Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EG02 
Mechanism of action
Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine- threonine kinase, the activity of which is known to be upregulated in a number of human cancers.
Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with the AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell cycle, angiogenesis and glycolysis. S6K1is thought to phosphorylate the activation function domain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation.
Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour angiogenic processes. In patients with TSC, treatment with everolimus increases VEGF-A and decreases VEGF-D levels. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce glycolysis in solid tumours in vitro and in vivo.

Two primary regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, a ras family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1 activation leads to a downstream kinase signaling cascade, including activation of the S6 kinase. In TSC syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body.

Clinical efficacy and safety in oncology
Hormone receptor-positive advanced breast cancer
BOLERO-2 (study CRAD001Y2301), a randomised, double-blind, multicentre phase III study of Afinitor + exemestane versus placebo + exemestane, was conducted in postmenopausal women with oestrogen receptor-positive, HER2/neu negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomisation was stratified by documented sensitivity to prior hormonal therapy and by the presence of visceral metastasis. Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥24 weeks) from at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence.

The primary endpoint for the study was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on the investigator’s assessment (local radiology). Supportive PFS analyses were based on an independent central radiology review.

Secondary endpoints included overall survival (OS), objective response rate, clinical benefit rate, safety, change in quality of life (QoL) and time to ECOG PS (Eastern Cooperative Oncology Group performance status) deterioration.
A total of 724 patients were randomised in a 2:1 ratio to the combination everolimus (10 mg daily) + exemestane (25 mg daily) (n=485) or to the placebo + exemestane arm (25 mg daily) (n=239). At the time of the final OS analysis, the median duration of everolimus treatment was 24.0 weeks (range 1.0-199.1 weeks). The median duration of exemestane treatment was longer in the everolimus + exemestane group at 29.5 weeks (1.0-199.1) compared to 14.1 weeks (1.0-156.0) in the placebo + exemestane group.

The efficacy results for the primary endpoint were obtained from the final PFS analysis (see Table 4 and Figure 1). Patients in the placebo + exemestane arm did not cross over to everolimus at the time of progression.


AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Table 4             BOLERO-2 efficacy results

Analysis             Afinitora       Placeboa                          Hazard ratio            p value n=485           n=239
Median progression-free survival (months) (95% CI)
Investigator radiological review       7.8             3.2                                 0.45              <0.0001 (6.9 to 8.5)    (2.8 to 4.1)                       (0.38 to 0.54)
Independent radiological review       11. 0            4.1                                 0.38              <0.0001 (9.7 to 15.0)   (2.9 to 5.6)                       (0.31 to 0.48)
Median overall survival (months) (95% CI)
Median overall survival               31.0             26.6                               0.89                0.1426 (28.0 – 34.6)   (22.6 – 33.1)                        (0.73 – 1.10) Best overall response (%) (95% CI)
Objective response rateb             12.6%            1.7% n/ad             <0.0001e
(9.8 to 15.9)    (0.5 to 4.2)

Clinical benefit ratec                   51.3%                    26.4% n/ad             <0.0001e
(46.8 to 55.9)           (20.9 to 32.4) a
Plus exemestane b
Objective response rate = proportion of patients with complete or partial response c
Clinical benefit rate = proportion of patients with complete or partial response or stable disease ≥24 weeks d
Not applicable e p value is obtained from the exact Cochran-Mantel-Haenszel test using a stratified version of the Cochran-Armitage permutation test.



AFI API SEP22 V11                                                REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Figure 1        BOLERO-2 Kaplan-Meier progression-free survival curves (investigator radiological review)


100

Hazard Ratio = 0.45
95% CI [0.38, 0.54]
Log-rank p value: <0.0001
80                                                                      Kaplan-Meier medians Everolimus 10 mg + exemestane: 7.82 months
Placebo + exemestane: 3.19 months

Censoring Times
Probability (%)



60                                                                      Everolimus 10 mg + exemestane (n/N = 310/485) Placebo + exemestane (n/N = 200/239) of event



40



20


0

0     6    12    18   24    30    36    42    48    54 60 66       72    78   84    90     96   102 108 114 120 Time (weeks)
Number of Patients still at Risk
Time(weeks)    0   6    12    18    24    30    36    42    48    54   60   66    72   78   84      90   96   102   108   114   120 Everolimus    485 436   366   304   257   221   185   158   124   91   66   50    35   24   22      13   10     8     2     1     0 Placebo       239 190   132   96    67    50    39    30    21    15   10    8     5    3    1       1    1     0     0     0     0 


The estimated PFS treatment effect was supported by planned subgroup analysis of PFS per investigator assessment. For all analysed subgroups (age, sensitivity to prior hormonal therapy, number of organs involved, status of bone-only lesions at baseline and presence of visceral metastasis, and across major demographic and prognostic subgroups) a positive treatment effect was seen with everolimus + exemestane with an estimated hazard ratio (HR) versus placebo + exemestane ranging from 0.25 to 0.60.

No differences in the time to ≥5% deterioration in the global and functional domain scores of QLQ-C30 were observed in the two arms.

