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1. Awad MM, et al. J Clin Oncol 2016;34:721–30; 2. Frampton GM, et al. Cancer Discov 2015;5:850–9; 3. Cancer Genome Atlas Research Network. Nature 2014;511:543–50; 4. Paik PK, et al. Cancer Discov 2015;5:842–9; 5. Tong JH, et al. Clin Cancer Res 2016;22:3048–56; 6. Pruis MA, et al. Lung Cancer 2020;140:46–54; 7. Falchook GS, et al. Clin Cancer Res 2020;26:1237–46; 8. Ryoo BY, et al. Ann Oncol 2018;29:ix58–ix9; 9. Decaens T, et al. Ann Oncol 2018;29:ix48; 10. Paik PK, et al. Presented at ASCO 2019. Poster 341.

Acknowledgments: The authors would like to thank patients, all investigators and co-investigators, and the study teams at all participating centers and at Merck KGaA, Darmstadt, Germany. The trial was sponsored by Merck KGaA, Darmstadt, Germany. Medical writing and editorial assistance was provided by Syneos Health, UK, and funded by Merck KGaA, Darmstadt, Germany.Disclosures: Xiuning Le: consulting or advisory role – AstraZeneca, Eli Lilly, EMD Serono, research funding – Eli Lilly, Boehringer Ingelheim. Enriqueta Felip: advisory/consultancy – Pfizer, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Guardant Health, Novartis, Takeda, AbbVie, Blue Print Medicines, Lilly, Merck KGaA, Merck Sharp & Dohme, Janssen, Samsung; speaker bureau/expert testimony – Pfizer, Roche, AstraZeneca, Bristol-Myers Squibb, Novartis, Takeda, Lilly, Merck Sharp & Dohme, Medscape, prIME Oncology, Touchtime; research grant/funding (self) – Fundación Merck Salud, Grant for Oncology Innovation (GOI); Officer/Board of Directors – Grifols (Independent Member). Remi Veillon: consulting or advisory role – MSD, Pfizer, Novartis; speaker bureau – MSD, BMS, Roche; research funding – Roche, Takeda, AbbVie, Merck, BMS. Hiroshi Sakai: none. Alexis B. Cortot: research funding – Merck KGaA, Novartis; honoraria – AstraZeneca, BMS, Novartis, MSD, Pfizer, Roche, Takeda; consulting or advisory role – AstraZeneca, BMS, Novartis, Pfizer, Roche, Takeda; travel expenses – AstraZeneca, MSD, Novartis, Pfizer, Roche, Takeda. Marina Chiara Garassino: advisory role – Boehringer Ingelheim, Novartis, Pfizer, Seattle Genetics, Daiichi Sankyo, Sanofi; invited speaker – Otsuka Pharma, Incyte; speaker, advisory role – Eli Lilly, BMS, Roche, Celgene, Takeda; speaker, advisory role, steering committee – MSD, AstraZeneca; honoraria for speaker/advisory role – Takeda. Julien Mazieres: advisory boards – Roche, BMS, MSD, AstraZeneca, Pfizer, Novartis. Santiago Viteri: consulting or advisory role – AbbVie, BMS, Roche; speaker’s bureau fees – BMS, MSD, Roche; travel expenses – Roche, OSE Pharma, BMS, Merck. Helene Senellart: none. Jan Van Meerbeeck: advisor – Amgen; travel expenses – BMS. Niels Reinmuth: consultant/advisor – AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Merck KGaA, MSD, Pfizer, Roche, Takeda; speaker bureau fees – Boehringer Ingelheim, AstraZeneca, Roche, Takeda, AbbVie, MSD, BMS, Pfizer; travel expenses – Boehringer Ingelheim, AstraZeneca, Roche, Takeda, BMS. Pierfranco Conte: research funding (self) – Novartis, Roche, Merck KGaA; speaker bureau fees (self) – Novartis, AstraZeneca, Roche; travel expenses (self) – Celgene, Novartis, AstraZeneca, Tesaro. Dariusz Kowalski: consultancy and advisory board – Roche/Genentech, AstraZeneca, Boehringer Ingelheim, BMS, Pfizer, MSD. Byoung Chul Cho: research funding – Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; consulting role – Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; stock ownership – TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics; royalty – Champions Oncology. Josef Straub, Jürgen Scheele, Dilafruz Juraeva, Rolf Bruns, John Heymach: employees of Merck KGaA, Darmstadt, Germany. Paul Paik: advisor – AbbVie, BMS, Calithera, Celgene, Lilly, Takeda; research expenses – EMD Serono; research institution research expenses – Celgene, EMD Serono.

