Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01EX07.

Mechanism of action
Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodelling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

Pharmacodynamic effects
Cabozantinib exhibited dose-related tumour growth inhibition, tumour regression, and/or inhibited metastasis in a broad range of preclinical tumour models.

Cardiac electrophysiology
An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10 – 15 ms on Day 29 (but not on day 1) following initiation of cabozantinib treatment (at a dose of 140 mg once daily) was observed in a controlled clinical trial in medullary thyroid cancer patients. This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects in this study had a confirmed QTcF >500 ms, nor did any cabozantinib-treated subjects in the RCC or HCC studies (at a dose of 60 mg).

Clinical efficacy and safety

Renal cell carcinoma
Randomized study in RCC patients who have received prior vascular endothelial growth factor (VEGF)- targeted therapy (METEOR)
The safety and efficacy of CABOMETYX for the treatment of renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy were evaluated in a randomized, open-label, multicenter phase 3 study (METEOR). Patients (N=658) with advanced RCC with a clear cell component who had previously received at least 1 prior VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) were randomized (1:1) to receive cabozantinib (N=330) or everolimus (N=328). Patients could have received other prior therapies, including cytokines, and antibodies targeting VEGF, the programmed death 1 (PD-1) receptor, or its ligands. Patients with treated brain metastases were allowed. Progression-free survival (PFS) was assessed by a blinded independent radiology review committee, and the primary analysis was conducted among the first 375 subjects randomized. Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumour assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter.

The baseline demographic and disease characteristics were similar between the cabozantinib and everolimus arms. The majority of the patients were male (75%), with a median age of 62 years. Seventy-one percent (71%) received only one prior VEGFR TKI; 41% of patients received sunitinib as their only prior VEGFR TKI. According to the Memorial Sloan Kettering Cancer Center criteria for prognostic risk category, 46% were favourable (0 risk factors), 42% were intermediate (1 risk factor), and 13% were poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%). The median duration of treatment was 7.6 months (range 0.3 – 20.5) for patients receiving cabozantinib and 4.4 months (range 0.21 – 18.9) for patients receiving everolimus.

A statistically significant improvement in PFS was demonstrated for cabozantinib compared to everolimus (Figure 1 and Table 4). A planned interim analysis of OS was conducted at the time of the PFS analysis and did not reach the interim boundary for statistical significance (202 events, HR=0.68 [0.51, 0.90], p=0.006).
In a subsequent unplanned interim analysis of OS, a statistically significant improvement was demonstrated for patients randomized to cabozantinib as compared with everolimus (320 events, median of 21.4 months vs. 16.5 months; HR=0.66 [0.53, 0.83], p=0.0003; Figure 2). Comparable results for OS were observed with a follow-up analysis (descriptive) at 430 events.

Exploratory analyses of PFS and OS in the ITT population have also shown consistent results in favour of cabozantinib compared to everolimus across different subgroups according to age (<65 vs. ≥65, sex, MSKCC risk group (favourable, intermediate, poor), ECOG status (0 vs. 1), time from diagnosis to randomisation (<1 year vs. ≥1 year), tumour MET status (high vs. low vs. unknown), bone metastases (absence vs. presence), visceral metastases (absence vs. presence), visceral and bone metastases (absence vs.
presence), number of prior VEGFR-TKIs (1 vs. ≥2), duration of first VEGFR-TKI (≤6 months vs. >6 months).

Objective response rate findings are summarized in Table 5.

Figure 1: Kaplan Meier curve for progression-free survival by independent radiology review committee, in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (first 375 subjects randomized) (METEOR)

1 .0
Probability of Progression-free Survival
P r o b a b ilit y o f P r o g r e s s io n - f r e e S u r v iv a l



0 .9
0 .8

0 .7

0 .6
0 .5

0 .4

0 .3
0 .2       CABOMETYX

0 .1       Everolimus

0 .0
0     3          6     9           12   15   18
Number   at risk:                                                                                                                                     Months M o n th s
No. at Risk
CABOMETYX
CABOMETYX         187                                                                                                                152         92    68          20    6    2 Everolimus
Everolimus        188                                                                                                                 99         46    29          10    2    0 

Table 4: Summary of PFS findings by independent radiology review committee in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR) Primary PFS analysis population                  Intent-to-treat population Endpoint                                                                   CABOMETYX         Everolimus                  CABOMETYX           Everolimus N = 187           N = 188                     N = 330            N = 328 Median PFS (95%                                                            7.4 (5.6, 9.1)   3.8 (3.7, 5.4)               7.4 (6.6, 9.1)     3.9 (3.7, 5.1) CI), months
HR (95% CI),                                                                   0.58 (0.45, 0.74), p<0.0001                    0.51 (0.41, 0.62), p<0.0001 p-value1
1 stratified log-rank test

