Found 1 Presentation For Request " 147P"

ePoster (ID 65) ePoster

147P - Pharmacokinetics, safety, and efficacy of trastuzumab deruxtecan (T-DXd) with OATP1B/CYP3A inhibitors in patients with HER2-expressing advanced solid tumours

Presentation Number
147P
Lecture Time
12:00 - 12:00
Presenter
  • Masato Takahashi (Sapporo, Hokkaido, Japan)
Session Name
ePoster (ID 65)
Room
ePosters
Date
23.05.2020
Time
12:00 - 20:00
Authors
  • Masato Takahashi (Sapporo, Hokkaido, Japan)
  • Yung-Jue Bang (Seoul, Korea, Republic of)
  • Masato Karayama (Hamamatsu, Japan)
  • Junichiro Watanabe (Shizuoka, Shizuoka, Japan)
  • Hironobu Minami (Kobe, Japan)
  • Noboru Yamamoto (Chuo-ku, Japan)
  • Ichiro Kinoshita (Sapporo, Japan)
  • Chia Chi Lin (Taipei, Taiwan)
  • Young-Hyuck Im (Seoul, Korea, Republic of)
  • Toshitaka Fujiki (Tokyo, Japan)
  • Issei Achiwa (Tokyo, Japan)
  • Emi Kamiyama (Tokyo, Japan)
  • Yasuyuki Okuda (Tokyo, Japan)
  • Caleb Lee (Basking Ridge, United States of America)
  • Shunji Takahashi (Tokyo, Japan)

Abstract

Background

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload (DXd; exatecan derivative). DXd is a substrate for CYP3A enzymes and OATP1B drug transporter. T-DXd demonstrated antitumor activity and manageable safety in HER2-expressing/mutated solid tumors (NCT02564900). This study (NCT03383692) assessed the effect of concomitant ritonavir (OATP1B/CYP3A inhibitor) or itraconazole (CYP3A strong inhibitor) on the PK profile of T-DXd and DXd.

Methods

Eligible patients (pts) had HER2-expressing (IHC ≥1+ and/or ISH+) unresectable/metastatic solid tumors. T-DXd 5.4 mg/kg was administered IV in 3-week cycles (C). Ritonavir 200 mg bid (cohort 1) or itraconazole 200 mg qd/bid (cohort 2) were administered from day 17 of C 2 to end of C 3. Primary endpoints were Cmax and AUC17d. TEAEs and objective tumor response rate (ORR) were secondary endpoints.

Results

Forty pts were enrolled (17 in cohort 1; 23 in cohort 2). Breast cancer was the most common cancer (42.5%). In the PK analysis set (n = 26; majority of exclusions were due to inhibitor drug noncompliance), there was a small increase in AUC17d for DXd and T-DXd with concomitant ritonavir or itraconazole (Table). In the safety analysis set (n = 40), 39 (97.5%) had a TEAE, 5 (12.5%) reported ≥1 serious TEAE, and 2 had ILD/pneumonitis (both grade 1 or 2 and had resolved). The most common TEAEs included nausea (80.0%), decreased appetite (55.0%), and constipation (37.5%). TEAE incidence did not increase in C 3 vs 2. Confirmed ORR was 15/36 (41.7%) in pts with measurable tumors at baseline (n = 36).

Pharmacokinetics of T-DXd and DXd without (cycle 2) and with (cycle 3) concomitant ritonavir (CYP3A/OATP1B inhibitor) or itraconazole (CYP3A strong inhibitor)

Ritonavir
Parameters LS means Ratio 90% CI
C2 C3 C3/C2 Lower Upper
AUC17d(d*ng/mL)a 30.2 36.6 1.215 1.078 1.370
DXd Cmax (ng/mL)b 8.49 8.38 0.987 0.854 1.140
T-DXd AUC17d (d*ug/mL)a 623 742 1.192 1.140 1.246
Cmax (ug/mL)b 131 138 1.049 0.976 1.128
Itraconazole
Parameters LS means Ratio 90% CI
C2 C3 C3/C2 Lower Upper
DXd AUC17d (d*ng/mL)c 28.8 33.9 1.178 1.108 1.252
Cmax (ng/mL)c 8.43 8.78 1.042 0.917 1.184
T-DXd AUC17d(d*ug/mL)c 617 685 1.110 1.073 1.147
Cmax (ug/mL)c 137 140 1.025 0.963 1.091

aN = 8; bN = 12; cN = 14.

Conclusions

There was a small increase in AUC17d for T-DXd and DXd with concomitant ritonavir and itraconazole that was not considered to be clinically meaningful. Efficacy and safety of T-DXd were consistent with previous trials.

Clinical trial identification

NCT03383692.

Editorial acknowledgement

Medical editorial assistance was funded by Daiichi Sankyo and provided by John Togneri, PhD (Articulate Science LLC).

Legal entity responsible for the study

Daiichi Sankyo Co., Ltd.; AstraZeneca is a collaborator.

