Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE08 
Mechanism of action

Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in cell lines and in primary Philadelphia-chromosome positive leukaemia cells. The substance binds with high affinity to the ATP-binding site in such a manner that it is a potent inhibitor of wild-type BCR- ABL and maintains activity against 32/33 imatinib-resistant mutant forms of BCR-ABL. As a consequence of this biochemical activity, nilotinib selectively inhibits the proliferation and induces apoptosis in cell lines and in primary Philadelphia-chromosome positive leukaemia cells from CML patients. In murine models of CML, as a single agent nilotinib reduces tumour burden and prolongs survival following oral administration.

Pharmacodynamic effects

Nilotinib has little or no effect against the majority of other protein kinases examined, including Src, TAS API AUG21 V13                                       EU SmPC July 21 except for the PDGF, KIT and Ephrin receptor kinases, which it inhibits at concentrations within the range achieved following oral administration at therapeutic doses recommended for the treatment of CML (see Table 5).

Table 5      Kinase profile of nilotinib (phosphorylation IC 50 nM)

BCR-ABL                    PDGFR                         KIT
20                         69                          210

Clinical efficacy

Clinical studies in newly diagnosed CML in chronic phase
An open-label, multicentre, randomised Phase III study was conducted to determine the efficacy of nilotinib versus imatinib in 846 adult patients with cytogenetically confirmed newly diagnosed Philadelphia chromosome positive CML in the chronic phase. Patients were within six months of diagnosis and were previously untreated, with the exception of hydroxyurea and/or anagrelide.
Patients were randomised 1:1:1 to receive either nilotinib 300 mg twice daily (n=282), nilotinib 400 mg twice daily (n=281) or imatinib 400 mg once daily (n=283). Randomisation was stratified by Sokal risk score at the time of diagnosis.

Baseline characteristics were well balanced between the three treatment arms. Median age was 47 years in both nilotinib arms and 46 years in the imatinib arm, with 12.8%, 10.0% and 12.4% of patients were ≥65 years of age in the nilotinib 300 mg twice daily, nilotinib 400 mg twice daily and imatinib 400 mg once daily treatment arms, respectively. There were slightly more male than female patients (56.0%, 62.3% and 55.8%, in the nilotinib 300 mg twice daily, 400 mg twice daily and imatinib 400 mg once daily arm, respectively). More than 60% of all patients were Caucasian and 25% of all patients were Asian.

The primary data analysis time point was when all 846 patients completed 12 months of treatment (or discontinued earlier). Subsequent analyses reflect when patients completed 24, 36, 48, 60 and 72 months of treatment (or discontinued earlier). The median time on treatment was approximately 70 months in the nilotinib treatment groups and 64 months in the imatinib group. The median actual dose intensity was 593 mg/day for nilotinib 300 mg twice daily, 772 mg/day for nilotinib 400 mg twice daily and 400 mg/day for imatinib 400 mg once daily. This study is ongoing.

The primary efficacy endpoint was major molecular response (MMR) at 12 months. MMR was defined as ≤0.1% BCR-ABL/ABL% by international scale (IS) measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardised baseline. The MMR rate at 12 months was statistically significantly higher for nilotinib 300 mg twice daily compared to imatinib 400 mg once daily (44.3% versus 22.3%, p<0.0001). The rate of MMR at 12 months, was also statistically significantly higher for nilotinib 400 mg twice daily compared to imatinib 400 mg once daily (42.7% versus 22.3%, p<0.0001).

The rates of MMR at 3, 6, 9 and 12 months were 8.9%, 33.0%, 43.3% and 44.3% for nilotinib 300 mg twice daily, 5.0%, 29.5%, 38.1% and 42.7% for nilotinib 400 mg twice daily and 0.7%, 12.0%, 18.0% and 22.3% for imatinib 400 mg once daily.

The MMR rate at 12, 24, 36, 48, 60 and 72 months is presented in Table 6.




