Summary Basis of Decision for Tepmetko

 

Clinical Pharmacology

The mesenchymal-epithelial transition (MET) tyrosine kinase receptor is a cell surface receptor. Mesenchymal-epithelial transition and its ligand, hepatocyte growth factor (HGF), are involved in carcinogenesis and tumour progression. Oncogenic activation of MET has been shown to promote cancer cell proliferation, survival, migration, invasion, and tumour angiogenesis, as well as to mediate resistance to cancer therapies.

Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib inhibits HGF-dependent and HGF-independent MET phosphorylation and MET-dependent downstream signaling pathways. Tepotinib also inhibits the melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations.

The proposed clinical dose of tepotinib is 450 mg (500 mg as tepotinib hydrochloride) taken once daily in patients with advanced non-small cell lung cancer (NSCLC) harbouring MET tyrosine kinase receptor exon 14 (METex14) skipping alterations (METex14-altered NSCLC).

Pharmacodynamic (PD) profiling in KP-4 xenograft tumours suggest that near-complete inhibition of MET kinase activity (≥95% reduction in phospho-MET) is required to achieve tumour regression. Therefore, this level of MET inhibition was used as the target to achieve in humans. Human pharmacokinetic (PK)/PD model simulations suggest that a tepotinib dose of 450 mg (500 mg as tepotinib hydrochloride) once daily is sufficient to achieve sustained inhibition of phospho-MET at a level >95% in more than 90% of a mixed solid tumour population. According to a translational PK/PD model, a dose reduction to 250 mg is predicted to maintain biologically meaningful target inhibition with ≥95% phospho-MET inhibition in more than 80% of the population.

No clinical maximum tolerable dose was reached in a dose-escalation administration up to 1,400 mg once daily. Tepotinib exposure increased in the presence of food, with an increase in the area under the plasma concentration-time curve (AUC) by about 1.6-fold and an increase in the maximum observed plasma concentration (C_max) by 2-fold, compared with the fasted state. It is recommended that tepotinib be taken with food. In human plasma, tepotinib is highly protein-bound (98%). Following a single intravenous dose of carbon 14-labelled tepotinib, the volume of distribution during the terminal phase was shown to be large, with a geometric mean (geometric coefficient of variation) of 574 L.

Tepotinib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C8 enzymes. One major circulating plasma metabolite, M506, has been identified and found to be a minor contributor to the overall efficacy of tepotinib.

Tepotinib is mainly excreted in the feces (approximately 85% of administered radioactivity, adjusted for total recovery), with urine being a minor excretion pathway. Metabolites account for 48% of the tepotinib-related radioactivity recovered in feces and urine. Following a single oral administration of a radiolabelled tepotinib dose of 500 mg, M506 accounted for only about 3% of the total radioactivity in feces.

Following a single intravenous dose of tepotinib, the geometric mean (geometric coefficient of variation) clearance was estimated to be 12.8 L/hour. The effective half-life for tepotinib was approximately 32 hours, based on the population PK analysis. After multiple daily administrations of tepotinib at a dose of 500 mg, median accumulation was 3.3-fold for AUC from time 0 to 24 hours (AUC_0-24h) and 2.5-fold for C_max.

Co-administration of Tepmetko with a strong CYP3A or permeability-glycoprotein (P-gp) inhibitor may increase tepotinib exposure. Co-administration with Tepmetko also increased the concentration of certain P-gp substrates. Tepotinib had no clinically relevant effect on the PK of the CYP3A4 substrate, midazolam. No clinically significant differences in tepotinib were observed when co-administrated with omeprazole. No clinically significant differences in glucose levels were observed when metformin (a multidrug and toxin extrusion 2 and organic cation transporter 2 substrate) was co-administered with tepotinib. No clinically significant difference in the adverse events were observed when rosuvastatin (a substrate to the drug transporter breast cancer resistance protein) was co-administered with tepotinib.

Exposure-safety analyses revealed that the risk of peripheral oedema increased with increasing tepotinib exposure. An analysis of pooled integrated exposure-corrected QT interval (QTc) data from four studies and an analysis of data from the pivotal VISION study (see Clinical Efficacy section) concluded that tepotinib at the proposed clinical dose of 450 mg (500 mg as tepotinib hydrochloride) once daily is not associated with prolongation of the QTc interval to a clinically relevant extent. The QTc effect of supratherapeutic tepotinib exposure was not evaluated.

Overall, the clinical pharmacological data support the use of Tepmetko for the recommended indication.

