Abstract 901
Background
[Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody drug conjugate comprised of a humanized HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload (MAAA-1181a; exatecan derivative). MAAA-1181a is a substrate for CYP3A enzymes and OATP1B. 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 MAAA-1181a.
Methods
Eligible subjects 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. Ritonavir 200 mg BID (cohort 1) or itraconazole 200 mg QD/BID (cohort 2) were administered from day 17 of cycle 2 to end of cycle 3. Primary endpoints were Cmax and AUC17d. TEAEs and objective tumor response rate (ORR) were secondary endpoints.
Results
Forty subjects 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 due to inhibitor drug noncompliance), there was a small increase in AUC17d for MAAA-1181a 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 (grade ≤3). The most common TEAEs included nausea (80.0%), decreased appetite (55.0%), and constipation (37.5%). TEAE incidence did not increase in cycle 3 vs 2. Confirmed ORR was 15/36 (41.7%) in subjects with measurable tumors at baseline (n = 36).Table:
330P Pharmacokinetics of T-DXd and MAAA-1181a 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 | ||
MAAA-1181a | AUC17d(d*ng/mL)a | 30.2 | 36.6 | 1.215 | 1.078 | 1.370 |
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 | ||
MAAA-1181a | 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 |
N = 8;
bN = 12;
cN = 14. AUC17d, area under the concentration-time curve from cycle day 1–17; CI, confidence interval; Cmax, maximum plasma concentration; C2, cycle 2; C3, cycle 3; LS, least squares; MAAA-1181a, topoisomerase I inhibitor payload (exatecan derivative) that is released from T-DXd; T-DXd, [fam-] trastuzumab deruxtecan.
Conclusions
There was a small increase in AUC17d for T-DXd and its payload with concomitant ritonavir and itraconazole that did not appear to be clinically meaningful. Efficacy and safety of T-DXd were consistent with previous trials.
Clinical trial identification
NCT03383692.
Editorial acknowledgement
Medical writing and editorial support was provided by Alicia Salinero, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC, and funded by Daiichi Sankyo, Co., Ltd.
Legal entity responsible for the study
Daiichi Sankyo, Co., Ltd.
Funding
Daiichi Sankyo, Co., Ltd.
Disclosure
Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Merck Serano; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Taiho; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy, Research grant / Funding (institution): Green Cross; Advisory / Consultancy: Samyang Biopharm; Advisory / Consultancy: Hanmi; Advisory / Consultancy, Research grant / Funding (institution): Genexine; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Boeringer-Ingelheim; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): FivePrime; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Ono; Research grant / Funding (institution): CKD Pharma. M. Takahashi: Honoraria (self): Chugai; Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Kyowa Hakko-Kirin; Honoraria (self): Eisai; Honoraria (self): Eli Lilly; Honoraria (self): Taiho; Honoraria (self): Daiichi Sankyo. J. Watanabe: Honoraria (self): Daiichi Sankyo. H. Minami: Honoraria (self), Research grant / Funding (institution), clinical trial: Novartis; Research grant / Funding (institution): Asahi-Kasei Pharma; Research grant / Funding (institution): Astellas; Research grant / Funding (institution), clinical trial: AstraZeneca; Honoraria (self), Research grant / Funding (institution), clinical trial: Bayer; Honoraria (self), Research grant / Funding (institution): Behringer; Honoraria (self), Research grant / Funding (institution), clinical trial: Bristol-Myers Squibb; Honoraria (self): Celgene; Honoraria (self), Research grant / Funding (institution), clinical trial: Chugai; Research grant / Funding (institution), clinical trial: Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): DaiNihonSumitomo; Honoraria (self), Research grant / Funding (institution): Eizai; Honoraria (self): Janssen; Honoraria (self): Kowa; Honoraria (self), Research grant / Funding (institution): Kyowa-Kirin; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self), Research grant / Funding (institution), clinical trial: MSD; Research grant / Funding (institution): Nihon