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

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.

Background

HER2 is an actionable biomarker for mCRC, though the impact of concomitant genomic alterations is unknown. On the basis of the MOUNTAINEER study, TUC + Tras was approved by the FDA for use in pts with chemo-refractory HER2+, RAS-WT mCRC. Here we present the impact of concomitant baseline genomic alterations on the clinical activity of TUC + Tras.

Methods

MOUNTAINEER enrolled pts w/ locally assessed HER2+ mCRC by tissue immunohistochemistry (IHC), in situ hybridization (ISH), and/or next-generation sequencing (NGS). Baseline tissue and blood samples were retrospectively analyzed by IHC/FISH, PGDx tissue NGS and Guardant 360 blood NGS. cORRs (proportion of pts w/ CR or PR per RECIST v1.1 by BICR) and DoR were calculated for selected genomic alterations (SNVs and CNVs) occurring in ≥5 pts treated with TUC + Tras. This analysis was descriptive; no statistical comparisons were made.

Results

From 84 pts treated with TUC+Tras, 65 samples were available for FISH testing. cORR was numerically higher w/ greater HER2 amplification as measured by either HER2/CEP17 ratio (>5, n=50: cORR [95%CI] = 44.0% [30.0, 58.7]; ≤5, n=15: cORR [95%CI] = 26.7% [7.8, 55.1]) or HER2 copy number (>9.45, n=57: cORR [95%CI] = 42.1% [29.1, 55.9]; ≤9.45, n=8: cORR [95%CI] = 25.0% [3.2, 65.1]). NGS testing of tissue (n=45) and blood (n=66) samples from pts w/ a central HER2+ test result identified concomitant mutations and/or genomic amplifications in key genes including ERBB2, PIK3CA, APC, and TP53. In these pts, cORR and DOR were generally similar to those observed overall (Table).

Conclusions

This exploratory analysis of the MOUNTAINEER trial found generally consistent clinical efficacy of TUC + Tras to the primary analysis across subsets of pts w/ HER2+ RAS-WT mCRC and other clinically relevant genomic alterations.

Table: 551O

Clinical trial identification

EudraCT Number 2020-000540-60.

Editorial acknowledgement

The authors thank Sarah Canestaro, MS, of Populus Group, Troy, MI, supported by Seagen Inc. for providing medical writing and editorial support in accordance with Good Publication Practice guidelines.

Legal entity responsible for the study

Seagen Inc.

Funding

This study was sponsored by Seagen Inc., Bothell, WA, USA, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