For further details, please refer to the Tepmetko Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Tepmetko was evaluated in the pivotal VISION study, an ongoing, single-arm, open-label, multicentre, non-randomized, multicohort, two-part, Phase II study. The VISION study assessed the antitumour activity and tolerability of Tepmetko monotherapy (450 mg tepotinib [as 500 mg tepotinib hydrochloride] orally once daily) in adult patients with confirmed locally advanced unresectable (Stage IIIb) or metastatic (Stage IV) METex14-altered NSCLC. Patients with confirmed advanced METex14-altered NSCLC or MET amplification status were assigned after screening to either Cohort A (METex14 skipping alterations, regardless of MET amplification status), Cohort B (MET amplification and negative for METex14 skipping alterations), or Cohort C (METex14 skipping alterations, regardless of MET amplification status). The clinical efficacy of Tepmetko was assessed in Cohort A. Cohort C was a confirmatory cohort intended to extend and confirm the existing results for Cohort A. Interim results were obtained using a data cut-off date (DCO) of January 1, 2020 (DCO Jan 01 2020). These results were updated on July 1, 2020 (DCO Jul 01 2020).

The primary efficacy outcome measure of the VISION study was a confirmed objective response (OR), evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 guideline and based on an evaluation by a blinded independent review committee (BIRC). Patients were identified as having an OR if they achieved either a confirmed complete response or partial response from the first administration of Tepmetko to the first observation of progressive disease. The confirmed objective response rate (ORR) was evaluated. The duration of response (DOR; as per the BIRC), a secondary efficacy endpoint, was the time from when the complete response or partial response criteria were first met until progressive disease or death due to any cause within 84 days of the last evaluable tumour assessment, whichever occurred first. This endpoint was considered a clinically relevant antitumour activity endpoint for this study.

The efficacy analysis population comprised 146 patients from Cohort A who had received at least one dose of Tepmetko prior to October 2, 2019 and who had undergone at least two post baseline assessments or had discontinued study treatment for any reason (intention-to-treat [ITT]-02 Oct 2019 [DCO Jul 01 2020]). Further, these patients had at least 9 months of follow-up from the start of treatment (which was expected to yield 6 months of follow-up beyond the onset of response in responders), and were regarded as adequate to support stable OR and meaningful DOR results. Of note, within the ITT-02 Oct 2019 (DCO Jul 01 2020) population, 99 patients received their first dose prior to April 2, 2019 and had at least 15 months of follow-up from the start of treatment (ITT-02 Apr 2019 [DCO Jul 01 2020]).

At baseline, patients in the ITT-02 Oct 2019 (DCO Jul 01 2020) population had a median age of 73 years and were distributed equally with respect to gender. In addition, there was a higher proportion of smokers than would be expected from an NSCLC population whose tumours are driven by other oncogenes. Ninety-eight percent of patients had metastatic disease and 87% had adenocarcinoma histology. Patients were either treatment naive (n = 65) or had received up to two lines of prior systemic anticancer therapies (n = 81). Among previously treated patients, 89% had received prior platinum-based chemotherapy.

Patients in Cohort A were enrolled based on a positive test for METex14 by either liquid biopsy (65%) or tissue biopsy (58%). Thirty-three patients (23%) were identified as METex14-positive by both liquid biopsy and tissue biopsy. To account for potential differences in the detection of METex14 by different testing methodologies, three primary analysis sets were derived from the ITT analysis set: liquid biopsy positive (L+ analysis set; n = 95), tumour biopsy positive (T+ analysis set; n = 84), and all patients who tested positive for METex14 skipping alterations, irrespective of testing methodology (combined analysis set; n = 146). Patients in the combined analysis set included patients who were tested with only one test.

The study aimed to show an ORR (as per the BIRC) in the range of 40% to 50% and to demonstrate that the lower limit of the corresponding exact two-sided 95% confidence interval (CI) for ORR exceeded 20% across lines of therapy. Given the lack of published evidence documenting treatment outcomes in the METex14-altered NSCLC population at the time of study planning, the threshold of 20% was chosen taking into consideration the ORRs achieved with available therapies in patients with advanced NSCLC (i.e., platinum-based chemotherapy in first-line therapy, immune-checkpoint inhibitor monotherapy in second-line therapy, and single-agent chemotherapy in third-line therapy).

