Abstract PS5-02-09: Unconjugated MMAE Pharmacokinetics in Combination with Tucatinib in Patients with HER2 Expressing Locally Advanced or Metastatic Breast and Gastric Cancer

Abstract Background: Disitamab vedotin (DV) is a human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload via a maleimidocaproyl-valine-citrulline (MC-VC) linker. MMAE is primarily metabolized in vitro by cytochrome P450 3A4 (CYP3A4) and is a substrate of P-glycoprotein (P-gp). A clinical drug-drug interaction (DDI) study previously showed that ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased unconjugated MMAE exposure 1.34-fold following brentuximab vedotin (BV) treatment in patients with CD30+ hematologic malignancies1. Thus, current recommendations for concomitant use of MMAE-conjugated ADCs and a strong CYP3A4 inhibitor are limited to close monitoring for adverse events. However, it’s unclear whether a similar trend of increased exposure holds true for other MMAE-conjugated ADCs. In this study, unconjugated MMAE PK following DV administration was characterized with and without tucatinib, a strong CYP3A4 inhibitor and a known P-gp inhibitor currently approved for previously treated HER2 expressing metastatic breast cancer, to assess the impact of tucatinib-mediated CYP3A4 and P-gp inhibition on unconjugated MMAE PK. Methods: C5731004/SGNDV-004 (NCT06157892) is a phase 1b/2 open-label, multicenter study designed to identify the maximum tolerated dose (MTD) and/or optimal dose of DV when administered in combination with tucatinib in participants with HER2+ (IHC 3+ or IHC 2+/ISH+) and HER2-low (IHC 1+ or IHC 2+/ISH-) expressing locally advanced or metastatic breast cancer (LA/mBC) and locally advanced or metastatic gastric cancer and gastroesophageal junction adenocarcinoma (LA/mGC/GEJC). Participants in the dose escalation phase of SGNDV-004 received DV (1.25 mg/kg or 1.50 mg/kg IV Q2W) starting Cycle 1 Day 1 and tucatinib (TUC, 300 mg PO BID) starting Cycle 1 Day 8. Unconjugated MMAE PK blood samples were collected on Days 1, 2, 3, and 8 in Cycle 1 (DV alone) and Cycle 2 (DV+TUC). Unconjugated MMAE plasma concentrations were analyzed using validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The DDI assessment was made using unconjugated MMAE PK parameters following DV administration including plasma area under the concentration-time curve up to Day 8 (AUC0-168h) and maximal concentrations (Cmax) in Cycle 2 (test) relative to Cycle 1 (reference) and were calculated using PKNCA (R v4.3.1, PKNCA v0.10.2). Results: PK data were available for 6 patients at 1.25 mg/kg and 3 patients at 1.50 mg/kg. The geometric mean (geometric CV%) of Cycle 1 and Cycle 2 dose-normalized MMAE AUC0-168h values were 232.2 (83%) and 275.7 (101%) ng*hr/mL/(mg/kg), respectively. The geometric mean (geometric CV%) of Cycle 1 and Cycle 2 dose-normalized MMAE Cmax values were 1.87 (88%) and 2.40 (94%) ng/mL/(mg/kg), respectively. Geometric mean ratios (CI90%) for Cycle 2/Cycle 1 MMAE AUC0-168h and Cmax were 1.18 (1.05-1.35) and 1.28 (1.17-1.40), respectively. Conclusions: Unconjugated MMAE exposure following DV administration of 1.25 mg/kg or 1.5 mg/kg Q2W was increased