Shinyaku; Honoraria (self), Research grant / Funding (institution): Nippon Chemiphar; Honoraria (self), Research grant / Funding (institution), clinical trial: Ono Yakuhin; Honoraria (self): Ohtsuka; Honoraria (self), Research grant / Funding (institution), clinical trial: Pfizer; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self): Shire Japan; Honoraria (self), Research grant / Funding (institution), clinical trial: Taiho; Research grant / Funding (institution): Taisho-Toyama; Honoraria (self), Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Teijin Pharma; Research grant / Funding (institution): Yakult; Honoraria (self): Genomic Health; Research grant / Funding (institution): CSL Behring; Research grant / Funding (institution): Nihon Kayaku; Research grant / Funding (institution): Shionogi. N. Yamamoto: Honoraria (self), Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Taiho; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Quintiles; Research grant / Funding (institution): Astellas; Honoraria (self), Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Kyowa-Hakko Kirin; Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): ONO PHARMACEUTICAL CO., LTD; Honoraria (self): Chugai; Honoraria (self): AstraZeneca; Advisory / Consultancy: Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy: Cimic; Research grant / Funding (institution): Janssen Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (self): Merck. C. Lin: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Roche; Research grant / Funding (institution): Daiichi Sankyo; Travel / Accommodation / Expenses: BeiGene. T. Fujiki: Full / Part-time employment: Daiichi Sankyo. I. Achiwa: Full / Part-time employment: Daiichi Sankyo. E. Kamiyama: Full / Part-time employment: Daiichi Sankyo. Y. Okuda: Full / Part-time employment: Daiichi Sankyo. C. Lee: Full / Part-time employment: Daiichi Sankyo. S. Takahashi: Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self): Novartis; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Quintiles. All other authors have declared no conflicts of interest.
Resources from the same session
4906 - Tumor-infiltrating lymphocytes (TILs) in patients with epithelial ovarian cancer undergoing neoadjuvant chemotherapy: A restrospective study
Presenter: Sara Giovannoni
Session: Poster Display session 2
Resources:
Abstract
3919 - Prognostic significance of elements of the adaptive immunity in the microenvironment of epithelial ovarian cancer.
Presenter: Periklis Foukas
Session: Poster Display session 2
Resources:
Abstract
5139 - Neutrophil-to-lymphocyte ratio predicts platinum sensitivity in epithelial ovarian cancer patients: a MITO24 retrospective study
Presenter: Alberto Farolfi
Session: Poster Display session 2
Resources:
Abstract
4212 - The prognostic impact of monocyte to lymphocyte ratio (MLR) in advanced epithelial ovarian cancer (EOC)
Presenter: Marc Cucurull Salamero
Session: Poster Display session 2
Resources:
Abstract
5123 - TP53 Hotspot mutations as immunoreactive neoantigens define a signature with differential survival outcomes in advanced ovarian cancer
Presenter: Marica Garziera
Session: Poster Display session 2
Resources:
Abstract
3795 - Use of bevacizumab (Bev) in real life for first-line (fl) treatment of ovarian cancer (OC)/ The GINECO ENCOURAGE cohort of 500 French patients
Presenter: Dominique Berton-Rigaud
Session: Poster Display session 2
Resources:
Abstract
2359 - Phase II study: Letrozole maintenance therapy after first line chemotherapy in patients with advanced serous and endometrioid ovarian cancer
Presenter: Alexandra Tyulyandina
Session: Poster Display session 2
Resources:
Abstract
3619 - Baseline IPI (Immune Prognostic Index) predicts survival in patients with advanced cervical cancer treated with immune checkpoint inhibitors (ICI).
Presenter: Felix Blanc-Durand
Session: Poster Display session 2
Resources:
Abstract
3474 - Preselecting tumor-infiltrating lymphocyte subsets to implement adoptive inmmunotherapy in ovarian cancer
Presenter: Diego Salas-Benito
Session: Poster Display session 2
Resources:
Abstract
5134 - Early prediction of the platinum-resistant relapse risk using the CA125 modeled kinetic parameter KELIM: a pooled analysis of AGO-OVAR 7 & 9; ICON 7 (AGO/GINECO/ MRC CTU/GCIG trials).
Presenter: OLIVIER COLOMBAN
Session: Poster Display session 2
Resources:
Abstract