Figure 2: Kaplan-Meier curve of overall survival in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR)

1 .0

0 .9
S u r v iv a l
O v e r a llSurvival


0 .8

0 .7 o fOverall



0 .6
0 .5
P r o b a b ilit yof



0 .4
Probability



0 .3
CABOMETYX
CABO M ETYX
0 .2
E v e ro lim u s
Everolimus
0 .1
0 .0
0   3            6            9     12          15      18        21       24       27       30 Number at risk:                                                                                              Months M o n th s
CABOMETYX 330                                                         318         296          264    239       178       105       41       6         3       0 Everolimus 328                                                        307         262          229    202       141        82       32       8         1       0 

Table 5: Summary of ORR findings per independent radiology committee review (IRC) and investigator review, in RCC subjects following prior vascular endothelial growth factor (VEGF)- targeted therapy

Primary analysis ORR intent-to-                   ORR per investigator review treat population (IRC)                        intent-to-treat population Endpoint                                                                 CABOMETYX            Everolimus                 CABOMETYX            Everolimus N = 330            N = 328                      N = 330            N = 328 ORR (partial                                                            17% (13%, 22%)      3% (2%, 6%)                 24% (19%, 29%)      4% (2%, 7%) responses only)
(95% CI) p-value1                                                                                     p<0.0001                                  p< 0.0001 Partial response                                                               17%                      3%                    24%                    4% Median time to first                                                      1.91 (1.6, 11.0)         2.14 (1.9, 9.2)       1.91 (1.3, 9.8)        3.50 (1.8, 5.6) response, months
(95% CI)
Stable disease as                                                                 65%                     62%                   63%                  63% best response
Progressive disease                                                               12%                     27%                   9%                   27% as best response
1 chi-squared test
Randomized study in treatment-naïve renal cell carcinoma patients (CABOSUN) The safety and efficacy of CABOMETYX for the treatment of treatment-naïve renal cell carcinoma were evaluated in a randomized, open-label, multicenter study (CABOSUN). Patients (N=157) with previously untreated, locally advanced or metastatic RCC with a clear cell component were randomized (1:1) to receive cabozantinib (N=79) or sunitinib (N=78). Patients had to have intermediate or poor risk disease as defined by the International Metastatic RCC Database Consortium (IMDC) risk group categories. Patients were stratified by IMDC risk group and presence of bone metastases (yes/no). Approximately 75% of patients had a nephrectomy prior to onset of treatment.
For intermediate risk disease, one or two of the following risk factors were met, while for poor risk, three or more factors were met: time from diagnosis of RCC to systemic treatment < 1 year, Hgb < LLN, corrected calcium > ULN, KPS < 80%, neutrophil count > ULN and platelet count > ULN.

The primary endpoint was PFS. Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumour assessments were conducted every 12 weeks.

The baseline demographic and disease characteristics were similar between the cabozantinib and sunitinib arms. The majority of the patients were male (78%) with a median age of 62 years. Patient distribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% poor (≥3 risk factors). Most patients (87%) had ECOG performance status of 0 or 1; 13% had an ECOG performance status of 2. Thirty-six percent (36%) of patients had bone metastases.

A statistically significant improvement in PFS as retrospectively assessed by a blinded Independent Radiology Committee (IRC) was demonstrated for cabozantinib compared to sunitinib (Figure 3 and Table 6). The results from the investigator determined analysis and IRC-determined analysis of PFS were consistent.

Patients with both positive and negative MET status showed a favourable effect with cabozantinib compared to sunitinib, with greater activity in patients with a positive MET status compared to patients with a negative MET status (HR=0.32 (0.16, 0.63) vs 0.67 (0.37, 1.23)) respectively.

Cabozantinib treatment was associated with a trend for longer survival compared to sunitinib (Table 6). The study was not powered for the OS analysis and the data are immature.

Objective response rate (ORR) findings are summarized in Table 6.

