LBA52 - Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study

Background

A high unmet need exists for effective treatments post 1L osimertinib in NSCLC. For 15–30% of patients (pts) with resistance due to METamp, MET TKIs such as tepotinib may be effective.

Methods

In this open-label 2-arm Phase II study, pts with advanced EGFRm NSCLC with METamp after progression on 1L osimertinib received tepotinib 500 mg (450 mg active moiety) + osimertinib 80 mg once daily (TEP+OSI). 12 pts were initially randomized to tepotinib alone (TEP). METamp was centrally detected by FISH (MET GCN ≥5 and/or MET/CEP7 ≥2) in tissue biopsy (TBx) and/or by NGS (MET GCN ≥2.3; Archer®) in liquid biopsy (LBx); central testing was mandatory for both. Primary endpoint: ORR by IRC in TEP+OSI-treated pts with FISH METamp. Initial results are presented here; primary analysis is planned when all enrolled pts have ≥9 months’ follow-up.

Results

As of April 26, 2022, among 425 pre-screened pts, METamp was detected by FISH TBx in 139 (33%) pts and by NGS LBx in 47 (11%) pts. 100 pts received treatment (88 TEP+OSI and 12 TEP; 62% female, median age 61 yrs [20–84], 56% Asian, 68% ECOG PS 1). Confirmed ORR was 54.5% in 22 FISH METamp TEP+OSI-treated pts with ≥9 months’ follow-up, with 6/12 responders still on treatment. In 48 FISH METamp pts with ≥3 months’ follow-up, ORR was 45.8% (with high rate of NE as BOR; Table). Median DOR was not reached. In 12 FISH METamp TEP-treated pts, BOR was 1 PR (ORR of 8.3%). 7 pts switched to TEP+OSI at PD and 5 were still on treatment. Of 88 TEP+OSI-treated pts, 65 (73.9%)/21 (23.9%) had any grade/G≥3 treatment-related AEs (in >15% pts: diarrhea 40.9%/0%, peripheral edema 23.9%/4.5%, paronychia 17.0%/1.1%). Primary reason for discontinuation was AEs in 6 pts (6.8%). Table: 000LBA52

*Timeframe for primary analysis. Pts also included in analysis of 48 pts with ≥3 months’ follow-up. ^†Incomplete post-baseline assessments (n=2), SD <12 weeks (n=3), COVID-19-related early discontinuation (n=1), and PD/AE-related-early discontinuations (n=5).

Conclusions

In this initial analysis of INSIGHT 2, TEP+OSI was highly active and well tolerated in pts with EGFRm NSCLC with METamp after progression on 1L osimertinib and enables continuation of oral-only chemo-sparing therapy in this population with a high unmet need.

Clinical trial identification

NCT03940703.

Editorial acknowledgement

Medical writing assistance (funded by Merck Healthcare KGaA, Darmstadt, Germany) was provided by Rebecca Hurst of Syneos Health, London, UK.

Legal entity responsible for the study

Merck Healthcare KGaA, Darmstadt, Germany.

Funding

Merck Healthcare KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

Disclosure

J. Mazieres: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Novartis, Merck Healthcare KGaA, Darmstadt, Germany, Amgen, Takeda, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Roche/Genentech, AstraZeneca, Bristol Myers Squibb. T.M. Kim: Financial Interests, Personal, Advisory Board: AstraZeneca, Hanmi, Janssen, Novartis, Takeda; Financial Interests, Personal, Invited Speaker: Roche/Genentech; Financial Interests, Personal, Research Grant: AstraZeneca-KHIDI; Non-Financial Interests, Principal Investigator: AstraZeneca/MedImmune, Boryung, Hanmi, Janssen, Boehringer-Ingelheim, Novartis, Takeda, Sanofi, Roche/Genentech, Merck Sharp & Dohme Corp, Merck Serono, REGENERON, Genmab, Bayer. M. Wislez: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Novartis, Merck Healthcare KGaA, Darmstadt, Germany, Janssen, Roche. C. Dooms: Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Pfizer, Roche, Novartis, Merck Healthcare KGaA, Darmstadt, Germany, Bristol Myers Squibb, MSD; Financial Interests, Personal, Advisory Board: Amgen, Eli Lilly, Pfizer, Roche, Novartis, Merck Healthcare KGaA, Darmstadt, Germany, Bristol Myers Squibb, MSD. G. Finocchiaro: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Merck Healthcare KGaA, Darmstadt, Germany, MSD, Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Merck Healthcare KGaA, Darmstadt, Germany, MSD, Amgen. H. Hayashi: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb Co. Ltd, AstraZeneca K.K, Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Merck Biopharma Co. Ltd, MSD K.K., Novartis Pharmaceuticals K.K, Pfizer, Takeda Pharmaceutical Co. Ltd, Janssen Pharmaceutical K.K.; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb Co. Ltd, Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K, Shanghai Haihe Biopharm, Pfizer, AstraZeneca K.K; Financial Interests, Institutional, Funding: AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Novartis Pharma K.K., grants, Pfizer Japan Inc., Bristol Myers Squibb Company, Eli Lilly Japan K.K., Chugai Pharmaceutical Co.,Ltd., Daiic; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd., and Ono Pharmaceutical Co. Ltd.; Non-Financial Interests, Principal Investigator: Ono Pharmaceutical Co. Ltd. and Bristol Myers Squibb Co; Non-Financial Interests, Member: West Japan Oncology Group, Japan Society of Medical Onclogy. C.K. Liam: Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Pfizer, Roche. J. Raskin: Financial Interests, Personal, Advisory Role: Pfizer, Eli Lilly; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Bristol Myers Squibb; Financial Interests, Personal, Other, Travel Expense: Roche. L.M. Tho: Financial Interests, Personal, Research Grant: EMD Serono, an affiliate of Merck KGaA; Financial Interests, Personal, Other, Honoraria: Pfizer, Roche, AstraZeneca. F. de Marinis: Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Roche, Pfizer. E. Nadal: Financial Interests, Personal, Advisory Role: Merck Healthcare KGaA, Darmstadt, Germany, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, Takeda; Financial Interests, Personal, Research Grant: Merck Healthcare KGaA, Darmstadt, Germany, Pfizer, Roche, Bristol Myers Squibb. E. Smit: Financial Interests, Institutional, Advisory Role: Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol Myers Squibb, Merck Healthcare KGaA, Darmstadt, Germany, MSD Oncology, Takeda, Bayer, Regeneron, Novartis, Daiichi Sankyo, Seattle Genetics; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca, Bristol Myers Squibb. X. Le: Financial Interests, Personal, Advisory Role: AstraZeneca, Eli Lilly, Novartis, Daiichi Sankyo, Hengrui Therapeutics, EMD Serono, an affiliate of Merck KGaA; Financial Interests, Personal, Research Grant: Eli Lilly, Boehringer Ingelheim. S. Brutlach: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. A.M. O'Brate Grupp: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. S. Adrian: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. B. Ellers-Lenz: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. N. Karachaliou: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. Y. Wu: Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Roche, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, MSD, Eli Lilly, Pfizer. All other authors have declared no conflicts of interest.