In the ITT-02 Oct 2019 (DCO Jul 01 2020) population, the ORR was 45.2% (95% CI: 37.0, 53.6). All responders (n = 66) achieved a best overall response of partial response; no patients achieved a best overall response of complete response. Most responses were achieved within three months of the initial dose, and the majority (44 of 66 responders; 66.7%) of responses were deep (i.e., a shrinkage of target lesions of 50% or more). The depth of response was an exploratory outcome measure. While the ORR was consistent between the primary L+ and T+ analysis sets, clinical data were very limited for patients who tested positive via liquid biopsy but negative via tumour tissue biopsy (L+/T-). Overall, the ORR (as per the BIRC) was consistent between the ITT-02 Oct 2019 (DCO Jul 01 2020) population and the ITT-02 Apr 2019 (DCO Jul 01 2020) population and between the DCO Jan 1 2020 and the DCO Jul 01 2020. Additionally, the ORR as per the investigator evaluation was supportive of the primary BIRC analysis.

The median DOR (as per the BIRC) for the ITT-02 Oct 2019 (DCO Jul 01 2020) population was 11.1 months (95% CI: 8.4, 18.5). The proportion of responders with DOR ≥6, ≥9, and ≥12 months was 74.2%, 43.9%, and 21.2%, respectively. While the proportion of responders with sustained DOR ≥6 months and ≥9 months had increased considerably at the update compared with the DCO Jan 01 2020, a smaller difference was observed for the proportion with DOR ≥12 months.

Overall, the benefit with Tepmetko was observed to be stable and independent of whether patients were treatment naive or previously treated. In treatment-naive patients compared with previously treated patients, there were 72.4% and 75.7% responders, respectively, with DOR ≥6 months; 34.5% and 51.4%, respectively, with DOR ≥9 months; and 17.2% and 24.3%, respectively, with DOR ≥12 months. The enrolment of treatment-naive patients occurred via a protocol amendment approximately six months after the first patient was enrolled, resulting in a shorter observation period for first-line therapy compared with later lines. Based on the current understanding of oncogene-driven NSCLC, an extrapolation from the metastatic stage (98% of patients) to the locally advanced unresectable stage was considered reasonable.

Efficacy results placed in the context of 1) intra-study comparisons in the VISION study before and after initiation of Tepmetko and 2) published evidence on available therapies for NSCLC used to treat METex14-altered NSCLC suggested increased clinical benefit with Tepmetko, primarily based on response rates. However, definitive conclusions could not be drawn. Real-world effectiveness outcomes were also inconclusive.

Taken together, the observed ORR and median DOR are considered promising evidence supporting clinical benefit in patients with METex14-altered NSCLC.

Indication

The New Drug Submission for Tepmetko was filed by the sponsor with the following indication:

Tepmetko (tepotinib) is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harbouring MET tyrosine kinase receptor exon 14 (METex14) skipping alterations.

To ensure safe and effective use of the product, Health Canada approved the following indication:

Tepmetko (tepotinib) is indicated for the treatment of adult patients with locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition (MET) tyrosine kinase receptor exon 14 skipping alterations.

Documentation of MET tyrosine kinase receptor exon 14 (METex14) skipping alteration status based on a validated METex14 assay is required prior to treatment with Tepmetko.

Efficacy in patients with NSCLC harbouring METex14 skipping alterations was based on objective response rate and duration of response in a single-arm study.

For more information, refer to the Tepmetko Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Tepmetko was primarily evaluated in data from the Safety Analysis Set (SAF) from the ongoing pivotal VISION study (see Clinical Efficacy section).

At the DCO 01 Jul 2020, the SAF comprised a pooled cohort of 255 patients with advanced METex14-altered NSCLC from Cohort A (n = 152) and Cohort C (n = 103), all of whom had received at least one dose of Tepmetko monotherapy at the recommended dose of 450 mg tepotinib (as tepotinib hydrochloride) once daily.

At the DCO 01 Jul 2020, the median duration of therapy in the SAF was 22.3 weeks (range: 0 to 188 weeks), with 42% and 18% of patients exposed for ≥6 months and >12 months, respectively. Long-term safety data are therefore considered limited. The median age was 72 years (range: 41 to 94 years), with 79% of patients ≥65 years of age and 43% of patients ≥75 years of age. Gender was well-balanced (52% female). The most common race was White (67%), followed by Asian (28%). Study treatment was ongoing in 40% of patients, with disease progression, adverse events, and death representing the most common reasons for permanent treatment discontinuation.

Treatment-emergent adverse events (TEAEs) occurred in 96.5% of patients with the most common (≥20%) TEAEs being edema (69.0%), mainly peripheral edema (60.0%); fatigue (27.5%); nausea (26.7%); diarrhea (26.3%); increase in creatinine (25.9%); musculoskeletal pain (24.3%); hypoalbuminemia (23.9%); and dyspnea (20.4%). Treatment-related TEAEs, based on investigator assessment, were reported in 86.3% of patients.

