Sacituzumab govitecan induces response in cisplatin-ineligible urothelial carcinoma
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SAN FRANCISCO — Sacituzumab govitecan induced response among one-third of platinum-ineligible patients with metastatic urothelial carcinoma whose disease progressed after checkpoint inhibitor therapy, according to study results.
The agent also exhibited a manageable safety profile, researchers reported at ASCO Genitourinary Cancers Symposium.
The data indicate further evaluation of sacituzumab govitecan for metastatic urothelial carcinoma after checkpoint inhibitor therapy is warranted, Daniel P. Petrylak, MD, professor of medicine and urology and chief of genitourinary oncology at Yale School of Medicine, as well as a HemOnc Today Editorial Board member, told Healio.
“If you think back to the early part of this century, we had [gemcitabine-cisplatin] or MVAC as our only primary treatments. If a patient developed progressive disease, you had a 6-month median survival,” Petrylak told Healio. “Now we have checkpoint inhibition therapy, we have combinations of checkpoint inhibitors with [antibody-drug conjugates] and we have individual [antibody-drug conjugates]. The take-home message is we need to develop the optimal sequence, and we need to develop molecular markers to help us determine the right treatment for each patient.”
Background and methodology
Patients with locally advanced or metastatic urothelial carcinoma who are ineligible for platinum-based chemotherapy and experience disease progression after checkpoint inhibitor therapy have limited treatment options and face a poor prognosis, according to study background.
Sacituzumab govitecan (Trodelvy, Gilead) is an antibody-drug conjugate consisting of an anti-Trop-2 antibody.
In a prior analysis of 113 patients with locally advanced or metastatic urothelial carcinoma who progressed after platinum and checkpoint inhibitor therapies, sacituzumab govitecan induced an overall response rate of 27%. Researchers reported a median 7.2-month response duration, with median OS of 10.9 months.
These results led to accelerated FDA approval of the agent in this setting.
At ASCO GU, Petrylak presented the primary analysis of cohort 2 of the phase 2 TROPHY-U-01 study. The cohort included 38 patients (median age, 73 years; range, 41-87; 61% men) with metastatic urothelial carcinoma who were platinum-ineligible at the start of the study and whose disease progressed after checkpoint inhibitor therapy.
Nineteen patients (50%) had ECOG performance status of 1, 25 (66%) had distant metastases at screening, 25 (66%) had visceral disease and 11 (29%) had liver metastases at baseline. Patients had received a median two (range, 1-5) prior anticancer regimens.
Patients received 10 mg/kg sacituzumab govitecan on days 1 and 8 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxicity.
ORR per central review served as the primary endpoint. Secondary endpoints included duration of response, clinical benefit rate and PFS per central review, as well as ORR, duration of response, clinical benefit rate and PFS per investigator assessment.
Results
Twelve patients (32%; 95% CI, 17.5-48.7) achieved objective response; all had partial responses. Median time to response was 1.4 months and median duration of response was 5.6 months).
Thirteen patients (34%) exhibited stable disease, four (11%) had progressive disease, four (11%) were not evaluable and five (13%) were not assessed.
Researchers calculated a clinical benefit rate of 42% (95% CI, 26.3-59.2).
They reported a 53.8% ORR among the 13 patients who had not received prior platinum or enfortumab vedotin (Padcev; Astellas, Seagen), an antibody-drug conjugate directed against nectin-4, a protein highly expressed in urothelial cancers.
More than two-thirds (69%) of patients experienced target lesion reduction, and two patients had an ongoing response at data cutoff.
After median follow-up of 9.3 months, researchers reported median PFS of 5.6 months (95% CI, 4.1-8.3) and median OS of 13.5 months (95% CI, 7.6-15.6).
Twenty-six patients (68%) experienced grade 3 or higher adverse events. The most common included neutropenia (34%), anemia (21%), leukopenia (18%), fatigue (18%) and diarrhea (16%).
Three patients (8%) had treatment-related febrile neutropenia (grade 3, n = 2; grade 4, n = 1). Researchers reported no treatment-related deaths.
Treatment-related adverse events prompted dose reductions for 14 patients (37%) and treatment discontinuation for seven patients (18%).
Next steps
In 2021, the FDA granted accelerated approval to sacituzumab govitecan for treatment of patients with locally advanced or metastatic urothelial cancer who previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.
That same year, the FDA approved enfortumab vedotin for treatment of adults with locally advanced or metastatic urothelial cancer.
The agents have different mechanisms and different targets, Petrylak said.
“This gives the patient with urothelial cancer more opportunities for long-term response,” Petrylak told Healio. “We have had patients who have achieved long-term responses with both, but there is no way to predict who that patient is going to be. They’re both excellent drugs and they’re both useful in urothelial carcinoma. For now, I think clinicians will have to decide based on toxicity what the right drug is for each patient to take.”
The ongoing randomized phase 3 TROPiCS-04 trial is designed to compare sacituzumab govitecan with physician’s choice of single-agent chemotherapy for patients whose disease progressed after prior platinum and checkpoint inhibitor therapies.
“We’re hoping it will confirm the data we’re seeing and lead to full approval of [sacituzumab govitecan],” Petrylak said.
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Petrylak DP, et al. Abstract 520. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 16-18, 2023; San Francisco.
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