TAS API AUG21 V13                                     EU SmPC July 21 Table 6      MMR rate

Nilotinib                Nilotinib              Imatinib
300 mg twice daily       400 mg twice daily     400 mg once daily
n=282                    n=281                  n=283
(%)                      (%)                    (%)
MMRat 12 months
Response (95% CI)                     44.31 (38.4; 50.3)     42.71 (36.8; 48.7)        22.3 (17.6; 27.6) MMR at 24 months
Response (95% CI)                     61.71 (55.8; 67.4)     59.11 (53.1; 64.9)        37.5 (31.8; 43.4) 2
MMR at 36 months
Response (95% CI)                     58.51 (52.5; 64.3)     57.31 (51.3; 63.2)        38.5 (32.8; 44.5) 3
MMR at 48 months
Response (95% CI)                     59.91 (54.0; 65.7)      55.2 (49.1; 61.1)        43.8 (38.0; 49.8) 4
MMR at 60 months
Response (95% CI)                     62.8 (56.8; 68.4)       61.2 (55.2; 66.9)        49.1 (43.2; 55.1) MMR at 72 months5
Response (95% CI)                     52.5 (46.5; 58.4)       57.7 (51.6; 63.5)        41.7 (35.9; 47.7) 1
Cochran-Mantel-Haenszel (CMH) test p-value for response rate (vs. imatinib 400 mg) <0.0001 2
Only patients who were in MMR at a specific time point are included as responders for that time point. A total of 199 (35.2%) of all patients were not evaluable for MMR at 36 months (87 in the nilotinib 300 mg twice daily group and 112 in the imatinib group) due to missing/unevaluable PCR assessments (n=17), atypical transcripts at baseline (n=7), or discontinuation prior to the 36-month time point (n=175).
3
Only patients who were in MMR at a specific time point are included as responders for that time point. A total of 305 (36.1%) of all patients were not evaluable for MMR at 48 months (98 in the nilotinib 300 mg BID group, 88 in the nilotinib 400 mg BID group and 119 in the imatinib group) due to missing/unevaluable PCR assessments (n=18), atypical transcripts at baseline (n=8), or discontinuation prior to the 48-month time point (n=279).
4
Only patients who were in MMR at a specific time point are included as responders for that time point. A total of 322 (38.1%) of all patients were not evaluable for MMR at 60 months (99 in the nilotinib 300 mg twice daily group, 93 in the nilotinib 400 mg twice daily group and 130 in the imatinib group) due to missing/unevaluable PCR assessments (n=9), atypical transcripts at baseline (n=8) or discontinuation prior to the 60-month time point (n=305).
5
Only patients who were in MMR at a specific time point are included as responders for that time point. A total of 395 (46.7%) of all patients were not evaluable for MMR at 72 months (130 in the nilotinib 300 mg twice daily group, 110 in the nilotinib 400 mg twice daily group and 155 in the imatinib group) due to missing/unevaluable PCR assessments (n=25), atypical transcripts at baseline (n=8) or discontinuation prior to the 72-month time point (n=362).

MMR rates by different time points (including patients who achieved MMR at or before those time points as responders) are presented in the cumulative incidence of MMR (see Figure 1).




TAS API AUG21 V13                                        EU SmPC July 21 Figure 1                                    Cumulative incidence of MMR 
100                               Nilotinib 300 mg twice daily (n = 282) Nilotinib 400 mg twice daily (n = 281)
Imatinib 400 mg once daily (n = 283)
90                                                                                                                   By 6 years By 4 years           By 5 years
By 3 years                                                  79%; P < .0001 Cumulative incidence of MMR, %




80                               By 2 years                             76%; P < .0001       77%; P < .0001 73%; P < .0001
71%; P < .0001                                                                      77%; P < .0001 70                                                                                           77%; P < .0001 73%; P < .0001
By 1 year                             70%; P < .0001
60                                     61%;                                                                                61% 55%; P < .0001                                                                               60% P < .0001
50            51%;                                                               56% P < .0001                                          53%

40
44%
30

20
27%

10

0
0        6          12       18          24       30          36       42          48       54          60       66          72 Months since randomisation


For all Sokal risk groups, the MMR rates at all time points remained consistently higher in the two nilotinib groups than in the imatinib group.