Poster 322 presented at the American Society of Clinical Oncology | May 29–31, 2020 | Virtual format

Primary efficacy and biomarker analyses from the VISION study of tepotinib in patients with NSCLC with MET exon 14 skipping

CONCLUSIONS

RESULTS

• The oncogenic driver MET exon 14 skipping occurs in 3–4% of patients with non-small cell lung cancer (NSCLC).1–4 MET exon 14 skipping typically occurs in older patients,5,6 and is rarely found alongside other oncogenic drivers1,2

• Tepotinib is an oral, once-daily highly selective MET inhibitor that has shown activity in patients with MET-driven tumors7–9

• In the Phase II VISION study, we evaluated the efficacy and tolerability of tepotinib in patients with advanced NSCLC harboring MET exon 14 skipping, prospectively detected through liquid or tissue biopsies; results from this study have led to regulatory approval of tepotinib and its companion diagnostic in Japan in March 2020

• Here, we report primary efficacy, safety, and biomarker results; patient-reported outcomes from this population are reported in poster 34110

Xiuning Le,1 Enriqueta Felip,2 Remi Veillon,3 Hiroshi Sakai,4 Alexis B. Cortot,5 Marina Chiara Garassino,6 Julien Mazieres,7 Santiago Viteri,8 Helene Senellart,9 Jan Van Meerbeeck,10 Niels Reinmuth,11 Pierfranco Conte,12 Dariusz Kowalski,13 Byoung Chul Cho,14 Josef Straub,15

Jürgen Scheele,16 Dilafruz Juraeva,17 Rolf Bruns,18 John Heymach,1 Paul K. Paik19

Patients • As of 01 January 2020, 152 patients received tepotinib (safety population) and 99 patients

comprised the primary efficacy population with ≥9 months’ follow-up data (Table 1)• 60/152 and 22/99 patients were still receiving tepotinib at data cut-off

Table 1. Baseline characteristicsBaseline characteristic Combined* (n=100)

Median age, years (range) 74.0 (41–94)Sex (%) Male / Female 54 / 46Race† (%) Asian / White 21 / 75Smoking history‡ (%) Yes 47ECOG performance status (%) 0 / 1 23 / 77

Lines of prior therapy for advanced/metastatic disease (%)

0 43 (43.0)1 34 (34.0)2+ 23 (23.0)

*Combined = liquid-biopsy positive and/or tissue-biopsy positive; one patient was not included in the primary efficacy population as they were not confirmed to be positive for MET exon 14 skipping; †Race was unknown or missing in four patients; ‡Smoking history was unknown or missing in eight patients.ECOG, Eastern Cooperative Oncology Group.

• In the combined group, median (95% CI) progression-free survival was 8.5 (6.7, 11.0) months by independent review (Figure 2) and 8.6 (6.7, 11.2) months by investigator assessment

• Median (95% CI) overall survival was 17.1 months (12.0, 26.8) in the combined group, 15.8 months (9.5, not estimable) in the liquid-biopsy group and 22.3 months (15.3, not estimable) in the tissue-biopsy group

Figure 2. Progression-free survival

Activity in patients with brain metastases• Outcomes in patients with

baseline brain metastases (n=11), all of which were non-target lesions, were comparable to the overall population • Objective response rate by

independent review: 54.5% (95% CI: 23.4, 83.3)

• Median duration of response of 9.5 months (95% CI: 6.6, not estimable)

• Median progression-free survival was 10.9 months (95% CI: 8.0, not estimable) Images courtesy of Dr Remi Veillon

• 72-year-old female former smoker, diagnosed with metastatic adenocarcinoma of the lung cT3N2M1a (pleura)

• 6/2017 to 11/2017: treated with 1st-line platinum chemotherapy with partial response

• 12/2017: disease progression (lung and bones) treated with 2nd-line pembrolizumab with partial response