BOLERO-6 (Study CRAD001Y2201), a three-arm, randomised, open-label, phase II study of everolimus in combination with exemestane versus everolimus alone versus capecitabine in the treatment of postmenopausal women with oestrogen receptor-positive, HER2/neu negative, locally AFI API SEP22 V11                                                           REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 advanced, recurrent, or metastatic breast cancer after recurrence or progression on prior letrozole or anastrozole.

The primary objective of the study was to estimate the HR of PFS for everolimus + exemestane versus everolimus alone. The key secondary objective was to estimate the HR of PFS for everolimus + exemestane versus capecitabine.

Other secondary objectives included the evaluation of OS, objective response rate, clinical benefit rate, safety, time to ECOG performance deterioration, time to QoL deterioration, and treatment satisfaction (TSQM). No formal statistical comparisons were planned.

A total of 309 patients were randomised in a 1:1:1 ratio to the combination of everolimus (10 mg daily) + exemestane (25 mg daily) (n=104), everolimus alone (10 mg daily) (n=103), or capecitabine (1250 mg/m2 dose twice daily for 2 weeks followed by one week rest, 3-week cycle) (n=102). At the time of data cut-off, the median duration of treatment was 27.5 weeks (range 2.0-165.7) in the everolimus + exemestane arm, 20 weeks (1.3-145.0) in the everolimus arm, and 26.7 weeks (1.4-177.1) in the capecitabine arm.

The result of the final PFS analysis with 154 PFS events observed based on local investigator assessment showed an estimated HR of 0.74 (90% CI: 0.57, 0.97) in favour of the everolimus + exemestane arm relative to everolimus arm. The median PFS was 8.4 months (90% CI: 6.6, 9.7) and 6.8 months (90% CI: 5.5, 7.2), respectively.

Figure 2                    BOLERO-6 Kaplan-Meier progression-free survival curves (investigator radiological review)


Hazard Ratio = 0.74
90% CI [0.57;0.97]
Kaplan-Meier medians
Everolimus/Exemestane: 36.57 [28.71;42.29] weeks
Everolimus: 29.43 [24.00;31.29] weeks
Probability (%) of event



Censoring Times
Everolimus/Exemestane (n/N=80/104)
Everolimus (n/N=74/103)



No of patients still at risk                         Time (Weeks)
Time (weeks)
Everolimus/Exemestane
Everolimus

For the key secondary endpoint PFS the estimated HR was 1.26 (90% CI: 0.96, 1.66) in favour of capecitabine over the everolimus + exemestane combination arm based on a total of 148 PFS events observed.

AFI API SEP22 V11                                                                    REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Results of the secondary endpoint OS were not consistent with the primary endpoint PFS, with a trend observed favouring the everolimus alone arm. The estimated HR was 1.27 (90% CI: 0.95, 1.70) for the comparison of OS in the everolimus alone arm relative to the everolimus + exemestane arm. The estimated HR for the comparison of OS in the everolimus + exemestane combination arm relative to capecitabine arm was 1.33 (90% CI: 0.99, 1.79).

Advanced neuroendocrine tumours of pancreatic origin (pNET)
RADIANT-3 (study CRAD001C2324), a phase III, multicentre, randomised, double-blind study of Afinitor plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pNET, demonstrated a statistically significant clinical benefit of Afinitor over placebo by a 2.4-fold prolongation of median progression-free-survival (PFS) (11.04 months versus 4.6 months), (HR 0.35; 95% CI: 0.27, 0.45; p<0.0001) (see Table 5 and Figure 3).

RADIANT-3 involved patients with well- and moderately-differentiated advanced pNET whose disease had progressed within the prior 12 months. Treatment with somatostatin analogues was allowed as part of BSC.

The primary endpoint for the study was PFS evaluated by RECIST (Response Evaluation Criteria in Solid Tumors) Following documented radiological progression, patients could be unblinded by the investigator. Those randomised to placebo were then able to receive open-label Afinitor.

Secondary endpoints included safety, objective response rate, response duration and overall survival (OS).

In total, 410 patients were randomised 1:1 to receive either Afinitor 10 mg/day (n=207) or placebo (n=203). Demographics were well balanced (median age 58 years, 55% male, 78.5% Caucasian).
Fifty-eight percent of the patients in both arms received prior systemic therapy. The median duration of blinded study treatment was 37.8 weeks (range 1.1-129.9 weeks) for patients receiving everolimus and 16.1 weeks (range 0.4-147.0 weeks) for those receiving placebo.

Following disease progression or after study unblinding, 172 of the 203 patients (84.7%) initially randomised to placebo crossed over to open-label Afinitor. The median duration of open-label treatment was 47.7 weeks among all patients; 67.1 weeks in the 53 patients randomised to everolimus who switched to open-label everolimus and 44.1 weeks in the 172 patients randomised to placebo who switched to open-label everolimus.



AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Table 5                          RADIANT-3 – efficacy results

Population                   Afinitor          Placebo                                        Hazard ratio             p-value n=207             n=203                                          (95% CI) Median progression-free survival (months) (95% CI)
Investigator radiological      11.04             4.60                                             0.35                 <0.0001 review                     (8.41, 13.86)     (3.06, 5.39)                                     (0.27, 0.45) Independent radiological       13.67             5.68                                             0.38                 <0.0001 review                    (11.17, 18.79)     (5.39, 8.31)                                     (0.28, 0.51) Median overall survival (months) (95% CI)
Median overall survival        44.02            37.68                                             0.94                  0.300 (35.61, 51.75)    (29.14, 45.77)                                    (0.73, 1.20) 
Figure 3                     RADIANT-3 – Kaplan-Meier progression-free survival curves (investigator radiological review)

100
Hazard Ratio = 0.35
95% CI [0.27, 0.45]
90                                                                                    Log-rank p value = <0.001 Kaplan-Meier medians
80                                                                                    Afinitor : 11.04 months Placebo : 4.60 months

70                                                                                          Censoring times Afinitor (n=207)
Placebo (n=203)
60
Probability (%)



50

40


30

20

10


0
0    2     4    6     8     10     12      14        16      18      20     22        24      26       28    30 

Time (months)
No. of patients still at risk
Afinitor 207       189        153        126   114   80      49       36      28      21       10     6         2       0        0    0 Placebo 203        117        98         59    52    24      16       7       4       3        2      1         1       1        1    0 


AFI API SEP22 V11                                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Advanced neuroendocrine tumours of gastrointestinal or lung origin
RADIANT-4 (study CRAD001T2302), a randomised, double-blind, multicentre, phase III study of Afinitor plus best supportive care (BSC) versus placebo plus BSC was conducted in patients with advanced, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin without a history of and no active symptoms related to carcinoid syndrome.

The primary endpoint for the study was progression-free survival (PFS) evaluated by Response Evaluation Criteria in Solid Tumors (RECIST), based on independent radiology assessment.
Supportive PFS analysis was based on local investigator review. Secondary endpoints included overall survival (OS), overall response rate, disease control rate, safety, change in quality of life (FACT-G) and time to World Health Organisation performance status (WHO PS) deterioration.

A total of 302 patients were randomised in a 2:1 ratio to receive either everolimus (10 mg daily) (n=205) or placebo (n=97). Demographics and disease characteristics were generally balanced (median age 63 years [range 22 to 86], 76% Caucasian, history of prior somatostatin analogue [SSA] use). The median duration of blinded treatment was 40.4 weeks for patients receiving Afinitor and 19.6 weeks for those receiving placebo. After primary PFS analysis, 6 patients from the placebo arm crossed over to open-label everolimus.


The efficacy results for the primary endpoint PFS (independent radiological review) were obtained from the final PFS analysis (see Table 6 and Figure 4). The efficacy results for PFS (investigator radiological review) were obtained from the final OS analysis (see Table 6).


Table 6             RADIANT-4 – Progression-free survival results
Population                       Afinitor             Placebo               Hazard ratio              p-valuea n=205               n=97                  (95% CI)
Median progression-free survival (months) (95% CI)
Independent radiological           11.01                3.91                     0.48                  <0.001 review                          (9.2, 13.3)          (3.6, 7.4)              (0.35, 0.67) Investigator radiological          14.39                5.45                     0.40                  <0.001 review                        (11.24, 17.97)        (3.71, 7.39)             (0.29, 0.55) a
One-sided p-value from a stratified log-rank test



AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Figure 4                        RADIANT-4 – Kaplan-Meier progression-free survival curves (independent radiological review)
100
Hazard Ratio = 0.48
90                                                                           95% CI [0.35, 0.67] 80                                                                            Kaplan-Meier medians 70
Everolimus + BSC: 11.01 [9.23;13.31] months
Probability (%) of event



Placebo + BSC: 3.91 [3.58;7.43] months
60
Log-rank p value = <0.001
50

40
30

20
Censoring times
10
Everolimus + BSC (n/N = 113/205)
Placebo + BSC (n/N = 65/97)
0

0        2       4      6      8      10    12             15          18          21           24          27         30 Time (months)
Number of Patients still at Risk
Time(months)
0       2       4      6      8     10     12            15          18         21         24          27         30 Everolimus                      205    168      145    124   101    81     65            52          26          10        3            0          0 Placebo                         97     65       39     30    24     21     17            15          11          6         5            1          0 

In supportive analyses, positive treatment effect has been observed in all subgroups with the exception of the subgroup of patients with ileum as primary site of tumour origin [Ileum: HR=1.22 (95% CI: 0.56 to 2.65); Non-ileum: HR=0.34 (95% CI: 0.22 to 0.54); Lung: HR=0.43 (95% CI: 0.24 to 0.79)] (see Figure 5).



