Durvalumab and guadecitabine in advanced clear cell renal cell carcinoma: results from the phase Ib/II study BTCRC-GU16-043

Yousef Zakharia (), Eric A. Singer, Satwik Acharyya, Rohan Garje, Monika Joshi, David Peace, Veera Baladandayuthapani, Annesha Majumdar, Xiong Li, Claudia Lalancette, Ilona Kryczek, Weiping Zou and Ajjai Alva
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Yousef Zakharia: University of Iowa Holden Comprehensive Cancer Center
Eric A. Singer: Ohio State University Comprehensive Cancer Center
Satwik Acharyya: University of Michigan
Rohan Garje: University of Iowa Holden Comprehensive Cancer Center
Monika Joshi: Penn State Cancer Institute
David Peace: University of Illinois at Chicago
Veera Baladandayuthapani: University of Michigan
Annesha Majumdar: Big Ten Cancer Research Consortium
Xiong Li: University of Michigan
Claudia Lalancette: BRCF Epigenomics Core University of Michigan
Ilona Kryczek: University of Michigan
Weiping Zou: University of Michigan
Ajjai Alva: University of Michigan

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Epigenetic modulation is well established in hematologic malignancies but to a lesser degree in solid tumors. Here we report the results of a phase Ib/II study of guadecitabine and durvalumab in advanced clear cell renal cell carcinoma (ccRCC; NCT03308396). Patients received guadecitabine (starting at 60 mg/m2 subcutaneously on days 1-5 with de-escalation to 45 mg/m2 in case of dose limiting toxicity) with durvalumab (1500 mg intravenously on day 8). The study enrolled 57 patients, 6 in phase Ib with safety being the primary objective and 51in phase II, comprising 2 cohorts: 36 patients in Cohort 1 were treatment naive to checkpoint inhibitors (CPI) with 0-1 prior therapies and 15 patients in Cohort 2 were treated with up to two prior systemic therapies including one CPI. The combination of guadecitabine 45 mg/m2 with durvalumab 1500 mg was deemed safe. The primary objective of overall response rate (ORR) in cohort 1 was 22%. Sixteen patients (44%) experienced stable disease (SD). Secondary objectives included overall survival (OS), duration of response, progression-free survival (PFS), clinical benefit rate, and safety as well as ORR for Cohort 2. Median PFS for cohort 1 and cohort 2 were 14.26 and 3.91 months respectively. Median OS was not reached. In cohort 2, one patient achieved a partial response and 60% achieved SD. Asymptomatic neutropenia was the most common adverse event. Even though the trial did not meet the primary objective in cohort 1, the tolerability and PFS signal in CPI naive patients are worth further investigation.

Date: 2024
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DOI: 10.1038/s41467-024-45216-z

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