Brendan J. Guercio, MD
Jonathan E. Rosenberg, MD
The results of Cohort 1 of the phase II trial TROPHY-U-01 (IMMU-132-06; ClinicalTrials.gov identifier NCT03547973), published in the Journal of Clinical Oncology by Tagawa et al and reviewed in this issue of The ASCO Post, led to the recent accelerated U.S. Food and Drug Administration (FDA) approval of sacituzumab govitecan-hziy for select patients with locally advanced or metastatic urothelial cancer,1,2 making it the second antibody-drug conjugate approved for metastatic urothelial cancer.3 Cohort 1 of this multicenter, single-arm study demonstrated efficacy of sacituzumab govitecan in a heavily pretreated population of 113 patients with metastatic urothelial cancer, with an objective response rate of 27% confirmed by central review, a median progression-free survival of 5.4 months, and a clinical benefit rate of 37%. Approval of sacituzumab govitecan for patients with metastatic urothelial cancer following prior platinum-containing chemotherapy and either a PD-1 or a PD-L1 inhibitor marks another key advancement in the management of metastatic urothelial cancer and builds upon a rapid and welcome influx of FDA-approved agents for this disease in recent years.
In TROPHY-U-01, sacituzumab govitecan was reasonably well tolerated, with just 6% of patients (n = 7) discontinuing therapy due to treatment-related adverse events and a side-effect profile consistent with prior studies of sacituzumab govitecan in triple-negative breast cancer.4 Sacituzumab govitecan showed efficacy even among patients with visceral metastases, including an objective response rate of 32% in patients with liver metastases, a known marker of poor prognosis in patients treated with traditional cytotoxic chemotherapies.5-8 Full FDA approval for sacituzumab govitecan in metastatic urothelial cancer will ultimately hinge on results of the ongoing confirmatory phase III TROPiCS-04 trial.9 Notably, the FDA recently granted regular approval to sacituzumab govitecan for the treatment of metastatic triple-negative breast cancer, based on positive findings from the phase III ASCENT trial.4,10
Questions About Optimal Sequencing in Clinical Practice
The first antibody-drug conjugate to receive accelerated FDA approval in previously treated metastatic urothelial cancer was enfortumab vedotin-ejfv in 2019, based on the results of the phase II EV-201 study.11 Given recent positive results of the confirmatory, global phase III EV-301 trial,12 full FDA approval for enfortumab vedotin is likely. With two antibody-drug conjugates and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib now approved for previously treated metastatic urothelial cancer, the optimal sequence of these agents remains a key question in clinical practice. Notably, use of erdafitinib is restricted to patients with susceptible genetic alterations of FGFR2/3, present in only ~20% of metastatic urothelial cancer. Prior treatment with anti–PD-L1 inhibitors is not mandated by the U.S. FDA label, though in practice most patients receive immunotherapy prior to erdafitinib.13,14
Indeed, although sacituzumab govitecan, enfortumab vedotin, and erdafitinib all have demonstrated objective response rates of between 27% and 41% in clinical trials,1,12,15 whether these agents retain the same level of efficacy when administered in sequence remains largely unstudied. Fortunately, substantial differences in mechanism between these agents suggest the potential for preserved efficacy independent of sequence: sacituzumab govitecan targets the transmembrane glycoprotein Trop-2 with a payload of the topoisomerase inhibitor SN-38,1 whereas enfortumab vedotin targets Nectin-4 with a payload of the microtubule disrupter monomethyl auristatin E,12 and erdafitinib is a pan-FGFR tyrosine kinase inhibitor. Among 10 patients in -TROPHY-U-01 previously treated with enfortumab vedotin, just 1 achieved a partial response to sacituzumab govitecan (objective response rate of 10%), and an additional 6 had stable disease. Ultimately, firm conclusions cannot be drawn from such small subgroup analyses, and additional studies on optimal sequencing are needed.
“Full FDA approval for sacituzumab govitecan in metastatic urothelial cancer will ultimately hinge on results of the ongoing confirmatory phase III TROPiCS-04 trial.”— Brendan J. Guercio, MD, and Jonathan E. Rosenberg, MD
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In the absence of comparative clinical trials to conclusively guide sequencing of these agents, we prefer to treat with enfortumab vedotin prior to sacituzumab govitecan and erdafitinib, given level 1 evidence supporting the use of enfortumab vedotin after platinum and anti–PD-(L)1 treatment; however, patient-specific factors such as preexisting peripheral neuropathy and hyperglycemia are important to consider.12 Currently, enfortumab vedotin remains the only one of these agents with a proven overall survival benefit compared with traditional cytotoxic chemotherapy in a randomized controlled trial. Regardless, sacituzumab govitecan now offers a valuable option for patients.
