Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, protein kinase inhibitors, ATC code: L01EX12.

Mechanism of action

Larotrectinib is an adenosine triphosphate (ATP)-competitive and selective tropomyosin receptor kinase (TRK) inhibitor that was rationally designed to avoid activity with off-target kinases. The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM. The only other kinase activity occurred at 100-fold higher concentrations. In in vitro and in vivo tumour models, larotrectinib demonstrated anti-tumour activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.

In-frame gene fusion events resulting from chromosomal rearrangements of the human genes NTRK1, NTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. These resultant novel chimeric oncogenic proteins are aberrantly expressed, driving constitutive kinase activity subsequently activating downstream cell signalling pathways involved in cell proliferation and survival leading to TRK fusion-positive cancer.

Acquired resistance mutations after progression on TRK inhibitors have been observed. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

The molecular causes for primary resistance to larotrectinib are not known. It is therefore not known if the presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy of TRK inhibition. The measured impact of any concomitant genomic alterations on larotrectinib efficacy is provided below (see clinical efficacy).

Pharmacodynamic effects

Cardiac electrophysiology
In 36 healthy adult subjects receiving single doses ranging from 100 mg to 900 mg, VITRAKVI did not prolong the QT interval to any clinically relevant extent.
The 200 mg dose corresponds to a peak exposure (Cmax) similar to that observed with larotrectinib 100 mg BID at steady state. A shortening of QTcF was observed with VITRAKVI dosing, with a maximum mean effect observed between 3 and 24 hours after Cmax, with a geometric mean decrease in QTcF from baseline of -13.2 msec (range -10 to -15.6 msec). Clinical relevance of this finding has not been established.

Clinical efficacy

Overview of studies
The efficacy and safety of VITRAKVI were studied in three multicentre, open-label, single-arm clinical studies in adult and paediatric cancer patients (Table 4). The studies are still ongoing Patients with and without documented NTRK gene fusion were allowed to participate in Study 1 and Study 3 (“SCOUT”). Patients enrolled to Study 2 (“NAVIGATE”) were required to have TRK fusion-positive cancer. The pooled primary analysis set of efficacy includes 302 patients with TRK fusion-positive cancer enrolled across the three studies that had measurable disease assessed by RECIST v1.1, a non-CNS primary tumour and received at least one dose of larotrectinib as of July 2023. These patients were required to have received prior standard therapy appropriate for their tumour type and stage of disease or who, in the opinion of the investigator, would have had to undergo radical surgery (such as limb amputation, facial resection, or paralysis causing procedure), or were unlikely to tolerate, or derive clinically meaningful benefit from available standard of care therapies in the advanced disease setting. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC).
In addition, 55 patients with primary CNS tumours and measurable disease at baseline were treated in Study 2 (“NAVIGATE”) and in Study 3 (“SCOUT”). Forty of the 55 primary CNS tumour patients had received prior cancer treatment (surgery, radiotherapy and/or previous systemic therapy). Tumour responses were assessed by the investigator using RANO or RECIST v1.1 criteria.

Identification of NTRK gene fusions relied on tissue samples for the molecular test methods: next generation sequencing (NGS) used in 320 patients, polymerase chain reaction (PCR) used in 14 patients, fluorescence in situ hybridization (FISH) used in 18 patients, and other testing methods (Sequencing, Nanostring, Sanger sequencing, or Chromosome Microarray) used in 5 patients.


Table 4: Clinical studies contributing to the efficacy analyses in solid and primary CNS tumours 

Study name, design and patient         Dose and                   Tumour types included in       n population                             formulation                efficacy analysis Study 1                                Doses up to 200 mg         Thyroid (n=4)                  13 NCT02122913                            once or twice daily        Salivary gland (n=3) (25 mg, 100 mg             GIST (n=2)a
• Phase 1, open-label, dose escalation capsules or 20 mg/mL       Soft tissue sarcoma (n=2) and expansion study; expansion phase oral solution)             NSCLC (n=1)b,c required tumours with an NTRK gene fusion                                                          Unknown primary cancer
• Adult patients (≥ 18 years) with                                (n=1) advanced solid tumours with an NTRK gene fusion
Study 2 “NAVIGATE”                     100 mg twice daily         NSCLC (n=29)b, c NCT02576431                            (25 mg, 100 mg             Soft tissue sarcoma (n=28) capsules or 20 mg/mL       Thyroid (n=26)b
• Phase 2 multinational, open label,   oral solution)             Salivary gland (n=24)          208 tumour “basket” study                                           Colon (n=24)
• Adult and paediatric patients                                   Primary CNS (n=19) ≥ 12 years with advanced solid tumours with an NTRK gene fusion                                Melanoma (n=10)b Breast, non-secretory (n=9)b
Pancreas (n=7)

