
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01437-6
10.1016/j.esmoop.2024.103668
103668
Original Research
A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19-17)
Kang E.J. 1
Yang Y. 2
Lee S. 3
Kim Y.J. 4
Lim S.M. 5
Ahn M.-J. 6
Choi Y.J. 3
Lee Y. 7
Kim T.M. 8
Kim I. 9
Ahn H.K. 10
Jeung H.-C. 11
Lee S.I. 12
Oh S.Y. 13
Bae W.K. 14
Ryu H. 15
Park K.H. 3
Lee K.H. kihlee@chungbuk.ac.kr
2∗
1 Division of Hematology-Oncology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul
2 Division of Hematology-Oncology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University School of Medicine, Choengju
3 Division of Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul
4 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam
5 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul
6 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
7 Center for Lung Cancer, National Cancer Center, Goyang
8 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul
9 Division of Oncology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan
10 Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon
11 Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
12 Department of Internal Medicine, Dankook University College of Medicine, Cheonan
13 Division of Hematology and Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University College of Medicine, Yangsan
14 Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun
15 Division of Hematology-Oncology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Republic of Korea
∗ Correspondence to: Prof. Ki Hyeong Lee, Division of Hematology-Oncology, Department of Internal Medicine, Chungbuk National University Hospital, 776, 1sunhwan-ro, Seowon-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea. Tel: +82-043-269-6015 kihlee@chungbuk.ac.kr
29 8 2024
9 2024
29 8 2024
9 9 103668© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification.

Patients and methods

A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test.

Results

Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2.

Conclusions

Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.

Highlights

• Tepotinib demonstrated favorable antitumor activity in patients with solid cancers harboring METex14.

• Tepotinib demonstrated promising antitumor activity in patients with various cancers harboring MET amplification.

• The response rate of tepotinib was higher in patients with MET alteration detected by plasma NGS test at baseline.

• Adverse events with tepotinib were generally mild and manageable.

Key words

tepotinib
MET exon 14 skipping mutation
MET amplification
solid tumor
==== Body
pmcIntroduction

The role of c-mesenchymal epithelial transition factor (c-MET) signaling in tumorigenesis and treatment resistance in several cancers has been extensively investigated. The MET gene is located at 7q21-q31 on chromosome 7 and encodes a protein tyrosine kinase of the hepatocyte growth factor (HGF) receptor family.1 The binding of MET to its sole ligand, HGF, leads to homodimerization and transphosphorylation of intracellular tyrosine residues, triggering the activation of multiple downstream oncogenic signaling pathways, such as phosphatidylinositol 3-kinase-Akt, mitogen-activated protein kinase, and Janus kinase/signal transducer and activator of transcription.2

Various types of MET aberrations have been reported to be associated with carcinogenesis in solid tumors; however, MET exon 14 skipping is currently the only established target in non-small-cell lung cancer (NSCLC). Overexpression or amplification of MET has been extensively investigated in clinical trials; however, with variable or disappointing results, only high MET amplification remains a potential biomarker.3,4

Several MET inhibitors, including multi-kinase MET inhibitors and antibodies against MET or HGF have been investigated in numerous preclinical and clinical trials.5 Among these, two small-molecule MET-selective tyrosine kinase inhibitors (TKIs), tepotinib and capmatinib, have recently shown clinical benefits and manageable side-effects in patients with NSCLC harboring MET exon 14 skipping mutation (METex14).6,7 Currently, these two drugs are approved by the Food and Drug Administration and recommended as standard treatments for NSCLC with METex14.8

However, data on the use of MET TKIs in other cancers with METex14 or MET amplification are limited. In Korea, the K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise (K-MASTER project) was launched in June 2017 as a nationwide precision medicine oncology clinical trial platform. Targetable gene alterations were screened using next-generation sequencing (NGS) tests in patients with advanced solid tumors and patients with detected targetable gene alterations were assigned to appropriate clinical trials.9 As a biomarker-matched clinical trial of the K-MASTER study, this trial aimed to investigate the clinical efficacy of tepotinib, a selective MET TKI, in various solid cancers with METex14 or MET amplification detected using the NGS panel of the K-MASTER study or of each institution.