• 6/2018: disease progression (lung, adenopathy, and CNS frontal lesion)

• 8/2018 to 7/2019: on-treatment with 3rd-line tepotinib. Disappearance of brain metastasis with systemic partial response

• Disease progression in the liver (no CNS progression)

Safety• Grade ≥3 treatment-related adverse events were reported in 27.6% of patients (Table 3)• Treatment-related adverse events led to dose reductions in 32.9% of patients and to permanent discontinuations

in 11.2% of patients

Table 3. Treatment-related adverse events

Category, n (%)Tepotinib (n=152)

All grades Grade 1/2 Grade 3 Grade 4Any adverse event* 135 (88.8) 93 (61.2) 38 (25.0) 3 (2.0)

Peripheral edema 96 (63.2) 85 (55.9) 11 (7.2) 0

Nausea 39 (25.7) 38 (25.0) 1 (0.7) 0

Diarrhea 33 (21.7) 32 (21.1) 1 (0.7) 0

Blood creatinine increased 27 (17.8) 26 (17.1) 1 (0.7) 0

Hypoalbuminemia 24 (15.8) 21 (13.8) 3 (2.0) 0

Amylase increased 17 (11.2) 13 (8.6) 3 (2.0) 1 (0.7)*A 79-year-old patient had a Grade 5 adverse event of respiratory failure and dyspnea, secondary to interstitial lung disease.

• Tepotinib is a promising targeted therapy with durable clinical activity in NSCLC patients with MET exon 14 skipping identified by liquid or tissue biopsy

• The efficacy of tepotinib in patients with brain metastases was comparable to the overall population

• Tepotinib had a manageable tolerability profile, with few adverse events leading to discontinuation

• On-treatment liquid-biopsy biomarker analyses showed that patients with molecular ctDNA responses (reduction in MET exon 14 mutant allele frequency) had high objective response rates

• Association between molecular ctDNA and clinical responses support that MET inhibition in MET exon 14 skipping tumor cells can lead to clinical benefit

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99 67 53 33 10 6 1420 115Patients at risk:

066 44 36 23 8 6 1414 110 060 42 32 22 7 4 1216 111 0

CI, confidence interval.

Seventeen patients had molecular ctDNA clearance <75%: clinical response by independent review was partial response in two patients, stable disease in four patients, and progressive disease in six patients; five patients were not evaluable. ctDNA, circulating tumor DNA; SNV, single nucleotide variant.

No. of events Median (95% CI) months

Combined (n=99) 60 8.5 (6.7, 11.0)

Liquid-biopsy group (n=66) 43 8.5 (5.1, 11.0)

Tissue-biopsy group (n=60) 32 11.0 (5.7, 17.1)

Copies of this poster obtained through Quick

Response (QR) Code are for personal use only and may not be reproduced without

permission from ASCO® and the author of this poster.

Efficacy• Objective response rate by independent review (primary endpoint) was 46.5–50.0% and by investigator

assessment was 55.6–61.7% (Table 2)

Table 2. Clinical response in the primary efficacy populationLiquid-biopsy group†

(n=66)Tissue-biopsy group‡

(n=60)Combined*

(n=99)IRC INV IRC INV IRC INV

Objective response rate, % (95% CI)

48.5(36.0, 61.1)

56.1(43.3, 68.3)

50.0(36.8, 63.2)

61.7(48.2, 73.9)

46.5(36.4, 56.8)

55.6(45.2, 65.5)

Duration of response, medianmonths (95% CI)

9.9(7.2, ne)

14.0(7.3, ne)

15.7(9.7, ne)

16.4(9.7, ne)

11.1(7.2, ne)

14.0(9.7, 18.3)

Disease control rate, % (95% CI)

65.2 (52.4, 76.5)

69.7(57.1, 80.4)

68.3 (55.0, 79.7)

78.3(65.8, 87.9)

65.7 (55.4, 74.9)

72.7(62.9, 81.2)

†Two patients were liquid-biopsy positive only. ‡25 patients were tissue-biopsy positive only; objective response rate by independent review was 40.0% (95% CI: 21.1, 61.3) and 48.0 (95% CI: 27.8, 68.7) by investigator assessment. *Combined = liquid-biopsy positive and/or tissue-biopsy positive.INV, investigator assessment; IRC, independent review committee; ne, not estimable; CI, confidence interval.