Breast, secretory (n=5)
Cholangiocarcinoma (n=4)
GIST (n=3)a
Gastric (n=3)
Prostate (n=2)
Appendix,
Atypical carcinoid lung cancer, Bone sarcoma
, Cervix, Hepatice

Duodenal, External auditory canalb, Oesophageal,
SCLCb, d, Rectal, Testesb,
Thymus, Unknown primary cancer, Urothelial, Uterus
(n=1 each)
Study 3 “SCOUT”                           Doses up to             Infantile fibrosarcoma         136 NCT02637687                               100 mg/m2 twice daily   (n=49) (25 mg, 100 mg          Soft tissue sarcoma (n=42)b
• Phase 1/2 multinational, open-label,    capsules or 20 mg/mL    Primary CNS (n=36) dose escalation and expansion study;    oral solution)          Congenital mesoblastic Phase 2 expansion cohort required                               nephroma (n=2) advanced solid tumours with an NTRK                             Bone sarcoma (n=2) gene fusion, including locally                                  Breast, secretory, Cervix, advanced infantile fibrosarcoma                                 Lipofibromatosis,
• Paediatric patients from birth to                               Melanoma, Thyroid (n=1 21 years with advanced cancer or with                           each) primary CNS tumours
Total number of patients (n)*


357
*  consist of 302 patients with IRC tumour response assessment and 55 patients with primary CNS tumours (including astrocytoma, ganglioglioma, glioblastoma, glioma, glioneuronal tumours, neuronal and mixed neuronal-glial tumours, and primitive neuro-ectodermal tumour, not specified) with investigator tumour response assessment a GIST: gastrointestinal stromal tumour b brain metastases were observed in some patients in the following tumour types: lung ( NSCLC, SCLC), thyroid,  melanoma, breast (non-secretory) , external auditory canal, soft tissue sarcoma and testes c NSCLC: non-small cell lung cancer d SCLC: small cell lung cancer
 e hepatocellular carcinoma

Baseline characteristics for the pooled 302 patients with solid tumours with an NTRK gene fusion were as follows: median age 44 years (range 0-90 years); 33% < 18 years of age, and 67% ≥ 18 years; 55% white and 47% male; and ECOG PS 0-1 (88%), 2 (10%), or 3 (2%). Ninety-one percent of patients had received prior treatment for their cancer, defined as surgery, radiotherapy, or systemic therapy. Of these, 71% had received prior systemic therapy with a median of 1 prior systemic treatment regimen.
Twenty-six percent of all patients had received no prior systemic therapy. Of those 302 patients the most common tumour types represented were soft tissue sarcoma (24%), infantile fibrosarcoma (16%), lung cancer (11%), thyroid cancer (10%), salivary gland tumour (9%) and colon cancer (8%).
Baseline characteristics for the 55 patients with primary CNS tumours with an NTRK gene fusion assessed by investigator were as follows: median age 11 years (range 0-79 years); 38 patients < 18 years of age, and 17 patients ≥ 18 years, and 36 patients white and 27 patients male; and ECOG PS 0-1 (47 patients), or 2 (5 patients). Fifty-two (95%) patients had received prior treatment for their cancer, defined as surgery, radiotherapy, or systemic therapy. There was a median of 1 prior systemic treatment regimen received.

Efficacy results
The pooled efficacy results for overall response rate, duration of response and time to first response, in the primary analysis population (n=302) and with post-hoc addition of primary CNS tumours (n=55) resulting in the pooled population (n=357), are presented in Table 5 and Table 6.