Figure 3: Kaplan Meier curve for progression-free survival by IRC in treatment-naïve RCC subjects 1.0
Probability of Progression-free Survival



0.9

0.8
0.7

0.6

0.5
0.4

0.3

0.2
CABOMETYX
0.1
Sunitinib
0.0
0     3         6   9   12     15     18   21   24       27         30 Months
Number at risk:
CABOMETYX
Sunitinib


Table 6: Efficacy results in treatment-naïve RCC subjects (ITT population, CABOSUN) 
CABOMETYX                    Sunitinib
(N=79)                     (N=78)
Progression-free survival (PFS) by IRC a
Median PFS in months (95% CI)                   8.6 (6.2, 14.0)                   5.3 (3.0, 8.2) HR (95% CI); stratified b,c                                     0.48 (0.32, 0.73) Two-sided log-rank p-value: stratified b                           p=0.0005 Progression-free survival (PFS) by investigator
Median PFS in months (95% CI)                   8.3 (6.5, 12.4)                   5.4 (3.4, 8.2) HR (95% CI); stratified b,c                                     0.56 (0.37, 0.83) Two-sided log-rank p-value: stratified b                           p=0.0042 Overall survival
Median OS in months (95% CI)                  30.3 (14.6, NE)                    21.0 (16.3, 27.0) HR (95% CI); stratified b,c                                     0.74 (0.47, 1.14) Objective response rate n (%) by IRC
Complete responses                                     0                                 0 Partial responses                                  16 (20)                             7 (9) ORR (partial responses only)                       16 (20)                             7 (9) Stable disease                                     43 (54)                           30 (38) Progressive disease                                14 (18)                           23 (29) Objective response rate n (%) by investigator
Complete responses                                   1 (1)                               0 Partial responses                                  25 (32)                            9 (12) ORR (partial responses only)                       26 (33)                            9 (12) Stable disease                                     34 (43)                           29 (37) Progressive disease                                14 (18)                           19 (24) a in accord with EU censoring b Stratification factors per IxRS comprise IMDC risk categories (intermediate risk, poor risk and bone metastasis (yes, no) c Estimated using the Cox proportional hazard model adjusted for stratification factors per IxRS. Hazard ratio < 1 indicates  progression-free survival in favour of cabozantinib
Randomised phase 3 study of cabozantinib in combination with nivolumab vs. sunitinib (CA2099ER) The safety and efficacy of cabozantinib 40 mg orally daily in combination with nivolumab 240 mg intravenously every 2 weeks for the first-line treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open label study (CA2099ER). The study included patients (18 years or older) with advanced or metastatic RCC with a clear cell component, Karnofsky Performance Status (KPS) > 70%, and measurable disease as per RECIST v1.1 were included regardless of their PD-L1 status or IMDC risk group.
The study excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression, patients who had prior treatment with an anti-PD-1, anti PD-L1, anti-PD-L2, anti- CD137, or anti-CTLA-4 antibody, poorly controlled hypertension despite antihypertensive therapy, active brain metastases and uncontrolled adrenal insufficiency. Patients were stratified by IMDC prognostic score, PD-L1 tumour expression, and region.

A total of 651 patients were randomised to receive either cabozantinib 40 mg once daily orally in combination with nivolumab 240 mg (n=323) administered intravenously every 2 weeks or sunitinib (n = 328) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off. Treatment continued until disease progression or unacceptable toxicity with nivolumab administration up to 24 months. Treatment beyond initial Investigator-assessed RECIST version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug, as determined by investigator. First tumour assessment post-baseline was performed at 12 weeks (± 7 days) following randomisation. Subsequent tumour assessments occurred at every 6 weeks (± 7 days) until Week 60, then every 12 weeks (± 14 days) until radiographic progression, confirmed by the Blinded Independent Central review (BICR). The primary efficacy outcome measure was PFS as determined by a BICR. Additional efficacy measures included OS and ORR as key secondary endpoints.

Baseline characteristics were generally balanced between the two groups. The median age was 61 years (range: 28-90) with 38.4%  65 years of age and 9.5%  75 years of age. The majority of patients were male (73.9%) and white (81.9%). Eight percent of patients were Asian, 23.2% and 76.5% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. Patient distribution by IMDC risk categories was 22.6% favourable, 57.6% intermediate, and 19.7% poor. For tumour PD-L1 expression, 72.5% of patients had PD-L1 expression < 1% or indeterminate and 24.9% of patients had PD-L1 expression ≥ 1%. 11.5% of patients had tumours with sarcomatoid features. The median duration of treatment was 14.26 months (range: 0.2-27.3 months) in cabozantinib with nivolumab-treated patients and was 9.23 months (range: 0.8-27.6 months) in sunitinib-treated patients.

The study demonstrated a statistically significant benefit in PFS, OS, and ORR for patients randomised to cabozantinib in combination with nivolumab as compared to sunitinib. Efficacy results from the primary analysis (minimum follow-up 10.6 months; median follow-up 18.1 months) are shown in Table 7.