Patients and methods

Study design and patients’ eligibility

This investigator-initiated, prospective, open-label trial was conducted at 25 Korean Cancer Study Group-affiliated hospitals in Korea. This was a biomarker-matched clinical trial of the K-MASTER study involving Korean patients. Patients ≥19 years of age with pathologically confirmed solid cancer who were intolerant to standard treatment or had progressive disease after prior standard treatment for advanced disease were eligible. All patients had to submit METex14 status or MET gene copy number (CN) alterations in the archival or fresh tumor tissue specimen identified by the SNUH FIRST Cancer Panel or K-MASTER Cancer Panel, which were used for screening in the K-MASTER study. The results of the local NGS panel from each institution were also acceptable. The NGS reports of all patients suspected of having METex14 or MET amplification were submitted to the molecular steering committee and reviewed before making decisions regarding eligibility. For MET amplification, CN of ≥6.0 using the NGS panel was allowed and eligible for this study.

Other eligibility criteria included the presence of at least one measurable disease according to RECIST version 1.1; Eastern Cooperative Oncology Group performance status of 0-1; adequate organ functions including bone marrow, kidney, and liver; and life expectancy judged by the investigator for at least 3 months. Exclusion criteria were as follows: prior treatment with any agent targeting the HGF/c-MET pathway; prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment for EGFR-activating mutant NSCLC; patients who received local treatment within 4 weeks before the first administration of tepotinib (e.g. major surgery, radiation therapy, hepatic arterial embolization, transcatheter arterial chemoembolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) except for palliative radiotherapy which was completed at least 7 days before the first administration of tepotinib; patients with impaired cardiac function; pre-existing uncontrolled hypertension >150/90 mmHg despite adequate medical therapy; history of neoplasm other than current cancer; history of organ transplantation; known central nervous system or brain metastasis that is either symptomatic or untreated; clinically significant gastrointestinal bleeding; patients with a family history of long QT syndrome or taking any agent that is known to prolong QT/QTc interval or with a marked prolongation of QT/QTc interval; known human immunodeficiency virus infection; known or suspected drug hypersensitivity to any ingredients of tepotinib; female patients who were pregnant or lactating, or males and females of reproductive potential not willing or not able to employ a highly effective method of birth control/contraception; patients with concurrent treatment with anticancer therapy; previous anticancer treatment-related toxicities not recovered to baseline or grade 1 (except alopecia) before administration of tepotinib; and clinically significant third space fluid accumulation (despite the use of diuretics), e.g. uncontrolled pleural effusion or ascites and uncontrolled venous or arterial thromboembolism.

Treatment

Tepotinib was administered orally at 500 mg once daily without an off day until disease progression, occurrence of unacceptable toxicities, or withdrawal of consent. Each cycle lasted 21 days. Dose modifications or delays in the study drug administration were carried out based on the worst grade of toxicity according to the protocol. When grade 3 or 4 toxicities were observed, tepotinib treatment was discontinued until the toxicities resolved to grade 1 or lower. Tepotinib could be re-administered with one dose level reduction. The reduced dose was 250 mg once daily. When administration of the study medication was delayed, all evaluations, including tumor evaluation, adhered to the original schedule. When the administration of the study medication was either delayed for 3 weeks or more or the medication was discontinued because of toxicity, the patient was withdrawn from the study.

Plasma circulating tumor DNA sequencing

Serial plasma circulating tumor DNA (ctDNA) sequencing was planned for three occasions: before the administration of tepotinib initiation (baseline), after two cycles of treatment (T1), and at the time of disease progression (T2). A DNA NGS library was constructed using an c NGS DNA Library Prep Kit. Solution-based target enrichment was carried out at IMBdx, Inc. (Seoul, South Korea), using the AlphaLiquid® 100 target capture panel. The targeted gene panel included 118 cancer-related genes and was designed to cover all gene exons (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.103668). Captured DNA libraries were sequenced using the Illumina NovaSeq 6000 platform (Illumina, San Diego, CA) in 2 × 150 bp paired-end mode. All sequencing reads from the samples were generated in bcl format and demultiplexed into fastq files using the Burrows–Wheeler Aligner (BWA, version 0.7.17-r1188). Initial assessments were conducted based on fragment counts derived from both single-stranded consensus sequences (SSCS) and duplex consensus sequences (DCS) using fgbio tools (http://fulcrumgenomics.github.io/fgbio, accessed on 3 February 2022). The molecular depth (X) with an average sequencing depth of 56 603X was approximated by adding the SSCS and DCS counts within the coding sequence region. Subsequently, these assessments were scored using a machine learning model that differentiated genuine from spurious variants. Subsequently, they were annotated for functional effect prediction. We applied a cut-off for cfDNA mutations of variant allele frequency (VAF) ≥0.1% and altered the DCS count ≥4. A few unsatisfactory variants that showed high VAF at other time points were rescued. Unsatisfactory variants refer to mutations that did not meet the conditions of VAF >0.1% and DCS count ≥4 at a given time point. Somatic variants were distinguished from germline variants and clonal hematopoiesis of indeterminate potential variants (ATM, CBL, CHEK2, IDH2, JAK2, MPL, and U2AF1) in matched peripheral blood mononuclear cell samples.10, 11, 12 To identify CN alterations, we used a pre-established sequencing depth profile of 50 healthy individuals, specifically targeting exonic regions covered by the panel as a reference. The log2 ratios were computed using a CN variation kit.13 We characterized CN gains as instances where CN ≥ 4, in conjunction with applying statistical criteria that required P values to be <0.01.