In a retrospective analysis, 91% (234/258) of patients on nilotinib 300 mg twice daily achieved BCR- ABL levels ≤10% at 3 months of treatment compared to 67% (176/264) of patients on imatinib 400 mg once daily. Patients with BCR-ABL levels ≤10% at 3 months of treatment show a greater overall survival at 72 months compared to those who did not achieve this molecular response level (94.5% vs. 77.1% respectively [p=0.0005]).

Based on the Kaplan-Meier analysis of time to first MMR the probability of achieving MMR at different time points was higher for both nilotinib at 300 mg and 400 mg twice daily compared to imatinib 400 mg once daily (HR=2.17 and stratified log-rank p<0.0001 between nilotinib 300 mg twice daily and imatinib 400 mg once daily, HR=1.88 and stratified log-rank p<0.0001 between nilotinib 400 mg twice daily and imatinib 400 mg once daily).

The proportion of patients who had a molecular response of ≤0.01% and ≤0.0032% by IS at different time points are presented in Table 7 and the proportion of patients who had a molecular response of ≤0.01% and ≤0.0032% by IS by different time points are presented in Figures 2 and 3. Molecular responses of ≤0.01% and ≤0.0032% by IS correspond to a ≥4 log reduction and ≥4.5 log reduction, respectively, of BCR-ABL transcripts from a standardised baseline.




TAS API AUG21 V13                                                                              EU SmPC July 21 Table 7                                                   Proportions of patients who had molecular response of ≤0.01% (4 log reduction) and ≤0.0032% (4.5 log reduction)

Nilotinib                            Nilotinib                              Imatinib 300 mg twice daily                   400 mg twice daily                     400 mg once daily n=282                                n=281                                  n=283 (%)                                  (%)                                    (%) ≤0.01%           ≤0.0032%            ≤0.01%           ≤ 0.0032%            ≤0.01%          ≤0.0032% At 12 months                                              11.7               4.3                8.5                4.6                 3.9                0.4 At 24 months                                              24.5               12.4              22.1                7.8              10.2                  2.8 At 36 months                                              29.4               13.8              23.8               12.1              14.1                  8.1 At 48 months                                              33.0               16.3              29.9               17.1              19.8                  10.2 At 60 months                                              47.9               32.3              43.4               29.5              31.1                  19.8 At 72 months                                              44.3               31.2              45.2               28.8              27.2                  18.0 
Figure 2                                                  Cumulative incidence of molecular response of ≤0.01% (4-log reduction) 
100                          Nilotinib 300 mg twice daily (n = 282)
(BCR-ABL ≤0.01% on the international scale), %




Nilotinib 400 mg twice daily (n = 281)
90             Imatinib 400 mg once daily (n = 283)

80
Cumulative incidence of MR4




By 5 years          By 6 years

70                                                                                                                 67%; P < .0001 By 4 years         66%; P < .0001

60                                                     By 3 years         56%; P < .0001                   63%; 65%; P < .0001
P < .0001
50%; P < .0001
50                                By 2 years
By 1 year                                                    50%; P < .0001 39%; P < .0001
40                                                           44%;
42%                 43%
20%; P < .0001
P < .0001
30                                                                                 32% 15%; P = .0004                 33%;
P < .0001
20                                                             26%

18%
10

0                   6%

0        6           12       18          24       30           36       42          48         54           60      66          72 Months since randomisation




TAS API AUG21 V13                                                                                              EU SmPC July 21 Figure 3                                                    Cumulative incidence of molecular response of ≤0.0032% (4.5 log reduction) 
100
(BCR-ABL ≤0.0032% on the international scale), %                    Nilotinib 300 mg twice daily (n = 282) Nilotinib 400 mg twice daily (n = 281)
90               Imatinib 400 mg once daily (n = 283)

