinuria 37 (11) 8 (2) 0 28 (9) 2 (1) 0
Blood creatinine increased 17 (5) 1 (<1) 0 39 (12) 0 0
Hypertriglyceridaemia 17 (5) 4 (1) 0 31 (10) 7 (2) 3 (1)
Hyperglycaemia 15 (5) 2 (1) 1 (<1) 46 (14) 16 (5) 0

 

1. CABOMETYX® SmPC
2. Choueiri TK, et al. Lancet Oncol 2016;17:917-27

Please refer to the SmPC for more information on adverse events.

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The recommended dose of CABOMETYX® is 60 mg once-daily, taken orally1


1. CABOMETYX® Summary of Product Characteristics.
2. Cabometyx Patient Information Leaflet

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DOSE MODIFICATIONS


  • As most events can occur early in the course of CABOMETYX® therapy, patients should be evaluted closely during the first 8 weeks of treatment to determine if dose modifications are necessary1
  • CABOMETYX® treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs1
  • Management of suspected adverse reactions may require temporary interruption and / or dose reduction of CABOMETYX® therapy1
    • Dose interruptions are recommended for the management of Grade 3 or greater toxicities or intolerable Grade 2 toxicities1
    • Dose reductions are recommended for events that, if persistent, could become serious or intolerable1
  • For patients undergoing surgery, stop treatment with CABOMETYX® at least 28 days prior to scheduled surgery, including dental surgery1
Adverse reaction and severity Treatment modification
Grade 1 and Grade 2 adverse reactions which are tolerable and easily managed Dose adjustment is usually not required.
Consider adding supportive care as indicated.
Grade 2 adverse reactions which are intolerable and cannot be managed with a dose reduction or supportive care Interrupt treatment until the adverse reaction resolves to Grade ≤ 1.
Add supportive care as indicated. Consider re-initiating at a reduced dose.
Grade 3 adverse reactions (except clinically non-relevant laboratory abnormalities) Interrupt treatment until the adverse reaction resolves to Grade ≤ 1.
Add supportive care as indicated. Re-initiate at a reduced dose.
Grade 4 adverse reactions (except clinically non-relevant laboratory abnormalities) Interrupt treatment. Institute appropriate medical care.
If adverse reaction resolves to Grade ≤ 1, re-initiate at a reduced dose.
If adverse reaction does not resolve, permanently discontinue CABOMETYX®.

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4)

1. CABOMETYX® Summary of Product Characteristics

Please refer to the SmPC for more information on adverse events.

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Special populations

 

Population Considerations
Elderly patients No specific dose adjustment for the use of CABOMETYX® in older people (≥65 years) is recommended.
Race There is little experience with CABOMETYX® in non-white patients.
Patients with renal impairment CABOMETYX® should be used with caution in patients with mild or moderate renal impairment. CABOMETYX® is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population.
Patients with hepatic impairment In patients with mild or moderate hepatic impairment the recommended dose of CABOMETYX® is 40 mg once daily. Patients should be monitored for adverse events and dose adjustment or treatment interruption should be considered as needed. CABOMETYX® is not recommended for use in patients with severe hepatic impairment as safety and efficacy have not been established in this population.
Patients with cardiac impairment There is limited data in patients with cardiac impairment. No specific dosing recommendations can be made.
Paediatric population The safety and efficacy of CABOMETYX® in children and adolescents aged <18 years have not yet been established. No data are available.
Women of childbearing potential/contraception in males and females Women of childbearing potential must be advised to avoid pregnancy while on CABOMETYX®. Female partners of male patients taking CABOMETYX® must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as “effective methods of contraception”, they should be used together with another method, such as a barrier method.
Pregnancy There are no studies in pregnant women using CABOMETYX®. Studies in animals have shown embryo-foetal and teratogenic effects. The potential risk for humans is unknown. CABOMETYX® should not be used during pregnancy unless the clinical condition of the woman requires treatment with CABOMETYX®.
Breast-feeding It is not known whether CABOMETYX® and/or its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should discontinue breast-feeding during treatment with CABOMETYX®, and for at least 4 months after completing therapy.