Statistical analysis

At first, we designed a basket study so that patients with all kinds of solid tumors with MET alterations could participate in this study. We planned this trial with two strata (NSCLC and other cancers) and planned a phased decision of number of patients in two strata by interim analysis using an adaptive Bayesian hierarchical model design. We assumed ɣ = 0.55 (the prior probability that the drug is active in any particular stratum) and λ = 0.6 (the probability that the activities are perfectly correlated across strata). The target response rate was assumed to be 60% (p_hi), and a rate of 20% (p_lo) or below was considered futile. We set the threshold posterior probability of activity as 0.8 for the two strata. Therefore, accrual to each stratum was planned to be curtailed following interim analysis if the posterior probability is below 0.2 after analysis of 30 patients. In addition, accrual to each stratum were planned to be continued if the posterior probability is between 0.2 and 0.8. In case the posterior probability is higher than 0.8 of each stratum, accrual to each stratum was supposed to discontinue regarding the result of this stratum as success. The prevalence of each stratum was assumed as same for NSCLC and other cancer types. This design yielded a true-positive rate of 0.99, false-negative rate of 0.01, true-negative rate of 0.96, false-positive rate of 0.04, and the probability of no false positives when all strata are negative: 0.96. Therefore, the expected minimal sample size of two strata was 30 and maximum sample size of two strata was 100.

However, two global prospective studies on capmatinib and tepotinib were reported and got accelerated approval by Food and Drug Administration. Moreover, the very low detection rate of METex14 and MET amplification caused slow accrual, therefore we re-planned the number of study participants and amended the protocol.

Therefore, we revised the statistical plan for the single-arm phase II study. Considering heavily pre-treated patients with any solid tumors who can be included in this study, we set the estimation of H0 = 0.2 and H1 = 0.4 with one-side type I error of 5% at 85% power and the target of the total number of participants as 35 patients.

The progression-free survival (PFS) was defined as the time from the date of the first dosing to the date of disease progression or death. The overall survival (OS) was defined from the date of the first dosing to the date of death. The probability of survival and the duration of response (DoR) were estimated with the Kaplan–Meier method. Comparisons of survival between the different groups were made with log-rank tests. All analyses were carried out with SPSS for Windows 21.0 (IBM Corporation, Armonk, NY). Data were analyzed in April 2023.

Endpoints and assessment

The primary endpoint was the objective response rate (ORR) as determined by the investigators in accordance with RECIST 1.1.14 Secondary endpoints included PFS, DoR, OS, disease control rate (DCR), and toxicities. All patients were included in an intention-to-treat analysis. Non-assessable patients were excluded from the per-protocol analyses. The efficacy analysis was carried out on a per-protocol basis.

Response evaluations were carried out using RECIST 1.1 and carried out every 6 weeks until disease progression. Tumor assessment was carried out every 6 weeks in both arms. If disease progression was suspected due to symptomatic aggravation, an earlier image assessment was carried out based on each investigator’s decision. Adverse events (AEs) were monitored and severity recorded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0, during the treatment phase and for 28 days after the last dose of tepotinib.

Ethical consideration

This trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, and National Policies on Bioethics and Human Biological Specimens. This trial is registered at ClinicalTrials.gov (NCT04647838). The study protocol was approved by the institutional review board of each participating institution (IRB number of the Chungbuk National University Hospital: 2019-09-015-002). Written informed consent was obtained from all patients before participation.