Table 5: Pooled efficacy results in solid tumours including and excluding primary CNS tumours Efficacy parameter                          Analysis in solid         Analysis in solid tumours excluding         tumours including primary CNS tumours       primary CNS tumours
(n=302)a                  (n=357)a, b
Overall response rate (ORR) % (n)           65% (195)                 59% (210) [95% CI]                                    [59, 70]                  [54, 64] Complete response (CR)                      22% (65)                  19% (68) Pathological complete response  c
6% (17)                   5% (17)
Partial response (PR)                       37% (113)                 35% (125) Time to first response (median, months) 1.84                          1.84 [range]                                     [0.89, 22.90]             [0.89, 22.90] Duration of response (median, months) 43.3                            43.3 [range]                                     [0.0+, 73.7+]             [0.0+, 73.7+] % with duration ≥ 12 months                 79%                       78% % with duration ≥ 24 months                 67%                       65% % with duration ≥ 36 months                 55%                       54% % with duration ≥ 48 months 48%                                       47% + denotes ongoing a Independent review committee analysis by RECIST v1.1 for solid tumours except primary CNS tumours (302 patients).
b Investigator assessment using either RANO or RECIST v1.1 criteria for primary CNS tumours (55 patients).
c A pathological CR was a CR achieved by patients who were treated with larotrectinib and subsequently underwent surgical  resection with no viable tumour cells and negative margins on post-surgical pathology evaluation. The pre-surgical best response for these patients was reclassified pathological CR after surgery following RECIST v.1.1 
Table 6: Overall response rate and duration of response by tumour type* 

Patients                ORRa                                                              DO Tumour type                      (n=357                                                                                     R months                                        Range
%           95% CI
≥ 12 ≥ 24           ≥ 36                        (months)
56%,                                           55%                  0.03+, Soft tissue sarcoma                72          68%              79%               80%          72%                                72.7 Primary CNS                        55             27%          16%, 41%           63%          32%            32%                   5.8, NE Infantile                                                                                                     55% 49          94%            83%, 99%            81%          64%                               1.6+, 73.7+ fibrosarcoma

Lung                               32             66%          47%, 81%           73%          59%            47%                 1.9+, 56.2+ Thyroid                            31          65%            45%, 81%            85%          63%            54%                 3.7, 72.4+ 

Salivary gland                     27          81%            62%, 94%            90%          86%             75                 5.5, 65.3+ %


Colon                              24          46%            26%, 67%                         81%            40%                 3.9, 45.2+ 81%
Breast                             15
Non-secretory     c
7%                                         NR                     7.4 9          33%                                   67%
70%                          NR                                   12.5+ 80%                   11.1,
Secretoryb                          6          83%           36%, 100%               80%       80% 58.2+
Melanoma                                                                                                     NR                    1.9+, 23.2+ 11          45%                17%            50%           NR
77%
Pancreas                                                                                                     0%                    5.8, 5.8 7             14           0%, 58%             0%          0%
Gastrointestinal                                                                                             38%                   9.5, 5          80%            28%, 99%           75%           38% stromal tumour                                                                                                                     50.4+ 
Bone sarcoma                        3          33%             1%, 91%               0%        0%             0%                   9.5, 9.5 Congenital                                                                                            50% 100 mesoblastic                         2         100%           16%, 100%                         100%                               32.9, 44.5 % nephroma

Cervix                       2              50%           1%, 99%                NR        NR         NR                    2.1+, 2.1+ 
Unknown primary                      2              100%          16%, 100%              0         0          0                     5.6, 7.4 cancer
External auditory                     1              100%          3%, 100%               100       100%       NR                    33.8+, 33,8+ canal                                                                             % DOR: duration of response
NE: not evaluable
NR: not reached
* no data are available for the following tumour types: cholangiocarcinoma (n=4); gastric (n=3); prostate (n=2 ); appendix, hepatic, duodenal, lipofibromatosis, oesophageal, rectal, testes, thymus, urothelial, uterus (n=1 each) + denotes ongoing response a evaluated per independent review committee analysis by RECIST v1.1 for all tumour types except  patients with a primary CNS tumour who were evaluated per investigator assessment using either RANO or RECIST v1.1 criteria b with 3 complete, 2 partial response

c   with 1 complete, 2 partial response

Due to the rarity of TRK fusion-positive cancer, patients were studied across multiple tumour types with a limited number of patients in some tumour types, causing uncertainty in the ORR estimate per tumour type. The ORR in the total population may not reflect the expected response in a specific tumour type.