Funding

Daiichi Sankyo Co., Ltd.

Disclosure

M. Takahashi: Honoraria (self), personal fees: Chugai; Honoraria (self), personal fees: AstraZeneca; Honoraria (self), personal fees: Novartis; Honoraria (self), personal fees: Pfizer; Honoraria (self), personal fees: Kyowa Hakko-Kirin; Honoraria (self), personal fees: Eisai; Honoraria (self), personal fees: Eli Lilly; Honoraria (self), personal fees: Taiho; Honoraria (self), personal fees: Daiichi Sankyo. Y-J. Bang: Advisory/Consultancy: Samyang; Advisory/Consultancy, Research grant/Funding (institution): Beigene; Advisory/Consultancy, Research grant/Funding (institution): Green Cross; Advisory/Consultancy, Research grant/Funding (institution): Taiho Pharmaceutical; Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca/MedImmune; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): MSD Oncology; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Hanmi; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Astellas Pharma; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Genexine; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Macrogenics. J. Watanabe: Honoraria (self), personal fees: Daiichi Sankyo. H. Minami: Research grant/Funding (institution), personal fees and grant, clinical trials: Novartis; Research grant/Funding (institution): Asahi-Kasei Pharma; Research grant/Funding (institution): Astellas; Non-remunerated activity/ies, Other-clinical trial: AstraZeneca; Research grant/Funding (institution), grant and personal fees, clinical trials: Bayer; Research grant/Funding (institution), grant and personal fees: Behringer; Research grant/Funding (institution), grant and personal fees: Bristol-Myers Squibb; Honoraria (self), Other-personal fees: Celgene; Research grant/Funding (institution), grant and personal fees, clinical trials: Chugai; Research grant/Funding (institution), clinical trial: Daiichi Sankyo; Research grant/Funding (institution), grant and personal fees: DaiNihonSumitomo; Research grant/Funding (institution), grant and personal fees: Tamagawa Eizai; Honoraria (self), Other-personal fees: Janssen; Honoraria (self), Other-personal fees: Kowa; Research grant/Funding (institution), grant and personal fees: Kyowa-Kirin; Research grant/Funding (institution), grant and personal fees: Lilly; Research grant/Funding (institution), grant and personal fees: Merck Serono; Research grant/Funding (institution), grant and personal fees, clinical trials: MSD; Research grant/Funding (institution): Nihon Shinyaku; Research grant/Funding (institution), grant and personal fees, clinical trials: Nippon Chemiphar. N. Yamamoto: Honoraria (institution), Research grant/Funding (institution): Chugai; Research grant/Funding (institution): Taiho; Advisory/Consultancy, Research grant/Funding (institution), consulting fees: Eisai; Honoraria (institution), Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Quintiles; Research grant/Funding (institution): Astellas; Honoraria (institution), Research grant/Funding (institution): BMS; Research grant/Funding (institution): Novartis; Research grant/Funding (self): Daiichi Sankyo; Honoraria (institution), Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution), consulting fees: Boehringer Ingelheim; Research grant/Funding (institution): Kyowa-Hakko Kirin; Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (institution): AstraZeneca; Advisory/Consultancy, consulting fees: Otsuka; Advisory/Consultancy, consulting fees: Takeda; Advisory/Consultancy, consulting fees: Cimic; Research grant/Funding (institution): Janssen Pharma; Research grant/Funding (institution): MSD. Y-H. Im: Advisory/Consultancy, advisory board role/grant: AstraZeneca; Leadership role, other- advisory board role: Novartis; Leadership role, other- advisory board role: Hanmi; Leadership role, advisory board role/grant: Pfizer; Leadership role, other- advisory board role: Eisai; Leadership role, other- advisory board role: Amgen; Leadership role, other- advisory board role: MediPacto; Leadership role, other- advisory board role: Roche; Leadership role, other- advisory board role: Lilly. T. Fujiki: Full/Part-time employment: Daiicho Sankyo. I. Achiwa: Full/Part-time employment: Daiichi Sankyo. E. Kamiyama: Shareholder/Stockholder/Stock options, Full/Part-time employment: Daiichi Sankyo. Y. Okuda: Full/Part-time employment: Daiichi Sankyo Co., Ltd. C. Lee: Shareholder/Stockholder/Stock options, Full/Part-time employment: Daiichi Sankyo, Inc. S. Takahashi: Research grant/Funding (institution), grants and personal fees: Daiichi Sankyo; Research grant/Funding (institution), grants and personal fees: Novartis; Research grant/Funding (institution), grants and personal fees: Chugai; Research grant/Funding (institution), grants and personal fees: Merck Sharp & Dohme (MSD); Research grant/Funding (institution), grants and personal fees: Eisai; Research grant/Funding (institution), grants and personal fees: Bayer; Research grant/Funding (institution), grants and personal fees: AstraZeneca; Research grant/Funding (institution): Quintiles; Research grant/Funding (institution), grants and personal fees: Taiho. All other authors have declared no conflicts of interest.

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