Long-term Data in Patients with Metastatic Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping Alterations

Targeted oncology therapies are often used as part of the treatment paradigm, particularly for hard-to-treat cancers, such as metastatic non-small cell lung cancer (NSCLC).1 Tepotinib is an orally available, adenosine triphosphate (ATP)-competitive, type Ib mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor (TKI) that blocks MET-mediated signaling and can penetrate the blood-brain barrier.2 

In February 2021, TEPMETKO® (tepotinib) was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. Accelerated approval was based on the primary analysis of Cohort A of the pivotal ongoing Phase II VISION study (NCT02864992), the largest trial of its kind, which was published in The New England Journal of Medicine (NEJM) in May 2020.2-4

TEPMETKO recently received full approval from the FDA for the above indication.2 The conversion to full FDA approval was based on data from the pre-planned confirmatory long-term follow-up analysis of Cohort C of the VISION study. TEPMETKO is the only FDA-approved once-daily oral MET inhibitor and may be dose-reduced in order to help manage adverse reactions.2

VISION is a single-arm, open-label, multicenter, non-randomized, multicohort Phase II trial evaluating the efficacy and safety of TEPMETKO in adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations.2 The VISION study is the first trial to prospectively investigate outcomes in patients based on MET exon 14 skipping detected via liquid biopsy (LBx) and/or tissue biopsy (TBx).

The primary efficacy outcome measure was confirmed overall response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as evaluated by a Blinded Independent Review Committee (BIRC).2 An additional outcome efficacy measure was duration of response (DOR) by BIRC.2

In treatment-naïve patients (N=164), ORR was 57% and DOR ranged from 1.3 months to 56.6 months.2 Among previously treated patients (N=149), ORR was 45%, with DOR ranging from 1.4 months to 67.6 months.2

Data from the above long-term follow-up analysis of Cohort C (>18 months of follow-up) of the VISION study was published in JAMA Oncology in September 2023.5 This long-term follow-up analysis was designed to confirm findings from Cohort A (>35 months of follow-up).5 Learn more below about this published long-term follow-up analysis of the VISION trial, which includes objective response rate (ORR) and safety outcomes, and represents the largest data set for this patient population.

Selected Safety Information

TEPMETKO can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ILD/pneumonitis occurred in 2% of patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death.

Long-term Follow-up Analysis

Following the initial primary analysis of Cohort A of the VISION trial, a follow-up analysis from Cohort C (>18 months of follow-up) and a combined analysis of Cohorts A and C of at least 18 months follow-up was conducted to assess the long-term efficacy and safety of tepotinib. Cohort C was an independent cohort designed to confirm findings from Cohort A (>35 months of follow-up).

LIMITATIONS: Due to the single-arm design of the VISION trial for TEPMETKO, no formal statistical comparisons were conducted, and data were analyzed in a descriptive manner. For these reasons, results from this analysis should be interpreted with caution. The confirmatory Cohort C analysis was also limited by positive results in Cohort A being reported while enrollment was ongoing, which may have encouraged recruitment of patients in better clinical condition into Cohort C.

Results of the Long-term Follow-up Analysis5

The recent long-term follow-up analysis reported outcomes from Cohort C of the VISION trial, along with the combined outcomes from Cohorts A and C after at least 18 months of follow-up.

Cohorts A and C included 313 patients (50.8% female, 33.9% Asian, median [range] age 72 [41-94] years). ORR was 51.4% (95% CI, 45.8%-57.1%) (see the following figures).

In Cohort C (n = 161), an ORR of 55.9% (95%CI, 47.9%-63.7%) was reported across treatment lines, comparable to Cohort A (n = 152). In treatment-naive patients (Cohorts A and C; n = 164), ORR was 57.3% (95%CI, 49.4%-65.0%). In previously treated patients (n = 149), ORR was 45.0% (95%CI, 36.8%-53.3%).

ORR was consistent between patients in LBx (n=178) and TBx (n=208) populations (51.7% vs. 54.3%). Treatment-naïve patients in the TBx population (n=111) had an ORR of 58.6%. In previously treated patients in the TBx population (n=97), ORR was 49.5%.

Treatment-naïve patients in the LBx population (n=95) had an ORR of 58.9%. In previously treated patients in the LBx population (n=83), ORR was 43.4%.

The safety profile of TEPMETKO in the long-term follow-up was consistent with safety results observed in the primary analysis.

In Cohorts A and C, treatment-related AEs (TRAEs) occurred in 287 (91.7%) patients, and were Grade 3 or higher in 109 (34.8%); 105 patients (33.5%) had dose reduction and 46 (14.7%) discontinued due to TRAEs.

Peripheral edema was the most common TRAE (210 patients [67.1%]), with 35 (11.2%) experiencing grade 3 or higher peripheral edema. Other TRAEs occurring in more than 20% of patients included hypoalbuminemia (74 [23.6%]), nausea (73 [23.3%]), diarrhea (70 [22.4%]), and blood creatinine level increase (69 [22.0%]) and were mostly grades 1 to 2.

