1321MO - Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2 (ERBB2)-mutant (HER2m) metastatic non–small cell lung cancer (NSCLC) with and without brain metastases (BMs): Pooled analyses from DESTINY-Lung01 and DESTINY-Lung02

Background

∼20% of pts with HER2m NSCLC have BM at metastatic diagnosis. T-DXd is the first HER2-directed therapy for pts with pretreated, advanced HER2m NSCLC. We report post hoc pooled analyses of T-DXd efficacy/safety in this population with vs without baseline (BL) BMs from DESTINY-Lung01 (DL-01) and DESTINY-Lung02 (DL-02).

Methods

Pts with and without BMs were evaluated from the DL-01 (data cutoff [DCO], Dec 3, 2021) HER2m cohort (6.4 mg/kg; 35 and 56 pts) and the DL-02 (DCO, Dec 23, 2022) cohorts treated with T-DXd 5.4 mg/kg (32 and 70 pts) or 6.4 mg/kg (19 and 31 pts); 6.4 mg/kg arms were pooled. Pts with stable BL BMs (asymptomatic; not requiring treatment) were eligible. Tumor assessments were performed every 6 weeks (MRI/CT). Systemic objective response rates (ORRs), duration of response (DoR), sites of progression, and treatment-emergent adverse events (TEAEs) were determined in pts with and without BL BMs. Intracranial (IC)-ORR, IC-DCR, and IC-DoR were analyzed in pts with measurable and nonmeasurable BL BMs.

Results

31% and 38% of pts given T-DXd 5.4 mg/kg and 6.4 mg/kg, respectively, had detectable BL BMs, among whom 46.9% and 55.6% had untreated BMs. Systemic ORRs were similar (Table). IC-ORRs were 25.0% (5.4 mg/kg) and 18.5% (6.4 mg/kg) with complete IC responses in 4 and 1 pts. In pts with BL BMs, IC progression occurred in 13/32 and 20/54 pts on T-DXd 5.4 mg/kg and 6.4 mg/kg, respectively; in pts without BL BMs, 1/70 and 8/87 had IC progression. Generally similar safety outcomes were seen in pts with vs without BMs, with a trend of higher rates of grade ≥3 TEAEs in pts with BMs (64.5% vs 47.1% [5.4 mg/kg]; 75.9% vs 63.2% [6.4 mg/kg]).

Conclusions

T-DXd showed IC activity in pts with metastatic HER2m NSCLC, some with complete IC responses. The presence of BL BMs did not impact systemic response among pts treated with T-DXd. Table: 1321MO

Efficacy summary

^aIC response per modified RECIST v1.1; all measurable brain lesions were considered target lesions. Nonmeasurable BL BMs only: 18/32 (5.4 mg/kg); 24/54 (6.4 mg/kg).

Clinical trial identification

NCT03505710; NCT04644237.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Eileen McIver, PhD and Cindy M. Rigby, 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

