151P - Baseline circulating tumor DNA (ctDNA) biomarker analysis of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic non–small cell lung cancer (NSCLC) treated with trastuzumab deruxtecan (T-DXd)

Background

DESTINY-Lung01 (NCT03505710) showed encouraging and consistent antitumor activity for T-DXd in heavily pretreated patients with HER2-overexpressing (immunohistochemistry [IHC] 3+/2+) NSCLC. We investigated associations between baseline gene mutations using ctDNA and clinical outcomes in these patients (data cutoff, May 2021).

Methods

Among 90 patients in the DESTINY-Lung01 HER2-overexpressing cohorts, 85 had baseline ctDNA samples analyzed at Guardant Health OMNI. Activating mutations in key oncogenes (EGFR, RAS, BRAF) and other genes of interest at baseline were assessed for their association with clinical efficacy (objective response rate [ORR] and progression-free survival [PFS]) with T-DXd treatment (cohort 1, 6.4 mg/kg [N = 49]; cohort 1a, 5.4 mg/kg [N = 41] every 3 weeks); analyses were not adjusted for baseline characteristics.

Results

The 85 evaluable patients had an ORR of 27.1% (95% CI, 18.0-37.8) and a median PFS (mPFS) of 5.9 months (95% CI, 4.5-7.4). Activating mutations were identified in EGFR (15 patients [17.6%]: 7 T790M, 7 L858R, 1 S768I, 4 E746_A750del, 2 G719A), KRAS (20 patients [23.5%]), NRAS (1 patient [1.2%]), and BRAF (1 patient [1.2%]). 13 of the 15 patients with EGFR-activating mutations had prior EGFR tyrosine kinase inhibitor treatment. No clear effects of EGFR- and RAS-activating mutations on ORR and mPFS were observed; however, mutations in STK11 and KEAP1 were associated with significantly shorter mPFS (Table).

Conclusions

Baseline ctDNA analysis showed that the presence of activating mutations in EGFR, KRAS, or NRAS did not impact the clinical efficacy of T-DXd in patients with HER2-overexpressing NSCLC whereas mutations in STK11 and KEAP1 were associated with shorter mPFS. Updated results will be presented (data cutoff, December 2021). Table: 151P

Efficacy according to mutation status

Mut, mutant; WT, wild-type. ^a KRAS/NRAS. ^bTop 4 genes based on log rank test significance for PFS.

Clinical trial identification

NCT03505710.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Brian Brennan, PhD, and Sara Duggan, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc., and AstraZeneca.

Funding

Daiichi Sankyo, Inc., and AstraZeneca.