J.H. Strickler: Financial Interests, Personal, Advisory Board: SeaGen, AstraZeneca, Amgen, Pfizer, Bayer, AbbVie, Natera, Viatris, Inivata, Silverback Therapeutics; Financial Interests, Personal, Other, Consulting: Mereo, GSK, Pionyr Immunotherapeutics; Financial Interests, Institutional, Invited Speaker: SeaGen, Roche Genentech, AbbVie, AstraZeneca, Amgen, Astar D3, Sanofi, Curegenix, Nektar, Leap Therapeutics, Daiichi Sankyo, Erasca, Gossamer Bio, Silverback Therapeutics. A. Cercek: Financial Interests, Personal, Advisory Board: Bayer, GSK, Janssen, Merck, Seagen, Pfizer; Financial Interests, Personal, Stocks/Shares: Haystack; Financial Interests, Personal, Royalties, Pending patent neoadjuvant PD1 blocked in mismatch repair deficient solid tumors: Memorial Sloan Kettering; Financial Interests, Personal, Royalties, Pending patent for HAI FUDR in DPD metastatic colorectal cancer: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Invited Speaker, Clinical trial funding: Seattle Genetics; Financial Interests, Institutional, Invited Speaker, Clinical trial: GSK. K. Ng: Financial Interests, Personal, Advisory Board, Was also a paid speaker as well for colorectal cancer awareness in March 2022: Bayer; Financial Interests, Personal, Advisory Board: Bicara Therapeutics, GSK, Pfizer, Redesign Health; Financial Interests, Institutional, Funding: Evergrande Group; Financial Interests, Institutional, Research Grant: Janssen, Revolution Medicines; Non-Financial Interests, Leadership Role, Chair of Scientific Program Committee for 2023 Annual Meeting: ASCO; Non-Financial Interests, ,Advisory Role: Colorectal Cancer Alliance, Colon Cancer Foundation, Fight CRC, Prevent Cancer Foundation; Non-Financial Interests, Principal Investigator: Alliance for Clinical Trials in Oncology; Non-Financial Interests, Institutional, Product Samples, Provides product for an NCI cooperative group phase III trial for which I am National Study Chair: Pharmavite. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, Bristol Myers Squibb, Checkmab, Daiichi Sankyo, GSK, Novartis, Seagen, T-One-Therapeutics. T. André: Financial Interests, Personal, Advisory Board, Advosiry Board on February 12, 2021: Astellas Pharma; Financial Interests, Personal, Advisory Board, Advisory Board on February 2021: Kaleido Biosciences; Financial Interests, Personal, Invited Speaker, and advisory board 2021: Amgen; Financial Interests, Personal, Invited Speaker, Invited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract 2021 and 2022: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in Janaury 2020 : Clovis; Financial Interests, Personal, Advisory Board, Advisory board in January 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board, Advisory board 2020: Haliodx; Financial Interests, Personal, Advisory Board, and consultant fees/consultant contract and invited speaker: MSD Oncology; Financial Interests, Personal, Invited Speaker, and other: Pierre Fabre; Financial Interests, Personal, Invited Speaker, in an symposuim in 2020: Roche; Financial Interests, Personal, Invited Speaker, in a meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker, In a educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposuim in 2020: Servier; Financial Interests, Personal, Expert Testimony, Consultant with personnal fees and invited speaker: Servier; Financial Interests, Personal, Advisory Board, in 2019: GSK; Financial Interests, Personal, Invited Speaker, in 2020 and 2021: GSK; Financial Interests, Personal, Invited Speaker, Virtual symposuimLecture: 1 MSI-H CRC: Implementation of Immunotherapy in clinical practice (30 minutes) – (this will be pre-recorded) Q&A – Live Q&A – (10 minutes) (on July 2, 2021): MSD Oncology; Financial Interests, Personal, Invited Speaker, June 2022 : Sanofi; Financial Interests, Personal, Advisory Board, Contract 2021, 2022, 2023: Merck & Co., Inc; Financial Interests, Personal, Advisory Board, Contrat 2019, 2020, 2021, 2022: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Contract 2021: Gritstone Oncologie; Financial Interests, Personal, Invited Speaker, June 2022 and June 2023 during ESMO GI meeting: Seagen; Financial Interests, Personal, Invited Speaker, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022 : GSK, Seagen; Financial Interests, Personal, Invited Speaker, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Invited Speaker, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merck Serono; Financial Interests, Personal, Other, Educationnal in 2022: Roche; Financial Interests, Personal, Other, Contract of consulting 2020, 2021, 2022,2023: Servier; Financial Interests, Personal, Advisory Board, 2023: Aptide Health, Glilead; Financial Interests, Institutional, Other, Investigator and scientific committee president: Gercor Academic group; Financial Interests, Institutional, Invited Speaker, PI Garnet study: GSK; Financial Interests, Institutional, Invited Speaker, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Invited Speaker, Bristol Myers Squibb CA209-8HW, Bristol Myers Squibb CA209-142, Bristol Myers Squibb CA209-577: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, SPOTLIGHT study: Astellas; Financial Interests, Personal, Invited Speaker, and International PI (trial chair Solstice study): Servier; Financial Interests, Personal, Invited Speaker, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Non-Financial Interests, Invited Speaker, Investigator: Gercor group; Non-Financial Interests, Invited Speaker, President since October 2022: ARCAD Foundation . 