World Kidney Cancer Day: The future of RCC treatment

Renal cell carcinoma (RCC) accounts for approximately 90% of all kidney cancer cases and poses significant treatment challenges due to its complex biology and relative lack of specific biomarkers, which has historically made it difficult to develop targeted treatments that are both highly effective and have minimal off-target effects. However, new therapies have made progress in improving patient outcomes, and with new cutting edge treatments now entering the clinic, prospects for those diagnosed with RCC are taking a big step forward.

The introduction of immune checkpoint inhibitors (ICI) in 2015 revolutionised the treatment paradigm for RCC by providing more effective and durable treatment options, with significant improvements in patient survival and quality of life. BMS’ Opdivo (anti-PD-1 mAb) showed a 6-month improvement in mOS over the mTOR inhibitor everolimus (25 vs 19.6 mos)¹, with Merck’s Keytruda (anti-PD-1 mAb) in combination with axitinib (receptor tyrosine kinase inhibitor, RTKi) also demonstrating mPFS (15.1 vs 11 mos) benefit over RTKi alone in 2019².

Despite these advancements, outcomes remain relatively poor for patients with advanced RCC, with only 15% of stage IV patients surviving for 5 years³. While ongoing combinations of SoC anti-PD-(L)1 mAbs, RTKis, and CTLA-4 mAbs may represent a small step forward, innovative, novel approaches will be required to make further meaningful improvements in patient outcomes.

Personalised cancer vaccines, such as Moderna/Merck’s mRNA-4157 and Roche/BioNTech’s BNT122, could represent such a step forward. At the recent ASCO conference, the combination of mRNA-4157 with Keytruda was shown to reduce the risk of recurrence or death by 49% compared to Keytruda alone in melanoma⁴, with a Ph2 study of this combination initiated in RCC in April 2024⁵.

Cancer vaccines may also provide patients long-term anti-tumour immunity, with BNT122 demonstrating responses which persisted for 3 years in patients with PDAC, showing promise in tumours that are historically difficult to treat and typically unresponsive to classical ICI. BNT122 is currently in a Ph1 study in combination with Tecentriq across multiple solid tumours, including RCC⁶.

RCC tumours often accumulate regulatory T cells (Treg), which can cause patients to respond poorly to current treatment options. Treg depletion approaches may provide the key to restoring sensitivity and drastically improving responses to ICI. Roche’s RO7502175, a mAb targeting CCR8, has been shown to effectively deplete Treg cells in preclinical studies, and is currently in a Ph1 study with Tecentriq in RCC and other solid tumours⁷.