disitamab vedotin

Shows activity

Also known as:

RC48 Aidixi

Cancer types include:

bladder cancer breast cancer stomach cancer

HealthScout AI Analysis

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Overview

Disitamab vedotin (DV; RC48; Aidixi) is a HER2‑directed antibody–drug conjugate (ADC) consisting of the humanized anti‑HER2 antibody hertuzumab linked via a protease‑cleavable mc‑val‑cit‑PABC linker to the microtubule inhibitor monomethyl auristatin E (MMAE). It has shown antitumor activity across multiple HER2‑expressing solid tumors, including urothelial, gastric/gastroesophageal junction (G/GEJ), and breast cancers. DV received its first approval in China in June 2021 for previously treated HER2‑overexpressing G/GEJ cancer. (pmc.ncbi.nlm.nih.gov)

Mechanism of action

Target: human epidermal growth factor receptor 2 (HER2). The hertuzumab antibody has high HER2 affinity and enhanced ADCC compared with trastuzumab in preclinical work. (ncbi.nlm.nih.gov)
Linker/payload: MMAE is attached via a cleavable maleimidocaproyl‑valine‑citrulline‑PABC linker (average drug‑to‑antibody ratio ≈4), enabling intracellular release after lysosomal protease cleavage. The cleavable linker confers a “bystander effect,” potentially benefiting heterogeneous HER2 expression. (pmc.ncbi.nlm.nih.gov)
Payload action: released MMAE disrupts microtubules, causing G2/M arrest and apoptosis. (pmc.ncbi.nlm.nih.gov)

Efficacy

Urothelial carcinoma (UC) - Phase II pooled analysis (RC48‑C005/C009; HER2‑positive la/mUC after ≥1 prior systemic therapy; n=107):
- ORR 50.5% (95% CI 40.6–60.3) by blinded independent review; median DoR 7.3 months; median PFS 5.9 months; median OS 14.2 months. Activity was seen across subgroups, including those with liver metastases and prior PD‑1/L1 therapy. (pubmed.ncbi.nlm.nih.gov) - Phase Ib/II combination with toripalimab (RC48‑C014; HER2‑unselected la/mUC; n=41; RP2D DV 2.0 mg/kg q2w + toripalimab 3 mg/kg q2w):
- Confirmed ORR 73.2%; median PFS 9.3 months; median OS 33.1 months (data cutoff March 1, 2024). (pubmed.ncbi.nlm.nih.gov) - Additional real‑world/retrospective data suggest clinically meaningful activity of DV plus PD‑1 inhibitors in metastatic upper tract UC, with ORR ~59% and median PFS ~13 months (limitations: retrospective design, China‑only cohorts). (pubmed.ncbi.nlm.nih.gov)

Gastric/gastroesophageal junction (G/GEJ) cancer - DV received its first approval in China (June 2021) for previously treated HER2‑overexpressing G/GEJ cancer. (pubmed.ncbi.nlm.nih.gov) - Early‑phase combination studies of DV with PD‑1 inhibitors have reported encouraging activity in HER2‑expressing G/GEJ disease (dose‑escalation/expansion study with toripalimab established RP2D of DV 2.5 mg/kg + toripalimab 3 mg/kg q2w; preliminary efficacy reported). (pubmed.ncbi.nlm.nih.gov) - A multicenter real‑world third‑line‑and‑beyond cohort showed higher ORR and longer PFS with DV plus immune checkpoint inhibitors versus DV alone in HER2‑positive or HER2‑low G/GEJ cancer (ORR 36% vs 10%; median PFS 6.2 vs 3.9 months). (bmccancer.biomedcentral.com)

Breast cancer - Phase I/Ib pooled analysis in advanced breast cancer (HER2‑overexpressing and HER2‑low): at the 2.0 mg/kg q2w dose, confirmed ORR was 42.9% in HER2‑overexpressing and 33.3% in HER2‑low cohorts; median PFS 5.7 and 5.1 months, respectively. (onlinelibrary.wiley.com) - Retrospective real‑world series in previously trastuzumab‑treated metastatic HER2‑positive disease reported ORR 29.6% and median real‑world PFS 5.9 months. (pubmed.ncbi.nlm.nih.gov)

Safety

Across trials, the most frequent treatment‑related adverse events (TRAEs) include peripheral sensory neuropathy, hematologic toxicity (neutropenia, leukopenia), and transaminase elevations—generally consistent with MMAE‑based ADCs. In the pooled phase II UC analysis, any‑grade peripheral sensory neuropathy occurred in 68.2% (grade ≥3 in 18.7%); leukopenia in 50.5%; neutropenia in 42.1%. (pubmed.ncbi.nlm.nih.gov)

