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DOI: 10.1055/s-0041-1731968
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]
|
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
© 2022. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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