Durvalumab Plus Guadecitabine Induces Responses in Checkpoint Inhibitor–Naïve ccRCC

Yousef Zakharia, MD

The combination of durvalumab (Imfinzi) and guadecitabine (SGI-110) generated early signs of clinical activity and tolerability in patients with advanced clear cell renal cell carcinoma (ccRCC), particularly those with no prior exposure to checkpoint inhibitors, according to findings from a phase 1b/2 trial (NCT03308396) presented at the 2023 Genitourinary Cancers Symposium.¹

Of the patients who had received 1 or fewer prior therapies for advanced ccRCC (cohort 1; n = 36), treatment with the combination resulted in an overall response rate (ORR) of 23% (n = 8), including a complete response (CR) in 2.7% (n = 1) of patients and a partial response (PR) in 20% (n = 7) of patients. Additionally, 44% (n = 16) of these patients achieved a best response of stable disease (SD) lasting more than 6 months. These CR, PR, and SD rates translated to a disease control rate of 67% in this cohort. Of the patients treated with the combination who had received 2 or fewer prior therapies (cohort 2; n = 15), the ORR was 7% (n = 1), with that 1 patient achieving a PR. In addition, 60% (n = 9) of patients in this cohort achieved a best response of SD.

Previously, the authors reported initial safety findings from the phase 1b dose de-escalation part of this trial, where 6 patients received intravenous (IV) durvalumab at 1500 mg on day 8 of each 28-day cycle plus guadecitabine at either 60 mg/m2 or 45 mg/m2 on days 1 through 5 of each 28-day cycle. Notably, guadecitabine at 60 mg/m2 was associated with 1 dose-limiting toxicity: grade 3 neutropenia. Based on these findings, the investigators confirmed the safety of guadecitabine at 45 mg/m2 on days 1 through 5 plus IV durvalumab at 1500 mg on day 8 and deemed this the recommended phase 2 dose.²

“We hypothesized that the combination of guadecitabine plus durvalumab would increase T lymphocyte infiltration and result in antitumor activity,” lead study author Yousef Zakharia, MD, of the University of Iowa Holden Comprehensive Cancer Center, in Iowa City, and colleagues, wrote in a poster of the data.

To be eligible for enrollment on this single-arm, multi-site trial, patients needed to have histologically confirmed renal cell carcinoma (RCC) with a pure or mixed clear cell component, histologic or radiologic evidence of metastatic disease, and an ECOG performance status (PS) of 0 or 1.1 In cohort 1, patients could have received up to 1 prior therapy for advanced ccRCC, although prior PD-1/PD-L1/CTLA-4 inhibitors were not permitted. In cohort 2, patients could have received up to 2 prior therapies for advanced ccRCC and were required to have received and not responded to a PD-1/PD-L1 inhibitor.

Upon initiating study treatment, patients received a computed tomography scan every 2 cycles for 8 weeks. Patients could remain on study treatment until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients were permitted to continue durvalumab treatment after 1 confirmed progression if they discussed this decision with the sponsor investigator and reconsented to this treatment. Survival follow-up evaluations took place every 3 months for 2 years after each patient’s trial registration date.

The primary end point of this trial was investigator-assessed ORR in cohort 1. Key secondary end points included ORR in cohort 2, progression-free survival (PFS), and overall survival (OS).

In cohort 1, the median age was 68 years (range, 40-85), 69% (n = 25) of patients were male, 92% (n = 33) of patients were White, and 97% (n = 35) of patients were non-Hispanic. In total, 94% (n = 34) and 6% (n = 2) pf patients in cohort 1 had intermediate- and poor-risk disease, respectively, per International Metastatic RCC Database Consortium criteria. Additionally, 81% (n = 29) and 19% (n = 7) of patients in cohort 1 had pure and mixed ccRCC, respectively.

Furthermore, of the patients in cohort 1, 17% (n = 6) had sarcomatoid histology, 64% (n = 23) of patients did not have sarcomatoid histology, and in 19% (n = 7) histology could not be assessed. In addition, 56% (n = 20) and 44% (n = 16) of patients in cohort 1 had an ECOG PS of 0 and 1, respectively, and 42% (n = 15) had received prior therapy.

In cohort 2, the median age was 65 years (range, 46-93), 73% (n = 11) of patients were male, 100% (n = 15) of patients were White, and 93% (n = 14) of patients were non-Hispanic. In total, 87% (n = 13) and 13% (n = 2) of patients in cohort 1 had intermediate- and poor-risk disease, respectively, per International Metastatic RCC Database Consortium criteria. Additionally, 67% (n = 10) and 33% (n = 5) of patients in cohort 1 had pure and mixed ccRCC, respectively.

Furthermore, of the patients in cohort 1, 27% (n = 4) had sarcomatoid histology and 60% (n = 9) did not have sarcomatoid histology; histology could not be assessed in 13% (n = 2) of patients. In addition, 40% (n = 6) and 60% (n = 9) of patients in cohort 1 had an ECOG PS of 0 and 1, respectively. All patients in this cohort had received prior therapy.

The median PFS was 18.4 months in cohort 1 and 3.9 months in cohort 2. The media OS was not reached.

A biomarker analysis using flow cytometry on peripheral blood that was collected prior to treatment showed that the presence of myeloid-derived suppressor cells was inversely associated with response. Additionally, the patients who responded to durvalumab/guadecitabine treatment had the highest expression of interferon-gamma in their CD8+ T cells. Across lymphocyte subtypes, responders also had higher expression of tumor necrosis factor alpha than non-responders.

“Promising efficacy, mainly PFS in checkpoint inhibitor–naïve patients, is worth further investigation,” the study authors concluded.

Editor’s Note: Dr Zakharia reports consulting or advisory roles with Amgen, Bayer, Bristol-Myers Squibb/Medarex, Cardinal Health, Castle Biosciences, Clovis Oncology, Eisai, EMD Serono, Exelixis, Janssen, Myovant Sciences, Novartis, Pfizer, Roche/Genentech, Seagen, and TTC Oncology; research funding from Eisai (Inst), Exelixis (Inst), and Pfizer (Inst); and travel, accommodations, and expenses from Newlink Genetics.

References

1. Zakharia Y, Singer EA, Acharyya S, et al. Final results of a phase Ib/II study of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma (ccRCC) and biomarker analysis. J Clin Oncol. 2023;41(suppl 6):696. doi:10.1200/JCO.2023.41.6_suppl.696
2. Zakharia Y, Sun Y, Garje R, et al. Phase Ib/II study of durvalumab plus guadecitabine in advanced clear cell renal cell cancer (ccRCC). Ann Oncol. 2020;31(suppl 4):S594-S595. doi:10.1016/j.annonc.2020.08.844