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 patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy.1 The trial supported the April 2021 accelerated approval of sacituzumab govitecan in this setting.
As explained by the investigators, sacituzumab govitecan is a Trop-2–directed antibody-drug conjugate consisting of an anti–Trop-2 humanized monoclonal antibody coupled to SN-38 (active metabolite of the topoisomerase 1 inhibitor irinotecan) with a high drug-to-antibody ratio. The hydrolyzable linker permits a dual mechanism of action: internalization of Trop-2–bound sacituzumab govitecan delivers SN-38 inside tumor cells, resulting in cell death; the hydrolyzable linker enables SN-38 to be released into the tumor microenvironment, resulting in killing of adjacent tumor cells.
As stated by the investigators: “Patients with metastatic urothelial carcinoma who progress on platinum-based combination chemotherapy and checkpoint inhibitors … have limited options that offer objective response rates of approximately 10% with a median overall survival of 7 to 8 months.”
The current report presents findings in cohort 1 of the multicohort trial enrolled from August 2018 to November 2019. In the cohort, 113 patients with locally advanced unresectable or metastatic disease received sacituzumab govitecan at 10 mg/kg on days 1 and 8 of 21-day cycles until loss of clinical benefit or unacceptable toxicity. The primary outcome measure was overall response rate on blinded independent central review. Safety analyses included specific evaluation of the effect of UGT1A1 genotype status on incidence of adverse events.
Among all patients, median age was 66 years (range = 33–90 years, 23% ≥ 75 years), 78% were male, and 74% were White (no reported race for 20%). The Eastern Cooperative Oncology Group performance status was 0 (28%) or 1 in all patients; 96% had metastatic and 4% had locally advanced unresectable disease; 66% had visceral metastases, including lung in 43%, liver in 34%, and other in 13%. Overall, 96% had received prior systemic therapy for metastatic disease; 99% had prior checkpoint inhibitor therapy; 79% had prior cisplatin and 21% had prior carboplatin; and 8.8% had prior enfortumab vedotin. The median number of prior systemic regimens was three (range = 1–8), and the lines of metastatic regimens were one for 20%, two for 27%, and at least three for 50%. Bellmunt risk scores were 0 in 16%, 1 in 48%, 2 in 28%, and 3 in 8%.(The Bellmunt score is based on the presence of the following risk factors: liver metastases, hemoglobin < 10 g/dL, Eastern Cooperative Oncology Group performance status score > 0, and time since completion or discontinuation of therapy < 3 months.) UGT1A1 status was wild-type (*1/*1) in 40%, heterozygous (*1/*28) in 42%, homozygous (*28/*28) in 12%, and unknown in 7%.
Data cutoff was in September 2020. An objective response was observed in 31 patients (27.4%, 95% confidence interval [CI] = 19.5%–36.6%), including a complete response in 6 (5.3%). Stable disease was observed in an additional 38 patients (33.6%). A reduction in the size of target lesions was observed in 72 of 94 patients (77%) with at least one postbaseline target lesion measurement.
Median time to objective response was 1.6 months (range = 1.2–5.5 months). At a median follow-up of 9.1 months (range = 0–19.9 months), median duration of response was 7.2 months (95% CI = 4.7–8.6 months). Response durations ranged from 1.4 to 13.7 months among patients with a complete response. At data cutoff, 30 of 31 patients with an objective response remained alive, and 4 had an ongoing response.
Responses were observed in all evaluated subgroups, including patients with at least two prior lines of therapy (response rate = 27.3%), those with any visceral (response rate = 28.0%) and liver metastases (response rate = 31.6%) at baseline, and in all Bellmunt risk groups (response rates = 27.8%, 35.2%, 18.8%, and 11.1% for risk scores of 0, 1, 2, and 3, respectively). Response rates were 22.2%, 31.9%, and 30.8% among patients with UGT1A1 status of wild-type, heterozygous, and homozygous, respectively. Among 10 patients who received prior enfortumab vedotin, response was observed in 3 (30.0%); 2 of these patients had progressive disease as best response to enfortumab vedotin.
Median progression-free survival was 5.4 months (95% CI = 3.5–7.2 months; range = 2.4–8.9 months). Median overall survival was 10.9 months (95% CI = 9.0–13.8 months; range = 3.8–19.8 months).
The most common treatment-related adverse events of any grade were diarrhea (65%), nausea (60%), fatigue (52%), alopecia (47%), and neutropenia (46%). The most common grade ≥ 3 treatment-related adverse events were neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), febrile neutropenia (10%), lymphopenia (7%), and urinary tract infection (6%). Grade ≥ 3 serious treatment-related adverse events occurring in more than one patient included febrile neutropenia (n = 10), diarrhea (n = 4), urinary tract infection (n = 4), sepsis (n = 2), and thrombocytopenia (n = 2). One case of interstitial lung disease (grade 2) was observed.
Treatment-related adverse events led to discontinuation of treatment in seven patients (6%), most commonly due to neutropenia, febrile neutropenia, and sepsis. One treatment-related death occurred (febrile -neutropenia and sepsis).
In an analysis according to UGT1A1 status, any-grade neutropenia and grade ≥ 3 neutropenia were numerically more common in homozygous patients (54% and 54%) than in heterozygous (51% and 34%) and wild-type patients (38% and 31%). Any-grade diarrhea occurred in 69%, 75%, and 53% of patients, respectively. Discontinuation of treatment due to adverse events occurred in 8%, 6%, and 7%, respectively. Treatment interruption due to adverse events occurred in 69%, 36%, and 42%, respectively.
The investigators concluded: “SG [sacituzumab govitecan] is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated [metastatic urothelial carcinoma] that has progressed on both prior [platinum-based combination chemotherapy] regimens and [checkpoint inhibitors]. The results from this study supported accelerated approval of SG in this population.”
DISCLOSURE: The study was supported by Immunomedics. Dr. Tagawa has served as a consultant or advisor to 4D Pharma, AbbVie, Alkido Pharma, Amgen, Astellas Pharma, Bayer, Blue Earth Diagnostics, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Endocyte, Genentech, Genomic Health, Gilead Sciences, Immunomedics, Janssen, Karyopharm Therapeutics, Medivation, Novartis, Pfizer, POINT Biopharma, QED, Sanofi, Seattle Genetics, Telix Pharmaceuticals, and Tolmar; has received institutional research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Aveo, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Dendreon, Endocyte, Exelixis, Genentech, Immunomedics, Inovio Pharmaceuticals, Janssen, Karyopharm Therapeutics, Lilly, Medivation, Merck, Millennium, NewLink Genetics, Novartis, Point Biopharma, Progenics, Rexahn Pharmaceuticals, Sanofi, and Stem CentRx; holds intellectual property in Immunomedics and Gilead; has been reimbursed for travel, accommodations, or other expenses by Amgen, Immunomedics, and Sanofi; and has held uncompensated relationships with Atlab Pharma and Phosplatin Therapeutics.
1. Tagawa ST, Balar AV, Petrylak DP, et al: TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. April 30, 2021 (early release online).
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...