84MO - A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01

Background

T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody and topoisomerase I inhibitor payload. Early studies have shown promising activity in advanced HER2-expressing tumors. DESTINY-CRC01 (NCT03384940) is a phase II, open-label, multicenter study of T-DXd in HER2-expressing mCRC.

Methods

Patients (pts) with centrally confirmed HER2-expressing, RAS-wild type mCRC that progressed on ≥ 2 prior regimens received T-DXd 6.4 mg/kg every 3 weeks (q3w) in 3 cohorts (A: HER2 IHC 3+ or IHC 2+/ISH+; B: IHC 2+/ISH−; C: IHC 1+). The primary endpoint was confirmed objective response rate (ORR) by independent central review in cohort A; secondary endpoints included, disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and ORR in cohorts B and C.

Results

At data cutoff (Aug 9, 2019), 78 pts (A, 53; B, 7; C, 18) had received T-DXd. Median age was 58.5 y, 52.6% of pts were male, and 89.7% had left colon or rectum cancer; median number of prior regimens was 4; all pts had prior irinotecan. Median treatment duration was 3.5 mo; 38.5% of pts remained on T-DXd treatment. The confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6-59.6%) in cohort A, including 1 CR and 23 PRs; median DOR was not reached. The ORR in pts with prior anti-HER2 treatment was 43.8% (7/16 pts; 95% CI, 19.8-70.1%). The DCR was 83.0% (44/53 pts; 95% CI, 70.2-91.9%); median PFS was 6.9 mo (95% CI, 4.1 mo-NE); median OS was not reached. No responses were observed in cohort B or C. Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 61.5% of 78 pts; the most common (≥10%) were neutrophil count decreased (21.8%) and anemia (14.1%). Seven pts (9.0%) had TEAEs leading to drug discontinuation. Five pts (6.4%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (2 grade 2; 1 grade 3; 2 grade 5 [the only drug related deaths]).

Conclusions

T-DXd demonstrated remarkable activity in pts with HER2-expressing mCRC refractory to standard therapies, with a safety profile consistent with previous results. ILD is an important risk and requires careful recognition and intervention.

Clinical trial identification

NCT03384940.

Editorial acknowledgement

Legal entity responsible for the study

Daiichi Sankyo Co., Ltd.

Funding

Daiichi Sankyo Co., Ltd.

Disclosure

T. Yoshino: Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Eli Lilly Japan K.K.; Bayer Yakuhin, Ltd.; Merck Biopharma Co., Ltd.; Takeda Pharmaceutical Company Limited; Research grant/Funding (institution): MSD K.K.; Ono Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Sumitomo Dainippon Pharma Co., Ltd; Parexel International Inc.; Sanofi K.K.; Amgen K.K. S. Siena: Advisory/Consultancy, Travel/Accommodation/Expenses, Licensing/Royalties: Amgen; Advisory/Consultancy: Roche/Genetech; Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy: Bristol-Myers Squibb; Clovis Oncology; Daiichi Sankyo; Incyte; Merck; Novartis; Seattle Genetics; CheckmAb; Research grant/Funding (institution): MSD Oncology; Travel/Accommodation/Expenses: Roche; Shareholder/Stockholder/Stock options: Guardant Health; Shareholder/Stockholder/Stock options: Myriad Genetics. M. Di Bartolomeo: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly SpA; Honoraria (self), Speaker Bureau/Expert testimony: MSD; Honoraria (self): Merck Serono; Honoraria (self): Servier; Travel/Accommodation/Expenses: Roche. K. Raghav: Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: AstraZeneca. T. Masuishi: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Merck Serono; Honoraria (self): Chugai Pharma; Honoraria (self): Yakult ; Honoraria (self): Takeda; Honoraria (self): Eli Lilly; Honoraria (self): Bayer Yakuhin; Honoraria (self): Sanofi; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Ono Pharmaceutical. F. Loupakis: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono. H. Kawakami: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory/Consultancy: Eli Lilly Japan; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self): Takeda; Honoraria (self), Advisory/Consultancy: MSD KK; Research grant/Funding (institution): Eisai. K. Yamaguchi: Honoraria (institution): Daiichi Sankyo; Honoraria (institution): Taiho Pharmaceutical; Honoraria (institution): Chugai Pharma; Honoraria (institution): Ono Pharmaceutical; Honoraria (institution): Eli Lilly; Honoraria (institution): Sanofi; Honoraria (institution): MSD; Honoraria (institution): Sumitomo Dainippon Pharma; Honoraria (institution): Gilead Sciences; Honoraria (institution): Boehringer Ingelheim; Honoraria (institution): Eisai; Honoraria (institution): Yakult; Speaker Bureau/Expert testimony: Bristol-Myers Squibb Japan; Speaker Bureau/Expert testimony: Takeda. T. Nishina: Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Chugai Pharma; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Merck Serono; Honoraria (self): Takeda; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Nihonkayaku; Research grant/Funding (institution): Sumitomo Dainippon Pharma; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Ono Pharmaceutical. M. Fakih: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Amgen; Advisory/Consultancy: Array BioPharma; Advisory/Consultancy: Bayer; Advisory/Consultancy: Pfizer; Speaker Bureau/Expert testimony: Guardant360; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): AstraZeneca. E. Elez: Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: F. Hoffman-La Roche; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Servier; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Array Biopharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (institution): MSD; AbbVie; GSK; AstraZeneca; Novartis; Boehringer Ingelheim. F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Pierre; Research grant/Funding (institution): Ipsen. K. Saxena; E. Yamamoto; K. Kobayashi; E. Bako; Y. Okuda: Full/Part-time employment, employee: Daiichi Sankyo. A. Grothey: Honoraria (self): Elsevier; Aptitude Health; Imedex; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Boston Biomedical; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Array BioPharma; Advisory/Consultancy: Guardant Health; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Eisai; Travel/Accommodation/Expenses: Boehringer Ingelheim; Travel/Accommodation/Expenses: Merck Sharp & Dohme. All other authors have declared no conflicts of interest.