From the Desk of Evan Yu: "Antibody Drug Conjugates for Urothelial Carcinoma, a Cool Technology with Promising Results"

Antibody drug conjugates (ADCs) are a promising method of selective intensification of therapy, offering increased drug concentration to the target with minimal collateral damage to healthy tissue.1   Structurally, ADCs are monoclonal antibodies specific for a tumor antigen connected by a linker molecule to a cytotoxic drug payload.  After endocytotic internalization of the complex, the linker is degraded in a lysosome, releasing the cytotoxic payload.  There are now many FDA approved ADCs, including brentuximab vedotin for anaplastic2 and refractory Hodgkin lymphomas,3 trastuzumab emtansine for refractory HER/neu positive breast cancer4 and inotuzumab ozogamicin for relapsed B-cell precursor acute lymphoblastic leukemia.5 Currently, there are no regulatory approved ADCs for urothelial bladder cancer; however, there is promising early data and many agents in current clinical trial investigation.

Sacituzumab govitecan is an ADC targeted to Trop-2, a cell-surface glycoprotein highly expressed in muscle-invasive bladder cancer.  The antibody to Trop-2 is conjugated to SN-38, the active metabolite of irinotecan.  In a phase 1/II trial, 41 patients with urothelial carcinoma demonstrated a 34% overall response rate (ORR) to Sacituzumab govitecan, with good tolerability and a significant number of durable responses.6

ASG-15ME is a ADC targeted to SLITRK, a protein expressed in 90% of bladder cancers.7  In a phase 1 trial of heavily pre-treated metastatic urothelial carcinoma patients, 1 mg/kg was identified as the maximum tolerated dose (MTD) and toxicity was predictable, with reversible ocular adverse events occurring in 29.4% of patients.8  Among the 51 patients across all dosing levels, there were 1 complete response and 17 partial responses for a 37.5% ORR.  However, unique subgroups showed impressive results with ORR 50% at the MTD, 53% in checkpoint inhibitor exposed patients and 46% in patients with hepatic metastases.

Another ADC with impressive phase 1 results is enfortumab vedotin, an ADC targeting Nectin-4, which is highly expressed in urothelial carcinoma.9  Of 68 metastatic urothelial carcinoma patients treated, the agent was well tolerated with grade ≥3 hypophosphatemia occurring only in 9%.  Significant antitumor activity was noted with ORR 40% for the entire dose range (3 with CR), 46% for prior checkpoint inhibitor treated patients, and 44% for those with liver metastasis.  As a result, a phase 2 trial (NCT03219333) has been initiated with the goal of achieving accelerated approval in the 3rd line metastatic setting.  Additionally, a phase 1 trial (NCT03299545) in combination with either atezolizumab or pembrolizumab was recently launched.  A randomized phase 3 is currently being designed.

Multiple other targets are promising for ADC development in urothelial carcinoma.  For instance, HER2 is highly expressed in 37-50% of urothelial carcinoma,10 and targeting of such with antibodies, like trastuzumab, have previously led to high response rates when combined with standard platinum-based chemotherapy.11  DS-8201a, is a ADC that links trastuzumab to a novel topoisomerase I inhibitor, DXd.  Early results have shown 45.5% response rates in HER2 expressing gastric cancer when combined with chemotherapy.12 In HER2 expressing breast cancer, 61.4% ORR was observed in a heavily pretreated population.13 In HER2 low expressing breast cancers, 31.6% ORR was observed in a heavily pre-treated population.  As a result, the FDA has granted breakthrough therapy designation for DS-8201a for HER2 positive locally advanced or metastatic breast cancer previously treated with trastuzumab/pertuzumab and disease progression after trastuzumab emtansine.  Given the high expression of HER2 in urothelial bladder cancer, DS-8201a is primed for future evaluation in this disease.

Please see below for select trials of some ADCs where patients with urothelial carcinoma are either the target population or accrual of such patients are allowed.

Select Trials with Antibody Drug Conjugates


Written by: Evan Yu, MD


References

  1. Ngayama A, Ellisen LW, Chabner B, Bardia A.  Antibody drug conjugates for the treatment of solid tumors: Clinic experience and latest developments.  Target Oncol 2017; 12:719-39.
  2. Pro B, Advani R, Price P, et al.  Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study.  J Clin Oncol 2012; 30:2190-6.
  3. Moskowitz CH, Nademanee A, Masszi T, et al.  Brentuximab vedotin as consolidation therapy  after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomized, double-blind, placebo-controlled, phase 3 trial.  Lancet 2015; 385:1853-62.
  4. Verma S, Miles D, Gianni L, et al.  Trastuzumab emtansine for HER2-positive advanced breast cancer.  N Engl J Med 2012; 367:1783-91.
  5. Kantarjian HM, DeAngelo DJ, Stelljes M, et al.  Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia.  N Engl J Med 2016; 375:740-53.
  6. Tagawa ST, Faltas B, Lam E, et al.  Sacituzumab govitecan (IMMU-132) for patients with pretreated metastatic urothelial cancer: interim results.  Ann Oncol 2017; 28(suppl_5):v295-v329.
  7. Morrison K, Challita-eid PM, Raitano A, et al.  Development of ASG-15ME, a novel antibody-drug conjugate targeting SLITRK6, a new urothelial cancer biomarker.  Mol Cancer Ther 2016; 15:1301-10.
  8. Petrylak DP, Heath E, Sonpavde G, et al.  Interim analysis of a phase 1 dose escalation trial of the antibody drug conjugate AGS-15E (ASG-15ME) in patients with metastatic urothelial carcinoma.  Ann Oncol 2016; 27:abstr 780PD.
  9. Petrylak DP, Perez RP, Zhang J, et al.  A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer.  J Clin Oncol 2017; 35 (suppl; abstr 106).
  10. Mejri N, Sellami R, Lamia C, et al.  Status of Her2 over expression in muscle invasive urothelial bladder carcinoma: Report of 21 cases.  Urol Ann 2014;6:63-7.
  11. Hussain M, MacVicar GR, Petrylak DP, et al.  Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial.  J Clin Oncol 2007; 25:2218-24.
  12. Iwasa S, Shitara K, Takahashi S, et al.  Updated results of phase 1 study of DS-8201a in subjects with HER2-expressing gastric cancer.  J Clin Oncol 2018; 36:no. 4_suppl; abstr 118)
  13. Modi S, Tsurutani J, Takahashi S, et al.  Safety and efficacy results from a phase 1 study fo DS-8201a in patients with HER2 expressing breast cancers.  SABCS 2017; abstract 1094.
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