Table 7: Efficacy results (CA2099ER)
 nivolumab + cabozantinib                     sunitinib
(n = 323)                             (n = 328)
PFS per BICR
Events                                       144 (44.6%)                        191 (58.2%) Hazard ratioa                                             0.51
95% CI                                             (0.41, 0.64) p-valueb, c                                          < 0.0001
Median (95% CI)d                         16.59 (12.45, 24.94)                 8.31 (6.97, 9.69) OS
Events                                        67 (20.7%)                         99 (30.2%) Hazard ratioa                                               0.60
98.89% CI                                              (0.40, 0.89) p-valueb,c,e                                             0.0010
Median (95% CI)                                  N.E.                         N.E. (22.6, N.E.) Rate (95% CI)
At 6 months                            93.1 (89.7, 95.4)                  86.2 (81.9,89.5) ORR per BICR                                  180 (55.7%)                        89 (27.1%) (CR + PR)
(95% CI)f                                  (50.1, 61.2)                             (22.4, 32.3) Difference in ORR (95% CI)g                                           28.6 (21.7, 35.6) p-valueh                                                      < 0.0001 Complete response (CR)                               26 (8.0%)                                 15 (4.6%) Partial response (PR)                               154 (47.7%)                                74 (22.6%) Stable disease (SD)                                 104 (32.2%)                               138 (42.1%) Median duration of responsed
Months (range)                                  20.17 (17.31, N.E.)                       11.47 (8.31, 18.43) Median time to response
Months (range)                                     2.83 (1.0-19.4)                          4.17 (1.7-12.3) a    Stratified Cox proportional hazards model. Hazard ratio is nivolumab and cabozantinib over sunitinib.
b    2-sided p-values from stratified regular log-rank test.
c    Log-rank test stratified by IMDC prognostic risk score (0, 1-2, 3-6), PD-L1 tumour expression (1% versus <1% or indeterminate) and region (US/Canada/W Europe/N Europe, ROW) as entered in the IRT.
d
Based on Kaplan-Meier estimates.
e    Boundary for statistical significance p-value <0.0111.
f    CI based on the Clopper and Pearson method.
g    Strata adjusted difference in objective response rate (nivolumab+cabozantinib - Sunitinib) based on DerSimonian and Laird h    2-sided p-value from CMH test.
NE = non-estimable

The primary analysis of PFS included censoring for new anti-cancer treatment (Table 7). Results for PFS with and without censoring for new anti-cancer treatment were consistent.

PFS benefit was observed in the cabozantinib in combination with nivolumab arm vs. sunitinib regardless of tumour PD L1 expression. Median PFS for tumour PD L1 expression ≥ 1% was 13.08 for cabozantinib in combination with nivolumab, and was 4.67 months in the sunitinib arm (HR = 0.45; 95% CI: 0.29, 0.68).
For tumour PD L1 expression < 1%, the median PFS was 19.84 months for the cabozantinib in combination with nivolumab, and 9.26 months in the sunitinib arm (HR = 0.50; 95% CI: 0.38, 0.65).

PFS benefit was observed in the cabozantinib in combination with nivolumab arm vs. sunitinib regardless of the (IMDC) risk category. Median PFS for the favourable risk group was not reached for cabozantinib in combination with nivolumab, and was 12.81 months in the sunitinib arm (HR = 0.60; 95% CI: 0.37, 0.98).
Median PFS for the intermediate risk group was 17.71 months for cabozantinib in combination with nivolumab and was 8.38 months in the sunitinib arm (HR = 0.54; 95% CI: 0.41, 0.73). Median PFS for the poor risk group was 12.29 months for cabozantinib in combination with nivolumab and was 4.21 months in the sunitinib arm (HR = 0.36; 95% CI: 0.23, 0.58).

An updated PFS and OS analysis were performed when all patients had a minimum follow-up of 16 months and a median follow-up of 23.5 months (see figures 4 and 5). The PFS hazard ratio was 0.52 (95% CI: 0.43; 0.64). The OS hazard ratio was 0.66 (95% CI: 0.50; 0.87). Updated efficacy data (PFS and OS) in subgroups for the IMDC risk categories and PD-L1 expression levels confirmed the original results. With the updated analysis, median PFS is reached for the favourable risk group.
Figure 4: Kaplan-Meier curves of PFS (CA2099ER)
Probability of progression-free survival



Progression-free Survival per BICR (months)

Number of subjects at risk
Nivolumab + cabozantinib
323      280 236        201                                        166    145    102      56      26     5      2       0 Sunitinib
328      230 160        122                                        87     61      37      17       7     2      1       0 Nivolumab + cabozantinib (events: 175/323), median and 95.0% CI: 16.95 (12.58, 19.38) Sunitinib (events: 206/328), median and 95.0% CI:8.31 (6.93, 9.69)
Figure 5 : Kaplan Meier curves of OS (CA2099ER)
Probability of survival
Overall Survival (Months)

Number of subjects at risk
Nivolumab + cabozantinib
323     308      295    283        269     255     220     147       84      40       10           0 Sunitinib
328     295      272    254        236     217     189     118       62      22        4           0 Nivolumab + cabozantinib (events: 86/323), median and 95% CI: NE
Sunitinib (events: 116/328), median and 95% CI:29.47 (28.35, NE)

Hepatocellular carcinoma
Controlled study in patients who have received sorafenib (CELESTIAL)
The safety and efficacy of CABOMETYX were evaluated in a randomized, double-blind, placebo- controlled phase 3 study (CELESTIAL). Patients (N=707) with HCC not amenable to curative treatment and who had previously received sorafenib for advanced disease were randomized (2:1) to receive cabozantinib (N=470) or placebo (N=237). Patients could have received one other prior systemic therapy for advanced disease in addition to sorafenib. Randomization was stratified by aetiology of disease (HBV [with or without HCV], HCV [without HBV], or other), geographic region (Asia, other regions) and by presence of extrahepatic spread of disease and/or macrovascular invasions (Yes, No).

The primary efficacy endpoint was overall survival (OS). Secondary efficacy endpoints were progression- free survival (PFS) and objective response rate (ORR), as assessed by the investigator using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Tumour assessments were conducted every 8 weeks.
Subjects continued blinded study treatment after radiological disease progression whilst they experienced clinical benefit or until the need for subsequent systemic or liver-directed local anticancer therapy.
Crossover from placebo to cabozantinib was not allowed during the blinded treatment phase.

The baseline demographic and disease characteristics were similar between the cabozantinib and placebo arms and are shown below for all 707 randomised patients.

The majority of patients (82%) were male: the median age was 64 years. The majority of patients (56%) were Caucasian and 34% of patients were Asian. Fifty three percent (53%) of patients had ECOG performance status (PS) 0 and 47% had ECOG PS 1. Almost all patients (99%) were Child Pugh A and 1% were Child Pugh B. Aetiology for HCC included 38% hepatitis B virus (HBV), 21% hepatitis C virus (HCV), 40% other (neither HBV nor HCV). Seventy-eight percent (78%) had macroscopic vascular invasion and/ or extra-hepatic tumour spread, 41% had alfa-fetoprotein (AFP) levels ≥400μg/L, 44% had been treated by loco-regional transarterial embolisation or chemoinfusion procedures, 37% had radiotherapy prior to cabozantinib treatment. Median duration of sorafenib treatment was 5.32 months. Seventy-two percent (72%) of patients had received 1 and 28% had received 2 prior systemic therapy regimens for advanced disease.
A statistically significant improvement in OS was demonstrated for cabozantinib compared to placebo (Table 8 and Figure 6).

PFS and ORR findings are summarized in Table 8.

Table 8: Efficacy results in HCC (ITT population, CELESTIAL)
CABOMETYX                                    Placebo
(N=470)                                  (N=237)
Overall survival
Median OS (95% CI), months               10.2 (9.1, 12.0)                           8.0 (6.8, 9.4) 1,2
HR (95% CI)                                               0.76 (0.63, 0.92) p-value1                                                     p=0.0049 Progression-free survival (PFS)3
Median PFS in months (95% CI)              5.2 (4.0, 5.5)                           1.9 (1.9, 1.9) HR (95% CI)1                                              0.44 (0.36, 0.52) p-value1                                                     p<0.0001 Kaplan-Meier landmark estimates of percent of subjects event-free at 3 months
% (95% CI)                                  67.0% (62.2%, 71.3%)              33.3% (27.1%, 39.7%) Objective response rate n (%)3
Complete responses (CR)                                0                                0 Partial responses (PR)                               18 (4)                          1 (0.4) ORR (CR+PR)                                          18 (4)                          1 (0.4) 1,4 p-value                                                            p=0.0086 Stable disease                                     282 (60)                          78 (33) Progressive disease                                 98 (21)                         131 (55) 1
2-sided stratified log-rank test with aetiology of disease (HBV [with or without HCV], HCV [without
HBV], or other), geographic region (Asia, other regions), and presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, No) as stratification factors (per IVRS data) 2 estimated using the Cox proportional-hazard model
3 as assessed by investigator per RECIST 1.1
4 stratified Cochran-Mantel-Haenszel (CMH) test



Figure 6: Kaplan-Meier curve of overall survival (CELESTIAL)
Figure 7: Kaplan Meier curve for progression-free survival (CELESTIAL) 


The incidence of systemic non-radiation and local liver-directed systemic non-protocol anticancer therapy (NPACT) was 26% in the cabozantinib arm and 33% in the placebo arm. Subjects receiving these therapies had to discontinue study treatment. An exploratory OS analysis censoring for the use of NPACT supported the primary analysis: the HR, adjusted for stratification factors (per IxRS), was 0.66 (95% CI: 0.52, 0.84; stratified logrank p-value = 0.0005). The Kaplan- Meier estimates for median duration of OS were 11.1 months in the cabozantinib arm versus 6.9 months in the placebo arm, an estimated 4.2-month difference in the medians.