AFI API SEP22 V11                                                                         REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Figure 5         RADIANT-4 – Progression free survival results by pre-specified patient subgroup (independent radiological review)

All (N=302)
<65 years (N=159)
Age                    ≥65 years (N=143)
0 (N=216)
WHO PS                 1 (N=86)
Yes (N=157)
Prior SSA              No (N=145)
Yes (N=77)
Prior chemotherapy           No (N=225)
Lung (N=90)
Primary tumour         Ileum (N=71) origin                 Non-ileum* (N=141)
Grade 1 (N=194)
Tumour grading         Grade 2 (N=107)
≤10% (N=228)
Liver tumour           >10% (N=72) burden                 >2xULN (N=139)
Baseline CgA           ≤2xULN (N=138)
>ULN (N=87)
≤ULN (N=188)
Baseline NSE



Everolimus + BSC                           Placebo + BSC
In favour of
*Non-ileum: stomach, colon, rectum, appendix, caecum, duodenum, jejunum, carcinoma of unknown primary origin and other gastrointestinal origin
ULN: Upper limit of normal
CgA: Chromogranin A
NSE: Neuron specific enolase
Hazard ratio (95% CI) from stratified Cox model


The final overall survival (OS) analysis did not show a statistically significant difference between those patients who received Afinitor or placebo during the blinded treatment period of the study (HR=0.90 [95% CI: 0.66 to 1.22]).


No difference in the time to definitive deterioration of WHO PS (HR=1.02; [95% CI: 0.65, 1.61] and time to definitive deterioration in quality of life (FACT-G total score HR=0.74; [95% CI: 0.50, 1.10]) was observed between the two arms.

Advanced renal cell carcinoma
RECORD-1 (study CRAD001C2240), a phase III, international, multicentre, randomised, double-blind study comparing everolimus 10 mg/day and placebo, both in conjunction with best supportive care, AFI API SEP22 V11                                                REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 was conducted in patients with metastatic renal cell carcinoma whose disease had progressed on or after treatment with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy (sunitinib, sorafenib, or both sunitinib and sorafenib). Prior therapy with bevacizumab and interferon-α was also permitted. Patients were stratified according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic score (favourable- vs. intermediate- vs. poor-risk groups) and prior anticancer therapy (1 vs. 2 prior VEGFR-TKIs).

Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid Tumours) and assessed via a blinded, independent central review, was the primary endpoint.
Secondary endpoints included safety, objective tumour response rate, overall survival, disease-related symptoms, and quality of life. After documented radiological progression, patients could be unblinded by the investigator: those randomised to placebo were then able to receive open-label everolimus 10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at the time of the second interim analysis as the primary endpoint had been met.

In total, 416 patients were randomised 2:1 to receive Afinitor (n=277) or placebo (n=139).
Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88% Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]). The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving everolimus and 60 days (range 21-295 days) for those receiving placebo.

Afinitor was superior to placebo for the primary endpoint of progression-free survival, with a statistically significant 67% reduction in the risk of progression or death (see Table 7 and Figure 6).

Table 7             RECORD-1 – Progression-free survival results

Population                      n       Afinitor         Placebo                    Hazard ratio            p-value n=277            n=139                      (95%CI)
Median progression-free survival (months) (95% CI)
Primary analysis
All (blinded independent    416        4.9               1.9                              0.33              <0.0001a central review)                     (4.0-5.5)         (1.8-1.9)                       (0.25-0.43) Supportive/sensitivity analyses
All (local review by        416        5.5               1.9                              0.32              <0.0001a investigator)                       (4.6-5.8)         (1.8-2.2)                       (0.25-0.41) MSKCC prognostic score (blinded independent central review)
Favourable risk             120        5.8               1.9                              0.31              <0.0001 (4.0-7.4)         (1.9-2.8)                       (0.19-0.50)
Intermediate risk           235        4.5               1.8                              0.32              <0.0001 (3.8-5.5)         (1.8-1.9)                       (0.22-0.44)
Poor risk                   61         3.6               1.8                              0.44                0.007 (1.9-4.6)         (1.8-3.6)                       (0.22-0.85) a
Stratified log-rank test



AFI API SEP22 V11                                               REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Figure 6        RECORD-1 – Kaplan-Meier progression-free survival curves (independent central review)

Censoring Times
Everolimus (n/N = 155/277)
Placebo (n/N = 111/139)
Hazard Ratio = 0.33
95% CI [0.25, 0.43]

Kaplan-Meier medians
Probability (%)
Everolimus: 4.90 months
Placebo: 1.87 months

Log-rank p value = <0.0001



Time (months)
No. of patients still at risk
Time (months)
Afinitor
Placebo

Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo.

Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, while none were observed in patients receiving placebo. Therefore, the progression-free survival advantage primarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitor treatment group).

No statistically significant treatment-related difference in overall survival was noted (hazard ratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor following disease progression for patients allocated to placebo confounded the detection of any treatment-related difference in overall survival.

Clinical efficacy and safety in Tuberous Sclerosis complex (TSC)

Renal angiomyolipoma associated with TSC
EXIST-2 (study CRAD001M2302), a randomised, controlled phase III study was conducted to evaluate the efficacy and safety of Afinitor in patients with TSC plus renal angiomyolipoma. Presence of at least one angiomyolipoma ≥3 cm in longest diameter using CT/MRI (based on local radiology assessment) was required for entry.


