ESMO 2018: Challenging Established Frontline Therapies in Renal Cancer

Munich, Germany ( Dr. Laurence Albiges gave a talk on the challenges faced by established frontline therapies in renal cancer. In the ESMO meeting in 2017, the Checkmate 214 trial was presented, which compared sunitinib to Nivolumab + ipilimumab in the treatment of metastatic renal cell carcinoma (mRCC) patients. This trial demonstrated a benefit in favor of the nivolumab + ipilimumab combination in poor and intermediate risk mRCC patients, with median overall survival (OS) that was not reached compared to 26 months in the sunitinib group, p<0.0001. The complete response rate (CR) was 9% vs. 1% in favor of the combination treatment. However, in the favorable risk group of mRCC patients, sunitinib was shown to be better, demonstrating an objective response rate (ORR) of 52% vs. 29%, with higher median progression-free survival (PFS) of 25.1 months vs. 15.3 months, p<0.0001. This has resulted in the updated ESMO guidelines to recommend the combination treatment to be the first line treatment in intermediate and poor risk patients (Figure 1).

UroToday ESMO2018 ESMO guidelines for clear cell mRCC
Figure 1 – ESMO guidelines  for clear cell mRCC:

There are currently several ongoing trials attempting to challenge this guideline-recommended treatment. These include the IMmotion 151, analyzing the effect of atezolizumab + bevacizumab, the JAVELIN renal 101, analyzing the effect of Avelumab + axitinib, and Keynote 426, analyzing the effect of pembrolizumab + axitinib. The problem of all these new trials is that they compare to sunitinib and not to nivolumab +Ipilimumab, which is the new standard of care. Do we need to define what hazard ratio is needed to be compared to sunitinib in future trials? Should it be higher or the same? Do we need to know whether PFS is enough? Or is a new bar of OS required? From a clinical research perspective, if we only use PFS, without OS, we could have some confounding factors.

In the three trials mentioned, Checkmate 214, IMmotion 151, and JAVELIN renal, the new combination of ICI + VEGF inhibitor are setting a new bar, with objective response rate around 55-58%. In future studies, the response rate is going to be very important, especially in symptomatic and poor risk patients, where achieving disease control is required. One also raises the questions whether a patient who achieved CR and long-term remission, can stop taking his targeted therapy? Dr. Albiges hypothesized that soon VEGF receptor inhibitor + ICI would be the first line therapy in good risk mRCC patients, and function as second-line therapy in intermediate and poor risk patients. Some more analyses would need to be done to dissect the intermediate risk category and understand whether they are all the same, or they can divide as well.

There are several remaining open questions that will also need to be answered. These include:

  • Can a patient with complete response stop treatment? Is he cured?
  • What is the rescue strategy for patients who have failed therapy with VEGFR inhibitor + ICI?
  • What is the impact of frontline combination therapy on subsequent therapies?
Another important issue to remember is the significant impact that combination therapies have both on survival, but also on costs.

In summary, OS benefit with Nivolumab + Ipilimumab will be the new benchmark for indirect comparison of all new combinations trials with VEGFR inhibitor + ICI. Given the OS benefit in some of the studied combinations, this will be of great importance to the community. Lastly, the clinical strategy we currently use relies on the risk classification, but there is much more that can be done to increase patient selection.

Presented by: Laurence Albiges, Gustave Roussy Oncology Institute Villejuif, France

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany