Guadecitabine and Durvalumab in Advanced Clear Cell RCC

Yousef Zakharia, MD, of University of Iowa Holden Comprehensive Cancer Center, continues his commentary on the phase Ib/II BTCRC-GU16-043 study investigating guadecitabine and durvalumab in advanced clear cell renal cell carcinoma (RCC).

He notes any specific biomarkers that may predict response, as well as where he envisions the potential placement of the combination therapy in the treatment algorithm.

View his previous comments on Epigenetic Regulation for Immune Evasion in Advanced Kidney Cancer.

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Are there any specific biomarkers that may predict response to guadecitabine and durvalumab combination therapy in advanced RCC?

Dr. Zakharia: This study initially had an ambitious biomarker plan, especially regarding tissue samples. We planned treatment biopsies to evaluate biomarker changes before and after treatment. However, due to the COVID-19 pandemic, all research biopsies were aborted per hospital policy. Nevertheless, we were able to collect significant peripheral blood work, which we reported in our Nature Communications paper.

We studied the effect of different immune cell populations on response. We observed that myeloid-derived suppressor cells, known for their immune-suppressive properties, were inversely associated with response, with higher levels in patients with progressive disease and lower levels in patients who had partial response.

Patients responding to treatment had the highest expression of interferon and TNF-α in CD8 T-cells at baseline, which was not surprising. We also studied other transcription factors, including FOXP3 expression in CD4 T-cells, associated with regulatory T-cells known for their immunosuppressive properties. These transcription factors were significantly lower in patients who had partial response. Another transcription factor, RORγt, important for peripheral immune cell differentiation, was significantly higher in patients who had partial response compared to progressive disease. Notably, CD8 T-cells expressing RORγt, also called Tc17 cells, have been shown to promote inflammation and contribute to defense against infections and autoimmune diseases. It was interesting to see that RORγt was significantly higher in patients who had partial response in our peripheral blood at baseline.

Given that our study utilizes hypomethylating agents, it was a natural next step to study methylation at LINE-1, a marker for methylation. Measurement of LINE-1 in 25 samples at cycle 1, day 1, and cycle 2, day 8, showed a decrease in methylation in 22 out of 25 samples, accounting for about 88% of our patients, which was statistically significant. This suggests the overall efficacy of guadecitabine as a hypomethylating agent.

We also studied the chemokine expression CXCL9, 10, and 11, based on our preclinical data. We measured them at baseline and at cycle 2, day 8, and observed an increase in CXCL9, 10, and 11 induced by treatment. This increase was mainly observed in patients who had a response per the resistance criteria. There was also a trend towards improvement in progression-free survival with the increase in these chemokines. Nevertheless, this observation needs to be further validated in future studies.

What are the next steps of investigation? Where do you see the potential placement of guadecitabine and durvalumab combination therapy in the treatment algorithm for advanced RCC?

Dr. Zakharia: In the kidney cancer field, there is a significant need for new mechanisms of action beyond the current standard treatments like TKIs, VEGF inhibitors, and checkpoint inhibitors. While we now have HIF-2α inhibitors, the majority of drugs in use still target these pathways. Most drugs currently in development are still in the investigational phase. Therefore, discovering new pathways to tackle kidney cancer is of great interest to the community.

This trial, being a phase 1/2 early-phase clinical trial with a small sample size, did not meet its primary endpoint of improving overall response rate. However, the signal of progression-free survival and disease stability for a prolonged period in this patient population is intriguing and warrants further study. I would propose focusing on patients who are treatment-naïve to checkpoint inhibitors or those who progress on prior lines of therapy for a randomized phase 2 trial. Even though the signal was not observed in patients who failed checkpoint inhibitors, it was seen in those who were treatment-naïve.

The logistics of this trial might be challenging, given the 5-day consecutive dosing of guadecitabine compared to the daily oral pills of TKIs. However, this should not discourage further exploration of hypomethylating agents in kidney cancer. Perhaps a different dosing schedule could be explored. Hypomethylating agents have been successful in hematologic malignancies and are now making their way into solid tumors. Therefore, it is worth further investigation, especially in the kidney cancer population.