Summary5

The findings from Cohort C in this nonrandomized clinical trial supported the results from original Cohort A, which now has a follow-up of more than 35 months.

With updated results from a larger patient population, ORR increased, particularly in treatment-naïve patients with MET exon 14 skipping detection by TBx with an ORR of 58.6% compared with ORR of 46% previously reported by Paik et al. in NEJM.

In this long-term follow-up analysis, the researchers saw clinically meaningful outcomes with TEPMETKO, both in treatment-naïve and pretreated patients with MET exon 14 skipping NSCLC, particularly when considering outcomes with nontargeted therapies.

While results from this analysis should be interpreted with caution, given the above limitations, these findings, together with results from other studies, support the use of MET inhibitors across therapy lines for patients with MET exon 14 skipping NSCLC.

Indication

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

Important Safety Information

TEPMETKO can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ILD/pneumonitis occurred in 2% of patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death.

TEPMETKO can cause hepatotoxicity, which can be fatal. Monitor liver function tests (including alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin) prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or total bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO. Increased ALT/increased AST occurred in 18% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.7% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). The median time-to-onset of Grade 3 or higher increased ALT/AST was 47 days (range 1 to 262).

TEPMETKO can cause pancreatic toxicity in the form of elevations in amylase and lipase levels. Increased amylase and/or lipase occurred in 13% of patients, with Grade 3 and 4 increases occurring in 5% and 1.2% of patients, respectively. Monitor amylase and lipase levels at baseline and regularly during treatment with TEPMETKO and temporarily withhold, dose reduce, or permanently discontinue based on severity of the adverse event.

TEPMETKO can cause embryo-fetal toxicity. Based on findings in animal studies and its mechanism of action, TEPMETKO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the last dose.

Avoid concomitant use of TEPMETKO with certain P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

Fatal adverse reactions occurred in one patient (0.3%) due to pneumonitis, one patient (0.3%) due to hepatic failure, one patient (0.3%) due to dyspnea from fluid overload, one patient (0.3%) due to pneumonia, one patient (0.3%) due to sepsis, and one patient (0.3%) from unknown cause.

Serious adverse reactions occurred in 51% of patients who received TEPMETKO. Serious adverse reactions in >2% of patients included pleural effusion (6%), pneumonia (6%), edema (5%), general health deterioration (3.8%), dyspnea (3.5%), musculoskeletal pain (2.9%), and pulmonary embolism (2.2%).

The most common adverse reactions (≥20%) in patients who received TEPMETKO were edema (81%), nausea (31%), fatigue (30%), musculoskeletal pain (30%), diarrhea (29%), dyspnea (24%), rash (21%), and decreased appetite (21%).

Clinically relevant adverse reactions in <10% of patients who received TEPMETKO included ILD/pneumonitis, fever, dizziness, pruritus, and headache.

Selected laboratory abnormalities (≥20%) from baseline in patients receiving TEPMETKO in descending order were: decreased albumin (81%), increased creatinine (60%), decreased lymphocytes (57%), increased alkaline phosphatase (ALP) (52%), increased ALT (50%), increased AST (40%), decreased sodium (36%), decreased hemoglobin (31%), increased gamma-glutamyltransferase (GGT) (29%), increased potassium (26%), increased amylase (25%), decreased leukocytes (25%), decreased platelets (24%), and increased lipase (21%).

The most common Grade 3-4 laboratory abnormalities (≥2%) in descending order were: decreased lymphocytes (15%), decreased albumin (9%), decreased sodium (9%), increased GGT (6%), increased amylase (5%), increased lipase (5%), increased ALT (4.9%), increased AST (3.6%), and decreased hemoglobin (3.6%).

Please see the full Prescribing Information for TEPMETKO, and visit www.TEPMETKO.com.

References

  1. Araghi M, Mannani R, Heidarnejad Maleki A, et al.Recent advances in non-small cell lung cancer targeted therapy; an update review. Cancer Cell Int. 2023;11(23):162. doi:10.1186/s12935-023-02990-y
  2. TEPMETKO. Prescribing information. 2024; EMD Serono, Inc. Accessed April 10, 2024. https://www.emdserono.com/us-en/pi/tepmetko-pi.pdf
  3. Thomas M, Garassino M, Felip E, et al. Tepotinib in patients with MET exon 14 (METex14) skipping NSCLC: primary analysis of the confirmatory VISION cohort C. J Thorac Oncol. 2022;17(9; suppl):S9-S10. doi:10.1016/j.jtho.2022.07.024
  4. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407
  5. Mazieres J, Paik P, Garassino M, et al. Tepotinib treatment in patients with MET exon 14 skipping non-small cell lung cancer: long-term follow-up of the VISION phase 2 nonrandomized clinical trial. JAMA Oncol. 2023;9(9):1260-1266. doi:10.1001/jamaoncol.2023.1962

US-TEP-00750 05/24