80
Cumulative incidence of MR4.5




70
By 6 years
By 5 years
60                                                                                                                   56%; P < .0001 54%; P < .0001
By 4 years
50                                                                                                                   55%; P < .0001 40%; P < .0001
52%;
By 3 years
40                                                                                                  P < .0001 By 2 years         32%; P < .0001
By 1 year
30                                                                                  37%; 25%; P < .0001                                 P = .0002                 31%                 33% 11%; P < .0001
28%;
20       7%; P < .0001
P = .0003                 23%
1%                             19%;
P = .0006
10                                                              15%
9%
0
0          6          12       18          24        30          36       42          48       54          60         66         72 Months since randomisation

Based on Kaplan-Meier estimates of the duration of first MMR, the proportions of patients who were maintaining response for 72 months among patients who achieved MMR were 92.5% (95% CI: 88.6-96.4%) in the nilotinib 300 mg twice daily group, 92.2% (95% CI: 88.5-95.9%) in the nilotinib 400 mg twice daily group and 88.0% (95% CI: 83.0-93.1%) in the imatinib 400 mg once daily group.

Complete cytogenetic response (CCyR) was defined as 0% Ph+ metaphases in the bone marrow based on a minimum of 20 metaphases evaluated. Best CCyR rate by 12 months (including patients who achieved CCyR at or before the 12 month time point as responders) was statistically higher for both nilotinib 300 mg and 400 mg twice daily compared to imatinib 400 mg once daily, see Table 8.

CCyR rate by 24 months (includes patients who achieved CCyR at or before the 24 month time point as responders) was statistically higher for both the nilotinib 300 mg twice daily and 400 mg twice daily groups compared to the imatinib 400 mg once daily group.




TAS API AUG21 V13                                                                                                 EU SmPC July 21 Table 8      Best CCyR rate

Nilotinib             Nilotinib              Imatinib
300 mg twice daily    400 mg twice daily     400 mg once daily
n=282                 n=281                  n=283
(%)                    (%)                    (%)
By 12 months
Response (95% CI)                        80.1 (75.0; 84.6)      77.9 (72.6; 82.6)      65.0 (59.2; 70.6) No response                                    19.9                   22.1                   35.0 CMH test p-value for response rate           <0.0001                0.0005 (versus imatinib 400 mg once daily)
By 24 months
Response (95% CI)                        86.9 (82.4; 90.6)      84.7 (79.9; 88.7)     77.0 (71.7; 81.8) No response                                    13.1                   15.3                  23.0 CMH test p-value for response rate            0.0018                 0.0160 (versus imatinib 400 mg once daily)

Based on Kaplan-Meier estimates, the proportions of patients who were maintaining response for 72 months among patients who achieved CCyR were 99.1% (95% CI: 97.9-100%) in the nilotinib 300 mg twice daily group, 98.7% (95% CI: 97.1-100%) in the nilotinib 400 mg twice daily group and 97.0% (95% CI: 94.7-99.4%) in the imatinib 400 mg once daily group.

Progression to accelerated phase (AP) or blast crisis (BC) on treatment is defined as the time from the date of randomisation to the first documented disease progression to accelerated phase or blast crisis or CML-related death. Progression to accelerated phase or blast crisis on treatment was observed in a total of 17 patients: 2 patients on nilotinib 300 mg twice daily, 3 patients on nilotinib 400 mg twice daily and 12 patients on imatinib 400 mg once daily. The estimated rates of patients free from progression to accelerated phase or blast crisis at 72 months were 99.3%, 98.7% and 95.2%, respectively (HR=0.1599 and stratified log-rank p=0.0059 between nilotinib 300 mg twice daily and imatinib once daily, HR=0.2457 and stratified log-rank p=0.0185 between nilotinib 400 mg twice daily and imatinib once daily). No new events of progression to AP/BC were reported on-treatment since the 2-year analysis.

