Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

Mechanism of action

The mesenchymal-epithelial transition factor (MET) and its ligand, the hepatocyte growth factor (HGF), are involved in carcinogenesis and tumour progression. Oncogenic activation of MET signalling has been shown to promote cancer cell proliferation, survival, migration and invasion, and tumour angiogenesis, as well as to mediate resistance to cancer therapies.
Tepotinib is a selective and potent, reversible, Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of MET. Tepotinib inhibits HGF-dependent and -independent MET phosphorylation and MET-dependent downstream signalling through the phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular-signal regulated kinase pathways in a dose-dependent manner.


Pharmacodynamics
Treatment of susceptible tumour cells with tepotinib inhibited proliferation, anchorage-independent growth and migration of MET-dependent tumour cells. Treatment of tumour-bearing mice with tepotinib led to effective and sustained inhibition of MET phosphorylation and a change in pharmacodynamic biomarkers, indicating inhibition of tumour cell proliferation, increased tumour cell apoptosis and reduced tumour angiogenesis. Tepotinib inhibited tumour growth of MET-dependent tumours from different tumour types.
The anti-tumour activity of Tepotinib was particularly pronounced in tumours with oncogenic activation of MET, such as METex14 skipping.
The contribution of the major circulating metabolite to the anti-tumour activity of tepotinib is considered to be negligible.


Cardiac electrophysiology
In an exposure-QTc analysis, the QTcF interval prolongation potential of tepotinib was assessed in 392 patients with various solid tumours following single or multiple daily doses of tepotinib ranging from 27 mg to 1,261 mg. At the therapeutic dose, no major changes in the QTc interval (> 20 ms) were detected on average, but a concentration-dependent prolongation was found. The effect on the QTc interval at high exposure was not investigated.


Clinical efficacy
The efficacy of tepotinib was evaluated in a single-arm, open-label, multicentre study (VISION) in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring METex14 skipping alterations (n = 313). Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 and were either treatment-naïve or had progressed on up to 2 lines prior systemic therapies. Neurologically stable patients with central nervous system metastases were permitted. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) activating alterations were excluded.
The primary efficacy outcome measure was confirmed objective response (complete response or partial response, ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included complete response, partial response, duration of response (DOR) and progression-free survival (PFS), assessed by IRC, as well as overall survival (OS).


Patients had a median age of 72 years (range 41 to 94), 51% were female and 49% male. The majority of patients were white (62%), followed by Asian patients (34%) and were never (49%) or former smokers (45%). Most patients were ≥ 65 years of age (79%) and 41% of patients were ≥ 75 years of age.


The majority of patients had stage IV disease (94%), 81% had adenocarcinoma histology. Thirteen percent of the patients had stable brain metastases. Patients received tepotinib as first-line (52%) or second- or later line (48%) therapy.


METex14 skipping alterations were prospectively tested by next-generation sequencing in tumour (RNA- based) and/or plasma (ctDNA-based).


Patients received 450 mg tepotinib once daily until disease progression or unacceptable toxicity. Median treatment duration was 7.5 months (range 0 to 72 months).


In the initial efficacy analysis 152 adult patients with locally advanced or metastatic NSCLC harbouring METex14 skipping alterations with a follow up of at least 9 months were evaluated (see Table 3).


Table 3: Clinical outcomes in the VISION study by IRC assessment
Overall       Treatment-naïve Previously treated
Efficacy parameter
N = 152            N = 69           N = 83
Objective response rate, %                          44.7               44.9                  44.6 [95% CI]                                         [36.7, 53.0]       [32.9, 57.4]         [33.7, 55.9] Complete response, %                                  0                  0                    0 Partial response, %                                  44.7               44.9                 44.6 Median duration of response, monthsa                 11.1              10.8                  11.1 [95% CI]                                          [8.4, 18.5]        [6.9, NE]            [9.5, 18.5] Duration of responseb
≥ 6 months, % of responders                          72.1               67.7                 75.7 ≥ 9 months, % of responders                          42.6               32.3                 51.4 ≥ 12 months, % of responders                         20.6               16.1                 24.3 Median progression-free survival, monthsa             8.9                8.5                 10.9 [95% CI]                                          [8.2, 11.2]        [6.8, 11.3]          [8.2, 12.7] Median overall survival time, monthsa               17.6                17.6                 19.7 [95% CI]                                         [15.0, 21.0]        [9.7, 29.7]         [15.0, 21.0] IRC=Independent Review Committee, CI=confidence interval, ne=not estimable a:   Product-limit (Kaplan-Meier) estimates, 95% CI for the median using the Brookmeyer and Crowley method b
: A duration of response of ≥ 9 months or ≥ 12 months, respectively, could not be achieved by some patients due to the timing of their inclusion in the study.


In an extended efficacy analysis additional 161 adult patients with locally advanced or metastatic NSCLC harbouring METex14 skipping alterations were enrolled into the VISION study. Overall, efficacy results refer to 313 patients with a follow up of at least 18 months.


In the overall population of 313 patients, 161 patients showed either a partial (n = 160) or a complete (n = 1) response, resulting in an ORR of 51.4% (95%-CI 45.8, 57.1%). A median DOR of 18.0 months (95%-CI 12.4, 46.4 months) is observed, with 65.8%, 49.7%, and 38.5% out of 161 patients still showing continued response after 6, 9 or 12 months, respectively. A median PFS of 11.2 months (95%-CI 9.5, 13.8 months) and a median OS of 19.6 months (95%-CI 16.2, 22.9 months) was observed.


In 164 treatment naive patients, 94 patients showed either a partial (n = 93) or a complete (n = 1) response resulting in an ORR of 57.3% (95%-CI 49.4, 65.0%). A median DOR of 46.4 months (95%-CI 13.8, ne months) is observed, with 66.0%, 51.1%, and 40.4% out of 94 patients still showing continued response after 6, 9 or 12 months, respectively. A median PFS of 12.6 months (95%-CI 9.7, 17.7 months) and a median OS of 21.3 months (95%-CI 14.2, 25.9 months) was observed.


In 149 previously treated patients, 67 patients showed a partial response resulting in an ORR of 45.0% (95%-CI 36.8, 53.3%). A median DOR of 12.6 months (95%-CI 9.5, 18.5 months) is observed, with 65.7%, 47.8%, and 35.8% out of 67 patients still showing continued response after 6, 9 or 12 months, respectively.
A median PFS of 11.0 months (95%-CI 8.2, 13.7 months) and a median OS of 19.3 months (95%-CI 15.6, 22.3 months) was observed.



Efficacy outcome was independent of the testing modality (liquid biopsy or tumour biopsy) used to establish the METex14 skipping status. Consistent efficacy results in subgroups by prior therapy, presence of brain metastasis or age were observed.

Pharmacokinetic Properties