TEPMETKO is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymalepithelial transition (MET) exon 14 skipping alterations.

Merck...today announced that the European Commission (EC) has approved once-daily oral TEPMETKO® (tepotinib) as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy.

...Japanese Ministry of Health, Labour and Welfare (MHLW) has approved TEPMETKO®* (tepotinib) for the treatment of patients with unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations.

Merck...announced that the National Institute for Health and Care Excellence (NICE) has recommended TEPMETKO® (tepotinib), which is approved for the treatment of adult patients in Great Britain with advanced non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition factor gene (MET) exon 14 (METex14) skipping alterations....In the VISION study, efficacy was evaluated in 275 patients and the study demonstrated an objective response rate, the primary outcome measure, by independent review of 49.1% (95% confidence interval [CI], 43.0-55.2) in the combined-biopsy group.

Non-small cell lung cancer: MET exon 14 skipping mutation...first-line therapy/subsequent therapy…tepotinib

...EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, today announced that the US Food and Drug Administration (FDA) has accepted and granted Priority Review to the new drug application (NDA) for once-daily, orally-dosed tepotinib* for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition exon 14 (METex14) skipping, as detected by an FDA-approved test.

...Subjects with MET alterations, namely METex14 skipping alterations in plasma and/or tissue as determined by the central laboratory or by an assay with appropriate regulatory status...

Compared with prior Tx, tepotinib outcomes in 2L+ were greatly improved (ORR, 45.0%; mDOR, 12.6 mo; mPFS, 11.0 mo) and were consistent regardless of Tx line (2L, 3L+) or smoking history.

At a median follow-up of 19 months, the ORR was 57.6% for all patients, 52.2% for METex14, and 70% for MET amplification. Median PFS was 8 months (95% CI, 4.5-11.5) and median OS was 14 months (95% CI, 7.8-20.2) in all patients...Tepotinib demonstrated promising antitumor activity and manageable toxicity profiles in patients with various solid cancers harboring METex14 or amplification.

We conducted a phase 2, multicenter, single arm study evaluating tepotinib in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either MET exon 14 skipping mutation or MET amplification (copy number gain ≥6) detected by tissue-based next generation sequencing (NGS)....Tepotinib showed a favorable antitumor activity in NSCLC patients with MET exon 14 skipping mutation or amplification.

In Asian patients with METex14 skipping NSCLC, tepotinib demonstrated robust and durable efficacy, particularly as a first-line treatment, with stability in HRQoL and a manageable safety profile.

The VISION phase 2 nonrandomized clinical trial was a multicohort, open-label, multicenter study that enrolled patients with METex14-skipping advanced/metastatic NSCLC (cohorts A and C)….Patients received tepotinib....The objective response rate (ORR) was 51.4% (95% CI, 45.8%-57.1%) with a median (m)DOR of 18.0 (95% CI, 12.4-46.4) months. In cohort C (n = 161), an ORR of 55.9% (95% CI, 47.9%-63.7%) with an mDOR of 20.8 (95% CI, 12.6-not estimable [NE]) months was reported across treatment lines)...the long-term outcomes of VISION demonstrated robust and durable clinical activity following treatment with tepotinib, particularly in the treatment-naive setting, in the largest known clinical trial of patients with METex14-skipping NSCLC...

Clinical benefit was reported in 18/21 (86%) pts with METamp (12 PR, 57%), in 5/5 with MET overexpression (2 PR), and 2/2 with MET exon 14 skipping (2 PR)….Tepotinib plus an EGFR TKI showed promising clinical activity in pts with MET-altered NSCLC who have progressed on a previous EGFR TKI, including those with several lines of prior treatment.

Pts with advanced METex14 skipping NSCLC detected by liquid and/or tissue (T+) biopsy received tepotinib 500 mg (450 mg active moiety) once daily….The long-term outcomes of VISION demonstrate the robust and durable clinical activity of tepotinib, particularly in 1L T+ pts...

Pts with advanced/metastatic METex14 skipping NSCLC received 500 mg (450 mg active moiety) tepotinib QD….Robust and durable efficacy, particularly in the 1L setting, support early use of tepotinib in Tx sequence.

ORR was 57.5% (95% CI: 47.6, 67.1), DCR was 80.2% (71.3, 87.3), mDOR was 18.5 months (10.4, ne), mPFS was 13.8 months (9.6, 19.9), and mOS was 23.7 months (19.3, ne)….Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian pts with METex14 skipping NSCLC in VISION.

In VISION-the largest study of a MET inhibitor in pts with METex14 skipping NSCLC-tepotinib demonstrated robust and durable efficacy irrespective of prior therapies and had a tolerable safety profile.