AFI API SEP22 V11                                               REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 The primary efficacy endpoint was angiomyolipoma response rate based on independent central radiology review. The analysis was stratified by use of enzyme-inducing antiepileptics at randomisation (yes/no).

Key secondary endpoints included time to angiomyolipoma progression and skin lesion response rate.

A total of 118 patients were randomised, 79 to Afinitor 10 mg daily and 39 to placebo. Median age was 31 years (range: 18 to 61 years; 46.6% were <30 years at enrolment), 33.9% were male, and 89.0% were Caucasian. Of the enrolled patients, 83.1% had angiomyolipomas ≥4 cm (28.8% ≥8 cm), 78.0% had bilateral angiomyolipomas, and 39.0% had undergone prior renal embolisation/nephrectomy; 96.6% had skin lesions at baseline and 44.1% had target SEGAs (at least one SEGA ≥1 cm in longest diameter).


Results showed that the primary objective related to best overall angiomyolipoma response was met with best overall response rates of 41.8% (95% CI: 30.8, 53.4) for the Afinitor arm compared with 0% (95% CI: 0.0, 9.0) for the placebo arm (p<0.0001) (Table 8).

Patients initially treated with placebo were allowed to cross over to everolimus at the time of angiomyolipoma progression and upon recognition that treatment with everolimus was superior to treatment with placebo. At the time of the final analysis (4 years following the last patient randomisation), the median duration of exposure to everolimus was 204.1 weeks (range 2 to 278). The angiomyolipoma best overall response rate had increased to 58.0% (95% CI: 48.3, 67.3), with a rate of stable disease of 30.4% (Table 8).

Among patients treated with everolimus during the study, no cases of angiomyolipoma-related nephrectomy and only one case of renal embolisation were reported.

Table 8             EXIST-2 - Angiomyolipoma response

Primary Analysis3                             Final
Analysis
Afinitor               Placebo           p-value          Afinitor n=79                   n=39                              N=112
Primary analysis
Angiomyolipoma response rate1,2 – %               41.8                    0              <0.0001           58.0 95% CI                                          30.8, 53.4             0.0, 9.0                          48.3, 67.3 Best overall angiomyolipoma response – %
Response                                            41.8                   0                                  58.0 Stable disease                                      40.5                  79.5                                30.4 Progression                                         1.3                   5.1                                 0.9 Not evaluable                                       16.5                  15.4                                10.7 


AFI API SEP22 V11                                            REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 1
According to independent central radiology review
2
Angiomyolipoma responses were confirmed with a repeat scan. Response was defined as: ≥50% reduction in the sum of angiomyolipoma volume relative to baseline, plus absence of new angiomyolipoma ≥1.0 cm in longest diameter, plus no increase in renal volume >20% from nadir, plus absence of grade ≥2 angiomyolipoma-related bleeding.
3     Primary analysis for double blind period
4     Final analysis includes patients who crossed over from the placebo group; median duration of exposure to everolimus of 204.1 weeks

Consistent treatment effects on angiomyolipoma response rate were observed across all subgroups evaluated (i.e. enzyme-inducing antiepilepticuse versus enzyme-inducing antiepilepticnon-use, sex, age and race) at the primary efficacy analysis.

In the final analysis, reduction in angiomyolipoma volume improved with longer term treatment with Afinitor. At weeks 12, 96 and 192, ≥ 30% reductions in volume were observed in 75.0%, 80.6%, and 85.2% of the treated patients, respectively. Similarly, at the same timepoints, ≥ 50% reductions in volume were observed in 44.2%, 63.3%, and 68.9% of the treated patients, respectively.

Median time to angiomyolipoma progression was 11.4 months in the placebo arm and was not reached in the everolimus arm (HR 0.08; 95% CI: 0.02, 0.37; p<0.0001). Progressions were observed in 3.8% of patients in the everolimus arm compared with 20.5% in the placebo arm. Estimated progression-free rates at 6 months were 98.4% for the everolimus arm and 83.4% for the placebo arm.
At the final analysis, median time to angiomyolipoma progression was not reached. Angiomyolipoma progressions were observed in 14.3% of the patients. The estimated angiomyolipoma progression-free rates at 24 months and 48 months were 91.6% and 83.1%, respectively.

At the primary analysis, skin lesion response rates of 26.0% (95% CI: 16.6, 37.2) for the Afinitor arm and 0% (95% CI: 0.0, 9.5) for the placebo arm were observed (p=0.0002). At the final analysis, the skin lesion response rate had increased to 68.2% (95% CI: 58.5, 76.9), with one patient reporting a confirmed complete clinical skin lesion response and no patients experiencing progressive disease as their best response.

In an exploratory analysis of patients with TSC with angiomyolipoma who also had SEGA, the SEGA response rate (proportion of patients with ≥50% reduction from baseline in target lesion volumes in the absence of progression) was 10.3% in the everolimus arm in the primary analysis (versus no responses reported in the 13 patients randomised to placebo with a SEGA lesion at baseline) and increased to 48.0% in the final analysis.

