Nivolumab Plus Ipilimumab Improves Survival, Shows Activity in Sarcomatoid RCC

Nizar M. Tannir, MD

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has improved survival and response rates compared with sunitinib (Sutent), in patients with advanced renal cell carcinoma (RCC) with sarcomatoid histology, including those with intermediate and poor-risk features.¹

These findings are from a post hoc analysis of the phase 3 CheckMate 214 clinical trial, which, in 2018, showed that patients with intermediate- or poor-risk advanced RCC performed better on nivolumab plus ipilimumab compared with sunitinib.² The study ultimately led to the FDA’s approval of the combination as treatment of patients with intermediate or poor risk, previously untreated, advanced RCC.³

In the post hoc analysis, investigators led by Nizar M. Tannir, MD, professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, sought to further test the FDA-approved combination in the subset of patients with advanced RCC who have sarcomatoid features.¹

“Approximately 10% of patients with RCC will have sarcomatoid features in their tumors. I think the best way to identify those with certainty is by looking at the effect of the specimen rather than doing a biopsy of the primary tumor in the kidney or a biopsy of the metastatic site, which, you know, often may miss the underlying sarcomatoid differentiation.,” Tannir told Targeted Oncology in an interview. “The outcomes for these patients have traditionally been poor.”

The traditional treatments for advanced RCC with sarcomatoid features was cytotoxic chemotherapies and targeted therapies, like VEGF and mTOR inhibitors, but these treatments have provided limited benefit. Based on preliminary research about the potential efficacy of immune checkpoint inhibitors in this patient population, and the positive primary analysis data, Tannir et al administered nivolumab in combination with ipilimumab or the sunitinib control in a pool of 139 patients.

Randomization in the study was performed according to a 1:1 ratio. A total of 73 patients received the combination of nivolumab and ipilimumab and 65 patients received sunitinib. Patients in the immunotherapy combination arm received nivolumab 3 mg/kg and ipilimumab 1 mg/kg, every 3 weeks for 4 doses. Patients received nivolumab maintenance every 2 weeks after combination therapy was completed. Subjects in the sunitinib arm were given a 50 mg oral, once daily dose of the drug for 4 weeks on and 2 weeks off in each 6-week cycle. All therapies administered in the study were continued until disease progression or unacceptable toxicity.

End points explored in the post hoc analysis were similar to those explored in the primary analysis, including overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Safety was assessed in all patients.

Patients were stratified according to baseline tumor PD-L1 expression level (≥1% vs <1%).

Patients included in the analysis had a median age of 58 (range, 35-84) in the nivolumab/ipilimumab arm versus 61 (range, 39-79) in the sunitinib arm. Most patients in the study were male, which made up 74% of both arms. The IMDC prognostic score was largely intermediate, including for 73% of the nivolumab plus ipilimumab arm versus 74% of the sunitinib arm. The majority of patients who received combination immunotherapy were from the United States (46%), but patients in the sunitinib arm were largely from Canada or Europe (45%). Nephrectomy history was similar between the arms at 89% in the combination arm compared with 83% in the control arm. Finally, the most common site of metastasis was the lung, which was observed in 78% of the combination arm versus 77% of the control arm.

The median follow-up for the post hoc analysis was 47.7 months. Patients were on treatment with the immunotherapy combination for a median of 7.9 months (range, 4.2-14.5) and with sunitinib for 4.7 months (range, 2.9-6.4).

With nivolumab plus ipilimumab, the median OS was not reached (95% CI, 25.2 months–not estimable [NE]) versus 14.2 months (95% CI, 9.3-22.9) with sunitinib (HR, 0.45; 95% CI, 0.3-0.7; P = .0004). PFS, on the other hand, was significantly longer with nivolumab plus ipilimumab at 26.5 months (95% CI, 8.4 to NE) compared with the 5.1 months (95% CI, 4.0-6.9) seen with sunitinib (HR, 0.54; 95% CI, 0.3-0.9; P = .0093). Patients who received nivolumab with ipilimumab also achieved a higher ORR of 60.8% (95% CI, 49%-72%) compared with 23.1% (95% CI, 14%-35%) in the sunitinib arm (P < .0001). The complete response rate in the combination arm was 18.9% compared with only 3.1% in the control arm.

Notably, the benefit observed with nivolumab plus ipilimumab was irrespective of baseline PD-L1 expression.

In terms of safety, 97% of patients in the combination arm experienced treatment-related adverse events (AEs) as well as 97% of the sunitinib arm. In addition, grade 3/4 AEs were seen in 49% of patients in the combination arm versus 45% of patients. Discontinuation of treatment caused by the emergence of AEs was reported in 21% of patients in the immunotherapy arm versus 12% of the sunitinib monotherapy arm.

Immune-related events occurred included pulmonary events, which were observed in 10% of the nivolumab arm versus 0% in the sunitinib arm. Renal events were seen in 11% versus 6%, and skin-related events were observed in 52% versus 42%, and gastrointestinal events were observed in 25% versus 37%, respectively. There were also some patients who experienced any-grade hepatic-related events, including 21% of the combination arm versus 11% of the control arm. In addition, any-grade endocrine-related events were observed in 37% of the nivolumab plus ipilimumab arm versus 18% of the sunitinib arm.

_References:

_{1. Tannir NM, Signoretti S, Choueri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Can Res. Published Online January 2021. Accessed February 3, 2021. https://bit.ly/36W2gSr}

_{2. Motzer, RJ, Tannir N, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa171212}

_{3. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. News release. FDA. April 16, 2018. Accessed February 3, 2021. https://bit.ly/3oP4icW}