Including clonal evolution as a criterion for progression, a total of 25 patients progressed to accelerated phase or blast crisis on treatment by the cut-off date (3 in the nilotinib 300 mg twice daily group, 5 in the nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group).
The estimated rates of patients free from progression to accelerated phase or blast crisis including clonal evolution at 72 months were 98.7%, 97.9% and 93.2%, respectively (HR=0.1626 and stratified log-rank p=0.0009 between nilotinib 300 mg twice daily and imatinib once daily, HR=0.2848 and stratified log-rank p=0.0085 between nilotinib 400 mg twice daily and imatinib once daily).

A total of 55 patients died during treatment or during the follow-up after discontinuation of treatment (21 in the nilotinib 300 mg twice daily group, 11 in the nilotinib 400 mg twice daily group and 23 in the imatinib 400 mg once daily group). Twenty-six (26) of these 55 deaths were related to CML (6 in the nilotinib 300 mg twice daily group, 4 in the nilotinib 400 mg twice daily group and 16 in the imatinib 400 mg once daily group). The estimated rates of patients alive at 72 months were 91.6%, 95.8% and 91.4%, respectively (HR=0.8934 and stratified log-rank p=0.7085 between nilotinib 300 mg twice daily and imatinib, HR=0.4632 and stratified log-rank p=0.0314 between nilotinib 400 mg twice daily and imatinib). Considering only CML-related deaths as events, the estimated rates of overall survival at 72 months were 97.7%, 98.5% and 93.9%, respectively (HR=0.3694 and stratified log-rank p=0.0302 between nilotinib 300 mg twice daily and imatinib, HR=0.2433 and stratified log-rank p=0.0061 between nilotinib 400 mg twice daily and imatinib).

Clinical studies in imatinib-resistant or intolerant CML in chronic phase and accelerated phase An open-label, uncontrolled, multicentre Phase II study was conducted to determine the efficacy of TAS API AUG21 V13                                       EU SmPC July 21 nilotinib in adult patients with imatinib resistant or intolerant CML with separate treatment arms for chronic and accelerated phase disease. Efficacy was based on 321 CP patients and 137 AP patients enrolled. Median duration of treatment was 561 days for CP patients and 264 days for AP patients (see Table 9). Tasigna was administered on a continuous basis (twice daily 2 hours after a meal and with no food for at least one hour after administration) unless there was evidence of inadequate response or disease progression. The dose was 400 mg twice daily and dose escalation to 600 mg twice daily was allowed.

Table 9      Duration of exposure with nilotinib

Chronic phase                  Accelerated phase
n=321                            n=137
Median duration of therapy in days                        561                             264 (25th-75th percentiles)                                (196-852)                       (115-595) 
Resistance to imatinib included failure to achieve a complete haematological response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or haematological response. Imatinib intolerance included patients who discontinued imatinib because of toxicity and were not in major cytogenetic response at time of study entry.

Overall, 73% of patients were imatinib-resistant, while 27% were imatinib-intolerant. The majority of patients had a long history of CML that included extensive prior treatment with other antineoplastic agents, including imatinib, hydroxyurea, interferon, and some had even failed organ transplant (Table 10). The median highest prior imatinib dose had been 600 mg/day. The highest prior imatinib dose was ≥600 mg/day in 74% of all patients, with 40% of patients receiving imatinib doses ≥800 mg/day.

Table 10     CML disease history characteristics

Chronic phase                   Accelerated phase
(n=321)                          (n=137)*
Median time since diagnosis in months                 58                                71 (range)                                            (5–275)                           (2–298) Imatinib
Resistant                                   226 (70%)                        109 (80%) Intolerant without MCyR                      95 (30%)                         27 (20%) Median time of imatinib treatment in                  975                              857 days                                              (519-1,488)                      (424-1,497) (25th-75th percentiles)
Prior hydroxyurea                                     83%                              91% Prior interferon                                      58%                              50% Prior bone marrow transplant                           7%                               8% * Missing information on imatinib-resistant/intolerant status for one patient.

