He began by emphasizing that the advanced RCC landscape has changed dramatically over the last two decades. During this time, we have moved from the immunotherapy approach (the cytokine-era) to agents targeting angiogenesis (the VEGF-TKI era) to the current approach of combinations of immune checkpoint inhibitors with VEGF-TKI (the combination era). He emphasized that, compared with the prior standard of care of sunitinib, the current standard combination approaches have demonstrated a 40% benefit in progression-free survival with years of improvement in median overall survival.
He presented data from some of these recent trials. While survival is clearly improved compared to historical approaches, three-year survival remains approximately 60-70%, thus highlighting the potential for further improvements. Thus, novel strategies are warranted.
He began by discussing Abstract 4512, a randomized comparison of the novel anti-angiogenic agent vorolanib either alone or in combination with everolimus with everolimus alone in previously treated patients with mRCC. This study included patients with clear cell carcinoma who failed first like VEGF-TKI. Dr. de Velasco first highlighted the question of how this criterion fits within our current treatment landscape. Current guidelines fairly unanimously recommend combination approaches. Thus, most patients treated today will receive combination therapy with IO-IO or IO-TKI combinations in the first line. Thus, it is somewhat difficult to apply these data to our present practice.
He emphasized that this represents a large phase III trial of vorolanib, which targets both VEGF-R and PDGF-R, and was designed to improve the safety of tyrosine kinase inhibitors. The combination approach was supported based on phase I data, though the comparison with everolimus may be outdated.
The primary endpoint was progression-free survival which was improved in the combination arm, compared to the other two monotherapy approaches. This joins a number of other treatment approaches which have been shown to improve PFS in phase III RCTs (cabozantinib, nivolumab, and axitinib) and in phase II RCTs (lenvatinib and the combination of lenvatinib and everolimus). However, this trial did not show any improvement in overall survival. Previous trials have shown that both cabozantinib and nivolumab may increase overall survival in this setting. However, median OS in this trial was quite long in all arms.
Thus, Dr. de Velasco concludes that vorolanib and everolimus demonstrated improved PFS for patients who failed prior TKI, compared to everolimus. To consider its role, we can examine its safety profile. He emphasized that, overall, the profile appears similar to other agents though, somewhat unusually, rates of hypertension were not reported.
Thus, while vorolanib and everolimus met the primary endpoint and the study achieved an intriguingly long median overall survival, the treatment landscape has already changed with routine use of IO-based combination therapy in the first-line setting. Thus, while there is a need to identify treatment approaches for patients who progress after first-line therapy, this should focus on patients who receive first-line IO-based combination therapy.
Building on this idea of a combination of immunotherapy approaches, the second highlighted abstract considers the addition of CBM-588 to nivolumab and ipilimumab. While the CheckMate 214 data were transformative, there remains interest in further improving outcomes. Thus, there are numerous studies examining triplet combinations with nivolumab and ipilimumab.
Dr. de Velasco made an analogy to Copernicus’s discovery that the earth wasn’t the center of the universe, suggesting that the recent recognition of the so-called “human-microbiota superorganism” can represent a cataclysmic shift in our thinking. Thus, considering human health and disease, it is important to consider the contributions of the microbiome.
He highlighted data demonstrating that concomitant use of antibiotics may affect the intestinal microbiota of patients with advanced RCC and may compromise the efficacy of PD-1 blockade. Thus, modifying the microbiome may offer a novel treatment strategy.
Thus, this phase Ib study assessed the role of CBM-588 in combination with nivolumab and ipilimumab in patients with intermediate and poor-risk clear cell RCC.
He emphasized that this small (n=30) trials utilized a specific bacterial strain of Clostridium butyricum. The authors sought primarily to assess changes in the microbiome. While not statistically significant, the authors did demonstrate a change in the microbiome for patients who received CBM-588. However, Dr. de Velasco raised the question of whether this change was prompted by the response or by CBM-588, a question that this early phase study was unable to answer.
He then discussed secondary endpoints, including response, which was significantly higher for patients who received CBM-588 (58% vs 20%). However, he emphasized that it may be worthwhile to consider if CBM-588 can improve response rates among patients with stable disease or progressive disease. Further, it will be important to know how CBM-588 affects the safety of nivolumab and ipilimumab, given relatively frequent severe toxicity with this regime. In this small trial, there was no difference seen.
As a take-home, Dr. de Velasco highlighted that targeting the gut microbiome may become a promising treatment option though how best to do this is unclear. The use of CBM-588 improved outcomes for patients receiving nivolumab and ipilimumab without increasing toxicity. However, how to consider inter-individual variability may be difficult to consider and account for.
Presented by: Guillermo de Velasco, MD, PhD, Medical Oncologist, Department of Oncology, Hospital 12 de Octubre
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021