Results

Patient and disease characteristics

Thirty-five patients were enrolled in this study between March 2020 and March 2022. The baseline patient characteristics are shown in Table 1. Among these, 68.6% (n = 24) of patients had NSCLC and 31.4% (n = 11) of patients had other cancers, which included gastroesophageal cancer (n = 2), head and neck cancer (n = 2), glioblastoma multiforme (n = 2), breast cancer, colon cancer, melanoma, and cholangiocarcinoma. Two patients with lung adenocarcinoma had both METex14 and MET amplifications. These patients were allocated to the METex14 group for efficacy analysis. MET exon 14 skipping was observed almost exclusively in NSCLC (n = 21) but was also observed in other cancers (n = 3), including gastric, nasopharyngeal, and tonsillar cancers. The median number of lines of previous anticancer treatment was 1 (range 0-5). Fifteen patients (42.9%) in the study population were pre-treated with at least two previous systemic treatments before inclusion in this study.Table 1 Baseline characteristics of study participants

Characteristics	All	MET exon 14 skipping mutation	MET amplification	
No. of patients	35	24a	11	
Age				
 Median (range), years	70 (32-82)	74.5 (48-82)	56.0 (32-70)	
 ≥65years, n (%)	19 (54.3)	18 (75.0)	1 (9.1)	
Female, n (%)	18 (51.4)	14 (58.3)	4 (36.4)	
ECOG performance status, n (%)				
 0	8 (22.9)	5 (20.8)	3 (27.3)	
 1	27 (77.1)	19 (79.2)	8 (72.7)	
Smoking history, n (%)				
 Never smoked	20 (57.1)	16 (66.7)	4 (36.4)	
 Cigarette smoker	7 (20.0)	5 (20.8)	2 (18.2)	
 Current smoker	3 (8.6)	2 (8.3)	1 (9.1)	
 Unknown	5 (14.3)	1 (4.2)	4 (36.4)	
Primary tumor, n (%)				
 NSCLC	24 (68.6)	21 (87.5)	3 (27.3)	
 Others	11 (31.4)	3 (12.5)	8 (72.7)	
Brain metastases at baseline, n (%)	4 (11.4)	4 (16.7)	0 (0.0)	
Number of previous lines of anti-neoplastic therapy, n (%)				
 0	2 (5.7)	2 (8.3)	0 (0.0)	
 1	17 (48.6)	14 (58.3)	3 (27.3)	
 2	8 (22.9)	4 (16.7)	4 (36.4)	
 ≥3	7 (20.0)	4 (16.7)	3 (27.3)	
ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer.

a Two NSCLC patients harboring both METex14 and MET amplification were included in this group.

Efficacy

The efficacy population included subjects who met all the inclusion criteria and none of the exclusion criteria, received at least one dose of the investigational product, and underwent tumor response evaluation as per RECIST (Ver. 1.1) guidelines. Of all the included subjects, response evaluation was conducted in 33 assessable patients (23 in the METex14 arm and 10 in the MET amplification arm; Table 2). At a median follow-up of 19 months, the ORR was 57.6% for all patients, 52.1% for those with METex14, and 70% for those with MET amplification. The DCR was 90.9% in all patients (Table 2). The median DoR was 14.5 months [95% confidence interval (CI) 7.1-21.9 months] for all patients. The majority of patients (78.8%) experienced tumor shrinkage, and 94.7% of patients who showed partial response started this response within 5 months after starting treatment (Figure 1A and B).Table 2 Summary of tepotinib efficacy results

	All	MET exon14 skipping mutation	MET amplification	
Response	(n = 33)	NSCLC (n = 20)	Other cancers (n = 3)	NSCLC (n = 3)	Other cancersa (n = 7)	
Best response, n (%)						
 Complete response	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	
 Partial response	19 (57.6)	12 (60.0)	0 (0.0)	2 (66.7)	5 (71.4)	
 Stable disease	11 (33.3)	8 (40.0)	1 (33.3)	1 (33.3)	1 (14.3)	
 Progressive disease	3 (9.1)	0 (0.0)	2 (66.7)	0 (0.0)	1 (14.3)	
Objective responseb, n (%)	19 (57.6)	12 (60.0)	0 (0.0)	2 (66.7)	5 (71.4)	
Disease controlc, n (%)	30 (90.9)	20 (100.0)	1 (33.3)	3 (100.0)	6 (85.7)	
Duration of response, months	14.5 (7.1-21.9)	14.5 (7.1-21.9)	5.8d (3.7-7.9)	
14.5 (7.1-21.9)	NA	1.0 (NA)	7.0 (NA)	
 Progression-free survival, months (95% CI)	8.0 (4.5-11.5)	9.0 (1.6-13.6)	7.0 (1.5-12.5)	
Overall survival, months (95% CI)	14.0 (7.8-20.2)	17.0 (NA-NA)	10.0 (5.8-14.2)	
The data cut-off date was 28 February 2023.

