ESMO 2019: TROPHY-U-01: Initial Results of a Phase 2 Open-Label Study of Sacituzumab Givotecan in Patients with Metastatic Urothelial Cancer after Failure of Platinum-Based Regimens or Immunotherapy

Barcelona, Spain (UroToday.com) Human trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein which is highly expressed in urothelial carcinoma cells, thereby constituting a promising target for antibody-drug conjugate therapy.1 Sacituzumab govitecan is an antibody-drug conjugate comprised of the Trop-2 humanized monoclonal antibody sacituzumab coupled to SN-38, the active metabolite of irinotecan via a hydrolysable biochemical linker. Sacituzumab govitecan is a relatively unique antibody-drug conjugate in that it exhibits a high drug:antibody ratio and the linker is able to undergo hydrolysis both intracellularly and extracellularly, thereby targeting both Trop-2-expressing urothelial cancer cells as well as the tumor microenvironment so as to create a “bystander effect.”2,3 Sacituzumab govitecan has already demonstrated efficacy in a number of different solid tumors and a  is currently in phase III development for triple-negative breast cancer.4

Sacituzum_Govitecan.png

Scott Tagawa, MD, MS, previously presented data on 45 patients in the urothelial carcinoma cohort of a phase I/II basket study of sacituzumab govitecan across multiple epithelial cancers.5 Based on a promising 31% objective response rate among this cohort of heavily pre-treated advanced urothelial carcinoma patients, investigators sought to conduct TROPHY-U-01, a multicohort open-label phase II trial of sacituzumab govitecan (10 mg/kg on days 1 and 8 of a 28-day cycle) in patients with treatment-refractory metastatic urothelial cancer. Today, Dr. Tagawa presents an interim data analysis from 35 of 100 planned patients on cohort 1, which is comprised of patients who had progressed despite prior platinum-based chemotherapy and checkpoint blockade immunotherapy. Patients were treated until disease progression or unacceptable toxicity, and the primary endpoint was objective response rate.

TROPHY_StudyDesign.png

At baseline, the 35 evaluable patients had a median age of 64, were 80% male, and had received a median 3 prior lines of systemic therapy. Additionally, 63% (22/35) of patients had visceral metastases, including 23% (8/25) with liver metastases.

Demographic_Baseline.png

In general, treatment was well-tolerated. The most common grade ≥3 adverse events were leukopenia, anemia, febrile neutropenia, and infection. Of note only 9 of these 35 patients received prophylactic growth factor support. Diarrhea occurred in the majority of patients but was generally mild. No treatment-related deaths occurred. 

TreatmentAEs.png

At a median follow-up of 4.1 months, 57% of patients remained on treatment, and the objective response rate was 29% (10/35), including 6% (2/35) that had a complete response.

ObjectiveResponse.png

Of the 10 patients who achieved an objective response, 8 responses were ongoing at the time of last data cut-off.
ResponseDuration.png

Only two patients had progression of disease as their best response, and 74% (26/35) of patients achieved at least some tumor shrinkage.
ReductionTumorSize.png

While follow-up is not yet mature, it appears that in general responses and disease stability were maintained during treatment.
PercentChanges.png

In summary, this interim analysis from TROPHY-U-01 demonstrated that sacituzumab govitecan is generally well-tolerated with a manageable toxicity profile. The observed 29% objective response rate in the third-line setting or later is particularly encouraging in the context of known low response rates to cytotoxic chemotherapy and immunotherapy in platinum-refractory metastatic urothelial carcinoma. Ongoing follow-up data from TROPHY-U-1 are eagerly anticipated. Future work will aim to better characterize the toxicity profile from this agent which will be especially important in optimizing the managmenet of treatment-related neurtropenia. Combination therapy, especially with immune chekpoint blockade may be a promising approach in future studies. 

Presented by: Scott T. Tagawa, MD, The Richard A. Stratton Associate Professor in Hematology and Oncology, Weill Cornell Medical College, New York Presbyterian Hospital/Weill Cornell Medical Center, New York, New York

Written by: Michael Lattanzi, MD, Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center, Twitter: @MikeLattanzi, at the 2019 European Society for Medical Oncology Congress (#ESMO19), September 27 – October 1, 2019, Barcelona, Spain

References:

  1. Avellini C, Licini C, Lazzarini R, Gesuita R, Guerra E, Tossetta G, Castellucci C, Giannubilo SR, Procopio A, Alberti S, Mazzucchelli R. The trophoblast cell surface antigen 2 and miR-125b axis in urothelial bladder cancer. Oncotarget. 2017 Aug 29;8(35):58642.
  2. Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Arrojo R, Liu D, Rossi EA, Chang CH, Goldenberg DM. Sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate: characterization and efficacy in pancreatic, gastric, and other cancers. Bioconjugate chemistry. 2015 May 8;26(5):919-31.
  3. Govindan SV, Cardillo TM, Sharkey RM, Tat F, Gold DV, Goldenberg DM. Milatuzumab-SN-38 conjugates for the treatment of CD74+ cancers. Molecular cancer therapeutics. 2013 Jun 1;12(6):968-78.
  4. Bardia A, Vahdat LT, Diamond J, Kalinsky K, O’Shaughnessy J, Moroose RL, Isakoff SJ, Tolaney SM, Santin AD, Abramson V, Shah NC. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as≥ 3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results. San Antonio Breast Cancer Symposium 2017 Dec 6 (Vol. 12).
  5. Tagawa ST, Faltas BM, Lam ET, Saylor PJ, Bardia A, Hajdenberg J, Morgans AK, Lim EA, Kalinsky K, Simpson PS, Galsky MD. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study.
email news signup