Post-hoc sub-group analysis of EXIST-2 (study CRAD001M2302) carried out at time of primary analysis demonstrated that angiomyolipoma response rate is reduced below the threshold of 5 ng/ml (Table 9).



AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Table 9         EXIST-2 - Angiomyolipoma response rates by time-averaged Cmin category, at primary analysis

Time-averaged Cmin         Number of             Response rate               95% confidence interval category              patients
≤5 ng/ml                 20                      0.300                          0.099, 0.501 >5 ng/ml                 42                      0.524                          0.373, 0.675 1
Difference                                       -0.224                         -0.475, 0.027 1
Difference is “≤5 ng/ml” minus “>5 ng/ml”

SEGA associated with TSC
Phase III study in SEGA patients
EXIST-1 (Study CRAD001M2301), a randomised, double-blind, multicentre phase III study of Afinitor versus placebo, was conducted in patients with SEGA, irrespective of age. Patients were randomised in a 2:1 ratio to receive either Afinitor or matching placebo. Presence of at least one SEGA lesion ≥1.0 cm in longest diameter using MRI (based on local radiology assessment) was required for entry. In addition, serial radiological evidence of SEGA growth, presence of a new SEGA lesion ≥1 cm in longest diameter, or new or worsening hydrocephalus was required for entry.

The primary efficacy endpoint was SEGA response rate based on independent central radiology review. The analysis was stratified by use of enzyme-inducing antiepileptics at randomisation (yes/no).

Key secondary endpoints in hierarchal order of testing included the absolute change in frequency of total seizure events per 24-hour EEG from baseline to week 24, time to SEGA progression, and skin lesion response rate.

A total of 117 patients were randomised, 78 to Afinitor and 39 to placebo. The two treatment arms were generally well balanced with respect to demographic and baseline disease characteristics and history of prior anti-SEGA therapies. In the total population, 57.3% of patients were male and 93.2% were Caucasian. The median age for the total population was 9.5 years (age range for the Afinitor arm: 1.0 to 23.9; age range for the placebo arm: 0.8 to 26.6), 69.2% of the patients were aged 3 to <18 years and 17.1% were <3 years at enrolment.

Of the enrolled patients, 79.5% had bilateral SEGAs, 42.7% had ≥2 target SEGA lesions, 25.6% had inferior growth, 9.4% had evidence of deep parenchymal invasion, 6.8% had radiographic evidence of hydrocephalus, and 6.8% had undergone prior SEGA-related surgery. 94.0% had skin lesions at baseline and 37.6% had target renal angiomyolipoma lesions (at least one angiomyolipoma ≥1 cm in longest diameter).

The median duration of blinded study treatment was 9.6 months (range: 5.5 to 18.1) for patients receiving Afinitor and 8.3 months (range: 3.2 to 18.3) for those receiving placebo.

Results showed that Afinitor was superior to placebo for the primary endpoint of best overall SEGA response (p<0.0001). Response rates were 34.6% (95% CI: 24.2, 46.2) for the Afinitor arm compared with 0% (95% CI: 0.0, 9.0) for the placebo arm (Table 10). In addition, all 8 patients on the Afinitor arm who had radiographic evidence of hydrocephalus at baseline had a decrease in ventricular volume.


AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Patients initially treated with placebo were allowed to cross over to everolimus at the time of SEGA progression and upon recognition that treatment with everolimus was superior to treatment with placebo. All patients receiving at least one dose of everolimus were followed until medicinal product discontinuation or study completion. At the time of the final analysis, the median duration of exposure among all such patients was 204.9 weeks (range: 8.1 to 253.7). The best overall SEGA response rate had increased to 57.7% (95% CI: 47.9, 67.0) at the final analysis.

No patient required surgical intervention for SEGA during the entire course of the study.

Table 10            EXIST-1 – SEGA response
Primary analysis3                              Final analysis4
Afinitor     Placebo       p-value                         Afinitor
N=78         N=39                                         N=111

SEGA response rate1,2 - (%)            34.6           0           <0.0001                            57.7 95% CI                              24.2, 46.2     0.0, 9.0                                        47.9, 67.0 Best overall SEGA response - (%)
Response                               34.6           0                                                57.7 Stable disease                         62.8          92.3                                              39.6 Progression                              0           7.7                                                0 Not evaluable                           2.6           0                                                2.7 1 according to independent central radiology review
2
SEGA responses were confirmed with a repeat scan. Response was defined as: ≥50% reduction in the sum of SEGA volume relative to baseline, plus no unequivocal worsening of non-target SEGA lesions, plus absence of new SEGA ≥1 cm in longest diameter, plus no new or worsening hydrocephalus
3
Primary analysis for double blind period
4
Final analysis includes patients who crossed over from the placebo group; median duration of exposure to everolimus of 204.9 weeks

Consistent treatment effects were observed across all subgroups evaluated (i.e. enzyme-inducing antiepilepticuse versus enzyme-inducing antiepilepticnon-use, sex and age) at the primary analysis.

