I still remember the debates around treating sarcomatoid renal cell carcinoma (RCC) a decade ago when I started in practice. There were not many studies to cite – one that often came up was Naomi Haas’s trial of doxorubicin with gemcitabine (ECOG 8802). The study showed progression-free survival (PFS) of 3.5 months and overall survival (OS) of 8.8 months – sobering results, but at least an option we could pursue in the clinic. I only treated a handful of patients with this regimen, but it was certainly no walk in the park – massive fatigue, cytopenias and a range of other toxicities.

Fast forward a couple of years and the discussion shifted towards the use of targeted therapeutics such as sunitinib and pazopanib. The IMDC published a report comparing the outcomes of patients with and without sarcomatoid features. Patients with sarcomatoid features experienced a PFS of 4.5 months and OS of 10.4 months with the use of upfront vascular endothelial growth factor (VEGF)-directed therapies.

At this year’s ASCO meeting, it was really exciting to see some much more promising data for sarcomatoid patients. Brian Rini (Cleveland Clinic) had two key presentations, the first from KEYNOTE-426, a study comparing axitinib/pembrolizumab to sunitinib. Amongst 105 patients in the study with sarcomatoid features, axitinib/pembrolizumab resulted in a dramatic improvement in PFS, with a median PFS of 8.4 months with sunitinib versus not reached with axitinib/pembrolizumab (HR 0.54; 95%CI 0.29-1.00). The response rate was a whopping 58.8%. His second presentation, derived from the IMmotion151 trial comparing bevacizumab/atezolizumab to sunitinib, demonstrated similar hazard ratios for improvement in PFS and OS. His analysis from IMmotion151 further included a breakdown by PD-L1 status – there, it appeared as though the margin of benefit with immunotherapy was even larger.

Of course, a major dilemma we have in the clinic is whether to use the combination of VEGF-directed therapy with immunotherapy or to use a combination immunotherapy strategy. The combination of nivolumab/ipilimumab was approved back in April of 2018 based on data from the CheckMate 214 study. At this ASCO, Dave McDermott (Beth Israel Deaconess Medical Center) presented an update from CheckMate 214 including patients with sarcomatoid disease. Response rates with nivolumab/ipilimumab were nearly identical to that with axitinib/pembrolizumab, registering at 56.7% versus just 19.2% with sunitinib. The HR for PFS was 0.61 (95%CI 0.38-0.97).

The cumulative results from ASCO 2019 provided (first and foremost) hope for patients with sarcomatoid RCC. They also elicit equipoise, with data from KEYNOTE-426 and CheckMate 214 producing similar HRs for PFS and comparable response rates. So which to choose? Ultimately, either of these two regimens will constitute front-line therapy in the vast majority of cases. The clinician can feel comfortable selecting either regimen based on factors separate from the presence of sarcomatoid elements. In my practice, I tend to use nivolumab/ipilimumab in patients with de novo metastatic disease. My rationale for this is simple – there are fewer surgical considerations with a combined immunotherapy approach like nivolumab/ipilimumab. I can initiate therapy and the urologist can either operate immediately if indicated or defer surgery until a response is elicited. I’ve had more than a handful of cases in which we have taken this approach with successful outcomes. My colleagues Ulka Vaishampayan (Karmanos Cancer Center) and Hyung Kim (Cedars Sinai) will be running a trial soon to formally assess this approach within SWOG.

Written by: Sumanta Kumar Pal, MD,  Associate Clinical Professor, Department of Medical Oncology & Therapeutics Research, Co-director, Kidney Cancer Program, City of Hope’s Kidney Cancer Program

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