Several years ago, before the era of immunotherapy, when vascular endothelial growth factor (VEGF) receptor inhibitors were compared and used to treated advanced kidney cancer patients, the median overall survival was only 13 months (figure 1).
Figure 1 – Overall survival in metastatic renal cell carcinoma (RCC) with VEGF receptor inhibitors – pazopanib vs. sunitinib:
But in recent years, there has been great progress with new treatments being added to our armamentarium (Figure 2). As can be seen in figure 3, with the recently presented trial in ESMO 2020, comparing nivolumab and cabozantinib to sunitinib, there was a significant overall survival advantage to the immunotherapy arm with a median survival that has not yet been reached. This is a significant jump from a median survival of 13 months in the TKI era to a non- reachable median overall survival with immunotherapy, which is quite impressive.
Figure 2 – Current Approved systemic therapies in metastatic RCC:
Figure 3 – Overall survival: cabozantinib + nivolumab vs. sunitinib:
In the next few years, we have two options to improve survival and outcomes, according to Dr. Choueiri. These include changing the sequence of available drugs and applying different combinations and settings. The other option is the introduction of novel drugs such as HIF2 inhibitors, glutaminase inhibitors, and immunotherapy other than PD1/CTLA4.
Dr. Choueiri began discussing the first strategy of changing the sequence of the known drugs. One of the options is to integrate VEGF TKI and immunotherapy sequentially to maximize outcomes. The PDIGREE trial is an example of this kind of strategy (Figure 4). In this trial, the combination of immunotherapy and TKI will be assessed.
Figure 4 – PDIGREE trial design:
The goal is to maximize combinations in order to maximize outcomes. The COSMIC-313 trial will randomize patients with intermediate and poor-risk disease to a combination of three drugs vs. placebo.
Figure 5 – COSMIC-313 trial design:
Another option is to try a non-immunotherapy option as a front line treatment option, for example, comparing lenvatinib + everolimus or pembrolizumab to sunitinib (Figure 6).
Figure 6 – CLEAR trial design:
Another important aspect of concern is whether we should continue immunotherapy after previous treatment with immunotherapy. Retrospective data demonstrated that approximately 7/23 such patients had responded with an objective response rate of 30%.1 But there is also a phase 2 study showing that patients previously treated with immunotherapy has shown an objective response rate of 54% when treated with lenvatinib and pembrolizumab (Figure 7), so there might be some rationale for this approach of continuing immunotherapy after previous treatment with immunotherapy. Similar responses have been seen with nivolumab + ipilimumab after previous immunotherapy (Figure 8).
There is currently an ongoing phase 3 trial trying to assess this rationale, randomizing patients with previous treatment with immune checkpoint inhibitors to either cabozantinib or atezolizumab (Figure 9).
Figure 7 – levatinib + pembrolizumb - phase 2 trial:
Figure 8 – PHASE 2 – FRACTION-RCC – Nivo+Ipi post previous immunotherapy:
Figure 9 – CONTACT-03 phase 3 study:
We currently know that when a combination of immunotherapy drugs is given, the adverse event rate is higher. Therefore, there is a thought that we should first start with one PD-L1 inhibitor, and if there is no response, then we can add the CTLA4 inhibitor. There are currently several studies that are trying to assess this. The study design of two of these studies can be seen in figure 10.
Figure 10 – Salvage therapy – nivolumab followed by ipilimumab:
Next, Dr. Choueiri discussed the role of cytoreductive nephrectomy. There are currently planned studies assessing the role of cytoreductive nephrectomy with modern immune checkpoint inhibitors (Figure 11). Patients will get systemic therapy, and depending on their IMDC criteria, they will undergo cytoreductive nephrectomy.
Figure 11- Integrating cytoreductive nephrectomy with immune checkpoint inhibitors:
Next, Dr. Choueiri elaborated on novel drug therapies that are currently being investigated in trials. He began with the HIF2 inhibitor, which has shown favorable preclinical work. HIF2 alpha has shown a good pharmacokinetic profile, and it is now being investigated. The main adverse events shown from this treatment are anemia (due to decreased erythropoietin) and hypoxia with a 15% grade 3 adverse event rate. There is a pivotal phase 3 study to compare the HIF 2 alpha inhibitor to an MTOR inhibitor (Figure 12).
Another new agent is the glutaminase inhibitor. In normal cells, glucose is the major metabolite responsible for energy production. However, in cancer, due to the many alterations, there is an aberrant way of glucose metabolism, known as the Warburg effect, causing deprivation of the citric acid cycle of critical metabolites. Some cancer cells compensate for the Warburg effect by increasing glutamine metabolism to sustain the citric acid cycle for growth and proliferation (Figure 13). Therefore, a potential drug, the glutaminase inhibitor (Telaglenastat), is currently being assessed. It inhibits both glucose and glutamine metabolic pathways, inhibiting the energy sources of the cancer cells, and it has shown antiproliferative activity in vitro and in mouse xenografts. It has also shown synergy with VEGF and MTOR inhibitors. There is currently one proof of principle clinical trial combining telaglenstat with everolimus that showed promising results. Due to these promising results, there is an ongoing phase 2 study assessing this new drug with cabozantinib compared to placebo and cabozantinib (Figure 14).
Figure 12 – HIF2 alpha inhibitor (MK-6482): Phase 3 study:
Figure 13 – Dysregulated metabolism is a hallmark of cancer:
Figure 14 – CANTATA trial design:
The last novel drug group that was discussed was the immunotherapy drugs that are not PD1/CTLA4 inhibitors, and there are a lot of options, including the RCC immune microenvironment, and other ways, including precision immunotherapy, targeting surface antigens on the cancer cells or HLA-restricted antigens. There is an ongoing international phase 3 study assessing nivolumab and one of these new immunotherapy targets, the pegylated IL-2 agonist, compared to sunitinib or cabozantinib (Figure 15).
Figure 15 - The PIVOT-09 trial design:
There are also vaccine/cell-based therapies that are currently being investigated for clear cell RCC. These include the NEOVAX - personalized peptide vaccine, and the HERV-E TCR/Gene transfer approach. There is currently a phase 1 study assessing the NEOVAX vaccine (Figure 16).
Figure 16 – Phase 1 of the Neovax vaccine with subcutaneous ipilimumab:
Dr. Choueiri concluded his encompassing talk by stating that recently a kidney cancer research summit has been created to focus on translational research in novel methods of drug delivery, tumor microenvironment and epigenetics, rare kidney cancers, single-cell sequencing strategies, predictive biomarkers, and novel checkpoint inhibitors and cellular immunotherapy. Dr. Choueiri hopes this will greatly progress the treatment of advanced RCC.
Dr, Choueiri’s final take-home messages were to focus on current attempts to integrate known drugs, making their way in phase 3 trials, and explore the post-immunotherapy setting, which is a clear unmet need with existing and novel drugs. Lastly, we must invest more research in finding accurate and practical biomarkers.
Presented by: Toni Choueiri, MD, MS, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Written by: Hanan Goldberg, MD, MSc, Assistant Professor, Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
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