Trastuzumab deruxtecan with ritonavir, itraconazole safe to use for HER2+ diseases

Concomitant administration of the human epidermal growth factor receptor 2 (HER2)–targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) with the OATP1B/CYP3A inhibitor ritonavir or the strong CYP3A inhibitor itraconazole appears to be safe and does not produce a clinically meaningful change in the pharmacokinetics of T-DXd or DXd, according to a phase I study.

A total of 40 patients with HER2-expressing advanced solid tumours were given intravenous T-DXd 5.4 mg/kg every 3 weeks. Of these, 17 received ritonavir (cohort 1) and 23 received itraconazole (cohort 2) from day 17 of cycle 2 through the end of cycle 3.

Maximum serum concentration (C_max) and partial area under the concentration-time curve from beginning of cycle through day 17 (AUC_17d) for T-DXd and deruxtecan (DXd) with (cycle 3) and without (cycle 2) ritonavir or itraconazole treatment were the primary study endpoints.

T-DXd C_max did not significantly change whether administered with ritonavir (cycle 3/cycle 2 ratio, 1.05, 90 percent confidence interval [CI], 0.98–1.13) or itraconazole (cycle 3/cycle 2 ratio, 1.03, 95 percent CI, 0.96–1.09). While T-DXd AUC_17d increased from cycle 2 to 3, the cycle 3/cycle 2 ratio upper CI bound remained at ≤1.25 for both cohorts.

For DXd (cycle 3/cycle 2), the C_max ratio was 0.99 (90 percent CI, 0.85–1.14) for cohort 1 and 1.04 (0.92–1.18) for cohort 2. The corresponding AUC_17d ratio was 1.22 (90 percent CI, 1.08–1.37) and 1.18 (90 percent CI, 1.11–1.25).

In terms of the safety profile of T-DXd, additional risks were observed with the concomitant use of T-DXd and OATP1B/CYP3A inhibitors. Furthermore, T-DXd showed promising antitumour activity across tumour types.