 

Figure adapted from CABOMETYX® Summary of Product Characteristics.

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Special warnings

 

Event Considerations
Perforations and fi stulas Serious gastrointestinal (GI) perforations and fi stulas, sometimes fatal, have been observed with CABOMETYX®. Patients who have infl ammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), have tumour infi ltration in the GI tract, or have complications from prior GI surgery (particularly when associated with delayed or incomplete healing) should be carefully evaluated before initiating CABOMETYX® therapy and subsequently they should be monitored closely for symptoms of perforations and fi stulas including abscesses. Persistent or recurring diarrhoea while on treatment may be a risk factor for the development of anal fi stula. CABOMETYX® should be discontinued in patients who experience a GI perforation or a fi stula that cannot be adequately managed.
Thromboembolic events Events of venous thromboembolism, including pulmonary embolism, and events of arterial thromboembolism have been observed with CABOMETYX®. CABOMETYX® should be used with caution in patients who are at risk for, or who have a history of, these events. CABOMETYX® should be discontinued in patients who develop an acute myocardial infarction or any other clinically signifi cant arterial thromboembolic complication.
Haemorrhage Severe haemorrhage has been observed with CABOMETYX®. Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating CABOMETYX® therapy. CABOMETYX® should not be administered to patients that have or are at risk for severe haemorrhage.
Wound complications Wound complications have been observed with CABOMETYX®. CABOMETYX® treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery, if possible. The decision to resume CABOMETYX® therapy after surgery should be based on clinical judgment of adequate wound healing. CABOMETYX® should be discontinued in patients with wound healing complications requiring medical intervention.
Hypertension Hypertension has been observed with CABOMETYX®. Blood pressure should be well-controlled prior to initiating CABOMETYX®. During treatment with CABOMETYX®, all patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of antihypertensives, the CABOMETYX® dose should be reduced. CABOMETYX® should be discontinued if hypertensionis severe and persistent despite anti-hypertensive therapy and dose reduction of CABOMETYX®. In case of hypertensive crisis, CABOMETYX® should be discontinued.
PPES PPES has been observed with CABOMETYX®. When PPES is severe, interruption of treatment with CABOMETYX® should be considered. CABOMETYX® should be restarted with a lower dose when PPES has been resolved to grade 1.
Proteinuria Proteinuria has been observed with CABOMETYX®. Urine protein should be monitored regularly during CABOMETYX® treatment. CABOMETYX® should be discontinued in patients who develop nephrotic syndrome.
Reversible posterior leukoencephalopathy syndrome (RPLS) RPLS, also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been observed with CABOMETYX®. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. CABOMETYX® treatment should be discontinued in patients with RPLS.
Prolongation of QT interval CABOMETYX® should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using CABOMETYX®, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered.
CYP3A4 inducers and inhibitors CABOMETYX® is a CYP3A4 substrate. Concurrent administration of CABOMETYX® with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in CABOMETYX® plasma exposure. Caution is required when administering CABOMETYX® with agents that are strong CYP3A4 inhibitors. Concurrent administration of CABOMETYX® with the strong CYP3A4 inducer rifampicin resulted in a decrease in CABOMETYX® plasma exposure. Therefore chronic administration of agents that are strong CYP3A4 inducers with CABOMETYX® should be avoided.
P-glycoprotein substrates CABOMETYX® was an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, CABOMETYX® may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g. fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole,ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving CABOMETYX®.
MRP2 inhibitors Administration of MRP2 inhibitors may result in increases in CABOMETYX® plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution.
Excipient related warnings Patients with rare hereditary problems of galactose intolerance, the Lapp lactase defi ciency or glucose-galactose malabsorption should not take this medicine.

 

PPES: palmar-plantar erythrodysaesthesia. Figure adapted from CABOMETYX® Summary of Product Characteristics.

SmPC