Grade ≥3 TEAEs occurred in 52.9% of patients. Grade ≥3 TEAEs that occurred in ≥5% of patients included peripheral edema (7.8%), hypoalbuminemia (5.5%), and pleural effusion (5.1%). Treatment-related TEAEs of Grade ≥3 were reported in 25.1% of patients; peripheral edema (7.5%) was the only event occurring in ≥5% of patients.

Serious TEAEs occurred in 45.1% of patients. Serious TEAEs in ≥2% of patients included pleural effusion (6.7%), pneumonia (4.7%), dyspnea (3.9%), general health deterioration (3.5%), peripheral edema (2.4%), generalized edema (2.0%), pulmonary embolism (2.0%), and musculoskeletal pain (2.0%).

The most frequent TEAEs (≥1%) leading to permanent discontinuations of Tepmetko in 20.4% of patients were peripheral edema (3.5%), pleural effusion (2.0%), dyspnea (1.6%), general health deterioration (1.6%), pneumonitis (1.2%), and genital edema (1.2%). Temporary treatment discontinuations of Tepmetko due to a TEAE occurred in 43.9% of patients; the maximum permitted period of continuous treatment interruption was 21 days. Dose reductions of Tepmetko due to a TEAE occurred in 29.8% of patients.

Grade 5 TEAEs occurred in 11.8% of patients, and overall, seemed typical for an advanced NSCLC population. A fatal adverse reaction occurred in one patient (0.4%) due to interstitial lung disease. A case of fatal hepatic failure occurred in one patient (0.4%). While challenges with causality assessment in the case of fatal hepatic failure are acknowledged, a potential relationship with Tepmetko could not be ruled out. Additional considerations included the limited long-term safety data of Tepmetko and supportive pooled data (POOL) from five open-label, single-arm studies in which 448 patients with various solid tumours, including 255 patients from the SAF, received Tepmetko monotherapy at the proposed dose of 450 mg once daily. The median duration of exposure was 16.9 weeks, reflecting the short duration of exposure of Phase I studies or study parts. Data from the POOL studies were supportive of the hepatotoxicity observed in the VISION study. Furthermore, MET is involved in regeneration of damaged organs, in particular the liver. A case of fatal dyspnea from possible fluid overload occurred in one patient (0.4%). The causality of fatal dyspnea remained indeterminate as multifactorial events could have contributed, including fluid overload and progression of the underlying cancer with bilateral pleural effusions (cytology unknown).

The primary serious risks were identified as hepatotoxicity and interstitial lung disease/pneumonitis. Based on Tepmetko’s mechanism of action and findings from animal studies, it can cause fetal harm when administered to a pregnant woman.

Edema and hypoalbuminemia were very commonly reported and might be considered class effects. While acknowledging the potential for confounding by the underlying NSCLC, and possibly by the presence of METex14 skipping alterations, a contributory role of Tepmetko in the development of pleural effusion could not be excluded.

A median increase in serum creatinine of 31% was computed 21 days after initiation of Tepmetko in patients with and without renal failure TEAEs. One component of the observed increases in creatinine may be the inhibition of active tubular secretion by Tepmetko. Therefore, creatinine alone is not a reliable biomarker to assess renal function. Tepmetko did not appear to have a direct kidney toxicity. As the pathophysiology of pre-renal disease is multifactorial, the potential for Tepmetko indirectly contributing to acute kidney injury remains. While renal failure-type TEAEs were more commonly observed in patients with baseline renal impairment, many factors could have contributed to, and could explain, these observations.

Overall, the TEAE profile was similar between the DCO dates of January 1, 2020 and July 1, 2020 and the safety profile of the SAF was generally consistent with, and supported by, the data from the POOL studies.

Based on the information reviewed, Tepmetko has an acceptable and manageable safety profile, taking into consideration the intended patient population with advanced METex14-altered NSCLC. The identified safety issues can be managed through labelling, adequate monitoring, and dose modifications.

Appropriate warnings and precautions are in place in the approved Tepmetko Product Monograph to address the identified safety concerns, including a Serious Warnings and Precautions box describing the risk of hepatotoxicity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity. Treatment with Tepmetko should be initiated and supervised by a qualified physician experienced in the use of anticancer therapies.

A Risk Management Plan (RMP) for Tepmetko was submitted to Health Canada by EMD Serono, a Division of EMD Inc. Canada. Upon review, the RMP was considered acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

For more information, refer to the Tepmetko Product Monograph, approved by Health Canada and available through the Drug Product Database.