Biomarkers may predict outcomes with enfortumab vedotin for advanced urothelial carcinoma
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SAN FRANCISCO — Several potential genetic biomarkers may predict how patients with advanced urothelial carcinoma will respond to enfortumab vedotin, according to retrospective study results.
Patients with high tumor mutation burden achieved longer OS, findings presented at ASCO Genitourinary Cancers Symposium showed. Those with CDKN2A, CDKN2B or MTAP alterations achieved shorter PFS.
Enfortumab vedotin (Padcev; Astellas, Seagen) is an antibody-drug conjugate directed against nectin-4, a protein highly expressed in urothelial cancers. Data about biomarkers that may predict outcomes with the agent are limited, according to study background.
Tanya Jindal, senior clinical research coordinator at University of California, San Francisco, and colleagues used data from UNITE — a large, multi-institutional, retrospective cohort study of patients with advanced urothelial carcinoma treated with novel targeted agents — to investigate potential biomarkers of response to enfortumab vedotin. The data set included 592 patients treated at 16 sites in the United States.
Researchers identified 170 patients (median age, 70 years; range, 37-93; 78% men; 85% white) with advanced urothelial carcinoma treated with enfortumab vedotin monotherapy who had available next-generation sequencing results.
The molecular biomarkers assessed included tumor mutation burden, PD-L1 status and somatic alternations present in at least 10% of patients (TERTp, TP53, ARID1A, CDKN2A, CDKN2B, FGFR3, ERBB2, CCND1, KDM6A, MTAP, PIK3CA, RB1 and TSC1). Investigators also evaluated for presence of at least one DNA damage response mutation (ATM, BARD1, BRCA1, BRCA2, CDK12, CHEK2, PALB2, PPP2R2A or RAD51B).
At the start of enfortumab vedotin treatment, 79% of patients had visceral metastases and 35% had liver metastases. More than two-thirds (68%) had received at least two prior lines of therapy.
Investigators at each site calculated the observed response rate for patients who underwent scans after at least one treatment cycle.
Median follow-up was 9.4 months (range, 8.3-11).
Researchers reported a 47% overall response rate, with median PFS of 6 months (range, 5.3-7.4) and median OS of 12 months (range, 8.8-not reached).
Analyses of biomarker-specific outcomes showed higher ORRs among patients with ERBB2 alterations (67% vs. 44%; P = .05) and TSC1 alterations (68% vs. 25%; P = .04) than those who had wild-type disease.
Analyses of event-based endpoints identified several biomarkers that may be associated with outcomes after enfortumab vedotin treatment.
Results showed shorter median PFS among patients with CDKN2A alterations (4.6 months vs. 6 months; HR – 1.7; 95% CI, 1.1-2.8), CDKN2B alterations (4.4 months vs. 6 months; HR = 2; 95% CI, 1.2-3.4) and MTAP alterations (4.6 months vs. 6 months; HR = 1.7; 95% CI, 1-3) than those for whom those alterations were absent.
Patients with high tumor mutation burden status — defined as 10 or more mutations/megabase — achieved longer median OS than those with low tumor mutational burden status (13.6 months vs. 8.3 months; HR = 0.4; 95% CI, 0.2-0.9).
Jindal acknowledged study limitations, including the retrospective design, patient selection, confounding biases and use of various next-generation sequencing platforms.
“These findings are hypothesis generating and require external validation,” Jindal said during a presentation. “But in the future, they may help influence mechanistic work, clinical trial design, clinical decisions, and potential sequencing of enfortumab vedotin and other therapies.”
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Jindal T, et al. Abstract 450 Presented at: ASCO Genitourinary Cancers Symposium; Feb. 16-18, 2023; San Francisco.
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