Disclosure

E.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Boehringer Ingelheim, Roche, Eli Lilly, Takeda, Sanofi, Janssen, BMS; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck Seranno; Financial Interests, Institutional, Other, DSMB member: DSI; Financial Interests, Institutional, Local PI: Pfizer, AZ, Genmab, DSI, Sanofi. E. Felip: Financial Interests, Personal, Advisory Board: AstraZeneca, AbbVie, Amgen; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Touch Oncology, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, Bayer, Merck Sharp & Dohme, Peervoice, Pfizer, Sanofi, Takeda, Seom; Financial Interests, Personal, Other, Independent member ofthe board: Grifols; Financial Interests, Personal, Other, Member of the Nominating Commitee and Compliance Committee: ESMO; Financial Interests, Personal, Other, Member of Scientific Committee: ETOP. D. Uprety: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Advisory Board: Jazz Pharmaceuticals . M. Nagasaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis, EMD Serono, Pfizer, Lilly, Genentech; Financial Interests, Personal, Other, Consulting for tumor board: Caris Life Sciences; Financial Interests, Personal, Speaker’s Bureau: Takeda, Janssen, Mirati, Blueprint Medicines; Financial Interests, Other, Travel support: AnHeart Therapeutics. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bayer Yakuhin, Ltd., Incyte biosciences Japan, Merck Biopharma Co., Ltd., Janssen Pharmaceutical K.K., Bristol Myers Squibb Company, Medical Mobile Communications co., Ltd, Novartis Pharma K.K., Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K.; Financial Interests, Personal, Writing Engagement: Yodosha Co., Ltd.; Financial Interests, Institutional, Research Grant: Amgen Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co.,Ltd., EP-CRSU CO., LTD., EPS Corporation., Eisai Co., Ltd., GSK K.K., IQVIA Services Japan K.K., Janssen Pharmaceutical K.K., Kobayashi Pharmaceutical Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co.,Ltd., Nippon Kayaku Co.,Ltd., PRA HEALTHSCIENCES, SRL Medisearch Inc., Syneos Health Clinical K.K., Sanofi K.K., Taiho Pharmaceutical Co.,Ltd., Takeda Pharmaceutical Co.,Ltd., CMIC CO., Ltd., Pfizer R&D Japan G.K., Labcorp Development Japan K.K., Pfizer Japan Inc., Shionogi & Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Ascent Development Services, Eisai Inc., Bayer Yakuhin, Ltd. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AstraZeneca, Lilly, Pharmamar, BeiGene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, Pharmamar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President. ASEICA(Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, Member: Small Lung Cancer Group. J. Pacheco: Financial Interests, Personal, Other, Consulting Fees: Silverback therapeutics, Blueprint Medicines, AstraZeneca, Jazz Pharmaceuticals. B.T. Li: Financial Interests, Institutional, Funding, Clinical trial funding: Daiichi Sankyo, Amgen, Bolt Biotherapeutics, Genentech, Hengrui, Lilly; Financial Interests, Institutional, Funding, Clinical trial funding, uncompensated advisory: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Academic travel support: Amgen. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Novartis, GSK, NOVARTIS, Janssen, AbbVie, Roche, Pfizer, MSD, Gilead, Seagen, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo. C.S. Baik: Financial Interests, Institutional, Principal Investigator: Rain , AbbVie, Nuvalent, Blueprint, Turning Point, BMS, Lilly, AstraZeneca, Jansen, Daiichi, Spectrum, Pfizer, Loxo; Financial Interests, Personal, Advisory Board: Daiichi, Boehringer Ingelheim, Janssen, Regeneron, Silverback, Pfizer, AstraZeneca, Guardant, TurningPoint, Takeda. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fischer; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Preferred Network; Financial Interests, Personal and Institutional, Coordinating PI: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Financial Interests, Institutional, Coordinating PI: Guardant Health. H. Murakami: Financial Interests, Personal, Advisory Board: Chugai Pharma, Taiho Pharmaceutical, AstraZeneca, Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Takeda, Novartis, Daiichi Sankyo, Eisai, Nihonkayaku, Pfizer, Amgen, Chugai Pharma, Daiichi Sankyo, GAIA BioMedicine, Taiho Pharmaceutical, Amgen; Financial Interests, Institutional, Research Grant: Chugai Pharma, AstraZeneca, Takeda, Daiichi Sankyo, AbbVie, IQVIA, Bayer, Taiho Pharmaceutical. K.M.C. Pereira, A. Taguchi, M. Kogo, Y. Kuwahara, M. Zou, W. Feng, Z. Tsuchihashi: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P.A. Jänne: Financial Interests, Personal and Institutional, Funding: AstraZeneca, Boehringer Ingelheim, Eli Lilly Pharmaceuticals, Daiichi Sankyo, Takeda Oncology; Financial Interests, Personal, Advisory Board: Pfizer, Roche/Genentech, Chugai Pharmaceuticals, SFJ Pharmaceuticals, Voronoi, Biocartis, Novartis, Sanofi, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Allorion Therapeutics, Accutar Biotech, AbbVie, Monte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals; ; Financial Interests, Institutional, Funding: PUMA; Financial Interests, Personal, Invited Speaker: Revolution Medicines; Financial Interests, Personal, Royalties: LabCorp.