330P - Pharmacokinetics (PK), safety, and efficacy of [fam-] trastuzumab deruxtecan with OATP1B/CYP3A inhibitors in subjects with HER2-expressing advanced solid tumours.

[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. 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. 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) Table Ritonavir Parameters LS Means Ratio 90% CI C2 C3 C3/C2 Lower Upper MAAA-1181a AUC 17d (d*ng/mL) a 30.2 36.6 1.215 1.078 1.370 C max (ng/mL) b 8.49 8.38 0.987 0.854 1.140 T-DXd AUC 17d (d*ug/mL) a 623 742 1.192 1.140 1.246 C max (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 AUC 17d (d*ng/mL) c 28.8 33.9 1.178 1.108 1.252 C max (ng/mL) c 8.43 8.78 1.042 0.917 1.184 T-DXd AUC 17d (d*ug/mL) c 617 685 1.110 1.073 1.147 C max (ug/mL) c 137 140 1.025 0.963 1.091 a N = 8; b N = 12; c N = 14. AUC 17d , area under the concentration-time curve from cycle day 1–17; CI, confidence interval; C max , 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. 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. NCT03383692. 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. Daiichi Sankyo, Co., Ltd. Daiichi Sankyo, Co., Ltd. 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. [ABSTRACT FROM AUTHOR]