What question did this study set out to answer?

This study aims to evaluate the pharmacokinetics of unconjugated MMAE following the administration of disitamab vedotin in combination with tucatinib.

February 19, 2026

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

Q: What does this research mean for the field?

Unconjugated MMAE exposure is increased by less than 1.3-fold when administered with tucatinib in patients with HER2 expressing locally advanced or metastatic breast and gastric cancer. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Points

This study aims to evaluate the pharmacokinetics of unconjugated MMAE following the administration of disitamab vedotin in combination with tucatinib.
Open-label, multicenter Phase 1b/2 trial for HER2 expressing locally advanced or metastatic cancers.
Administered disitamab vedotin (1.25 mg/kg or 1.50 mg/kg IV) and tucatinib (300 mg PO) to participants.
Collected MMAE blood samples for pharmacokinetic analysis on specified days during treatment cycles.
Used validated HPLC-MS/MS to measure plasma concentrations of unconjugated MMAE.
Evaluated drug-drug interaction impact by comparing pharmacokinetic parameters in the presence and absence of tucatinib.
Data were analyzed for 9 patients (6 at 1.25 mg/kg, 3 at 1.50 mg/kg).
Cycle 1 and Cycle 2 dose-normalized MMAE AUC values: 232.2 ng*hr/mL/(mg/kg) and 275.7 ng*hr/mL/(mg/kg).
Cycle 1 and Cycle 2 dose-normalized MMAE Cmax values: 1.87 ng/mL/(mg/kg) and 2.40 ng/mL/(mg/kg).
Geometric mean ratios indicate a 1.18-fold increase for AUC and a 1.28-fold increase for Cmax in Cycle 2 compared to Cycle 1.
Overall findings suggest a weak drug-drug interaction impact associated with tucatinib.

Abstract

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 1.3-fold in the presence of tucatinib in participants with HER2 expressing LA/mBC or LA/mGC/GEJC, translating to an overall weak DDI impact. References 1.Han TH, Gopal AK, Ramchandren R, Goy A, Chen R, Matous JV, Cooper M, Grove LE, Alley SC, Lynch CM, O'Connor OA. CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies. J Clin Pharmacol. 2013 Aug;53(8):866-77. doi: 10.1002/jcph.116. Epub 2013 Jun 10. PMID: 23754575; PMCID: PMC3777854. Citation Format: A. SyBing, E. Garcia, J. Meyer, M. Miller, X. Li, V. Kumar, A. Topletz-Erickson. Unconjugated MMAE Pharmacokinetics in Combination with Tucatinib in Patients with HER2 Expressing Locally Advanced or Metastatic Breast and Gastric Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-09.

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

Key Points

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