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Hubbard: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Institutional, Advisory Board: Incyte, Bayer, BeiGene; Financial Interests, Institutional, Invited Speaker: Boston Biomedical, Senhwa Biosciences, Bayer, Merck, Taiho Pharmaceutical, TreoBio, Hutchison MediPharma, Seattle Genetics, Tovogene, Trioncology, Incyte, Pionyr, G1 Therapeutics, Effector Therapeutics, Roche. A.L. Coveler: Financial Interests, Institutional, Invited Speaker: Seagen, AbGenomics, Novocure, Amgen, Actuate Therapeutics, Surface Oncology, Nucana, Nextrast. C. Fountzilas: Financial Interests, Institutional, Research Grant: Pfizer Inc, Taiho Oncology, Merck Sharp & Dohme Corp., National Comprehensive Cancer Network; Financial Interests, Institutional, Invited Speaker: Seattle Genetics, Inc., TransThera Biosciences, AstraZeneca, Aravive, Inc., Merck Sharp & Dohme Corp., Puma Biotechnology, Kadmon, Astellas Pharma, Pfizer Inc, Dragonfly Therapeutics, MedImmune, LLC., Hoosier Cancer Research Network, Incyte Corporation, Rafael Pharmaceuticals, Kinex Phamaceuticals, Syndax Pharmaceuticals, SWOG, National Cancer Institute, Erythech Pharma, Lilly, Corcept Therapeutics, Ipsen, CG Pharmaceuticals, Biomea Fusion, Bellicum, Amgen Inc.; Non-Financial Interests, Institutional, Other, Principal Investigator on upcoming clinical trial evaluating biomarker for treatment selection in pancreatic cancer: Valar Labs. A. Kardosh: Financial Interests, Personal, Advisory Board: Exelixis, Eisai, Astellas Pharma, AstraZeneca, Genentech; Financial Interests, Research Grant: Natera Inc. P.M. Kasi: Financial Interests, Personal, Advisory Board, Consultancy/Advisory Board: Foundation Medicine, Natera Oncology, AstraZeneca, Merck MSD, Tempus, Bayer, Lilly, Delicath Systems, QED Therapeutics, Servier, Taiho Oncology, Exact Sciences, Eisai; Financial Interests, Institutional, Advisory Board, Consultancy/Advisory Board: Taiho, Ipsen; Financial Interests, Institutional, Funding, Investigator initiated trial cooperative group PI trial support and funding: Tersera; Financial Interests, Institutional, Funding, Investigator initiated trial trial support and funding: Boston Scientific. H.J. Lenz: Financial Interests, Personal, Advisory Board, Advisory Role and Lectures: Bayer; Financial Interests, Personal, Advisory Board, Advisory Role and Lectures: Merck; Financial Interests, Personal, Advisory Board, Advisory Role and lecture: Roche; Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals, oncocyte, Orion, Astellas, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: 3T Biosscience; Financial Interests, Personal, Advisory Board, Advisory Board: Fulgent, G1 Therapeutics, BioNtech; Financial Interests, Personal, Advisory Board, advisory board: Cardiff; Financial Interests, Personal, Stocks/Shares, Advisory Board: Fulgent. K.K. Ciombor: Financial Interests, Personal, Advisory Board: Pfizer, Merck, Lilly/Loxo, Seagen, Replimune, Personalis, Incyte; Financial Interests, Institutional, Invited Speaker: Genentech, Merck, Incyte, Seagen, Bristol Myers Squibb, Nucana, Daiichi Sankyo, Array. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD; Financial Interests, Personal, Invited Speaker: Organon, Novartis; Financial Interests, Personal, Other, Educational training: Seagen International GmbH; Financial Interests, Institutional, Funding: Hoffmann-La Roche Ltd, Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGAA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune; Non-Financial Interests, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Other, Travel, accommodations, expenses.: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol Myers Squibb. M. Stecher: Financial Interests, Personal, Full or part-time Employment: Seagen; Financial Interests, Personal, Stocks/Shares: Seagen. P. Cronin: Financial Interests, Institutional, Full or part-time Employment: Seagen; Financial Interests, Institutional, Stocks/Shares: Seagen. M. Bieda: Financial Interests, Institutional, Full or part-time Employment, I am an employee of Seagen: Seagen; Financial Interests, Personal, Stocks/Shares, I own stock and stock options in Seagen and have those promised for future: Seagen. T. Bekaii-Saab: Financial Interests, Institutional, Advisory Board: Bayer, Pfizer, Incyte, Ipsen, Seattle Genetics, Genentech, Merck KGA, Merus, Eisai, Servier; Financial Interests, Institutional, Other, DSMB: Merck; Financial Interests, Personal, Advisory Board: AbbVie, Boehringer Ingelheim, Janssen, AstraZeneca, Daiichi Sankyo, Natera, Celularity, Exact Science, Sobi, BeiGene, Xilis, Foundation Medicine, Stemline, Blueprint, Celularity, Caladrius, GSK, Deciphera, Zai Labs, Illumina, Sanofi; Financial Interests, Personal, Other, DSMB: AstraZeneca, Exelixis, The Valley Hospital, Fibrogen; Financial Interests, Personal, Other, DSMC: PanCAN; Financial Interests, Personal, Royalties, WO/2018/183488: HUMAN PD1 PEPTIDE VACCINES AND USES THEREOF – Licensed to Imugene: Imugene; Financial Interests, Personal, Royalties, WO/2019/055687: Methods And Compositions For The Treatment Of Cancer Cachexia – Licensed to Recursion: Recursion; Financial Interests, Institutional, Research Grant: Agios, Arys, Bayer, Amgen, Ipsen, Clovis, Pfizer, Celgene, Novartis, Arcus, Atreca, Mirati, Merus, Abgenomics, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Boston Biomedical, Incyte, Seattle Genetics; Non-Financial Interests, Advisory Role: Imugene, Sun Biopharma.

