386O - Exploratory biomarker analysis of DESTINY-CRC01, a phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd, DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC)

Background

T-DXd is an antibody–drug conjugate consisting of an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. In primary analyses of DESTINY-CRC01 (NCT03384940), T-DXd showed antitumor activity and a manageable safety profile in HER2+ mCRC pts (Siena ASCO 2020). We present exploratory biomarker data and its relation to response in HER2+ mCRC.

Methods

Pts with centrally confirmed HER2-expressing, RAS wildtype mCRC that progressed after ≥2 prior regimens received 6.4 mg/kg of T-DXd Q3W in 3 cohorts (A: HER2+, IHC3+, or IHC2+/ISH+, n = 53; B: IHC2+/ISH−, n = 15; C: IHC1+, n = 18). Circulating tumor DNA (ctDNA) samples at baseline (BL), cycle 4, day 1, and end of treatment, along with BL serum HER2 extracellular domain (HER2ECD) were analyzed as exploratory biomarkers. To correct for variation in plasma tumor fraction between samples, adjusted plasma ERBB2 copy number (ApCN) was calculated based on the maximum variant allele fraction (Siravegna CCR 2019). Exploratory cutoff values for ApCN in ctDNA and HER2ECD were defined as those with the maximum value of the Youden index for ORR.

Results

In cohort A, higher clinical response to T-DXd was observed with higher tumor or plasma HER2 expression (Table). Antitumor activity of T-DXd was seen in pts with or without ctDNA-detected activating RAS or PIK3CA mutations and was lower in pts with blood TMB high vs low (Table). In paired ctDNA samples collected at BL and disease progression from 30 pts, acquired alterations were observed in several genes, but none was common across pts (n = 12). Table: 386O

ORR by BL Biomarker Group

^aResponders had KRAS mutations.

Conclusions

This exploratory analysis of biomarker data in HER2+ mCRC pts administered T-DXd indicates that antitumor activity appears to be correlated with BL HER2 expression or amplification in tumor and liquid biopsy. Further investigations into potential mechanisms of resistance to and patient selection for T-DXd in HER2+ mCRC are warranted.

Clinical trial identification

NCT03384940.

Editorial acknowledgement

Under the guidance of the authors, assistance in medical writing and editorial support was provided by Alya R. Raphael, PhD, of ApotheCom.

Legal entity responsible for the study

Daiichi Sankyo.

Funding

Daiichi Sankyo and AstraZeneca.

Disclosure

S. Siena: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Amgen, AstraZeneca, Bayer, BMS, CheckmAb, Daiichi Sankyo, Merck, and Seattle Genetics. K. Raghav: Financial Interests, Personal, Other, Honoraria: Bayer, Daiichi, AstraZeneca, Seattle Genetics; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Bayer, Daiichi, AstraZeneca, Seattle Genetics. T. Masuishi: Financial Interests, Institutional, Research Grant: Daiichi Sankyo. K. Yamaguchi: Financial Interests, Personal, Research Grant: Daiichi Sankyo, Taiho Pharm, Sanofi, Ono, Yakurt Honsha; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharm, Eli Lilly, Takeda, Chugai Pharm, Ono, Bristol Myers Squibb, Bayer, Merck Biopharm. T. Nishina: Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Taiho Pharma, Chugai Pharma, MSD, Ono, Bristol Myers Squibb, Lilly, Dainippon Sumitomo Pharma. E. Elez: Financial Interests, Personal, Other, Honoraria: Amgen, Array Biopharma, Bayer, BristolMyersSquibb, Hoffman La-Roche, Merck Serono, Sanofi, Servier; Financial Interests, Institutional, Advisory Role, Advisory/Consultancy: Amgen, Array Biopharma, Bayer, BristolMyersSquibb, Hoffman La-Roche, Merck Serono, Sanofi, Servier; Financial Interests, Institutional, Research Grant: AbbVie, Amgen, Array Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, BristolMyersSquibb, GlaxoSmithKline, Hoffman La-Roche; Medimmune, Merck Serono, MSD, Novartis, Pierre-Fabre, Sanofi Aventis. I. Chau: Financial Interests, Personal, Advisory Board: Eli Lilly, Bristol Myers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, AstraZeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astellas; Financial Interests, Institutional, Research Grant: Eli Lilly, Janssen-Cilag; Financial Interests, Personal, Other, Honoraria: Eli Lilly, Eisai. M. Di Bartolomeo: Financial Interests, Personal, Other, Honoraria: Lilly, MSD, Servier; Financial Interests, Institutional, Other, Honoraria: Lilly; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: BMS; Financial Interests, Institutional, Research Grant: Lilly. H. Kawakami: Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb Co. Ltd., AstraZeneca K.K., Bayer yakuhin Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Taiho Pharmaceutical Co. Ltd.; l; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical Co. Ltd, and Eisai Co. Ltd.; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., and Chugai Pharmaceutical Co. Ltd. F. Suto: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. K. Kobayashi: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. M. Koga: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. K. Inaki: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. Y. Kuwahara: Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo Co., Ltd. I. Takehara: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. A. Grothey: Financial Interests, Institutional, Other, Honoraria: Bayer, Daiichi, Amgen, Regeneron, Merck/ MSD, Mirati, Natera, CARIS, Guardant Health, Boston Biomedicals, Roche/ Genentech, BMS, Foundation Medicine; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Bayer,Daiichi, Amgen, Regeneron, Merck/ MSD, Mirati, Natera, CARIS, Guardant Health, Boston Biomedicals, Roche/ Genentech, BMS, Foundation Medicine; Financial Interests, Institutional, Research Grant: Bayer, Boston Biomedicals, Natera, Caris, Foundation Medicine, Roche/ Genentech. T. Yoshino: Financial Interests, Personal, Other, Honoraria: Taiho, Chugai, Eli Lilly, Merc Biopharma, Bayer, Ono; Financial Interests, Institutional, Research Grant: Taiho, Sumitomo Dainippon, Ono, Chugai, Amgen, Parexel International, MSD, Daiichi Snakyo, Sanofi. All other authors have declared no conflicts of interest.