B.T. Li: Financial Interests, Institutional, Funding, Clinical trial funding: Daiichi Sankyo, Amgen, Bolt Biotherapeutics, Genentech, Hengrui, Eli Lilly; Financial Interests, Institutional, Funding, Clinical trial funding, uncompensated advisory: AstraZeneca; Financial Interests, Personal, Invited Speaker, Academic Travel Support: Amgen. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Novartis, GSK, Novartis, Janssen, AbbVie, Roche, Pfizer, Daiichi Sankyo, Inc., MSD, Gilead Sciences, Inc., Seagen, Pierre Fabre. K. Goto: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co., Ltd, AstraZeneca K.K.; Financial Interests, Institutional, Research Grant: Daiichi Sankyo Co., Ltd; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca K.K. 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 Serono; Financial Interests, Institutional, Other, DSMB member: DSI; Financial Interests, Institutional, Local PI: Pfizer, AZ, Genmab, DSI, Sanofi. J. De Langen: Financial Interests, Institutional, Advisory Role, Consultancy: AstraZeneca, MSD, Roche, Boehringer Ingelheim, Pfizer, Eli Lilly, Blueprint Medicines; Financial Interests, Institutional, Advisory Role, Consulting Fees: BMS; Financial Interests, Institutional, Research Funding: AstraZeneca, BMS, Merck Serono, MSD, Roche, Merus. 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 Fisher; Financial Interests, Personal, Other, Travel Grant: Daiichi Sankyo; 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: Preferred Network; Financial Interests, Institutional, Coordinating PI: Guardant Health; Non-Financial Interests, Member of Board of Directors: Cancer Net Japan, JAMT. K. Ninomiya: Financial Interests, Personal, Speaker’s Bureau: Kyowa Kirin, AstraZeneca, Lilly Japan, MSD KK, Chugai Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Bristol Myers Squibb, Janssen Pharmaceutical, Nippon Boehringer Ingelheim, Electa. T. Kubo: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical, BMS, Taiho Pharmaceutical, Kyowa Hakko Kirin, AstraZeneca, Ono Pharmaceutical, Nippon Kayaku, Chugai, MSD, Eli Lilly, Pfizer, Novartis, Boehringer Ingelheim, Towa Pharmaceutical. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, Eisai, Ipsen; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, BMS, Boehringer Ingelheim, Takeda, Illumina, Pfizer, Medscape; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Roche; Financial Interests, Personal, Other, DMSB: Roche. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, AbbVie, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GSK, Janssen, Merck Serono, Novartis, Peptomyc, Pfizer, Sanofi, Takeda; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, MedScape, Merck Sereno, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology; Financial Interests, Personal, Other, Independent member: Grifols; Non-Financial Interests, Personal, Other, Member of the Nominating Commitee and Compliance Committee: ESMO; Non-Financial Interests, Personal, Other, Member of Scientific Committee: ETOP; Non-Financial Interests, Personal, Leadership Role, President of the Spanish Society For Medical Oncology: SEOM. H. Hayashi: Financial Interests, Personal, Invited Speaker: Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd; Financial Interests, Personal, Advisory Board: AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd; Financial Interests, Personal, Advisory Board, Manuscript fee: Guardant Health ; Financial Interests, Personal, Funding: AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co. Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Bristol Myers Squibb Co. Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Merck Serono Co. Ltd., Merck Biopharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., SymBio Pharmaceuticals Ltd., AbbVie Inc., inVentiv Health Japan, ICON Japan K.K., Gritstone Oncology Inc., Parexel International Corp., Kissei Pharmaceutical Co. Ltd., EPS Corp., Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc./IQVIA Services Japan K.K., EP-CRSU Co. Ltd., Linical Co. Ltd., Eisai Co. Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co. Ltd., Bayer Yakuhin Ltd., EPS International Co. Ltd., Otsuka Pharmaceutical Co. Ltd.; Financial Interests, Personal, Full or part-time Employment: Nippon Boehringer Ingelheim Co. Ltd.. 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., MSD K.K., IQVIA Services Japan K.K., Janssen Pharmaceutical K.K., Kobayashi Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Nippon Kayaku Co.,Ltd., Sanofi K.K., PRA Healthsciences, SRL Medisearch Inc., Syneos Health Clinical 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. M. Nagasaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis, EMD Serona, Pfizer, Eli Lilly, Genentech; Financial Interests, Personal, Other, Consultant for tumor board: Caris Life Sciences; Financial Interests, Personal, Speaker’s Bureau: Takeda, Janssen, Mirati, Blueprint Medicine; Non-Financial Interests, Personal, Other, Travel Support: AnHeart Therapeutics. K.M.C. Pereira: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. A. Taguchi: Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo Co., Ltd. A. Ali: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. M. Karnoub: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. R. Yonemochi: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P.A. Jänne: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, SFJ Pharmaceuticals, Voronoi, Biocartis, Novartis, Sanofi, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Monte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality; Financial Interests, Personal, Funding: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Funding: Daiichi Sankyo, Takeda Oncology; Financial Interests, Personal, Advisory Board: Mirati Therapeutics; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals; Financial Interests, Institutional, Funding: Puma; Financial Interests, Personal, Invited Speaker: Revolution Medicines; Financial Interests, Personal, Royalties: LabCorp. All other authors have declared no conflicts of interest.