In the adult sub-population (n=220), the ORR was 50%. In the paediatric sub-population (n=137), the ORR was 72%.

In 247 patients with wide molecular characterisation before larotrectinib treatment, the ORR in 117 patients who had other genomic alterations in addition to NTRK gene fusion was 54%, and in 130 patients without other genomic alterations ORR was 68%.

Pooled primary analysis set

The pooled primary analysis set consisted of 302 patients and did not include primary CNS tumours.
Median time on treatment before disease progression was 14.4 months (range: 0.1 to 87.4 months) based on July 2023 cut-off. Fifty-three percent of patients had received VITRAKVI for 12 months or more, 36% had received VITRAKVI 24 months or more, and 24% had received VITRAKVI 36 months or more, with follow-up ongoing at the time of the analysis.
At the time of analysis, the median duration of response is 43.3 months (range: 0.0+ to 73.7+), an estimated 79% [95% CI: 72, 85] of responses lasted 12 months or longer, 67% [95% CI: 60, 74] of responses lasted 24 months or longer, and 55% [95% CI:47, 64] of responses lasted 36 months or longer. Eighty-three percent (83%) [95% CI: 79, 87] of patients treated were alive one year after the start of therapy 74% [95% CI: 68, 79] after two years after the start of therapy, and 70% [95% CI: 64, 75] after three years with the median for overall survival not yet being reached. Median progression free survival was 28.1 months at the time of the analysis, with a progression free survival rate of 62% [95% CI: 56, 68] after 1 year 54% [95% CI: 48, 60] after 2 years, and 43% [95% CI: 37, 50] after 3 years.
The median change in tumour size in the pooled primary analysis set was a decrease of 65%.

Patients with primary CNS tumours

At the time of data cut-off, of the 55 patients with primary CNS tumours confirmed response was observed in 15 patients (27%) with 3 of the 55 patients (5%) being complete responders and 12 patients (22%) being partial responders. Further 24 patients (44%) had stable disease. Twelve patients (22%) had progressive disease. At the time of data cut-off, time on treatment ranged from 1.2 to 62.9 months and was ongoing in 16 out of 55 patients with 15 of these patients receiving post- progression treatment.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

In cancer patients given VITRAKVI capsules, peak plasma levels (Cmax) of larotrectinib were achieved at approximately 1 hour after dosing. Half-life (t½) is approximately 3 hours and steady state is reached within 8 days with a systemic accumulation of 1.6 fold. At the recommended dose of 100 mg taken twice daily, steady-state arithmetic mean (± standard deviation) Cmax and daily AUC in adults were 914 ± 445 ng/mL and 5410 ± 3813 ng*h/mL, respectively. In vitro studies indicate that larotrectinib is not a substrate for either OATP1B1 or OATP1B3.

In vitro studies indicate that larotrectinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations and is unlikely to affect clearance of substrates of these CYPs.


In vitro studies indicate that larotrectinib does not inhibit the transporters BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations and is unlikely to affect clearance of substrates of these transporters.

Absorption

VITRAKVI is available as a capsule and oral solution formulation.
The mean absolute bioavailability of larotrectinib was 34% (range: 32% to 37%) following a single 100 mg oral dose. In healthy adult subjects, the AUC of larotrectinib in the oral solution formulation was similar to the capsule, with Cmax 36% higher with the oral solution formulation.
Larotrectinib Cmax was reduced by approximately 35% and there was no effect on AUC in healthy subjects administered VITRAKVI after a high-fat and high-calorie meal compared to the Cmax and AUC after overnight fasting.

Effect of gastric pH-elevating agents on larotrectinib
Larotrectinib has pH-dependent solubility. In vitro studies show that in liquid volumes relevant to the gastrointestinal (GI) tract larotrectinib is fully soluble over entire pH range of the GI tract. Therefore, larotrectinib is unlikely to be affected by pH-modifying agents.