CI, confidence interval; GBM, glioblastoma multiforme; NA, not applicable; NSCLC, non-small-cell lung cancer.

a Patients with colon cancer, gastric cancer, breast cancer, melanoma, or cholangiocarcinoma showed partial response. One patient with GBM showed stable disease and one patient with breast cancer showed progressive disease.

b Overall response was defined as a complete response or partial response.

c Disease control was defined as a complete response, partial response, stable disease, or non-complete response or non-progressive disease.

d Mean value (unable to calculate median).

Figure 1 Response and survival of study participants. (A) Maximum change in tumor size from baseline in individual patients. (B) Swimmer’s plot of treatment durations. (C) Progression-free survival in study patients. (D) Overall survival in study patients. CI, confidence interval; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival.

Interestingly, for the METex14 group, a response was observed only in patients with NSCLC with an ORR of 60%, and no response was observed in other cancers. In contrast to the METex14 group, a response was observed in the MET amplification group, regardless of the primary cancer. However, the DoR of the MET amplification group was shorter than that in the METex14 group, with a mean of 5.8 months (95% CI 3.7-7.9 months) while the median DoR of the METex14 group was 14.5 months (95% CI 7.1-21.9 months).

The median PFS was 8.0 months (95% CI 4.5-11.5 months) and the median OS was 14.0 months (95% CI 7.8-20.2 months) in all efficacy populations (Table 2; Figure 1C and D). For the METex14 group, the median PFS was 9.0 months (95% CI 4.6-13.6 months), and the median OS was 17 months [95% CI not applicable (NA)-NA] (Table 2). In the patients with NSCLC with METex14, the median PFS was 9.0 months (95% CI 4.7-13.4 months), and the median OS was not reached (Supplementary Figure S1A and B, available at https://doi.org/10.1016/j.esmoop.2024.103668). For MET amplification, the median PFS was 7.0 months (95% CI 1.5-12.5 months) and the median OS was 10.0 months (95% CI 5.8-14.2 months) (Table 2). Among patients with MET amplification, those with gastric cancer with a gene copy number (GCN) of 18 showed the longest PFS of 19 months.

Toxicities

A total 35 patients were included in safety analyses. The median number of tepotinib cycles received was 9.0 cycles (range 1-44 cycles). The average dose intensity of tepotinib was 88.4% (with a standard deviation of 16.6%) and the median was 99.2% (range 47.7%-100%). Eleven patients (31.4%) experienced dose interruption, 12 (34.2%) experienced dose reduction, and 5 (14.2%) discontinued tepotinib due to AEs.

An overall summary of the AEs reported during this study is presented in Table 3. Any-grade AEs were reported in 32 (91.4%) patients and were grade 3 or higher in 18 (51.4%); the most frequently reported AE was peripheral edema (40.3%), with three patients (8.6%) experiencing grade 3. Other AEs occurred in ≥20% of the patients, followed by fatigue (28.6%), elevated transaminase (22.9%), anorexia (22.9%), diarrhea (20.0%), dyspepsia (20.0%), and pneumonia (20.0%) mostly of grades 1 and 2 (22.9%). For serious adverse events (SAEs), seven SAEs were considered to be treatment related. Generalized edema (5.7%), pleural effusion (2.9%), pneumonia (2.9%), interstitial pneumonitis (2.9%), enteritis (2.9%), and oral mucositis (2.9%) grade 3 were reported as treatment-related SAEs.Table 3 Summary of adverse events during study period