The primary endpoint in the CP patients was major cytogenetic response (MCyR), defined as elimination (CCyR, complete cytogenetic response) or significant reduction to <35% Ph+ metaphases (partial cytogenetic response) of Ph+ haematopoietic cells. Complete haematological response (CHR) in CP patients was evaluated as a secondary endpoint. The primary endpoint in the AP patients was overall confirmed haematological response (HR), defined as either a complete haematological response, no evidence of leukaemia or return to chronic phase.




TAS API AUG21 V13                                       EU SmPC July 21 Chronic phase
The MCyR rate in 321 CP patients was 51%. Most responders achieved their MCyR rapidly within 3 months (median 2.8 months) of starting nilotinib treatment and these were sustained. The median time to achieve CCyR was just past 3 months (median 3.4 months). Of the patients who achieved MCyR, 77% (95% CI: 70% - 84%) were maintaining response at 24 months. Median duration of MCyR has not been reached. Of the patients who achieved CCyR, 85% (95% CI: 78% - 93%) were maintaining response at 24 months. Median duration of CCyR has not been reached. Patients with a CHR at baseline achieved a MCyR faster (1.9 versus 2.8 months). Of CP patients without a baseline CHR, 70% achieved a CHR, median time to CHR was 1 month and median duration of CHR was 32.8 months. The estimated 24-month overall survival rate in CML-CP patients was 87%.

Accelerated phase
The overall confirmed HR rate in 137 AP patients was 50%. Most responders achieved a HR early with nilotinib treatment (median 1.0 months) and these have been durable (median duration of confirmed HR was 24.2 months). Of the patients who achieved HR, 53% (95% CI: 39% - 67%) were maintaining response at 24 months. MCyR rate was 30% with a median time to response of 2.8 months. Of the patients who achieved MCyR, 63% (95% CI: 45% - 80%) were maintaining response at 24 months. Median duration of MCyR was 32.7 months. The estimated 24-month overall survival rate in CML-AP patients was 70%.

The rates of response for the two treatment arms are reported in Table 11.

Table 11     Response in CML

(Best response rate)                  Chronic phase                          Accelerated phase 
Intolerant    Resistant     Total         Intolerant    Resistant    Total* (n=95)        (n=226)       (n=321)       (n=27)        (n=109)      (n=137) Haematological
Response (%)
Overall (95%CI)          -             -             -             48 (29-68)    51 (42-61)   50 (42-59) Complete                 87 (74-94)    65 (56-72)    701 (63-76)   37            28           30 NEL                      -             -             -             7             10           9 Return to CP             -             -                           4             13           11 Cytogenetic
Response (%)
Major (95%CI)            57            49            51 (46-57)    33            29           30 Complete                 (46-67)       (42-56)       37            (17-54)       (21-39)      (22-38) Partial                  41            35            15            22            19           20 16            14                          11            10           10 
NEL = no evidence of leukaemia/marrow response
1
114 CP patients had a CHR at baseline and were therefore not assessable for complete haematological response
* Missing information on imatinib-resistant/intolerant status for one patient.

Efficacy data in patients with CML-BC are not yet available. Separate treatment arms were also included in the Phase II study to investigate Tasigna in a group of CP and AP patients who had been extensively pre-treated with multiple therapies including a tyrosine kinase inhibitor agent in addition to imatinib. Of these patients 30/36 (83%) were treatment resistant not intolerant. In 22 CP patients evaluated for efficacy nilotinib induced a 32% MCyR rate and a 50% CHR rate. In 11 AP patients, evaluated for efficacy, treatment induced a 36% overall HR rate.

After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54% of accelerated phase CML patients who were evaluated for mutations. Tasigna demonstrated efficacy TAS API AUG21 V13                                       EU SmPC July 21 in patients harboring a variety of BCR-ABL mutations associated with imatinib resistance, except T315I.

Treatment discontinuation in adult Ph+ CML patients in chronic phase who have been treated with nilotinib as first-line therapy and who have achieved a sustained deep molecular response In an open-label, single-arm study, 215 adult patients with Ph+ CML in chronic phase treated with nilotinib in first-line for ≥2 years who achieved MR4.5 as measured with the MolecularMD MRDx BCR-ABL test were enrolled to continue nilotinib treatment for additional 52 weeks (nilotinib consolidation phase). 190 of 215 patients (88.4%) entered the TFR phase after achieving a sustained deep molecular response during the consolidation phase, defined by the following criteria: -      the 4 last quarterly assessments (taken every 12 weeks) were at least MR4.0 (BCR-ABL/ABL ≤0.01% IS), and maintained for one year
-      the last assessment being MR4.5 (BCR-ABL/ABL ≤0.0032% IS)
-      no more than two assessments falling between MR4.0 and MR4.5 (0.0032% IS < BCR- ABL/ABL ≤0.01% IS).

The primary endpoint was the percentage of patients in MMR at 48 weeks after starting the TFR phase (considering any patient who required re-initiation of treatment as non-responder).



Table 12    Treatment-free remission after nilotinib first-line treatment 
Patients entered TFR phase                                              190 weeks after starting TFR phase             48 weeks                       264 weeks patients remaining in MMR or better        98 (51.6%, [95% CI: 44.2,      79[2] (41.6%, 95% CI: 34.5, 58.9])                         48.9)
Patients discontinued TFR phase            93 [1]                         109 due to loss of MMR                         88 (46.3%)                     94 (49.5%) due to other reasons                       5                              15 Patients restarted treatment after loss of 86                             91 MMR
regaining MMR                              85 (98.8%)                    90 (98.9%) regaining MR4.5                            76 (88.4%)                    84 (92,3%) [1] One patient did not lose MMR by week 48 but discontinued TFR phase.
[2] For 2 patients, PCR assessment was not available at week 264 therefore their response was not considered for the week 264 data cut-off analysis.

The time by which 50% of all retreated patients regained MMR and MR4.5 was 7 and 12.9 weeks, respectively. The cumulative rate of MMR regained at 24 weeks after treatment re-initiation was 97.8% (89/91 patients) and MR4.5 regained at 48 weeks was 91.2% (83/91 patients).

The Kaplan-Meier estimate of median treatment-free survival (TFS) was 120.1 weeks (95% CI: 36.9, not estimable [NE]) (Figure 4); 91 of 190 patients (47.9%) did not have a TFS event.




TAS API AUG21 V13                                     EU SmPC July 21 Figure 4            Kaplan-Meier estimate of treatment-free survival after start of TFR (full analysis set)

100

90

80
Treatment-free survival (%)




70

60

50

40

30

20           Pat Evt Cen
190 99 91
10              Censored observations


0
0        2          4            7     9      12        144    168     192       216     240     264     288     312 Time since TFR (weeks)
At risk : Events

190:0    120:70    99:89      95:91    93:93   92:94     89:97   88:97   85:97     85:97   82:98   67:98   10:99   0:99 



Treatment discontinuation in adult CML patients in chronic phase who have achieved a sustained deep molecular response on nilotinib treatment following prior imatinib therapy In an open-label, single-arm study, 163 adult patients with Ph+ CML in chronic phase taking tyrosine kinase inhibitors (TKIs) for ≥3 years (imatinib as initial TKI therapy for more than 4 weeks without documented MR4.5 on imatinib at the time of switch to nilotinib, then switched to nilotinib for at least two years), and who achieved MR4.5 on nilotinib treatment as measured with the MolecularMD MRDx BCR-ABL test were enrolled to continue nilotinib treatment for additional 52 weeks (nilotinib consolidation phase). 126 of 163 patients (77.3%) entered the TFR phase after achieving a sustained deep molecular response during the consolidation phase, defined by the following criterion: -    The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5 (BCR-ABL/ABL ≤0.0032% IS) during one year.

The primary endpoint was the proportion of patients without confirmed loss of MR4.0 or loss of MMR within 48 weeks following treatment discontinuation.




