Durvalumab Plus Guadecitabine Shows PFS Benefit in Cohort of Patients With ccRCC


Durvalumab in combination with guadecitabine was tolerable and led to a PFS benefit in patients with checkpoint inhibitor-naive ccRCC.

Durvalumab Plus Guadecitabine in ccRCC | Image Credit: © Nitiphol - stock.adobe.com

Durvalumab Plus Guadecitabine in ccRCC

| Image Credit: © Nitiphol - stock.adobe.com

Durvalumab (Imfinzi) in combination with the novel hypomethylating agent guadecitabine (SGI-110) was tolerable and displayed an encouraging progression-free survival (PFS) signal in patients with advanced clear cell renal cell carcinoma (ccRCC), according to findings from the phase 1b/2 BTCRC-GU16-043 trial (NCT03308396) published in Nature Communications.

Although phase 2 of the study did not meet its primary end point, with durvalumab plus guadecitabine yielding an objective response rate (ORR) of 22% among checkpoint inhibitor-naive patients (cohort 1; n = 36), the median PFS in this cohort was 14.26 months (95% CI, 7.13- 24.5). Comparatively, the ORR was 7% and the median PFS was 3.91 months (95% CI, 3.09- 9.1) in those who previously received a checkpoint inhibitor (cohort 2; n = 15) at the median follow-up of 20 months. The median overall survival (OS) was not reached in either cohort.

“Epigenetic modulation has demonstrated clinical benefit and been [used] extensively in hematologic malignancies; however, its use in solid tumors is being explored increasingly,” study authors wrote. “To our knowledge, this study is one of few evaluating the safety and efficacy of a hypomethylating agent with a checkpoint inhibitor in advanced solid tumors, specifically in RCC….We believe the observed median PFS in Cohort 1 deserves further validation in a randomized clinical trial.”

BTCRC-GU16-043 was a multicenter, single-arm study that enrolled patients with metastatic ccRCC of pure or mixed histology. Eligible patients were at least 18 years old and had at least 1 lesion measurable by RECIST 1.1, an ECOG performance status of 1 or less, and a life expectancy of at least 12 weeks, as well as adequate bone marrow, renal, and hepatic function. Those with a concurrent active infection requiring systemic therapy, another ongoing primary active malignancy within the last 5 years, or an active inflammatory or autoimmune disease were excluded from the trial; prior allogenic organ transplant was also not permitted. Central nervous system metastases were permitted only if they were adequately treated with at least 4 weeks of imaging stability.

Subcutaneous guadecitabine was given at a starting dose of 60 mg/m2 on days 1 to 5 with de-escalation to 45 mg/m2 in the instance of a dose-limiting toxicity (DLT). All patients received intravenous durvalumab 1500 mg on day 8.

The primary end point in phase 1b was safety by DLTs and identifying the recommended phase 2 dose of guadecitabine in combination with durvalumab. ORR per RECIST 1.1 in cohort 1 was the primary end point in phase 2. Secondary end points included 2-year OS, 12-month PFS, duration of response (DOR), and ORR in cohort 2.

The baseline patient characteristics were well-balanced between cohort 1 and 2; the median age was 68 years (range, 40-85) compared with 65 years (range, 46-93), respectively. Most patients in both cohorts were male (69% vs 73%) and White (92% vs 100%); patients had IMDC intermediate risk disease (94% vs 87%), pure ccRCC (81% vs 67%), and did not have sarcomatoid histology (64% vs 60%). Forty-two percent and 100% of patients in each cohort, respectively, received prior therapy.

Additional findings showed that 1 patient in cohort 1 achieved a complete response and 16 patients (44%) experienced a best response of stable disease lasting for a minimum of 6 months. In cohort 2, 1 patient experienced a partial response and 9 patients (60%) achieved stable disease. Overall, the median time to response was 1.8 months (95% CI, 1.6-2.1) and the median DOR was 7 months (95% CI, 3.2-15.6). In terms of survival in cohorts 1 and 2, 1-year OS rates were 92.9% and 78.0%, respectively, and the 2-year rates were 85.0% and 62.4%, respectively.

In the safety population (n = 57), any-grade treatment-related adverse effects (AEs) due to either guadecitabine or durvalumab occurred at a rate of 35.4%. The most common any-grade AEs included neutropenia (54.4%), fatigue (50.9%), and decreased white blood cell count (43.9%). Dose delays due to AEs occurred at a rate of 60%, and 16% of patients needed corticosteroids for the treatment of immune-related AEs (irAEs). Common any-grade irAEs included dyspnea (28.1%), diarrhea (22.8%), and increased lipase (19.3%).

“Our study had several limitations, including small sample size in both cohorts, single-arm design, and relatively slow accrual,” study authors wrote. “In conclusion, the combination of durvalumab and guadecitabine has an acceptable toxicity profile and promising activity especially in [patients with] checkpoint inhibitor-naive [disease] with advanced ccRCC as first and subsequent lines of therapy. It could be further tested in patient populations where TKI and immunotherapy [agents] are not well tolerated and can cause early treatment discontinuation.”


Zakharia Y, Singer EA, Acharyya S, et al. Durvalumab and guadecitabine in advanced clear cell renal cell carcinoma: results from the phase Ib/II study BTCRC-GU16-043. Nat Commun. 2024;15(1):972. doi:10.1038/s41467-024-45216-z

Related Videos
Kian-Huat Lim, MD, PhD
Benjamin Garmezy, MD
Kathryn Beckermann, MD, PhD
Robert Wang, MD, of Fox Chase Cancer Center
Jaime R. Merchán, MD
Nikhil A. Gopal, MD
Samer A. Srour, MB ChB, MS
Nizar M. Tannir, MD, FACP, professor; Ransom Horne, Jr. Professor for Cancer Research, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Samer A. Srour, MB ChB, MS