Non-disease specific quality of life (QoL) was assessed using the EuroQoL EQ-5D-5L. A negative effect of cabozantinib versus placebo on the EQ-5D utility index score was observed during the first weeks of treatment. Only limited QoL data are available after this period.

Differentiated thyroid carcinoma (DTC)
Placebo -Controlled study in adult patients who have received prior systemic therapy and are refractory or not eligible to radioactive iodine (COSMIC-311)
The safety and efficacy of CABOMETYX was evaluated in COSMIC-311, a randomised (2:1), double- blind, placebo-controlled, multicenter trial in adult patients with locally advanced or metastatic disease with differentiated thyroid cancer that had progressed following up to two prior VEGFR-targeting therapy (including, but not limited to, lenvatinib or sorafenib) and were radioactive iodine-refractory or not eligible.
Patients with measurable disease and documented radiographic progression per RECIST 1.1 per the Investigator, during or following treatment with VEGFR- targeting TKI, were randomised (N=258) to receive cabozantinib 60 mg orally once daily (N=170) or placebo (N=88).

Randomisation was stratified by prior receipt of lenvatinib (yes vs. no) and age (≤ 65 years vs. > 65 years).
Eligible patients randomised to placebo were allowed to cross-over to cabozantinib upon confirmation of progressive disease by blinded independent radiology review committee (BIRC).
Subjects continued blinded study treatment as long as they experienced clinical benefit or until there was unacceptable toxicity. The primary efficacy outcome measures were progression-free survival (PFS) in the ITT population, and objective response rate (ORR) in the first 100 randomised patients, as assessed by BIRC per RECIST 1.1. Tumour assessments were conducted every 8 weeks after randomisation during the first 12 months on study, then every 12 weeks thereafter. Overall survival (OS) was an additional endpoint.

The primary analysis of PFS included 187 randomised patients, 125 to cabozantinib and 62 to placebo.
Baseline demographics and disease characteristics were generally balanced for both treatment groups. The median age was 66 years (range 32 to 85 years), 51% being ≥ 65 years of age, 13% being ≥ 75 years of age.
The majority of patients were white (70%), 18% of patients were Asian and 55% were female.
Histologically, 55% had a confirmed diagnosis of papillary thyroid carcinoma, 48% had follicular thyroid carcinoma including 17% patients with Hürthle cell thyroid cancer.
Metastases were present in 95% of the patients: lungs in 68%, lymph nodes in 67%, bone in 29%, pleura in 18% and liver in 15%. Five patients had not received prior RAI due to ineligibility, 63% had received prior lenvatinib, 60% had received prior sorafenib and 23% had received both sorafenib and lenvatinib. Baseline ECOG performance status was 0 (48%) or 1 (52%).
The median duration of treatment was 4.4 months in the cabozantinib arm and 2.3 months in the placebo arm.

