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 C_max and AUC_17d. 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 AUC_17d 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)

Conclusions

There was a small increase in AUC_17d 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.