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Second- and third-line treatment options in mUC

ESMO 2020
Avelumab as maintenance therapy after first-line treatment prolonged overall survival (OS) in urothelial cancer (UC). However, predictive biomarkers are not yet found. In addition, sacituzumab govitecan showed promising activity in third (or later) lines.

Platinum-based chemotherapy is an active first-line regimen for advanced and mUC. However, progression-free survival (PFS) and OS are generally short because of chemotherapy resistance. The phase 3 JAVELIN Bladder 100 trial (n=700) evaluated avelumab as maintenance therapy following response or stable disease with first-line platinum-based chemotherapy in patients with advanced UC [1]. The study met its primary objective, demonstrating significantly prolonged OS with maintenance avelumab plus best supportive care versus best supportive care alone in all randomised patients and patients with PD-L1 positive tumours.

In addition, an exploratory analysis of predictive biomarkers was performed to identify patients who would benefit most from maintenance avelumab [2]. However, none of the established biomarkers assessed, either alone or in combination, optimally predicted OS benefit with avelumab: elevated PD-L1 on either tumour cells or immune cells, irrespective of tumour mutation burden (TMB); elevated TMB and mutation signatures, irrespective of PD-L1 status. Multiple other biomarkers – e.g. expression of Fc receptors and gene signatures of tumour growth-promoting pathways – were identified as potential predictive, but need further research.

Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, the active metabolite of irinotecan. SN-38 is released both intracellularly and in the tumour microenvironment. Trop-2 is an epithelial cell surface antigen highly expressed in UC [3]. TROPHY-U-01 is a multicohort, global, open-label, phase 2 study evaluating SG clinical activity in patients with unresectable locally advanced or mUC with measurable disease [4]. Cohort 1 includes patients progressing after platinum-based chemotherapy and immune checkpoint inhibition, with unlimited prior lines of therapy.

A total of 113 patients were enrolled and treated with SG (10 mg/kg, days 1 and 8 of 21-day cycles) until loss of clinical benefit or unacceptable toxicity. The final objective response rate was 27% (complete response 5%, partial response 22%). Median duration of response was 5.9 months and clinical benefit rate was 37%. Median PFS and OS were 5.4 months and 10.5 months, respectively. Key grade ≥3 treatment-related adverse events were neutropenia (35%), anaemia (14%), febrile neutropenia (10%), and diarrhoea (10%). There was 1 treatment-related death (neutropenic sepsis). A phase 3 confirmation trial, TROPiCS-04, is underway.

  1. Powles T, et al. J Clin Oncol 38:2020(suppl; abstract LBA1)
  2. Powles TB, et al. Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): Association between clinical outcomes and exploratory biomarkers ESMO 2020 Virtual Meeting, abstract 699O.
  3. Bardia A, et al. N Engl J Med. 2019;380:741-751.
  4. Loriot Y, et al. TROPHY-U-01 cohort 1 final results: A phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI). ESMO 2020 Virtual Meeting, abstract LBA24.

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