ASCO 2019: Consistent Efficacy of Nivolumab plus Ipilimumab Across a Number of International Metastatic Database Consortium Risk Factors in CheckMate 214

Chicago, IL (UroToday.com) CheckMate 214 was a randomized, open-label, phase 3 trial of nivolumab plus ipilimumab (NIVO+IPI) followed by NIVO monotherapy versus sunitinib (SUN) in patients with previously untreated advanced renal cell carcinoma (RCC) with a clear cell component.1 Patients were randomized 1:1 to receive either NIVO 3 mg/kg plus IPI 1 mg/kg intravenously every three weeks for four doses followed by NIVO 3 mg/kg every two weeks maintenance therapy or SUN 50 mg orally once daily for four weeks on and two weeks off in each 6-week cycle.

This trial demonstrated superior overall survival (OS) and objective response rate (ORR) of NIVO+IPI over SUN in advanced RCC.1 These results led to the FDA and the European Medicines Agency approval of this combination for the first-line treatment of patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)–defined intermediate- or poor-risk advanced RCC. CheckMate-214 demonstrated consistent, durable efficacy of NIVO+IPI across the intention-to-treat (ITT) population and in patients with IMDC favorable- or intermediate/poor-risk disease, whereas the efficacy of SUN declined as the risk increased.2

It is noteworthy that the IMDC prognostic model was developed based on anti-vascular endothelial growth factor (VEGF) targeted treatments for advanced RCC,3 but this model may not be optimally designed to predict response to combination immunotherapy regimens such NIVO+IPI. In this post hoc analysis, the efficacy outcomes of CheckMate 214 were stratified by the number of individual IMDC risk factors. The authors aimed to investigate further the prognostic value of this model in advanced RCC patients treated with NIVO+IPI. 

The outcomes of interest in this analysis included OS, investigator-assessed ORR and progression-free survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The patients were categorized into favorable (0), intermediate (1–2), and poor (3–6) IMDC risk groups using an interactive voice response system (IVRS). Due to small patient numbers, patients with 4–6 risk factors were pooled for efficacy analyses.

The minimum follow-up was 30 months (median, 32.4 months). In this analysis, there were 1051 patients, of whom 24% had 0 risk factors, 60% had 1–2 risk factors, and 17% had 3–6 risk factors. Risk factors were generally balanced between the treatment arms. Table 1 elaborates the proportion of risk factors in the IMDC risk groups. In the ITT population, the OS benefit with NIVO+IPI was maintained with longer follow-up, and the median OS had not been reached (Figure 1A). Median OS was not reached with both NIVO+IPI and SUN in patients with 0 risk factors (Figure 1B). However, OS was notably improved with NIVO+IPI versus SUN across 1–6 IMDC risk factors (Figure 1C–F; Figure 2).
Table1_IMDCRiskFactors_CheckMate214pts.pngTable1IMDCRiskFactors_Pt2.pngTable1IMDCRiskFactors_Pt3.pngFigure1_OSbyIMDCRiskFactorNumber.pngFigure1_OSbyIMDCRiskFactorNumber_pt2.png
Figure2_20mth_SurvivalProb_IMDCRiskFactors.png
When assessing the ORR per investigator, it remained consistent with NIVO+IPI across the number of risk factors, while with SUN, the ORR decreased with an increasing number of risk factors (Figure 3). Similarly, the complete response (CR) rate was consistent across 0–3 risk factors. ORR was higher with NIVO+IPI versus SUN across 1–6 risk factors while the CR rate was higher with NIVO+IPI versus SUN across 0–3 risk factors.

In the ITT population, NIVO+IPI demonstrated a late benefit in investigator-assessed PFS, with the Kaplan–Meier curves separating after 12 months (Figure 4A). Median PFS was 13.9 months with NIVO+IPI and 19.9 months with SUN in patients with 0 risk factors (Figure 4B), whereas PFS was notably improved with NIVO+IPI versus SUN across 1–6 IMDC risk factors (Figure 4C–F).
Figure3_ORR_CRR_IMDCRIskFactors.png
In summary, with long-term follow-up, consistent differential benefit in OS, PFS, and ORR was observed across all ITT patients and patients with 1–6 IMDC risk factors with NIVO+IPI over SUN. ORR with NIVO+IPI was consistent in patients with 0–6 IMDC risk factors, while ORR with SUN decreased with an increasing number of risk factors. OS, PFS, and ORR benefits were observed with NIVO+IPI over SUN in patients prospectively categorized as having either intermediate- or poor-risk disease, and most of this intermediate/poor-risk group had just 1 or 2 IMDC risk factors. The CR rate was notably higher with NIVO+IPI versus SUN in patients with 0, 1, 2, or 3 IMDC risk factors. Importantly, no notable differences in OS, PFS, or ORR were observed between arms in the favorable-risk subgroup (0 risk factors; n = 249). These results suggest that the IMDC prognostic model, may not adequately predict outcomes with NIVO+IPI in the first-line setting. Therefore, additional studies are needed to better inform patient selection as the treatment landscape for advanced RCC continues to evolve. 

Presented by: Bernard Escudier, MD, Gustave Roussy, Villejuif, France

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Motzer RJ, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378:1277–1290.
  2. Tannir NM, et al. 2019 GU-ASCO
  3. Heng DY, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.J Clin Oncol 2009;27:5794–5799.
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