Recent Advances in First-Line Management of Metastatic Renal Cell Carcinoma

Introduction

For the past 15 years, vascular endothelial growth factor tyrosine kinase inhibitors (VEGF TKIs; sunitinib and pazopanib) were standard first-line treatment in metastatic renal cell carcinoma (mRCC). A phase-III randomized controlled trial included 750 treatment-naive patients comparing sunitinib vs interferon alpha and showed higher objective response rate (ORR; 31 vs. 6%, p < 0.001) and higher progression-free survival (PFS) rate with sunitinib as compared with interferon alpha (11 vs. 5 months, hazard ratio [HR] = 0.42, 95% confidence interval [CI]: 0.32–0.54, p < 0.001). There was no complete response.[1]

Updated analysis of the study showed response rate of 47 versus 12% (p < 0.001), improved PFS (11 vs. 5 months, p < 0.001), and improved overall survival (OS; 26.4 vs. 21.8 months, HR = 0.821, 95% CI: 0.673–1.001, p = 0.51) of sunitinib as compared with interferon alpha.[2]

Another phase-III placebo-controlled trial randomized 435 treatment-naive or cytokine-pretreated patients into pazopanib versus placebo arm. ORR (30 vs. 3%, p < 0.001) and median PFS (9.2 vs. 4.2 months, HR = 0.46, 95% CI: 0.34–0.62, p < 0.001) were higher in the pazopanib as compared with placebo arm.[3]

Cabozantinib was compared with sunitinib in a phase-II randomized study including 157 intermediate- and poor-risk international mRCC database criteria (IMDC) patients.[4] ORR was 33% (95% CI: 23–44) for cabozantinib versus 12% (95% CI: 5.4–21) for sunitinib. Cabozantinib significantly improved the median PFS 8.2 versus 5.6 months as compared with sunitinib (HR = 0.66; 95% CI: 0.46–0.95; one-sided p = 0.012).

There were no studies of VEGF TKI combinations in first-line therapy of mRCC before the arrival of immunooncology (IO) drugs into the picture.

Nivolumab was the first immunotherapy drug approved in second-line therapy after failure of VEGF TKI. Five out of six IO drug combinations have been recently Food and Drug Administration (FDA) approved in first-line mRCC treatment. A summary of these six trials have been provided in [Table 1].[5] [6] [7] [8] [9] [10]

Table 1 The various studies comparing outcomes of Immunotherapy and VEGF TKIs in patients with mRCC

Study (ref.)	Intervention	No. Of patients	ORR	CR	mPFS (months)	OS (months)	Comment
CheckMate 214[5]	Ipilimumab–nivolumab Sunitinib	550 446	65% 50%	10% 1%	11.6 8.4 (p = 0.02)	48 26.6 (HR = 0.65, 95% CI: 0.54–0.78)	Study showed OS advantage in intermediate- and poor-risk patients (and not in favorable risk)
KEYNOTE 426[6]	Axitinib–pembrolizumab Sunitinib	432 429	59.3% (95% CI: 54.5–63.9) 35.7% (95% CI: 31.5–40.4), p < 0.001	5.5% 1.9%	15.1 (95% CI: 12.6–17.7) 11.1 (95% CI: 8.7–12.5)	Not reached Not reached	Updated result: at a minimum follow-up of 23 months, median OS is not reached with pembrolizumab–axitinib vs. 36.7 month with Sunitinib. No OS advantage was seen in favorable risk disease but there was PFS and ORR benefit. A post hoc analysis found that achieving CR improved the chances of overall survival in both arms
JAVELIN Renal 101[7]	Avelumab–axitinib Sunitinib	442 444	51.4%(95% CI: 46.6–56.1) 25.7% (95% CI: 27.1–30.0)	3.4% 1.8%	13.8 (95% CI: 11.1 to could not be estimated 8.4, HR = 0.69; 95% CI: 0.56 to 0.84; p < 0.001		PDL1 positive population, similar result as overall population
IMmotion 151[8]	Atezolizumab–bevacizumab Sunitinib	454 461			PFS in PDL1 positive population 11.2 7.7, HR = 0.74, 95% CI: 0.57–0.96, p = 0.0217		In ITT population median OS had a HR of 0.93 (0.76–1.14)
CheckMate9ER[9]	Cabozantinib–nivolumab Sunitinib	323 328	55.7% (95% CI: 50.1–61.2) 27.1% (95% CI: 22.4–32.3) (p < 0.0001	8% 4%	16.6 8.3 (HR = 0.51; 95% CI: 0.41–0.64], p < 0.0001).	Median OS was not reached (HR = 0.60; 98.89% CI: 0.40–0.89; p = 0.0010)	Results apply to all IMDC subgroups
CLEAR[10]	Lenvatinib–pembrolizumab Lenvatinib–everolimus Sunitinib	355 357 357	71% 53.5% 36.1% (95% CI: 1.69–2.29)	16.1% 9.8% 4.2%	23.9 (20.8–27.7) 14.7 (11.1–16.7) 9.2 (6.0–11), HR (lenvatinib– pembrolizumab vs. sunitinib) = 0.39, 95% CI: 0.32–0.49, p < 0.001	Not reached	Survival with lenvatinib–pembrolizumab significantly longer than sunitinib HR for death 0.66, 95% CI: 0.49–0.88; p = 0.005) OS benefit seen in all subgroups except favorable risk IMDC

Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; IMDC, international metastatic renal cell carcinoma (mRCC) database criteria; ITT, intent to treat; mPFS, median progression-free survival; ORR, overall response rate; OS, overall survival; PDL1, program cell death ligand-1; TKI, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor.

Out of the six first-line phase-III studies, four have shown OS advantage of IO over sunitinib. The study of ipilimumab–nivolumab, pembrolizumab–axitinib, and lenvatinib–pembrolizumab has shown OS advantage in intermediate- and poor-risk IMDC groups, cabozantinib–nivolumab has shown survival advantage across three IMDC groups. Programmed cell death ligand-1 (PDL1) testing has been done in various studies, but none of the studies have shown correlation of PDL1 status with survival.[5] [6] [9] [10]

Publication History

Article published online:
03 February 2022

• References

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