• Tumor shrinkage was observed in 89% of patients (Figure 1)

Figure 1. Best overall response to treatment

Best overall response

Complete response

Partial response

Stable disease

Progressive disease

Not evaluable

Best molecular ctDNA response (MET exon 14 depletion)

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METalterations

Baseline ● ● ● ●

Post-baseline ●

MET exon 14 skipping

Variant type Variant effect *

SNV (49%)Indel (51%)Acceptor splice (31%)Donor splice (67%)

* Whole exon 14 deletion (2%)

MET exon 14● MET amplification

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INTRODUCTION

METHODS

Baseline brain MRI 7/2018

CNS lesion disappeared 7/2019

Patients with molecular ctDNA responses(reduction of MET exon 14)

Biomarker data• 34/51 patients (67%) had molecular ctDNA responses (depletion of MET exon 14) (Figure 3)• Of the 34 patients with molecular ctDNA response:

• 24 (71%) had radiographic response by independent review and 29 (85%) by investigator assessment• 30 (88%) had disease control by independent review and 32 (94%) by investigator assessment

Figure 3. Best overall response and molecular ctDNA response for patients with matched baseline and on-treatment liquid-biopsy samples (n=51)

Complete responsePartial responseStable diseaseProgressive diseaseNot evaluable

■ Ongoing treatment

• Patients with locally advanced or metastatic NSCLC with MET exon 14 skipping (identified using circulating tumor DNA (ctDNA) collected from plasma [liquid biopsy] or from RNA collected from tumor tissue [tissue biopsy]). Patients were EGFR/ALK wild type and had ≤2 lines of prior therapy. Asymptomatic brain metastases were allowed

• Patients received oral tepotinib 500 mg once daily until intolerable toxicity or disease progression. On-study treatment decisions were based on investigator assessment of response

• Primary endpoint: objective response rate by independent review analyzed in three primary analysis groups: 1) liquid-biopsy positive and/or tissue-biopsy positive (combined group); 2) liquid-biopsy positive; 3) tissue-biopsy positive

• Secondary endpoints: objective response rate by investigator; duration of response; progression-free survival; and safety

• Analysis of molecular ctDNA responses was an exploratory endpoint: baseline and on-treatment ctDNA plasma samples were analyzed using a 73-gene next-generation sequencing panel (Guardant360®). Molecular ctDNA responses were defined as >75% (deep) or 100% (complete) depletion of MET exon 14 mutant allele frequency in on-treatment liquid biopsies

• Efficacy was assessed in patients with ≥9 months’ follow-up. Safety was assessed in all patients who received tepotinib

1Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA (XLe1@mdanderson.org); 2Department of Oncology, Valld’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 3CHU Bordeaux, service des maladies respiratoires, Bordeaux, France; 4Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan; 5Univ. Lille, CHU Lille, CNRS, Inserm, Institut Pasteur de Lille, UMR9020 – UMR-S 1277 – Canther, F-59000 Lille, France; 6Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 7IUCT, CHU de Toulouse, Toulouse, France; 8Dr Rosell Oncology Institute, Dexeus University Hospital, QuironSalud Group, Barcelona, Spain; 9Department of Medical Oncology, Comprehensive Cancer Center, Institut de Cancérologie de l'Ouest, Saint-Herblain, France; 10Department of Pulmonology and Thoracic Oncology, Antwerp University Hospital (UZA), Edegem, Belgium; 11Thoracic Oncology, Asklepios Lung Clinic, Munich-Gauting, Germany; 12Department of Surgery, Oncology and Gastroenterology; University of Padova and Oncologia Medica 2, Istituto Oncologico Veneto, I.R.C.C.S., Padova, Italy; 13Department of Lung Cancer and Thoracic Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland; 14Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; 15Translational Medicine, Department of Clinical Biomarkers and Companion Diagnostics, Merck KGaA, Darmstadt, Germany; 16Global Clinical Development, Merck KGaA, Darmstadt, Germany; 17Translational Medicine, Department of Oncology Bioinformatics, Merck KGaA, Darmstadt, Germany; 18Department of Biostatistics, Merck KGaA, Darmstadt, Germany; 19Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA