Classification of metastatic renal cell carcinoma patients in immunotherapy era and positive responses for sarcomatoid tumours

Medical writer: Dr. Rachel H. Giles

Prof. Bernhard Escudier (Gustave Roussy Cancer Campus, Paris, France) presented a post-hoc analysis of CheckMate 214, concluding that the IMDC prognostic criteria, based on anti-VEGF treatment outcomes, may not be as relevant for immunotherapy treatment outcomes in metastatic renal cell carcinoma [1]. Prof. D. McDermott (Dana-Farber, Harvard Cancer Centre, USA) presented a subgroup analysis demonstrating that the ipilimumab + nivolumab arm provided improved efficacy and prolonged survival vs sunitinib, with consistent safety, in previously untreated, intermediate/poor-risk, advanced clear-cell RCC with sarcomatoid features [2].

The randomised controlled trial CheckMate 214 (ipilimumab + nivolumab vs sunitinib in 1st line metastatic renal cell carcinoma) demonstrated a complete response rate of 16% in patients with intermediate- and poor-risk features whose tumour tested positive for PD-L1. The key take-home message was that this combination resulted in an overall survival advantage, but those data were mainly driven by the patients who were defined as intermediate- or poor-risk at the outset of the study by the IMDC prognostic criteria. The study was ended prematurely after the first interim analysis because the results on overall survival were clearly in favour of the immunotherapy combination; the survival advantage was even more pronounced in patients with higher risk scores.

Prof. Escudier and colleagues compared efficacy with nivolumab + ipilimumab vs sunitinib by number of IMDC risk factors present in 1096 intent-to-treat patients in both arms: 21%, 61%, and 18% had favourable, intermediate, or poor-risk, respectively. Of intermediate-risk patients, 58% had 1 factor; and 42% had 2 factors. Of poor-risk pts, 58% had 3 factors, 29% had 4 factors, and few had 5 (10%) or 6 (3%) factors. Due to small numbers, pts with 4–6 factors were pooled. At 30-months minimum follow-up, RECIST v1.1-confirmed objective response rate and complete response rate per investigator remained consistently higher with nivolumab + ipilimumab vs sunitinib across pts with 1–4 factors, although with sunitinib, ORR decreased with increasing number of factors. The authors conclude that nivolumab + ipilimumab showed consistent efficacy across number of IMDC risk factors, while sunitinib decreased in efficacy with increasing number of factors. These results show a need for improved prognostic models for immunotherapies in aRCC.

Professor McDermott’s paper addressed the unmet need of patients with advanced renal cell carcinoma with sarcomatoid features (sRCC), who have poor prognosis with anti-VEGF targeted therapy. They performed a post-hoc exploratory analysis of 112 CheckMate 214 randomised sRCC patients with pathologically confirmed sRCC (nivolumab + ipilimumab, n=60; sunitinib, n=52). In descriptive analyses performed at a minimum follow-up of 30 months, confirmed overall response rate and complete response rate per investigator (RECIST v1.1), overall survival, and progression-free survival per investigator were improved with nivolumab + ipilimumab vs sunitinib in intermediate/poor-risk patients with sRCC.

There were two additional presentations assessing the response rates of patients with intermediate/poor risk features or sarcomatoid histologies to checkpoint inhibitor therapies [3-4]. These two abstracts similarly describe treatment of patients bearing sarcomatoid tumours with pembrolizumab plus axitinib, or atezolizumab plus bevacizumab, respectively. Presence of sarcomatoid cells in a tumour is typically associated with a worse prognosis, and patients with sarcomatoid tumours do not respond as well to targeted drugs like sunitinib or pazopanib. However, sarcomatoid tumours typically harbour more immune cells, and we see in each of the first three abstracts that patients with sarcomatoid kidney tumours respond to combinations including IO agents considerably better than to sunitinib alone, with complete disappearance of disease in a small but significant percentage of cases. These findings collectively open a therapeutic option for patients that in the past did not have any good treatment options.

1.  Escudier B et al. Abstract 4575. ASCO 2019, 31 May-4 June, Chicago, USA.
2. McDermott D et al. Abstract 4513. ASCO 2019, 31 May-4 June, Chicago, USA.
3. Rini B et al. Abstract 4500. ASCO 2019, 31 May-4 June, Chicago, USA.
4. Rini et al. Abstract 4512. ASCO 2019, 31 May-4 June, Chicago, USA.

Posted on 15 July 201925 March 2021