Patients with EGFR mutant (m) MET-altered NSCLC receiving tepotinib with an EGFR tyrosine kinase inhibitor (TKI): A case series.
Authors: Le Xiuning , Eisert Anna , Hsia Te-Chun , Raut Nirmal Vivek , Ahmad Azura , Chan Oscar Siu Hong , De Bondt Charlotte , Farrugia David , Froesch Patrizia , González-Cao Maria , Hendriks Lizza , Hochmair Maximilian J. , Mazieres Julien , O’Sullivan Hazel , Samol Jens , van der Wekken Anthonie J. , Yang Tsung-Ying , Joshi Kirti , Vlassak Soetkin , Chang Gee-Chen 
Published: June 2023

9070 Background: Oncogenic activation of MET is a common mechanism of acquired resistance to EGFR TKIs in patients (pts) with EGFRm NSCLC, with MET amplification (amp) constituting the most frequent cause of bypass pathway activation. Currently, there are no approved targeted treatment options for these pts. Data from the Phase II INSIGHT (NCT01982955) and INSIGHT 2 (NCT03940703) studies indicate the combination of the selective MET TKI tepotinib plus an EGFR TKI has encouraging activity. We present a case series of pts with EGFRm MET-altered NSCLC receiving tepotinib plus an EGFR TKI outside of clinical trials. Methods: Access to tepotinib was provided to pts with EGFRm MET-altered NSCLC and resistance to EGFR TKIs through unsolicited compassionate use requests. All pts received tepotinib (500 mg [450 mg active moiety] once daily; first dose by Oct 2022) plus an EGFR TKI. Participating physicians provided case information up to January 2023. Results: 28 cases of pts with EGFRm NSCLC and MET alterations who received tepotinib plus an EGFR TKI were collated. 21 pts had METamp after EGFR TKI treatment, 5 had MET overexpression, and 2 had MET exon 14 skipping. Pts were aged 41–86 years, 15 were Asian, 13 were white, 19 were female, 8 had smoking history, and all had adenocarcinoma histology. METamp was detected by tissue biopsy in 17 pts, and liquid biopsy in 4 pts. Of 12 pts with METamp detected by FISH, gene copy number ranged from 5.3–33.4, and MET:CEP7 ratio from 0.7–15.1. EGFR TKIs received in combination with tepotinib were osimertinib (n = 21, 19 of whom received prior osimertinib), gefitinib (n = 6), dacomitinib (n = 1), afatinib (n = 1), with 1 pt received gefitinib followed by osimertinib. Tepotinib plus EGFR TKI was received by 9 pts as second-line, 9 as third-line, and 10 as fourth-or-later line. Median treatment duration was 8.8 months (range 1.3–20.6), with treatment ongoing in 13 pts (10 with current duration ≥10 months). Per the physician’s assessment, 25/28 pts (89%) had clinical benefit, 16 of whom (57%) were considered to have a partial response (PR). 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). The most reported adverse event (AE) considered related to tepotinib was edema in 15 pts (most commonly peripheral edema). Grade 3 AEs related to tepotinib were reported in 5 pts (including Grade 3 edema in 2 pts), 1 of whom discontinued the combination due to Grade 3 pneumonitis. Conclusions: 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. Clinical benefit was observed irrespective of MET alteration type in this case series of pts treated outside of clinical trials, with a large proportion of patients continuing to benefit from ongoing treatment.