Distribution

The mean volume of distribution of larotrectinib in healthy adult subjects was 48 L following intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose. Binding of larotrectinib to human plasma proteins in vitro was approximately 70% and was independent of drug concentration. The blood-to-plasma concentration ratio was approximately 0.9.

Biotransformation

Larotrectinib was metabolised predominantly by CYP3A4/5 in vitro. Following oral administration of a single 100 mg dose of radiolabeled larotrectinib to healthy adult subjects, unchanged larotrectinib (19%) and an O-glucuronide that is formed following loss of the hydroxypyrrolidine-urea moiety (26%) were the major circulating radioactive drug components.

Elimination

The half-life of larotrectinib in plasma of cancer patients given 100 mg twice daily of VITRAKVI was approximately 3 hours. Mean clearance (CL) of larotrectinib was approximately 34 L/h following intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose of VITRAKVI.

Excretion

Following oral administration of 100 mg radiolabeled larotrectinib to healthy adult subjects, 58% of the administered radioactivity was recovered in faeces and 39% was recovered in urine and when an IV microtracer dose was given in conjunction with a 100 mg oral dose of larotrectinib, 35% of the administered radioactivity was recovered in faeces and 53% was recovered in urine. The fraction excreted as unchanged drug in urine was 29% following IV microtracer dose, indicating that direct renal excretion accounted for 29% of total clearance.

Linearity / non-linearity

The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of larotrectinib after a single dose in healthy adult subjects were dose proportional up to 400 mg and slightly greater than proportional at doses of 600 to 900 mg.


Special populations

Paediatric patients
Based on population pharmacokinetic analyses exposure (Cmax and AUC) in paediatric patients at the recommended dose of 100 mg/m2 with a maximum of 100 mg BID was higher than in adults (≥18 years of age) given the dose of 100 mg BID (see Table 7).
Data defining exposure in small children (1 month to <2 years of age) at the recommended dose is limited (n=40).

Table 7: Exposure (Cmax and AUC on day 1a) in patients grouped by age group at the recommended dose of 100 mg/m2 with a maximum of 100 mg BID
Fold difference compared to patients ≥ 18 years of agec
Age group              n=348b
Cmax                        AUCa
1 to < 3 months           9                 4.2                           4.5 3 to < 6 months           4                 2.6                           2.5 6 to < 12 months         18                 2.5                           1.9 1 to < 2 years            9                 2.0                           1.4 2 to < 6 years           31                 2.0                           1.4
6 to < 12 years          26                 1.5                           1.2 12 to < 18 years         27                 1.2                           1.0 ≥ 18 years              224                 1.0                           1.0 a   area under the plasma concentration-time curve for 24 hours on day 1 b   number of patients from 26 November 2020 data cut-off c   fold difference is the ratio of stated age group to ≥18 years group. A fold-difference of 1 equates to no difference.


Elderly
There are limited data in elderly. PK data is available only in 2 patients over 65 years.

Patients with hepatic impairment
A pharmacokinetic study was conducted in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, and in healthy adult control subjects with normal hepatic function matched for age, body mass index and sex. All subjects received a single 100 mg dose of larotrectinib. An increase in larotrectinib AUC0-inf was observed in subjects with mild, moderate and severe hepatic impairment of 1.3, 2 and 3.2-fold respectively versus those with normal hepatic function. Cmax was observed to increase slightly by 1.1, 1.1 and 1.5-fold respectively.

Patients with renal impairment
A pharmacokinetic study was conducted in subjects with end stage renal disease requiring dialysis, and in healthy adult control subjects with normal renal function matched for age, body mass index and sex. All subjects received a single 100 mg dose of larotrectinib. An increase in larotrectinib Cmax and AUC0-inf, of 1.25 and 1.46-fold respectively was observed in renally impaired subjects versus those with normal renal function.

Other special populations
Gender did not appear to influence larotrectinib pharmacokinetics to a clinically significant extent.
There was not enough data to investigate the potential influence of race on the systemic exposure of larotrectinib.