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.
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.
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]).
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.
NCT03384940.
Daiichi Sankyo Co., Ltd.
Daiichi Sankyo Co., Ltd.
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.