	Safety population (n = 35)	
Adverse events	All grade	Grade 1 or 2	Grade 3	Grade 4-5	
Any adverse events, n (%)	32 (91.4)	28 (80.0)	16 (45.7)	2 (5.7)	
Nausea	6 (17.1)	6 (17.1)	0	0	
Vomiting	3 (8.6)	3 (8.6)	0	0	
Anorexia	8 (22.9)	8 (22.9)	0	0	
Constipation	4 (11.4)	4 (11.4)	0	0	
Diarrhea	7 (20.0)	6 (17.1)	1 (2.9)	0	
Dyspepsia	7 (20.0)	7 (20.0)	0	0	
Abdominal pain	6 (17.1)	5 (14.3)	1 (2.9)	0	
Oral mucositis	4 (11.4)	3 (8.6)	1 (2.9)	0	
Dyspnea	3 (8.6)	3 (8.6)	0	0	
Myalgia	2 (5.7)	2 (5.7)	0	0	
Arthralgia	3 (8.6)	3 (8.6)	0	0	
Asthenia, fatigue	10 (28.6)	9 (25.7)	1 (2.9)	0	
Itching	6 (17.1)	6 (17.1)	0	0	
Rash	7 (20.0)	7 (20.0)	0	0	
Hand-foot syndrome	3 (8.6)	2 (5.7)	1 (2.9)	0	
Nail change	1 (2.9)	1 (2.9)	0	0	
Hyperkeratosis	3 (8.6)	3 (8.6)	0	0	
Alopecia	2 (5.7)	2 (5.7)	0	0	
Sweating	3 (8.6)	3 (8.6)	0	0	
Rhinorrhea	1 (2.9)	1 (2.9)	0	0	
Generalized edema	5 (14.3)	4 (11.4)	1 (2.9)	0	
Peripheral edema	14 (40.0)	11 (31.4)	3 (8.6)	0	
Pleural effusion	3 (8.6)	2 (5.7)	1 (2.9)	0	
Pneumonitis	3 (8.6)	2 (5.7)	1 (2.9)	0	
Pneumonia	7 (20.0)	2 (5.7)	3 (8.6)	2 (5.7)	
Urinary tract infection	3 (8.6)	3 (8.6)	0	0	
Laboratory abnormalities					
 Creatinine elevation	4 (11.4)	4 (11.4)	0	0	
 Amylase/lipase elevation	4 (11.4)	4 (11.4)	0	0	
 Hypoalbuminemia	6 (17.1)	5 (14.3)	1 (2.9)	0	
 Anemia	4 (11.4)	3 (8.6)	1 (2.9)	0	
 Thrombocytopenia	1 (2.9)	1 (2.9)	0	0	
 Neutropenia	2 (5.7)	0	2 (5.7)	0	
 Transaminase elevation	8 (22.9)	8 (22.9)	0	0	

Two patients experienced pneumonia after starting tepotinib treatment, and one died due to pneumonia. However, the investigators concluded that the tepotinib treatment was not associated with this AE. Common AEs leading to dose reduction were peripheral edema, diarrhea, pneumonitis, transaminase elevation, pleural effusion, and hand-foot syndrome.

Genomic analysis

Plasma ctDNA NGS testing at baseline was conducted in 28 patients. Among them, METex14 or MET amplification was detected in 18 patients. The sensitivity of plasma NGS testing for METex14 was 63% and that for MET amplification was 60%. Amplification of MET was detected in six patients, including one patient with both MET amplification and METex14. During the baseline plasma NGS, METex14 was detected in 13 patients. Among them, one patient had METex14 in plasma NGS, whereas MET amplification was detected in tissue NGS. In the baseline plasma NGS, the most frequently identified mutation, other than MET, was TP53 (18/28, 64.3%). Mutations in PIK3CA, ATM, and MYCN were also identified. All patients showed microsatellite stability and the median blood tumor mutational burden was 3.15 mut/Mb (Figure 2).Figure 2 Baselinemolecular profiles of plasma NGS test and response to treatment. NGS, next-generation sequencing; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

Interestingly, there was a difference in ORR between the MET alteration-detected and non-detected groups in baseline plasma NGS. The ORR of 18 patients with METex14 or MET amplification detected by baseline plasma NGS was 72.2%, whereas that of 10 patients without MET dysregulation was 30%.

Co-mutations of TP53 in tissue or blood NGS tests at baseline were found in 21 patients (60.0%). The ORR of patients with co-mutations on TP53 was not inferior at 57.9%; however, the patients with TP53 mutation demonstrated a trend of poor outcomes in terms of median PFS and OS. The median PFS in patients with TP53 was 6.0 months whereas the median PFS in patients without TP53 mutation was 11 months (P = 0.057). The median OS of patients with TP53 mutations was 12 months, whereas that of patients without TP53 mutations was not reached (P = 0.061).