During the double-blind period, reduction of SEGA volume was evident within the initial 12 weeks of Afinitor treatment: 29.7% (22/74) of patients had ≥50% reductions in volume and 73.0% (54/74) had ≥30% reductions in volume. Sustained reductions were evident at week 24, 41.9% (31/74) of patients had ≥50% reductions and 78.4% (58/74) of patients had ≥30% reductions in SEGA volume.

In the everolimus treated population (N=111) of the study, including patients who crossed over from the placebo group, tumour response, starting as early as after 12 weeks on everolimus, was sustained at later time points. The proportion of patients achieving at least 50% reductions in SEGA volume was 45.9% (45/98) and 62.1% (41/66) at weeks 96 and 192 after start of everolimus treatment. Similarly,
the proportion of patients achieving at least 30% reductions in SEGA volume was 71.4% (70/98) and 77.3% (51/66) at weeks 96 and 192 after start of everolimus treatment.

Analysis of the first key secondary endpoint, change in seizure frequency, was inconclusive; thus, despite the fact that positive results were observed for the two subsequent secondary endpoints (time AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 to SEGA progression and skin lesion response rate), they could not be declared formally statistically significant.

Median time to SEGA progression based on central radiology review was not reached in either treatment arm. Progressions were only observed in the placebo arm (15.4%; p=0.0002). Estimated progression-free rates at 6 months were 100% for the Afinitor arm and 85.7% for the placebo arm.
The long-term follow-up of patients randomised to everolimus and patients randomised to placebo who thereafter crossed over to everolimus demonstrated durable responses.

At the time of the primary analysis, Afinitor demonstrated clinically meaningful improvements in skin lesion response (p=0.0004), with response rates of 41.7% (95% CI: 30.2, 53.9) for the Afinitor arm and 10.5% (95% CI: 2.9, 24.8) for the placebo arm.
At the final analysis, the skin lesion response rate increased to 58.1% (95% CI: 48.1, 67.7).

Phase II study in patients with SEGA
A prospective, open-label, single-arm phase II study (Study CRAD001C2485) was conducted to evaluate the safety and efficacy of Afinitor in patients with SEGA. Radiological evidence of serial SEGA growth was required for entry.

Change in SEGA volume during the core 6-month treatment phase, as assessed via an independent central radiology review, was the primary efficacy endpoint. After the core treatment phase, patients could be enrolled into an extension phase where SEGA volume was assessed every 6 months.

In total, 28 patients received treatment with Afinitor; median age was 11 years (range 3 to 34), 61% male, 86% Caucasian. Thirteen patients (46%) had a secondary smaller SEGA, including 12 in the contralateral ventricle.
Primary SEGA volume was reduced at month 6 compared to baseline (p<0.001 [see Table 11]). No patient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and none required surgical resection or other therapy for SEGA.



AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Table 11            Change in primary SEGA volume over time

SEGA           Independent central review volume
(cm3)
Baseline    Month 6      Month 12           Month 24           Month 36          Month 48          Month 60 n=28        n=27          n=26             n=24               n=23              n=24              n=23 Primary tumour volume
Mean            2.45        1.33         1.26               1.19               1.26              1.16              1.24 (standard     (2.813)     (1.497)       (1.526)            (1.042)            (1.298)           (0.961)           (0.959) deviation)
Median          1.74        0.93         0.84                0.94                1.12           1.02              1.17 Range      0.49 -      0.31 -     0.29 - 8.18         0.20 - 4.63           0.22 -       0.18 - 4.19       0.21 - 4.39 14.23        7.98                                                 6.52 Reduction from baseline
Mean                        1.19         1.07            1.25 (1.994)           1.41            1.43              1.44 (standard                 (1.433)       (1.276)                                (1.814)         (2.267)           (2.230) deviation)
Median                      0.83         0.85                 0.71               0.71            0.83              0.50 Range                  0.06 -     0.02 - 6.05         -0.55 - 9.60          0.15 -          0.00 -         -0.74 - 9.84 6.25                                                 7.71           10.96 Percentage reduction from baseline, n (%)
≥50%                 9 (33.3)      9 (34.6)            12 (50.0)          10 (43.5)       14 (58.3)         12 (52.2) ≥30%                 21 (77.8)     20 (76.9)           19 (79.2)          18 (78.3)       19 (79.2)         14 (60.9) >0%                      27           26                  23                 23              23                21 (100.0)       (100.0)             (95.8)             (100.0)         (95.8)            (91.3) No                       0             0                   0                  0            1 (4.2)              0 change
Increase                 0             0                 1 (4.2)               0               0              2 (8.7) 
The robustness and consistency of the primary analysis were supported by the: −     change in primary SEGA volume as per local investigator assessment (p<0.001), with 75.0% and 39.3% of patients experiencing reductions of ≥30% and ≥50%, respectively −     change in total SEGA volume as per independent central review (p<0.001) or local investigator assessment (p<0.001).

One patient met the pre-specified criteria for treatment success (>75% reduction in SEGA volume) and was temporarily taken off trial therapy; however, SEGA re-growth was evident at the next assessment at 4.5 months and treatment was restarted.

