(UroToday.com) Following presentations from Dr. Maxime Meylan discussing predictive biomarkers in advanced renal cell carcinoma (RCC) based on ancillary analyses of the BIONIKK trial, Dr. Carolina Alves Costa Silva examining changes in gut microbiota during standard systemic therapy for metastatic RCC, and Dr. Ramaprasad Srinivasan providing updated longer-term follow-up of the LITESPARK-004 trial assessing the HIF-2alpha inhibitor belzutifan in von-Hippel-Lindau disease associated neoplasms, Dr. Guillermo De Velasco Oria provided an invited discussion to contextualize these results in the second Mini Oral session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers.
He noted that, in modern therapy, we do not have evidence for a biomarker to guide treatment in first-line renal cell carcinoma. This is not for a lack of analysis – prior studies have evaluable histology and immunohistochemistry, genomic analyses, mutational status, transcriptomic signatures, the tumor microenvironment, and gene set enrichment analyses. However, he emphasized that none of these are in routine clinical use to guide treatment decisions.
He did, however, note that the work to date has provided some interesting and valuable observations. For example, among patients receiving nivolumab and ipilimumab, gene set analysis has shown association between inflammatory signatures and progression-free survival. Similarly, for patients treated with VEGF-IO combinations, cluster-based stratification has shown important differences in survival.
He then summarizes results as presented by Dr. Myelan and Dr. Alves Costa, he noted that both abstracts suggest the use of tools (eg. TLS, Ki67 cell density, and gut microbiome) to guide treatment decision-making and sequencing in aRCC.
Highlighting data from the CheckMate 214 trial, Dr. De Veslasco Oria noted that clinical efficacy and toxicity may vary greatly between patients.
He then addressed the question of whether we can select patients who would be appropriate for monotherapy. He emphasized that previously published data have shown a small, but not insignificant, proportion of patients (~25%) may do very well with single-agent anti-PD-1. However, if we can select patients (such as, as suggested by Dr. Myelan, those with TLS >2) who derive oncologic benefits from monotherapy, we may spare these patients the additional toxicity of combination regimes.
He then dove a bit deeper into TLS – the tertiary lymphoid structure: this TLS signature is highly expressed in RCC. Further, there is substantial heterogeneity in both the components and location of TLS. In the context of mRCC, Dr. De Velasco highlighted that a definition of TLS positivity is not well defined. However, Dr. Meylan and colleagues used a cut-off of >2 and demonstrated that this was associated with ORR, but not PFS, in patients treated with the combination of nivolumab and ipilimumab. However, the association with PFS was much more pronounced in those who received nivolumab monotherapy.
He then described added layer of complexity, as suggested by Dr. Meylan who noted that the discriminative ability of TLS could be improved by also considering PD1*Ki67 positive cells. Dr. De Velasco noted that this allows better selection and a better understanding of the benefit/risk balance.
However, he considered whether we may be missing the point given our inability to identify patients. Instead of our exhaustive focus on the “-omics”, he suggested that the microbiome may allow insight. This is further assessed in the paper from Dr. Alves Costa. Dr. De Velasco noted that prior studies have demonstrated associations between various gut bacteria and response to treatment in advanced cancer. However, beyond understanding the baseline bacterial composition, this most updated work showed that there are longitudinal shifts in the gut microbiome during the course of therapy and that these differ on the basis of the systemic therapy being administered.
Further, he noted that patients with IMDC risk may have a more immunogenic and healthier commensual bacterial composition. However, he noted that it is unclear which (the tumor or the microbiome) is the “chicken” or the “egg” in terms of driving this relationship.
Most interestingly, the question is whether we can modify the gut microbiome to improve outcomes. Prior phase I work has shown that the addition of a probiotic to standard systemic therapy may improve both the bacterial composition of the gut as well as clinical outcomes. However, “no single species could be regarded as a consistent biomarker”, limiting the actionability of these findings. Thus, the relationship between the human gut microbiome and immune checkpoint inhibitor therapy is substantially more complex than was likely initially appreciated and moves beyond a binary interpretation of presence or absence.
Considering the treatment approach to patients with intermediate IMDC risk, he considered whether we may action the present findings to drive treatment choice. However, there are many limitations between today’s data and clinical practice.
He then moved on to discuss the last abstract, examining long-term outcome of belzutifan in patients with VHL disease-associated tumors. He noted that this may represent one of the biggest advances in RCC treatment in the last few years. The primary report of this trial was published in the NEJM in 2021 with a median follow-up of 21 months. In the data presented at this year’s ESMO, follow-up is now extended to a median of 37.8 months.
Compared with the first report of this cohort, he noted that the study was designed to assess an alternative hypothesis of 30% ORR. The first report, as published, showed a 49% ORR. The additional follow-up now shows an even more impressive response rate of 64%.
He further noted that there was evidence of increasing benefit at other VHL disease-associated tumor sites including pNETs and CNS and retinal hemangioblastomas. Further, he noted that there was a dramatic decrease in the number of disease-related surgeries required. Dr. De Velasco noted that this is likely to translate into substantial patient quality of life benefits. Considering the open questions, he first noted that 11 of 61 patients who initially began treatment stopped due to their choice. To explore this further, he noted that there was an 18% rate of grade 3 or greater toxicity. He noted that potential anemia may prove to be one of the most important toxicities. He noted that more than 90% of patients are likely to have some degree of anemia and it will be grade 3 in 10% or so. He further noted that this happens early and is maintained over time.
He raised the question of the role of erythropoiesis-stimulating agents as these were used in the context of the trial.
As a last thought, he suggested that the biomarker world is much like a puzzle, without context. If we consider the pathway development of belzutifan, he emphasized the timely and rapid progressive development and approval of this agent.Presented by: Guillermo A. De Velasco Oria, MD, PhD, Hospital 12 de Octubre, Madrid, Spain
Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2022 European Society for Medical Oncology (ESMO) Annual Congress, 9-13 September 2022.