The results of the primary analysis (with a cut-off date of 19 August 2020 and median follow up 6.2 months for the PFS), and the updated analysis (with a cut-off date of 08 February 2021 and median follow-up 10.1 months for the PFS) are presented in Table 9. The trial did not demonstrate a statistically significant improvement in ORR for patients randomised to cabozantinib (n=67) compared with placebo (n=33): 15% vs. 0%. The trial demonstrated a statistically significant improvement in PFS (median follow up 6.2 months) for patients randomised to cabozantinib (n=125) compared with placebo (n=62).
An updated analysis of PFS and OS (median follow up 10.1 months) was performed including 258 randomised patients, 170 to cabozantinib and 88 to placebo.
The overall survival analysis was confounded as placebo-treated subjects with confirmed disease progression had the option to cross over to cabozantinib.
Table 9: Efficacy Results from COSMIC-311
Primary Analysis1 (ITT)           Updated Analysis2 (Full ITT)
CABOMETYX               Placebo      CABOMETYX              Placebo
(n=125)              (n=62)           (n=170)             (n=88)
Progression-Free
Survival*
Number of Events, (%)         31 (25)             43 (69)           62 (36)            69 (78) Progressive Disease       25 (20)             41 (66)           50 (29)            65 (74) Death                     6 (4.8)              2 (3.2)         12 (7.1)            4 (4.5) Median PFS in Months
NE (5.7, NE)       1.9 (1.8, 3.6)  11.0 (7.4, 13.8)     1.9 (1.9, 3.7) (96% CI)
Hazard Ratio (96% CI)3             0.22 (0.13, 0.36)                    0.22 (0.15, 0.32) p-value4                               < 0.0001
Overall Survival
Events, n (%)                 17 (14)             14 (23)           37 (22)            21 (24) Hazard Ratio3 (95% CI)             0.54 (0.27, 1.11)                    0.76 (0.45, 1.31) Primary Analysis1
Objective response rate (ORR)5
CABOMETYX                                Placebo
(n=67)                               (n=33)
Overall response, (%)                   10 (15)                               0 (0) Complete response                      0                                    0 Partial response                    10 (15)                                 0 Stable disease                      46 (69)                              14 (42) Progressive disease                  4 (6)                               18 (55) * The primary analysis of PFS included censoring for new anti-cancer treatment. Results for PFS with and without censoring for new anti-cancer treatment were consistent.
CI, confidence interval; NE, not evaluable
1 The cut-off date of the primary analysis is 19 August 2020.
2 The cut-off date of the secondary analysis is 08 February 2021.
3 Estimated using the Cox proportional-hazard model.

4 Log-rank test stratified by receipt of prior lenvatinib (yes vs. no) and age (≤ 65 years vs. > 65 years) as stratification factors

(per IXRS data).
5 Based on the first 100 patients included in the study with a median follow-up of 8.9 months, n=67 in CABOMETYX group  and n=33 in placebo group. The improvement in ORR was not statistically significant.
Figure 8: Kaplan-Meier Curve of Progression-Free Survival in COSMIC-311 (updated analysis [cut-off date: 08 February 2021], N=258)
Probability of Progression-Free Survival
CABOMETYX

Placebo



Months
Number at risk:
CABOMETYX
Placebo


Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of some studies with CABOMETYX in one or more subsets of the paediatric population in treatment of solid malignant tumours (see section 4.2 for information on paediatric use).

ADVL 1211

A phase 1 study (ADVL1211) of cabozantinib in paediatric patients with solid tumours has been conducted by the Children Oncology Group (COG). Eligible patients were ≥2 years and ≤18 years. This study enrolled patients at 3 dose levels: 30 mg/m2, 40 mg/m2, and 55 mg/m2 once daily on a continuous dosing schedule (weekly dosing by BSA and rounded to the nearest 20 mg). Cabozantinib was dosed based on body surface area (BSA) according to a dosing nomogram
The objective was to define dose limiting toxicities (DLTs), to determine the recommended phase 2 dose (RP2D), to obtain preliminary pharmacokinetics data in children and to explore efficacy in solid tumours. Forty-one patients were enrolled, of whom 36 were fully evaluable. Patients had a variety of solid tumours: MTC (n=5), osteosarcoma (n=2), EWS (n=4), rhabdomyosarcoma (RMS) (n=2), other soft tissue sarcoma (STS) (n=4), Wilms tumour (WT) (n=2), hepatoblastoma (n=2), HCC (n=2), RCC (n=3), central nervous system (CNS) tumours (n=9), and others (n=6).
Of the 36 subjects in the evaluable population, four subjects (11.1%) had best overall response of PR and eight subjects (22.2%) had SD (lasting at least 6 cycles). Of the 12 subjects with PR or SD greater than or equal to 6 cycles 10 subjects were in the cabozantinib 40 mg/m2 or 55 mg/m2 groups (seven and three, respectively).
Based on central review, partial responses were seen in 2/5 patients with MTC, one patient with Wilms tumour, and one patient with clear cell sarcoma.

ADVL1622

ADVL1622 assessed the activity of cabozantinib in selected pediatric solid tumors. This multicenter, open label two-stage phase 2 trial included the following solid tumour strata: non-osteosarcoma strata (including Ewing sarcoma, rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and Wilms tumour), osteosarcoma stratum and rare solid tumours strata (including medullary thyroid carcinoma (MTC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), hepatoblastoma, adrenocortical carcinoma and other solid tumours). Cabozantinib was administered orally once daily on a continuous dosing schedule of 28-day cycles at a dose of 40 mg/m2/day (cumulative weekly dose of 280 mg/m2 using a dosing nomogram). Subjects were ≥2 and ≤30 years of age at the time of study entry for all strata except upper age limit of ≤18 years of age for MTC, RCC and HCC.
For non-osteosarcoma and rare tumors strata the primary endpoint was the objective response rate (ORR). For the osteosarcoma stratum, a two-stage design that incorporated dual endpoints of objective response (CR + PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria and treatment success as defined by SD for ≥4 months was utilized. The PK of cabozantinib in pediatric and adolescent subjects was assessed (please refer to section 5.2) 
Efficacy Results Summary

At the data cutoff date (30 June 2021), 108/109 subjects had received at least one dose of cabozantinib.
Each statistical cohort in the non-osteosarcoma strata included 13 subjects. No responses were observed in these statistical cohorts. The osteosarcoma stratum included in total 29 subjects including 17 children (aged 9 to 17 years) and 12 adults (aged 18 to 22 years).

In the osteosarcoma stratum, all subjects had received prior systemic therapy A PR was observed in one adult and one child. The Disease Control Rate (DCR) was 34.5% (95% CI: 17.9, 54.3).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 3 to 4 hours post-dose. Plasma-concentration time profiles show a second absorption peak approximately 24 hours after administration, which suggests that cabozantinib may undergo enterohepatic recirculation.

Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.

A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken 1 hour after administration of cabozantinib.

Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations following a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tablet formulation compared to the capsule formulation was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet and capsule formulations.

Distribution
Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population- pharmacokinetic (PK) model, the volume of distribution of the central compartment (Vc/F) was estimated to be 212 L.

Biotransformation
Cabozantinib was metabolized in vivo. Four metabolites were present in plasma at exposures (AUC) greater than 10% of parent: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxy sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (XL184-N-oxide and XL184 amide cleavage product), which possess <1% of the on-target kinase inhibition potency of parent cabozantinib, each represent <10% of total drug-related plasma exposure.
Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralizing antibody to CYP3A4 inhibited formation of metabolite XL184 N-oxide by >80% in a NADPH-catalysed human liver microsomal (HLM) incubation; in contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. A neutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation (ie, a <20% reduction).

Elimination
In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 healthy volunteers following oral administration of a range of doses from 20 to 140 mg, the plasma terminal half-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state was estimated to be 2.48 L/hr. Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine.

Pharmacokinetics in special patient populations

Renal impairment
In a renal impairment study conducted with a single 60 mg dose of cabozantinib, the ratios of geometric LS mean for total plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, for subjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to 171.26%) and 2% and 6-7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to 140.11%), for subjects with moderate renal impairment compared to subjects with normal renal function. The geometric LS means for unbound plasma cabozantinib AUC0-inf was 0.2% higher for subjects with mild renal impairment (90% CI 55.9% to 180%) and 17% higher (90% CI 65.1% to 209.7%) for subjects with moderate renal impairment compared to subjects with normal renal function. Subjects with severe renal impairment have not been studied.

Hepatic impairment
Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy subjects and cancer patients (including HCC), no clinically significant difference in the mean cabozantinib plasma exposure was observed amongst subjects with normal liver function (n=1425) and mild hepatic impairment (n=558). There is limited data in patients with moderate hepatic impairment (n=15) as per NCI-ODWG (National Cancer Institute – Organ Dysfunction working Group) criteria. The pharmacokinetics of cabozantinib was not evaluated in patients with severe hepatic impairment.

Race
A population PK analysis did not identify clinically relevant differences in PK of cabozantinib based on race.

Paediatrics
Data obtained from simulation performed with the population pharmacokinetic model developed in healthy subjects as well as adult patients with different type of malignancies show that in adolescent patients aged 12 years and older, a dose of 40 mg of cabozantinib once daily for patients < 40 kg, or a dose of 60 mg once daily in patients ≥ 40 kg results in a similar plasma exposure attained in adults treated with 60 mg of cabozantinib once daily (see section 4.2).

In the two clinical studies conducted by the COG in paediatric patients with solid tumours (ADVL1211 and ADVL1622), cabozantinib was dosed based on body surface area (BSA) according to a dosing nomogram, using available 20 mg and 60 mg tablets intended for adults. Among the 55 patients, median age was 13 years (range: 4 to 18 years). A population PK analysis was built using PK data collected in both studies. The PK of cabozantinib was adequately described by a two-compartment model with first- order elimination and first-order absorption processes. There was no evidence that age, sex, race ethnicity and tumour type affected cabozantinib PK in children and adolescent patients. Only BSA was found to be a significant predictor of cabozantinib PK. No dose dependency was seen in the developed model across the three tested dose levels (30, 40 and 55 mg/m²). The exposures in children and adolescent subjects following an administration of a BSA-based dose of 40mg/m² are similar to exposures in adults with a fixed dose of 60mg QD.