Epigenetic Regulation for Immune Evasion in Advanced Kidney Cancer

Yousef Zakharia, MD, of University of Iowa Holden Comprehensive Cancer Center, explains the current understandings and the rationale behind targeting epigenetic regulation in advanced renal cell carcinoma (RCC).

He also shares why combination guadecitabine and durvalumab may be a good approach in this population and the ensuing study that he and his colleagues designed to test this theory.

View his further comments on Guadecitabine and Durvalumab in Advanced Clear Cell RCC.

—

Can you elaborate on the rationale behind targeting epigenetic regulation in advanced RCC? What drove you to investigate this?

Dr. Zakharia: In general, DNA hypermethylation is associated with tumor progression, higher stage and grade, and generally carries a poorer prognosis. We have preclinical data suggesting that hypermethylation-induced silencing of chemokines, CXCL9 and 10 signaling, which are important for attracting immune cells to the tumor microenvironment. Silencing of these chemokines can result in tumor-immune evasion in RCC models. Combination therapy using hypomethylating agents like decitabine and checkpoint inhibitors led to higher levels of CXCL9 and 10 chemokines and reversal of immune evasion, resulting in potent tumor regression in preclinical data.

All of this sets the stage for our clinical trial in advanced metastatic clear cell RCC.

How does guadecitabine fit into this strategy? Why was guadecitabine and durvalumab chosen as the combination approach of investigation?

Dr. Zakharia: Guadecitabine is a hypomethylating agent, and previous data suggests that it can enhance chemokines, resulting in CD8 T-cell activation, proliferation, and cytolytic activity. This enhancement has been correlated with improved anti-tumor response and survival for patients with solid tumors.

Additionally, multiple pieces of data suggest a synergistic effect between epigenetic modulators and immunotherapy. For example, hypomethylating agents can up-regulate cancer antigen expression, leading to the simultaneous release of effector T cells and pro-inflammatory cytokines, resulting in T-cell activation and improved tumor killing.

What then was the design and methodology of your study? What type of patients did you sample and what were your intended outcomes?

Dr. Zakharia: This is a phase 1B/2 clinical trial conducted through the Big 10 Cancer Consortium, a collaborative effort across the Big 10 athlete universities. The trial combines guadecitabine and durvalumab in advanced clear cell RCC.

Initially, there was a phase 1B dose de-escalation where patients received 2 different doses of guadecitabine: 60 mg/m² subcutaneously for 5 days, which was later de-escalated to 45 mg/m² due to dose-limiting toxicity with neutropenia. Guadecitabine was combined with durvalumab, given at the standard dose of 1,500 milligrams IV on day 8. Treatment cycles were repeated every 28 days until disease progression or unacceptable toxicity.

The phase 2 trial followed the same dosing schedule. It consisted of 2 cohorts: cohort 1 included patients who were treatment-naïve to checkpoint inhibitors and allowed up to 1 prior line of therapy, while cohort 2 involved patients who progressed on prior checkpoint inhibitors and allowed up to 2 prior lines of therapy, one of which should have been a checkpoint inhibitor.

Regarding safety and efficacy, dose-limiting toxicity with guadecitabine at 60 mg/m² resulted in significant neutropenia. The recommended dose was adjusted to 45 mg/m². Six patients were enrolled in phase 1B, with safety as the primary endpoint, followed by 51 patients in phase 2 (36 in cohort 1 and 15 in cohort 2).

The most common side effect encountered was neutropenia, with dose adjustments mitigating this issue. Another common side effect was elevated lipase, with up to 10% of patients experiencing grade 3 elevation, mostly asymptomatic. No treatment-related deaths were reported.

In cohort 1, the overall response rate was 22%, lower than the predefined primary efficacy endpoint of 45%. However, significant disease stability was observed, with 44% of patients experiencing stable disease lasting more than 6 months and a median progression-free survival of 14.26 months, despite many having received prior therapy. This signal suggests potential for further investigation with larger, possibly randomized, phase 2 trials.

In cohort 2, patients with checkpoint inhibitor failure, the progression-free survival was lower at 3.9 months. However, there was still significant disease stability observed in a proportion of patients despite checkpoint refractoriness.