Tepotinib Generates Superior Responses in Adenocarcinoma vs Non-Adenocarcinoma MET Exon 14 Skipping NSCLC

Tepotinib (Tepmetko) demonstrated a superior objective response rate (ORR) and disease control rate (DCR) in patients with adenocarcinoma MET exon 14 skipping non–small cell lung cancer (NSCLC) compared with those with non-adenocarcinoma disease, according to a subanalysis of the REAL-MET study.¹

Findings from a subanalysis of the study, presented during the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer, revealed that the ORR was 70.6% and 40.9% in patients with adenocarcinoma (n = 56) compared with non-adenocarcinoma (n = 23) MET exon 14 skipping NSCLC, respectively (P = .021). Specifically, in patients with adenocarcinoma, complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were reported in 0%, 64.3%, 23.2%, and 3.6%, respectively. These respective rates were 0%, 39.1%, 34.9%, and 21.7% in patients with non-adenocarcinoma. Additionally, the DCR was 96.1% vs 77.3% in those with adenocarcinoma and non-adenocarcinoma, respectively (P = .023).

“The present real-world analysis found that non-adenocarcinoma histology accounted for 29.1% of patients with MET exon 14 skipping NSCLC, with squamous cell carcinoma, sarcomatoid carcinoma, and adenosquamous carcinoma being the most common subtypes,” Ryota Saito, MD, of Yamanashi Prefectural Central Hospital in Japan, and coauthors wrote in a poster presentation of the data.

In February 2024, the FDA approved tepotinib for the treatment of patients with metastatic NSCLC harboring MET exon 14 skipping alterations.² The previous February 2021 accelerated approval of the agent was supported by data from the phase 2 VISION trial (NCT02864992).

What Were the Background, Design, and Patient Characteristics of the REAL-MET Study?

The retrospective, multicenter, real-world REAL-MET study was conducted at 6 centers in Japan, which included patients treated between August 2020 and December 2024 with MET exon 14 skipping NSCLC (n = 98).¹ In particular, the subanalysis portion of the study evaluated the efficacy and safety of tepotinib for the treatment of patients with non-adenocarcinoma—including squamous cell carcinoma and sarcomatoid carcinoma—and adenocarcinoma MET exon 14 skipping NSCLC.

Of note, the primary objectives included ORR per RECIST 1.1 criteria, progression-free survival (PFS), overall survival (OS), and safety.

Patients included on the study (n = 79) had adenocarcinoma (70.9%), squamous cell carcinoma (10.1%), sarcomatoid carcinoma (6.3%), adenosquamous carcinoma (5.1%), and not otherwise specified (NOS) subtypes (7.6%).

Furthermore, in patients with non-adenocarcinoma (n = 23) and adenocarcinoma (n = 56), the median age was 73 years (range, 65-89) and 75 (range, 55-90), respectively. More than half of patients in both groups were male (non-adenocarcinoma, 52.2%; adenocarcinoma, 64.3%), and the majority had an ECOG performance status of 0 or 1 (73.9%; 75.0%). More than half had stage IV disease (52.2%; 64.3%) and were smokers (52.2%; 60.7%). Most patients had PD-L1 expression of 50% or greater among those with non-adenocarcinoma histology (60.9%), with 37.5% having a PD-L1 expression of 50% or greater in those with adenocarcinoma histology. Moreover, most patients in both groups received tepotinib as first-line treatment (73.9%; 80.4%).

What Were the Additional Efficacy Data from the REAL-MET Study?

Among patients with squamous cell carcinoma (n = 8), the CR, PR, SD, and PD rates were 0%, 37.5%, 37.5%, and 25.0%, respectively; these rates in those with sarcomatoid carcinoma (n = 5) were 0%, 40.0%, 20.0%, and 40.0%, respectively. Patients with adenosquamous carcinoma (n = 4) had CR, PR, SD, and PD rates of 0%, 50.0%, 50.0%, and 0% respectively; these respective rates in those with NOS disease were 0%, 33.3%, 33.3%, and 16.7%.

“Median PFS and median OS after tepotinib therapy were superior in patients with adenocarcinoma than in those with non-adenocarcinoma histology, although the difference was not significant,” Saito and coauthors wrote in the poster presentation.

In particular, the median PFS was 5.3 months (95% CI, 3.8-6.8) in patients with non-adenocarcinoma compared with 10.4 months (95% CI, 8.0-12.8) in those with adenocarcinoma (HR, 0.77; 95% CI, 0.45-1.34; P = .35). The median OS was 16.0 months (95% CI, 3.8-6.8) compared with 24.4 months (95% CI, 15.2-33.5) in patients with non-adenocarcinoma and adenocarcinoma histologies, respectively (HR, 0.60; 95% CI, 0.31-1.14; P = .12).

In patients with squamous cell carcinoma, sarcomatoid carcinoma, adenosquamous carcinoma, and NOS disease, the median PFS was 4.7 months (95% CI, 2.7-6.8), 5.3 months (95% CI, 0.0-12.9), 8.1 months (95% CI, 0.4-15.9), and 3.6 months (95% CI, 1.4-5.8), respectively. Among patients with the respective disease histologies, the median OS was 16.0 months (95% CI, 0.3-31.7), 5.9 months (95% CI, 5.6-6.1), 30.8 months, and 13.4 months (95% CI, 10.6-16.1).

“Although PFS and OS were shorter in patients with non-adenocarcinoma than in those with adenocarcinoma, tepotinib demonstrated clinical efficacy in the former subgroup, suggesting that the drug is effective against MET exon 14 skipping NSCLC, including cases with a non-adenocarcinoma histology,” Saito and coauthors concluded in the poster presentation.

References

1. Saito R, Misawa K, Kato Y, et al. Efficacy of tepotinib against non-adenocarcinoma MET exon 14 skipping NSCLC: a subanalysis of the REAL-MET study. Presented at: International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract P3.12.09.
2. FDA approves tepotinib for metastatic non-small cell lung cancer. FDA. Updated February 16, 2024. Accessed September 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tepotinib-metastatic-non-small-cell-lung-cancer