TAS API AUG21 V13                                                     EU SmPC July 21 Table 13    Treatment-free remission after nilotinib treatment following prior imatinib therapy 
Patients entered TFR phase                                          126 weeks after starting TFR phase                 48 weeks                   264 weeks patients remaining in MMR, no          73 (57.9%, [95% CI: 48.8, 54 (42.9% [54/126, 95% CI: confirmed loss of MR4.0, and no                 66.7])                    34.1, 52.0]) re-initiation of nilotinib
Patients discontinued TFR Phase                       53                         74 [1] due to confirmed loss of MR4.0 or             53 (42.1%)                  61 (82.4%) loss of MMR
due to other reasons                               0                           13 Patients restarted treatment after loss of            51                           59 MMR or confirmed loss of MR4.0
regaining MR4.0                               48 (94.1%)                  56 (94.9%) regaining MR4.5                               47 (92.2%)                  54 (91.5%) [1] two patients had MMR (PCR assessment) at 264 weeks but were discontinued later and had no further PCR assessment.

The Kaplan-Meier estimated median time on nilotinib to regain MR4.0 and MR4.5 was 11.1 weeks (95% CI:8.1, 12.1) and 13.1 weeks (95% CI:12.0, 15.9), respectively. The cumulative rate of MR4 and MR4.5 regained by 48 weeks after treatment re-initiation was 94.9% (56/59 patients) and 91.5% (54/59 patients), respectively.

The median TFS Kaplan-Meier estimate is 224 weeks (95% CI: 39.9, NE) (Figure 5); 63 of 126 patients (50.0%) did not have a TFS event.

Figure 5    Kaplan-Meier estimate of treatment-free survival after start of TFR (full analysis set)




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TAS API AUG21 V13                                   EU SmPC July 21

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Peak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib absorption following oral administration was approximately 30%. The absolute bioavailability of nilotinib has not been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability of nilotinib capsule is approximately 50%. In healthy volunteers, C max and area under the serum concentration-time curve (AUC) of nilotinib are increased by 112% and 82%, respectively, compared to fasting conditions when Tasigna is given with food. Administration of Tasigna 30 minutes or 2 hours after food increased bioavailability of nilotinib by 29% or 15%, respectively (see sections 4.2, 4.4 and 4.5).

Nilotinib absorption (relative bioavailability) might be reduced by approximately 48% and 22% in patients with total gastrectomy and partial gastrectomy, respectively.

Distribution

The blood-to-plasma ratio of nilotinib is 0.71. Plasma protein binding is approximately 98% on the basis of in vitro experiments.

Biotransformation

Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contribute significantly to the pharmacological activity of nilotinib. Nilotinib is primarily metabolised by CYP3A4, with possible minor contribution from CYP2C8.

Elimination

After a single dose of radiolabelled nilotinib in healthy subjects, more than 90% of the dose was eliminated within 7 days, mainly in faeces (94% of the dose). Unchanged nilotinib accounted for 69% of the dose.

The apparent elimination half-life estimated from the multiple-dose pharmacokinetics with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib pharmacokinetics was moderate to high.

Linearity/non-linearity

Steady-state nilotinib exposure was dose-dependent, with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once-daily dosing. Daily systemic exposure to nilotinib with 400 mg twice-daily dosing at steady state was 35% higher than with 800 mg once-daily dosing. Systemic exposure (AUC) of nilotinib at steady state at a dose level of 400 mg twice daily was approximately 13.4% higher than at a dose level of 300 mg twice daily. The average nilotinib trough and peak concentrations over 12 months were approximately 15.7% and 14.8% higher following 400 mg twice-daily dosing compared to 300 mg twice daily. There was no relevant increase in exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily.

Steady-state conditions were essentially achieved by day 8. An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing.

Bioavailability/bioequivalence studies


TAS API AUG21 V13                                      EU SmPC July 21 Single-dose administration of 400 mg nilotinib, using 2 capsules of 200 mg whereby the content of each capsule was dispersed in one teaspoon of apple sauce, was shown to be bioequivalent with a single-dose administration of 2 intact capsules of 200 mg.