In Cohort C, ORR was 54.7% (46.6, 62.5) with mDOR of 20.8 months (12.6, ne) and mPFS of 13.8 months (10.4, ne). Efficacy was robust and durable across therapy lines (Table). In Cohort C, METex14 skipping was detected by TBx in 120/161 patients (T+; 74.5%). In 1L T+ patients (n=69), ORR was 62.3% (95% CI: 49.8, 73.7) with mDOR ne (10.4, ne) and mPFS of 15.9 months (10.8, ne). Previously treated (2L+) T+ patients (n=51) had an ORR of 51.0% (36.6, 65.2) with mDOR of 12.6 months (4.3, ne) and mPFS of 13.8 months (6.9, ne). In VISION - the largest clinical trial of a MET inhibitor in METex14 skipping NSCLC - Cohort C primary analysis provided independent confirmation for robust and durable efficacy of tepotinib, with comparable or improved outcomes across endpoints compared to Cohort A. Efficacy was particularly durable in 1L T+ patients and promising intracranial activity was observed.

ORR was 54.4% (42.8, 65.7), mDOR was 18.5 months (8.3, ne), mPFS was 12.1 months (6.9, ne) and mOS was 20.4 months (19.1, ne)….In VISION, tepotinib showed robust and durable clinical activity in Asian pts with METex14 skipping NSCLC.

...the durable clinical activity of tepotinib 500 mg once daily (OD) in 152 patients with MET exon 14 altered NSCLC, 99 of whom were followed for at least 9 months. The authors reported that tepotinib was associated with a partial response in approximately half the patients, with an overall response rate of 46% (95% confidence interval [CI] 36–57) by independent review committee (IRC) review and of 56% (95% CI 45–66) by investigator assessment. PFS and OS were 8.5 and 17.1 months, respectively (Table 2).

Merck...oday announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of once-daily oral TEPMETKO® (tepotinib) as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping...The positive opinion is based on results from the pivotal Phase II VISION study evaluating TEPMETKO as a once-daily oral monotherapy treatment for patients with advanced NSCLC with METex14 skipping alterations.

This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases (BM)....Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy (ORR [95% CI]: 44.9% [32.9, 57.4] vs. 44.6% [33.7, 55.9]; median duration of response [95% CI]: 10.8 [6.9, not estimable] vs. 11.1 [9.5, 18.5] months). Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5/7 patients with measurable BM had partial intracranial responses.

Pts with advanced METex14 skipping NSCLC received 500 mg (450 mg active moiety) tepotinib orally once daily….Partial response...Patients <75 years (n=84)...41 (48.8)...Tepotinib demonstrated robust and durable efficacy in elderly pts…

Objective response rate (ORR) in L+ patients was 47.5% (95% CI: 37.3, 57.8), median (m) DOR was 10.8 months (7.6, 18.5), and mPFS was 8.5 months...Tepotinib demonstrated durable clinical activity in patients with METex14 skipping NSCLC, as detected by LBx or TBx.

Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping...

n the Phase II VISION study, pts with METex14 skipping NSCLC received 500 mg QD (450 mg active moiety) oral tepotinib….Systemic best objective responses (BORs) were partial response (PR, n = 9), stable disease (SD, n = 3), and progressive disease (PD; n = 3)....Tepotinib demonstrated robust systemic activity in pts with METex14 skipping NSCLC with BM...

Pts with advanced, EGFR/ALK wild-type, METex14 skipping NSCLC received oral tepotinib... best OR across all prior therapies were two CRs (2.4%) and 24 PRs (28.9%) with a median longest DOR of 7 months (range 1–17). As of July 1, 2020, objective response rate (ORR) was 44.7% (95% CI: 36.7, 53.0), and median DOR was 11.1 months (95% CI: 8.4, 18.5).

In VISION, the largest study in patients with NSCLC harboring METex14 skipping, treatment with tepotinib showed durable clinical activity that was consistent across clinically relevant subgroups. Tepotinib demonstrated a safety profile consisting of mostly mild-to-moderate AEs with few treatment discontinuations.

In VISION, the largest study in patients with NSCLC harboring METex14 skipping, treatment with tepotinib showed durable clinical activity that was consistent across clinically relevant subgroups.

Pts with advanced EGFR/ALK wild-type and METex14 skipping NSCLC, detected by liquid or tissue biopsy, received oral tepotinib...Disease control rate (confirmed complete or partial response, or stable disease lasting ≥12 weeks) was 68.4% (51.3, 82.5) by IRC and 81.6% (65.7, 92.3) by INV.

Patients with advanced, EGFR/ALK wild-type, METex14 skipping NSCLC received oral tepotinib 500 mg once daily. Overall ORR (95% CI) in evaluable patients (n=146; 95 L+, 84 T+) was 44.5% (36.3, 53.0) by IRC and 54.8% (46.4, 63.0) by INV. ORR was consistent across subgroups, supporting robustness of efficacy (table). Tepotinib has durable clinical activity across subgroups and manageable toxicity in the largest study of patients with METex14 skipping NSCLC identified by L+ or T+.