Discussion

In this study, tepotinib showed favorable efficacy in patients with advanced solid cancer with METex14 or MET amplification, as identified by tissue NGS. The response rate determined by investigator assessment was 57.6% for all patients, the median PFS was 8.0 months, and the median OS was 14 months. Even though patients with diverse primary cancers were included and 42.9% of the patients in this study population were heavily pre-treated with at least two previous systemic treatments before inclusion in this study, the overall results on clinical efficacy were comparable to those of global prospective clinical trials.6,7,15

In this study, the ORR and median PFS with tepotinib in patients with NSCLC with METex14 were 60% and 9.0 months, respectively. In the VISION study, a prospective global phase II study that investigated the efficacy of tepotinib in patients with NSCLC with METex14, the ORR was 56%, and the median PFS was 8.5 months, according to investigator assessment.6 Additionally, analyses of 15 Japanese patients from the VISION study demonstrated an ORR of 60.0% and a median PFS of 11.0 months, respectively [95% CI 1.4-not evaluable (NE)]. In the GEOMETRY mono-1 study, the ORR of capmatinib was 68% and PFS was 12.4 months in patients with NSCLC harboring METex14 who had not received treatment previously. The ORR was 41% and the PFS was 5.4 months in patients with METex14 who were previously treated.7 In a phase II study of savolitinib, the ORR was 53.2% and the median PFS was 6.9 months in Chinese patients with NSCLC with METex14.15

The METex14 mutation in solid tumors other than NSCLC is rarely observed, and there have been several reports suggesting the in vitro activity of MET inhibitors.4,16, 17, 18, 19 However, the clinical effects of MET inhibitors in these patients have rarely been reported. Three patients with extrapulmonary malignancies, each with gastric, nasopharyngeal, and tonsillar cancers, with METex14 were included in this study. Interestingly, all three patients showed no response to tepotinib, and the disease progressed rapidly. Although the number of patients was notably small, these findings render the therapeutic role of tepotinib questionable for cancers other than NSCLC. Our study also revealed the clinical effect of tepotinib on several cancers with MET amplification. In our study, 31.4% of all included patients had MET amplification with a GCN of at least 6. Particularly, among patients with NSCLC with MET amplification, patients with treatment resistance-related MET amplification after other TKI treatments were not included. For the efficacy of MET TKI in NSCLC with MET amplification, various results have been reported. In a study where the efficacy of crizotinib was evaluated in MET-amplified NSCLC, the response rate was 40.0% with MET GCN ≥6 in tissue NGS testing.20 Capmatinib shows a poor response in MET-amplified NSCLC. In the GEOMETRY mono-1 study, the ORR of capmatinib was 29% in previously treated patients and 40% in treatment-naïve patients with a MET GCN of at least 10 and 40% in treatment-naïve patients. For Cohort 1b with MET GCN 6-9, the response was decreased at 12% and the PFS was 2.7 months; therefore, it was closed after the interim analysis in the study.7 Tepotinib demonstrated an ORR of 41.7% for patients with NSCLC with MET amplification in liquid biopsy (GCN ≥2.5) and 71.4% (5/7) for treatment-naïve patients. However, PFS was only 4.2 months (95% CI 1.4 months-NE).21 In our study, a relatively high ORR of ∼70% was observed for NSCLC and other cancers with MET amplification (n = 10). Among these, two out of three patients with NSCLC showed partial response; however, consistent with previous reports, the DoR or PFS was notably short. In contrast, patients with other cancers with MET amplification showed a similar ORR (5/7) with a PFS of 8 months, which could be considered favorable given the extensive prior treatment. In our study, the patient with gastric cancer with MET amplification of GCN 18 showed a long PFS of 18 months. Considering MET amplification as a potential treatment target for gastric cancer, further investigations into the development of MET TKIs, particularly for MET-amplified gastric cancer, are anticipated.22,23

For study enrollment, only tissue-based NGS test results were included. However, we planned to test blood-based NGS from the start of the study treatment and follow it sequentially to investigate gene alterations related to treatment response or resistance. In the baseline testing, targetable MET alterations were detected in 18 of the 28 patients (64.3%) in baseline plasma NGS. In addition, our study revealed that patients with MET alterations detected using plasma NGS at baseline showed a profoundly better response rate than those without such detection. Similar to other studies that have reported the potential role of monitoring EGFR mutations or anaplastic lymphoma kinase (ALK) alterations in ctDNA as predictors of treatment response, we suggest that the detection of plasma MET alterations could be used as a predictor of response to tepotinib.24, 25, 26

In this study, concomitant TP53 mutations with MET alterations showed a trend toward poor PFS and OS in patients treated with tepotinib. Several studies have reported that concurrent TP53 mutations are associated with short treatment duration and OS in patients with EGFR or ALK mutations who were treated with TKIs.27, 28, 29 Although the number of patients in this trial was limited, this finding suggests the universal nature of concurrent TP53 mutations as negative regulators of targeted therapy.