With DV plus toripalimab in la/mUC (RC48‑C014), common TRAEs were AST increased (65.9%), ALT increased (63.4%), and peripheral sensory neuropathy (63.4%); grade ≥3 TRAEs occurred in 51.2%, and one treatment‑related death (pneumonitis) was reported. (pubmed.ncbi.nlm.nih.gov)

In the phase I/Ib breast cancer program, grade ≥3 events ≥5% included decreased neutrophil count (17.6%), GGT increased (13.2%), asthenia (11.0%), decreased WBC (9.6%); neuropathy events were observed but severe neurotoxicity was uncommon. (onlinelibrary.wiley.com)

Active trials using disitamab vedotin

Found 4 active trials using this drug:

A Phase 1b/2, Open-Label, Multicohort Study of Disitamab Vedotin in Adults With HER2 Expressing Advanced Breast Cancer

Sponsor: Pfizer (industry) Phase: 1/2 Start date: June 30, 2025

HealthScout AI summary: Enrolling adults with previously treated, locally advanced/metastatic breast cancer across HER2+ to HER2-low/ultralow (cohorts by HER2 and HR status, generally after standard HER2 therapies and/or CDK4/6i, PARPi, checkpoint inhibitors, and prior T-DXd as applicable). Single-arm disitamab vedotin (HER2-targeted MMAE antibody–drug conjugate) IV q2w until progression; excludes active CNS disease and prior MMAE ADCs.

ClinicalTrials.gov ID: NCT06966453

A Phase 1b/2 Open-Label Study of Disitamab Vedotin in Combination With Other Anticancer Therapies in Solid Tumors

Sponsor: Seagen, a wholly owned subsidiary of Pfizer (industry) Phase: 2 Start date: May 20, 2024

HealthScout AI summary: This trial enrolls patients with locally advanced or metastatic breast cancer or gastric/gastroesophageal junction adenocarcinoma—either HER2-low or HER2-positive—who have progressed on or are intolerant to standard therapy, and treats them with the combination of disitamab vedotin (an anti-HER2 antibody-drug conjugate delivering MMAE) and tucatinib (a HER2 tyrosine kinase inhibitor). Four cohorts are studied based on tumor type and HER2 expression.

ClinicalTrials.gov ID: NCT06157892

An Open-label, Randomized, Controlled Phase 3 Study of Disitamab Vedotin in Combination With Pembrolizumab Versus Chemotherapy in Subjects With Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma That Expresses HER2 (IHC 1+ and Greater)

Sponsor: Seagen, a wholly owned subsidiary of Pfizer (industry) Phase: 3 Start date: Sept. 22, 2023

HealthScout AI summary: Adults with previously untreated, unresectable locally advanced or metastatic urothelial carcinoma that is HER2-expressing (IHC ≥1+), ECOG 0–2, and eligible for cisplatin or carboplatin are randomized to disitamab vedotin (HER2-directed MMAE antibody-drug conjugate) plus pembrolizumab (anti–PD-1) versus standard gemcitabine/platinum chemotherapy. Key exclusions include active/untreated CNS metastases, significant prior immune-related toxicity or active autoimmune disease, prior anti-HER2/MMAE ADCs, and prior transplants.

ClinicalTrials.gov ID: NCT05911295

A Phase 2 Multi-Cohort, Open-Label, Multi-Center Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin (RC48-ADC) Alone or in Combination With Pembrolizumab in Subjects With Locally-Advanced Unresectable or Metastatic Urothelial Carcinoma That Expresses HER2

Sponsor: Seagen, a wholly owned subsidiary of Pfizer (industry) Phase: 2 Start date: May 3, 2022

HealthScout AI summary: Adults with HER2-expressing (IHC 1+–3+) locally advanced unresectable or metastatic urothelial carcinoma, across multiple lines/settings, receive disitamab vedotin (HER2-directed MMAE antibody–drug conjugate) alone or combined with pembrolizumab (anti–PD-1), including a randomized first-line chemo-eligible cohort comparing the combo vs DV monotherapy. Key exclusions include prior HER2-directed therapy and most prior MMAE-based ADCs; prior platinum/PD-(L)1/enfortumab exposure requirements vary by cohort.

ClinicalTrials.gov ID: NCT04879329