Pts with advanced, EGFR/ALK wild-type, METex14 skipping NSCLC received oral tepotinib 500 mg once daily….Median PFS in L+ pts was 8.5 months (6.7, 10.9) by IRC and 8.5 months (5.8, 11.0) by INV, and in T+ pts was 11.0 months (7.8, 17.1) by IRC and 12.2 months (6.8, 19.6) by INV....Tepotinib has durable clinical activity across subgroups and manageable toxicity in the largest study of pts with METex14 skipping NSCLC identified by L+ or T+.

Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients.

VISION Cohort A enrolled pts with advanced EGFR/ALK wt, METex14 skipping NSCLC (asymptomatic brain metastases [BM] allowed), who received oral tepotinib 500 mg QD….151 pts received tepotinib (safety set); 99 L+/T+,66 L+,60 T+ pts comprised the 3 ITT sets with ≥6-month [m] follow-up....ORR was similar in L+ or T+ pts (table) or in T+L− pts (n=25): 40% [21–61] by IRC and 48% [28–69] by INV.Only 2 pts were T−L+.Outcomes were also comparable in pts with BM (n=11): IRC ORR 55% [23–83] & mPFS 10.9 m [8.0–ne]. 34/51 pts (67%) with matched BL/on-treatment L+ samples had deep MR strongly associated with clinical response: 32/34 pts (94%) with MR had disease control (INV), including 29/34 pts (85%) with OR; 2/34 pts had progressive disease....Tepotinib is a promising targeted therapy with durable clinical activity and manageable toxicity in pts with METex14 skipping NSCLC L+ or T+, including pts with BM.

Merck...announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has granted SAKIGAKE ’fast-track’ designation for its investigational molecule tepotinib for patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations.

To provide analysis of the intracranial activity of tepotinib in patients with METex14 skipping NSCLC with BM from the VISION study….Fifty-seven patients had baseline BM (Cohorts A+C, n = 313). Systemic ORR was 56.1% (95% CI, 42.4-69.3), and mDOR was 9.0 months (95% CI, 5.6-not estimable [ne])....Overall intracranial disease control rate was 88.4% (95% CI, 74.9-96.1) with an intracranial progression-free survival of 20.9 months (95% CI, 5.7-ne)...the MET tyrosine kinase inhibitor tepotinib showed robust systemic activity in patients with METex14 skipping NSCLC with BM.

Tepotinib 500 mg QD has promising activity in METΔex14+ NSCLC.

Following a poor response to chemotherapy, neoadjuvant tepotinib treatment was initiated in a 54-year-old female, never-smoker with NSCLC harboring a MET exon 14 alteration. Owing to a good response to tepotinib, surgical resection of the tumor was decided by the tumor board given the downgrading (from IIIB to IA1) and resulting in a major pathological response....This is the first spatial genomic characterization of the effect of tepotinib on the tumor and its microenvironment in a patient with NSCLC over time. Results from this case report highlight the impact of MET inhibition by tepotinib on the tumor immune microenvironment, likely enabling the recruitment of antigen-presenting cells for tumor clearance, while reducing the expression of tumor-promoting genes.

An 84-year-old man was diagnosed with non-small cell lung cancer (cT3N2M1c stage IVB)...the patient was found to be positive for the MET exon 14 skipping mutation with ArcherMET...treatment with tepotinib (500 mg/day) was started. After the start of tepotinib administration, his PS improved to 0-1 after 1 week, and the partial response was maintained for more than 12 months (Fig. 1E, F). No serious side effects other than mild lower leg edema were observed....This report shows that targeted treatment of the MET exon 14 skipping mutation may be beneficial, even for elderly patients with poor PS.

An 84-year-old man was diagnosed with non-small cell lung cancer (cT3N2M1c stage IVB)….He was found to be positive for the mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation, and tepotinib, a c-Met inhibitor, was started. His PS improved to 0-1 and partial response was maintained for 12 months or more.

...we tested if anti-EGF VacAbs could improve the antitumor activity of capmatinib, tepotinib and sotorasib in MET amplified, MET Δ14 and KRAS mutant non-small cell lung cancer (NSCLC) cell lines....In combination, anti-EGF VacAbs significantly enhanced the antitumor activity of capmatinib and tepotinib in EBC1 (MET-amplified) and Hs746T (METΔ14), potentiating the blockade of EGFR, Akt and Erk 1/2 phosphorylation. The same effects were observed when combining anti-EGF VacAbs with sotorasib in H2122 and H23 (G12C) cells.