Another potential consideration for sequencing of sacituzumab govitecan with enfortumab vedotin and erdafitinib is UGT1A1 genotype, as UGT1A1 *28 allele homozygosity is associated with decreased SN-38 metabolism and increased sacituzumab govitecan toxicity.16 Notably, routine prescreening for UGT1A1 status is not currently required.1 However, for patients with clinical evidence of unconjugated hyperbilirubinemia, this should be taken into account when considering patient selection.
Combination Therapies: Searching for Synergy
Optimal sequencing of these agents may become further complicated by combinations of sacituzumab govitecan, enfortumab vedotin, or erdafitinib with other therapies. For example, addition of the PD-1 inhibitor pembrolizumab to enfortumab vedotin for first-line treatment of cisplatin-ineligible patients in the single-arm EV-103 study yielded an objective response rate of 73% and a median progression-free survival of 12.3 months.17 This combination remains under investigation in the EV-103 trial (NCT03288545) and in the phase III EV-302 study (NCT04223856).18
Building on this signal of potential synergy between immune checkpoint inhibitors and antibody-drug conjugates, Cohort 3 of TROPHY-U-01 will explore the addition of pembrolizumab to sacituzumab govitecan in checkpoint inhibitor–naive patients after platinum therapy, whereas Cohort 5 will investigate sacituzumab govitecan for patients with platinum-naive metastatic urothelial cancer combined with cisplatin and avelumab.19 Cohort 4 will test sacituzumab govitecan in combination with cisplatin,1 and a phase I study is also planned to investigate sacituzumab govitecan plus enfortumab vedotin (NCT04724018); this is a promising combination given the relatively tolerable, nonoverlapping toxicity profiles of these agents and their distinct and potentially complementary mechanisms of action.
Biomarker-Driven Correlative Analyses Needed
A limitation of TROPHY-U-01 appropriately noted by the authors is a paucity of biomarker-driven correlative analyses.1 Although sacituzumab govitecan’s target, Trop-2, is expressed in up to 83% of urothelial carcinomas, its expression is not -ubiquitous, and the relationship between Trop-2 expression in metastatic urothelial cancer and sensitivity to sacituzumab govitecan remains inadequately characterized.1,20,21 Hence, further investigation of Trop-2’s potential value as a predictive biomarker is warranted in future studies.
The findings of TROPHY-U-01 and the accelerated FDA approval of sacituzumab govitecan for previously treated metastatic urothelial cancer provide a significant new option for patients with refractory disease. Results of future and ongoing studies such as -TROPiCS-04 designed to confirm clinical benefit, as well as the remaining cohorts of TROPHY-U-01, are eagerly awaited to further clarify the optimal use of this agent in metastatic urothelial cancer.
Dr. Guercio works for Memorial Sloan Kettering Cancer Center, New York. Dr. Rosenberg works for Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College.
DISCLOSURE: Dr. Guercio has received honoraria from Medscape; has received institutional research funding from Bristol Myers Squibb, Genentech, Lilly, Oncocyte, Pfizer, and Sanofi; and has an immediate family member who has received research funding from Pfizer. Dr. Rosenberg has received honoraria from Clinical Care Options, Intellisphere, Medscape, MJH Life Sciences, PeerView, Physician Education Resource, Research to Practice, and UpToDate; has served as a consultant or advisor to Astellas Pharma, AstraZeneca, Bayer, BioClin Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Gilead/Immunomedics, Janssen Oncology, Lilly, Merck, Mirati Therapeutics, Pfizer/EMD Serono, Pharmacyclics, QED Therapeutics, Roche/Genentech, Seagen, and Tyra Biosciences; has received institutional research funding from Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, QED Therapeutics, and Seagen; and holds institutional intellectual property in Predictor of Platinum Sensitivity.
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2. U.S. Food & Drug Administration: FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. April 13, 2021. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer. Accessed June 14, 2021.
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Scott T. Tagawa, MD, MS
In a cohort of the phase II TROPHY-U-01 trial reported in the Journal of Clinical Oncology, Scott T. Tagawa, MD, MS, of Weill Cornell Medicine, New York, and colleagues, found that the antibody-drug conjugate sacituzumab govitecan-hziy produced durable responses in...