EAU 2018: Systemic Immunotherapy in Urological Cancers: Basics and Beyond - Monotherapy or Combinations for Renal Cell Carcinoma (RCC) and Urothelial Carcinoma (UCa)
Dr. Stenberg starts her presentation discussing the results of the CheckMate-214 trial. The CheckMate-214 trial assessed the combination of nivolumab (PD-1inibitor) and Ipilimumab (CTLA-4 inhibitor) versus Sutent in the treatment of patients with newly diagnosed metastatic kidney cancer. The trial recruited approximately 1100 patients with most of them presenting with intermediate (60%) and poor risk (17%) disease. All tumors were tested for PD-L1 expression on trial entry, with those presenting with favorable-risk disease showing significantly lower baseline expression level. The response rate in the NIVO+IPI groups was an astonishing 42% for patients with intermediate and poor-risk disease, compared to 27% in the Sutent group (p<0.0001). The CR rate was also significantly higher with 9% of patients in the NIVO-IPI group achieving and complete response compared to 1% in the Sutent group. On OS assessment, intermediate and poor-risk patients treated with NIVO+IPI has a 37% reduction in the risk of death (HR 0.63 [CI 0.44-.89], p<0.001) at a median follow-up of 25.2 months. PD-L1 tumor expression was noted to be a predictor of NIVO+IPI response in patients with intermediate and poor-risk disease, which will require further evaluation in follow-up trials. Surprisingly, patients with favorable-risk disease showed significantly higher response rates when treated with Sutent (52%) compared to NIVO+IPI (29%). NIVO+IPI is set to become the standard of care for the treatment of intermediate and poor-risk patients with treatment-naïve metastatic kidney cancer.
She transitions to the IMmotion 151 trial which randomized 915 patients with metastatic RCC to combination atezolizumab/bevacizumab (Atezo/Bev) or Sutent. As with CheckMate-214, the combination of Atezo/Bev showed improved PFS compared to Sutent (HR: 0.83 [CI 0.70-0.97]). The difference in PFS was higher in those with PD-1 + tumors (HR: 074 [CI 0.57-0.96]). Complete response rates were comparable to those seen in CheckMate-214 (9% vs. 4%), with impressive partial response rates (34% vs. 30%). Importantly, a significant advantage of using Atezo/Bev was seen in patients with favorable prognostic factors, which was not the case in CheckMate-214. Interestingly, the results were significantly blunted when the analysis was performed following independent radiological review the difference no longer considered statistically significant. This finding generated significant debate during its initial presentation in GU-ASCO, but the feeling was that the trend was the same and the results from OS will likely mimic those from Checkamte-214.
In summary, the treatment landscape of advanced kidney cancer has changed dramatically over the last 2 years (Figure 1) and it will likely continue to change with the reporting of the multiple ongoing combination trials. The future of treatment allocation will likely be based on whole exome sequencing genomic signatures. A recent evaluation of IMmotion 151 tumor signatures and response rates (McDermort D et al. IMmotion 151 Biomakers, AACR 2017) identified three distinct genomic signatures: Angiogenic, Immunogenic and Immune Suppressed (Figure 2) by which treatment can tailored.
The role of immunotherapy in bladder cancer continues to grow and currently is approved for the use in the second line setting and in the first line treatment in patient’s ineligible for platinum-based chemotherapy. As a second line agent immunotherapy has shown a marginal improvement compared to chemotherapy (20% vs. 10%), but patients who respond appear to become long time responders. The negative results of Imvigor-210 have questioned the use of checkpoint blockade as a second line agent leading National Health Service (NHS) to hold its approval for use in the UK until further data is available. In the first line setting, comparable response rates to chemotherapy are seen in those ineligible for platinum therapy
The focus of new trials has been on the combination of PD-1 inhibitors with other systemic agents. The combination of chemotherapy with PD-1 agents has gain significant interest due to the possible immune priming effect that chemotherapy may have by the release of tumor neo-antigens. Presently, three trials are enrolling patients in the first line setting, CheckMate-901 (Nivolumab /Ipilimumab + Gem-Cis), Keynote 361 (Pembrolizumab + Platinum chemotherapy), ImVigor 130 (Atezolizumab + platinum-based chemotherapy) and Denube trial (Durvalumab + Platinum chemotherapy). At this time, it is unclear which agent should be given first, there are theories supporting the use of immunotherapy first followed by chemo while others support the use of chemo first. An important trial being done at MSCKCC is attempting to answer this question performing tumor biopsies in between treatment agents. In addition to assessing the timing of each agent the investigators are hoping that the tumor biopsies will also shed some light in to possible pathways for treatment resistance.
Speaker: Cora N. Sternberg, MD, FACP, San Camilo Forlanini Hospital, Rome (Italy)
Written by: Andres F. Correa, MD, Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia, PA, at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark