Synergising hypomethylating agents with immunotherapy in renal cell carcinoma: unlocking the potential of an old classic

The use of immune checkpoint inhibitors (ICIs) has become the standard first-line treatment for clear cell renal cell carcinoma (RCC), typically in combination with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents and/or anti-angiogenic small molecules [or tyrosine kinase inhibitors (TKIs)]. Although these combinations have shown efficacy, not all patients benefit from these treatments, primarily due to primary resistance to therapy (1). Epigenetic modifications, such as DNA hypermethylation, have recently been described as associated with tumour progression and poor prognosis in RCC patients, mainly due to mechanisms of inhibition of the anti-tumour immune response. The benefit of pharmacologic epigenetic modulation in haematological tumours is well-established, but the translation of this anti-tumour effect to solid tumour treatment remains unclear (2). The main classes of epigenetic modulation agents include hypomethylating agents (HMAs), such as guadecitabine, decitabine and azacitidine, and histone deacetylase inhibitors like panobinostat. HMAs have been observed to upregulate cancer antigen expression, leading to the release of T-cell effector pro-inflammatory cytokines and subsequent T-cell-mediated tumour killing (3). For example, decitabine has been shown to enhance CD8⁺ T-cell activation, proliferation and cytolytic activity, correlating with improved anti-tumour responses and overall survival in animal tumour models (4,5). Could combining an HMA with ICI therapy potentially have synergistic effects as an RCC treatment?

To answer this, Zakharia et al. conducted a translational study to evaluate the safety and efficacy of combining HMAs with ICIs in RCC treatment (6). Specifically, they investigated the use of guadecitabine (an HMA) administered at 45 mg/m² subcutaneously on days 1–5, along with durvalumab (an ICI) at 1,500 mg intravenous (IV) on day 8 in 28-day cycles. This study enrolled 57 patients with metastatic RCC [intermediate or high international metastatic renal cell carcinoma database consortium (IMDC) risk], including 36 treatment-naive and 15 ICI-refractory patients. With a median follow-up of 20 months, treatment-naive patients showed an overall response rate (ORR) of 22%, median progression-free survival (mPFS) of 14.2 months and 2-year overall survival (OS) of 85%. On the other hand, in ICI-refractory patients, the ORR was 7%, mPFS was 3.9 months and 2-year OS was 62.4%. The most common adverse event related to guadecitabine was neutropenia, with no treatment-related deaths reported. Moreover, biomarker analysis revealed a decrease in LINE-1 and CXCL10 promoter methylation post-treatment, indicating the efficacy of guadecitabine. Th1 chemokines (CXCL9, CXCL10 and CXCL11) were significantly induced by ICI, with increases correlating with a better ORR. Responders had higher Foxp3 expression in CD4⁺ T cells and more retinoic acid-related orphan receptor expressing CD8⁺ (RORyT-expressing CD8⁺) T cells, which are linked to enhanced inflammation and anti-tumour activity. The biomarker analysis showed no significant differences in leukocyte subtypes across toxicity grades, but interleukin-2 (IL-2) production by innate lymphoid cells was linked to toxicity. Induction of IL-2 and interferon-gamma (IFN-γ) in T cells was observed only in patients with severe toxicity, indicating that therapy-induced cytokine responses may drive immune-mediated toxicity. In summary, the combination of durvalumab and guadecitabine showed an acceptable toxicity profile and promising activity, especially in ICI-naive patients with advanced RCC.

Currently, a wide range of first-line treatment schemes for metastatic RCC are available, including various combinations of ICIs [anti-programmed death-1 (anti-PD-1) and anti-CTLA4], anti-PD-1 and TKIs, and even anti-PD-1, anti-CTLA4 and TKI (1). Could an ICI-HMA combination be established as a new first-line treatment alternative for RCC patients? Current results indicate difficulty, but the data reported by Zakharia et al. are promising. There is no consensus yet on the correct combination for the first-line treatment of RCC. However, the choice is described to be based on the clinical profile of the patient rather than a specific biomarker (7). Are we ready to add the ICI-HMA combination to our first-line therapeutic arsenal? The answer—for now—is clearly no. Although the study presented by Zakharia et al. is methodologically well-designed (multicenter and single-arm phase Ib/II trial), HMAs have historically demonstrated only limited anti-tumour effects in solid tumours (8). For nearly 20 years, these drugs have been used to treat haematological malignancies, such as myelodysplastic syndrome and certain leukaemias, but these positive results have not translated to the treatment of solid tumours (9) Additionally, while the efficacy of immunotherapies (such as pembrolizumab, nivolumab and ipilimumab) and TKIs (such as cabozantinib and lenvatinib)—along with their respective combinations—is well-established in the first-line treatment of RCC patients (1), it is essential to establish the efficacy of different ICI-HMA combinations in well-designed phase III studies. These studies should be stratified according to IMDC risk and use various types of immunotherapies. They might also utilise specific biomarkers that can predict the response to the ICI-HMA combination, such as markers associated with DNA methylation or resistance to the anti-tumour immune response (10). Furthermore, the effectiveness of the ICI-HMA combination should be compared in these phase III studies with that of other combinations with demonstrated efficacy, such as the ICI-TKI and ICI-ICI (anti-PD-1 and anti-CTLA4) combinations. Therefore, while there are promising signs, the road ahead for this combination remains long. Also, it is important to clarify that durvalumab is not yet FDA-approved for the first-line treatment of metastatic renal cancer. Could there be a specific profile of patients that could benefit from treatment with ICI-HMA? This is difficult to predict with the current information, but we could speculate that this combination might be suitable for patients suspected of ICI resistance (11), such as those who have shown disease progression during adjuvant immunotherapy or have a low disease burden, among others.

Considering the extensive array of treatments accessible to first-line RCC patients, it is necessary to advance towards developing predictive molecular biomarkers to facilitate the choice of combination therapy, whether ICI-ICI, ICI-TKI, or—eventually—ICI-HMA (12). As research progresses, it will be crucial to identify the most effective combinations and patient profiles to optimise RCC treatment outcomes. The competition to find the perfect combination is tough, and the game is still open.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-86/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-86/coif). M.B. has received payments for lectures from Roche/Genentech, Bristol Myers Squib, MSD Oncology, Novartis, and AstraZeneca. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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