Is there a preferred sequence of therapy in renal cell carcinoma?

For many years, sunitinib and pazopanib have been the standard first line therapy for metastatic clear cell RCC. A new treatment paradigm is now evolving. Longer overall survival and higher response rate of nivolumab/ipilumimab and pembrolizumab/axitinib combinations vs. sunitinib were demonstrated in Checkmate 214 and Keynote 426 trials, respectively. Of note, the benefits of nivo/ipi were limited to IMDC intermediate and poor-risk groups, while pembro/axitinib showed benefits across all IMDC risk categories. Among the TKIs, cabozantanib demonstrated significant progression-free survival and response rate over sunitinib as a first line therapy in CABOSUN trial. Cabozantanib is particularly beneficial in patients with bone metastases (Escudier et al, Journal of Clinical Oncology, 2018). For 2nd line therapy, nivolumab and cabozantinib have been standard of care based on their superiority vs. everolimus in Checkmate 025 and METEOR trials, respectively. Lenvatinib and everlolimus combination also showed better progression free survival over everolimus in the 2nd line setting, but those data were based on a phase 2 trial (Motzer, et al, Lancet Oncology, 2015).

Based on these trials, I prefer pembro/axitinib combination (sunitinib or pazopanib for patients who are not a candidate for a check point inhibitor) as first line for favorable risk disease. For a patients with intermediate or poor risk disease, I choose pembro/axitinib, nivo/ipi or cabozantinib.  We do not have comparative data among the last 3 regimens. I consider the patient's comorbidities in selecting a regimen. For second line, my choice is either nivolumab (who progresses on TKI) or cabozantanib (who progresses on a check-point inhibitor). I put clinical trial, axitinib monotherapy or lenvima/everolimus for patients for subsequent lines of therapy. Patients who have not been exposed to a TKI and a clinical trial is not available, sunitinib or pazopanib may be reasonable for subsequent lines. 

To answer the second part of the question, my preference is to use combination over monotherapy in the front-line setting. We now have both immunotherapy combination (nivo/ipi) and immunotherapy/TKI combination (pembro/axitinib) available for first line use. In absence of side-by side comparison between these two regimens, it is difficult to conclude which one is more beneficial. My choice is based on the consideration of patient's comorbidity and tolerance to a particular regimen.

There is no one preferred sequence for all patients. Certainly, IO-based combinations are standard, and in my opinion, should be given to all pts unless an IO contraindication. There are advantages and disadvantages to IO/IO vs IO/TKI, and usually, MD preference drives this decision taking into account pt comorbidities, ability to tolerate Ipi, and interpretation of the non-comparative data. Starting with just IO monotherapy has not proven a viable strategy for most patients (based on several trials including a recent HCRN trial - NCT03117309), but no doubt a subset of pts exist who would do very well on IO monotherapy - we just don't know how to prospectively select those pts yet.