The safety profiles of tepotinib in our study were comparable to those of previous clinical trials, and AEs were mostly grade 1 or 2. In this study, the most common treatment-related AE was edema, including peripheral and generalized edema, in 54.3% of the population, and 11.5% of the patients experienced grade 3.

Our study has some limitations. We terminated the study earlier than planned because of the low MET detection rates in NGS testing and other competitive clinical trials of new MET TKIs conducted at several institutions. Therefore, the efficacy of tepotinib in small populations, such as other cancer groups or MET amplification groups, needs to be evaluated in large-sized trials. However, this study has the strength of evaluating the response and safety of tepotinib in Korean patients with cancer, regardless of cancer type or in patients with cancer harboring METex14 or MET amplification. Notably, this study offers novelty by presenting the first report of clinical outcomes with tepotinib in cancers other than NSCLC harboring METex14. In addition, we elucidated the potential role of MET alterations in plasma NGS as a method to detect METex14 or MET amplification in patients with cancer, as well as a potential predictor of therapeutic response.

In conclusion, we confirmed the efficacy and safety of tepotinib for patients with various solid cancers harboring METex14 or MET amplifications whose disease progressed during prior standard treatment. However, this anti-METex14 effect was not confirmed for tumors other than NSCLC. Tepotinib also showed promising activity against various cancers with MET amplification. Further clinical studies of the efficacy of targeted MET amplification are required to validate the efficacy of tepotinib.

Supplementary data

Supplementary Table S1

Supplementary Figure S1

Acknowledgements

The authors thank the patients, their families and caregivers, and all investigators involved in this study.

Funding

This work was supported by a grant from the Korea 10.13039/100018696 Health Technology R&D Project through the 10.13039/501100003710 Korea Health Industry Development Institute , funded by the Ministry of Health and Welfare, Republic of Korea [grant number HI17C2206]; the National R&D Program for Cancer Control through the National Cancer Center (NCC), funded by the 10.13039/100009647 Ministry of Health & Welfare, Republic of Korea [grant number HA22C0012]; and partially funded by Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). Tepotinib was provided by Merck KGaA (Darmstadt, Germany). The health care business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) reviewed this manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.

Disclosure

SL received research funding from Jeil Pharmaceutical Co and Yuhan and reported stocks of Pfizer and Celegene (shares of a publicly traded company equal or less than $50 000 in value, or an equity interest in a privately held company equal or less than 5%). SML received research funding from Yuhan, and Janssen; research support to institution from AstraZeneca, Boehringer Ingelheim, GSK, Roche, Hengrui, BridgeBio Therapeutics, Oscotec, and Daiichi-Sankyo; and served as a consultant for AstraZeneca, Boehringer Ingelheim, Lilly, Takeda, J Ints Bio, BMS, MSD. YL received consulting fee from Roche, Merck, Yuhan, and Bayer. MJA received honoraria from AstraZeneca, BMS, MSD, Lilly, Merck, ONO, Roche, TAKEDA,YUHAN, Amgen and served as an advisor or consultant for AstraZeneca, BMS, ONO, Takeda, Lilly, Merck, MSD, Amgen, Novartis, Roche, Yuhan, Arcus, Pfizer, Daiichi-Sankyo, Alpha pharmaceutical, Voronoi, Eutilex. TMK served as an advisor or consultant for Amgen, AstraZeneca/MedImmune, Boryung, Daiichi-Sankyo, HK inno.N, IMBdx. Inc., Janssen, Novartis, Regeneron, Roche/Genentech, Samsung Bioepis, Takeda, and Yuhan. KHP reports speaker’s engagement from Novartis and Roche; steering committee/advisory board role from 10.13039/100004325 AstraZeneca , 10.13039/100018592 Celltrion , 10.13039/501100002973 Daiichi-Sankyo , Eli Lilly, and Pfizer; stocks/shares from IMBdx, OncoMASTER, and SolBio; institutional research grant from AstraZeneca; licensing fees from Aston Sciences; non-remunerated research support from Boryung, Celcuity, Celltrion, Eli Lilly, and IMBdx. KHL received research funding from Merck and served as an advisor or consultant for BMS, MSD, AstraZeneca, Pfizer, and Lilly. All other authors have declared no conflicts of interest.
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