Background

Several analyses have shown prognostic impact of clinical and IHC markers in addition to genomic signatures in HR+/HER2 EBC. However, it remains unclear whether histology (e.g. invasive lobular BC (ILC) or further factors provide additional information. We present outcome from the prospective WSG-ADAPT HR+/HER- trial combining both static and dynamic biomarkers to optimize adjuvant therapy in luminal EBC.

Methods

pN0-1 with clinically high-risk HR+/HER2- EBC pts with RS0-11 OR RS12-25/Ki67_{postendocrine}≤10% after 3 +/- of preoperative ET received ET alone; the remaining high-risk cohort was randomized to the CT trial. Prognostic scores containing clinical factors with and w/out mutational/copy number data were derived retrospectively after splitting the data into training- and validation sets. LASSO and cross validation methods were used to predict iDFS in therapy subgroups. Additionally, multivariate Cox models were adapted using a forward-backward selection approach to identify prognostic markers.

Results

4491 pts were included (n=2246 ET- and n=2245 CT-treated). In the whole set, tumor and nodal (T/N) stage, RS and PR expression were prognostic for iDFS (Cox model). In ET-treated pts, only T-stage, RS and ER expression by RT-pCR were significant by Cox analysis, but prognostic score could not be determined. In CT-treated patients, T/N stage, G2-3 vs. G1, RS, ILC, and PR expression, but not IHC4 entered the model. In the CT cohort, a prognostic score consisting of T/N stage, age (≤50, >50), RS, ILC, PR expression and baseline and post-ET Ki67 yields a ROC AUC of 66% in the validation set. ILC was associated with lower RS than IDC (RS>25: 5.62% vs. 19.37%).High-risk CT-treated ILC had more frequently ERBB2 (11.6% vs. 2.5%) and a lower frequency of CDH1 mutations (60.5% vs 70.7%). Only CCND1 amplification was associated with worse iDFS in the NGS sub-cohort (n=584).

Conclusions

Use of RS in combination with further clinical and genetic factors improves prognostic ability; however, there is no treatment-independent prognostic model for HR+ HER2- EBC pts. For the first time, we have shown worse prognosis of the ILC high-risk subgroup, associated with distinct biological features.

Clinical trial identification

NCT01779206.

Legal entity responsible for the study

West German Study Group.

Funding

Exact Science.

Disclosure

O. Gluz: Financial Interests, Personal, Advisory Board: Roche, Lilly, Amgen, Novartis, Pierre Fabre, MSD, Celgene, Pfizer, Gilead, Molecular Health, Seagen, Agendia; Financial Interests, Personal, Invited Speaker: AstraZeneca, Exact Science; Financial Interests, Institutional, Coordinating PI: Roche, LIlly; Non-Financial Interests, Leadership Role: West German Study Group; Non-Financial Interests, Personal, Proprietary Information: West German Study Group. U.A. Nitz: Financial Interests, Personal, Advisory Board: Exact Science. S. Kummel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Seagen. Pfizer, pfm Medical, Roche, Somatex, Gilead. M. Braun: Financial Interests, Personal, Advisory Board: AstraZeneca, Exact Sciences, Novartis, Pfizer, Roche, Teva. B. Aktas: Financial Interests, Personal, Advisory Board: Pfizer, Roche Pharma, Merck Sharp & Dohme, onkowissen.de, Novartis Pharma, AstraZeneca, PharmaMar, Lilly, promedicis. R.F.L. Baehner: Financial Interests, Personal, Full or part-time Employment: Exact Science. M. Graeser: Financial Interests, Personal, Advisory Board: AstraZeneca. R. Würstlein: Financial Interests, Personal, Advisory Board: Agendia, Amgen, Apogheva, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, MSD, Nanostring, Novartis, Pfizer, Pierre Fabre, Riemser, Roche, Sanofi Genzyme, Seagen, Stemline, Clinsol; Financial Interests, Personal, Invited Speaker: Aristo, Clovis Oncology, Eisai, Palleos, PINK, FOMF, Aurikamed, Pomme Med, medconcept, MCI; Financial Interests, Personal, Writing Engagement: Hexal; Financial Interests, Institutional, Funding: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Coordinating PI: WSG, PINK; Financial Interests, Institutional, Local PI: BKFZ; Non-Financial Interests, Advisory Role: PINK, Brustkrebs Deutschland e.V., Junge Erwachsene Mit Krebs, AGO Kommission Mamma, AGSMO, DKG, TZM, CCC München, Mammamia. H. Kreipe: Financial Interests, Personal, Advisory Board: Roche Pharma, Novartis, Genomic Health, AstraZeneca, Lilly, Pfizer. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Art Tempi, Onkowissen, Medscape, Gilead, Sanofi, Zuelligpharma, Viatris; Financial Interests, Personal, Other, IDMC: Roche; Financial Interests, Personal, Advisory Board: Sandoz-Hexal, Seagen, Aptitude Health, Pfizer, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Palleos, Seagen, TRIO, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. All other authors have declared no conflicts of interest.