Long-term follow-up to a median duration of 67.8 months (range: 4.7 to 83.2) demonstrated sustained efficacy.

Other studies
Stomatitis is the most commonly reported adverse reaction in patients treated with Afinitor (see sections 4.4 and 4.8). In a post-marketing single-arm study in postmenopausal women with advanced breast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 ml alcohol-free oral solution AFI API SEP22 V11                                               REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 was administered as a mouthwash (4 times daily for the initial 8 weeks of treatment) to patients at the time of initiating treatment with Afinitor (everolimus, 10 mg/day) plus exemestane (25 mg/day) to reduce the incidence and severity of stomatitis. The incidence of Grade ≥2 stomatitis at 8 weeks was 2.4% (n=2/85 evaluable patients) which was lower than historically reported. The incidence of Grade 1 stomatitis was 18.8% (n=16/85) and no cases of Grade 3 or 4 stomatitis were reported. The overall safety profile in this study was consistent with that established for everolimus in the oncology and TSC settings, with the exception of a slightly increased frequency of oral candidiasis which was reported in 2.2% (n=2/92) of patients.

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

Absorption
In patients with advanced solid tumours, peak everolimus concentrations (Cmax) are reached at a median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or with a light fat-free snack. Cmax is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor of PgP.

Food effect
In healthy subjects, high fat meals reduced systemic exposure to everolimus 10 mg tablets (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile 24 hours post-dose.

Relative bioavailability/bioequivalence
In a relative bioavailability study in TSC patients, AUC0-inf of 5 x 1 mg everolimus tablets when administered as suspension in water was equivalent to 5 x 1 mg everolimus tablets administered as intact tablets, and Cmax of 5 x 1 mg everolimus tablets in suspension was 72% of 5 x 1 mg intact everolimus tablets.

Distribution
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is confined to plasma of cancer patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumours, Vd was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment.

Nonclinical studies in rats indicate:
•    A rapid uptake of everolimus in the brain followed by a slow efflux.
•    The radioactive metabolites of [3H] everolimus do not significantly cross the blood-brain barrier.
•    A dose-dependent brain penetration of everolimus, which is consistent with the hypothesis of saturation of an efflux pump present in the brain capillary endothelial cells.
•    The co-administration of the PgP inhibitor, cyclosporine, enhances the exposure of everolimus in the brain cortex, which is consistent with the inhibition of PgP at the blood-brain barrier.

There are no clinical data on the distribution of everolimus in the human brain. Non-clinical studies in rats demonstrated distribution into the brain following administration by both the intravenous and oral routes.
AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Biotransformation
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies and showed approximately 100 times less activity than everolimus itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological activity.

Elimination
Mean oral clearance CL/F of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h. The mean elimination half-life of everolimus is approximately 30 hours.

No specific excretion studies have been undertaken in cancer patients; however, data are available from the studies in transplant patients. Following the administration of a single dose of radiolabelled everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.

Steady-state pharmacokinetics
After administration of everolimus in patients with advanced solid tumours, steady-state AUC0-τ was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two weeks.
Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC0-τ and pre-dose trough concentration at steady-state.

Special populations
Hepatic impairment
The safety, tolerability and pharmacokinetics of Afinitor were evaluated in two single oral dose studies of Afinitor tablets in 8 and 34 adult subjects with impaired hepatic function relative to subjects with normal hepatic function.

In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh B) was twice that found in 8 subjects with normal hepatic function.

In the second study of 34 subjects with different impaired hepatic function compared to normal subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC0-inf) for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively.

Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects with hepatic impairment based on their Child-Pugh status.
Based on the results of the two studies, dose adjustment is recommended for patients with hepatic impairment (see sections 4.2 and 4.4).

Renal impairment
In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant 
AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients.

Paediatric population
In patients with SEGA, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.

In patients with SEGA, the geometric mean Cmin values normalised to mg/m2 dose in patients aged <10 years and 10-18 years were lower by 54% and 40%, respectively, than those observed in adults (>18 years of age), suggesting that everolimus clearance was higher in younger patients. Limited data in TSC patients <3 years of age (n=13) indicate that BSA-normalised clearance is about two-fold higher in patients with low BSA (BSA of 0.556 m2) than in adults. Therefore it is assumed that steady-state could be reached earlier in TSC patients <3 years of age (see section 4.2 for dosing recommendations).


The pharmacokinetics of everolimus have not been studied in patients younger than 1 year of age. It is reported, however, that CYP3A4 activity is reduced at birth and increases during the first year of life, which could affect the clearance in this patient population.

A population pharmacokinetic analysis including 111 patients with SEGA who ranged from 1.0 to 27.4 years (including 18 patients 1 to less than 3 years of age with BSA 0.42 m2 to 0.74 m2) showed that BSA-normalised clearance is in general higher in younger patients.

Elderly
In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years) on oral clearance of everolimus was detected.

Ethnicity
Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions.
Based on analysis of population pharmacokinetics, oral clearance CL/F is on average 20% higher in black transplant patients.