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

Abstract 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 5.4mg/kg was administered IV in 3-week cycles. Ritonavir 200mg BID (cohort 1) or itraconazole 200mg 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).Table330P Pharmacokinetics of T-DXd and MAAA-1181a without (cycle 2) and with (cycle 3) concomitant ritonavir (CYP3A/OATP1B inhibitor) or itraconazole (CYP3A strong inhibitor)TableRitonavirParametersLS MeansRatio90% CIC2C3C3/C2LowerUpperMAAA-1181aAUC17d(d*ng/mL)a30.236.61.2151.0781.370Cmax (ng/mL)b8.498.380.9870.8541.140T-DXdAUC17d(d*ug/mL)a6237421.1921.1401.246Cmax (ug/mL)b1311381.0490.9761.128ItraconazoleParametersLS MeansRatio90% CIC2C3C3/C2LowerUpperMAAA-1181aAUC17d(d*ng/mL)c28.833.91.1781.1081.252Cmax (ng/mL)c8.438.781.0420.9171.184T-DXdAUC17d(d*ug/mL)c6176851.1101.0731.147Cmax (ug/mL)c1371401.0250.9631.091aN=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; Hon ...