(UroToday.com) The 2023 ESMO annual meeting included a session on novel targets, therapies, and toxicities in genitourinary cancers, featuring a presentation by Dr. Samra Turajlic discussing advances in the molecular understanding of genitourinary cancers. The mapping of the molecular landscape of RCC identified several important genes, including: VHL inactivation (~90%), PBRM1 loss (~40%), SETD2 loss (~20%), and BAP1 loss (~20%). Thus, could cooperation and antagonism amongst RCC driver genes be exploited therapeutically?
Dr. Turajlic notes that chromosomal loss is the driver of metastatic disease, specifically loss of chromosome 9p with a second hit in CDKN2A, and loss of chromosome 14q. Importantly, the number of approved therapies has increased significantly in RCC without patient selection: there is no routine molecular profiling being done for patients' RCC, and there are no biomarkers for therapy selection. Furthermore, the clinical actionability of molecular alterations has not increased in RCC. However, among other cancers, there has been a near doubling of tumors with molecular alterations making them eligible for standard of care therapy. RCC dominates by alterations in tumor suppressor genes, but there is no “oncogene addition” in RCC (ie. kinases that can be exploited for selective inhibitors), thus there have been no “blockbuster” treatments.
It is well known that VHL loss leads to constitutive activation of HIF and that HIF has long been considered undruggable leading to downstream targeting of VEGF. This has led to many VEGF TKIs being approved (many multi-kinase inhibitors), but not all patients with VHL driven RCC respond. However, recently, we have had the emergence of the HIF2alpha inhibitor belzutifan, which affords for more precise pathway modulation:
VHL disease is the prototypical cancer model of HIF2 alpha activation. VEGF targeting in VHL disease has shown modest response rates in RCC, but no benefit in CNS hemangioblastomas, and a high rate of treatment discontinuation. Alternatively, belzutifan in VHL disease led to high response rates (including complete response) across all VHL driven tumors, with low levels of toxicity (LITESPARK-004):1
At ESMO 2023, we saw new data for belzutifan in the sporadic RCC setting, specifically the LITESPARK-005 trial presented by Dr. Albiges. This trial randomized very heavily pretreated clear cell mRCC patients (<3 systemic therapy regimens) 1:1 to belzutifan versus everolimus, reporting a PFS benefit for belzutifan of HR 0.74 (95% CI 0.63-0.88). Additionally, there was an improvement in ORR: 22.7% for belzutifan versus 3.5% for everolimus. There is also a role for belzutifan and cabozantinib, with Dr. Choueiri presented updates from the LITESPARK-003 trial demonstrating an ORR of 59% in cohort 1 and ORR of 32% in cohort 2:
The LITESPARK-024 trial is combining belzutifan with the CDK4/6 inhibitor palbociclib in the following trial design:
CDKN2A loss is associated with enrichment in metastatic disease and has been linked to IO resistance in other cancers, leading to the combination of VEGF, CDK4/6 inhibitors, and PDL1 inhibition in the APART trial:
Additionally, there are molecular targets outside the VHL driven pathways, such as PBRM1, with pleiotropic effects of PBRM1 loss as part of the SWI/SNF complex. Of note, PARP inhibitors are synthetically lethal to PBRM1 mutations, leading to an initial PARP inhibitor trial called the ORCHID trial:
A second molecular target outside the VHL driven pathway is SETD2, with pre-clinical data suggesting that SETD2 mutations may be a potential target for ATR inhibitors:
To date, Dr. Turajlic emphasized again that there are no biomarkers for any of the current standard of care therapies. As such, the Optimal Treatment by Invoking biologic Clusters in Renal Cell Carcinoma (OPTIC RCC) trial may help us use biomarkers to enrich for response. The trial design is as follows:
Dr. Turajlic concluded her presentation discussing advances in the molecular understanding of genitourinary cancers with the following take-home points:
- There has been substantial advancement in the molecular understanding of RCC (post VHL), but this work has not led to actionability
- Targeting HIF2-alpha directly is effective in VHL disease, VEGF-TKI + IO refractory RCC, and treatment-naïve sporadic clear cell RCC
- There is high efficacy of belzutifan observed in VHL-driven tumors, suggesting it may be effective in other pseudo hypoxic settings (ie FH and SDHB mutant RCC)
- CDK4/6 inhibitors may synergize with belzutifan and possibly impact IO resistance
- Targeting additional tumor suppressor genes PBRM1, SETD2, BAP1 remains challenging
- Our ability to molecular stratify patients for current standard of care and clinical trials is lacking
Presented by: Samra Turajlic, MD, The Francis Crick Institute, London, UK
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
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