Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective
Abstract
:1. Introduction
2. Methodology
3. Anti-PD-1/PD-L1 Single Agent
4. Anti-PD-1/PD-L1 Combined with Other Agents
5. Anti-PD1/PD-L1 in Non-Clear Cell RCC (nccRCC) and Rare Histological Subtype
6. Prognostic and Predictive Biomarkers
7. Current Treatment Strategies and Perspectives
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AE | adverse event |
CPS | combined positive score |
CR | complete response |
DCR | disease control rate |
G | grade |
HD | high dose |
HR | hazard ratio |
ICI | immune-checkpoint inhibitors |
IMDC | International Metastatic |
RCC | Database Consortium |
ITT | intention-to-treat |
IV | intravenously |
MoAb | monoclonal antibody |
MSKCC | Motzer Score For Renal Cell Carcinoma |
RCC | renal cell carcinoma |
nccRCC | non-clear cell RCC |
mRCC | metastatic RCC |
ORR | objective response rate |
OS | overall survival |
PD | progressive disease |
PD-L1 | programmed death-ligand 1 |
PD-1 | programmed death 1 |
PFS | progression-free survival |
PR | partial response |
RCC | renal cell carcinoma |
RFS | recurrence-free survival |
SD | stable disease |
TMB | tumor mutational burden |
TPS | tumor proportion score |
TKI | tyrosine kinase inhibitor |
tRCC | translocation RCC |
VEGF | vascular endothelial growth factor |
VEGF-R | vascular endothelial growth factor- receptor |
WHO | World Health Organization |
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Trial | Phase | Treatment Setting | Arms | Number of Patients | Risk Groups (%) | Previous Nephrectomy (%) | Primary End-Point | ORR (%) | DCR (%) | PFS (Months) | OS (Months) |
---|---|---|---|---|---|---|---|---|---|---|---|
NCT0135443/ | II | at least 2nd line in mRCC with a clear-cell component after previous antiangiogenic therapy | Nivolumab 0.3 mg/kg, 2 mg/kg, or 10 mg/kg IV every 3 weeks | 168 | MSKCC risk group: Favorable 33%, Intermediate 42%, Poor 25% | 98% of patients received prior surgery (type of surgery not specified) | PFS | 20%, 22%, and 20% in each arm respectively | NR | 2.7, 4.0, and 4.2 months in each arm respectively | 18.2, 25.5 and 24.7 months in each arm respectively |
NCT01668784/ CheckMate 025 | III | at least 2nd line in advanced or mRCC with a clear-cell component and previous treatment with one or two antiangiogenic therapies | Nivolumab 3 mg/kg IV every 2 weeks vs. everolimus daily oral dose of 10 mg | 821 | MSKCC risk group: Favorable 36%, Intermediate 49%, Poor 15% | 88% of patients received prior nephrectomy | OS | 25% with nivolumab and 5% with everolimus | NR | 4.6 months with nivolumab and 4.4 months with everolimus | 25.0 vs. 19.6 |
NCT03126331/ | II | mRCC of any histology (clear cell 93%, papillary 7%) who received at least one prior anti-angiogenic therapy | Single-arm: nivolumab for 12 w (240 mg every 2 w or 480 mg every 4 w), patients with ≥10% reduction in tumor burden entered a treatment-free observation phase | 14 | IMDC risk group: Favorable 7%, Intermediate 86%, Poor 7% | 100% of patients had a prior nephrectomy | feasibility of intermittent nivolumab (≥80% of patients eligible for intermittent therapy elect to receive intermittent nivolumab) | 29% | NR | 7.97 months | NR |
Trial | G3–4 AEs (%) | Most Commonly Reported G3–4 AEs | Discontinuation Rate Due to Treatment-Related AEs (%) |
---|---|---|---|
NCT01354431/ | 11% | Transaminases increased | 7% |
NCT01668784/CheckMate 025 | 19% with nivolumab 37% with everolimus | fatigue (3%), anemia (2%), pneumonitis (2%) with nivolumab; anemia (8%), hypertriglyceridemia (5%), hyperglycemia (4%), stomatitis (4%) with everolimus | 8% with nivolumab, 13% with everolimus |
Trial | Phase | Treatment Setting | Arms | Number of Patients | Previous Nephrectomy (%) | Primary End-Points | ORR (%) | DCR(%) | PFS (Months) | OS (Months) |
---|---|---|---|---|---|---|---|---|---|---|
Checkmate 214 | 3 | First line | Intermediate and poor risk: nivolumab + ipilimumab vs. sunitinib | 1096 | 82% vs. 80% | OS, ORR, PFS | 42% vs. 27% | 72% vs. 71% | 11.6 vs. 8.4 | NR vs. 26 |
KEYNOTE-426 | 3 | First-line | Pembrolizumab + axitinib vs. sunitinib | 861 | 82.6 vs. 83.4 | OS, PFS | 59.3 vs. 35.7 | 83.3 vs. 75.1 | 15.1 vs. 11.1 | NR |
JAVELIN Renal 101 | 3 | First-line | Avelumab + axitinib vs. sunitinib | 886 | 86.3 vs. 86.9 | OS and PFS in PDL1 < 1% | 55.2% vs. 25.5% | 13.8 vs. 7.2 | NR | |
IMmotion151 | 3 | First-line | Atezolizumab + bevacizumab vs. sunitninb | 915 (454 + 461) | 84% vs. 83% in PDL1+ | PFS in PDL1+ and OS in ITT | 43% vs. 34% in PDL1+ 36% vs. 32% in ITT | 75% vs. 69% in PDL1+ 75% vs. 72% in ITT | 11.2 vs. 7.7 in PDL1+ | NR |
Trial | G3–4 AEs (%) | Most Commonly Reported G3–4 AEs | Discontinuation Rate Due to Treatment-Related AEs (%) |
---|---|---|---|
Checkmate 214 | 43 vs. 63 | - increased lipase level, fatigue diarrhea - hypertension, palmar-plantar erythrodysesthesia, fatigue, increased lipase level | 22 vs. 12 |
KEYNOTE-426 | 75.8 vs. 70.6 | - Diarrhea, hypertension and hepatic toxicity - Diarrhea, hypertension | both drugs: 30.5, sunitinib: 13.9 |
JAVELIN Renal 101 | 71.2 vs. 71.5 | - hypertension, diarrhea, increased alanine aminotransferase level, palmar-plantar erythrodysesthesia - hypertension, palmar-plantar erythrodysesthesia, hematological toxicity | 7.6 vs. 13.4 |
IMmotion151 | 40 vs. 54 | - hypertension, - hypertension, thrombocytopenia, palmar-plantar erythrodysesthesia | 5 vs. 8 |
Biomarker | Clinical Significance | References |
---|---|---|
Immune gene expression signature | Better PFS among patients treated with axitinib plus avelumab | [39] |
B7-H1 expression | Negative prognostic factor for 5-year PFS and 5-year cancer-specific survival rate: | [40] |
PBRM1 loss of function | Better clinical benefit among patients who received nivolumab with or without ipilimumab. Higher ORR, clinical benefit rate, longer PFS, and OS among patients treated with nivolumab. | [41,42] |
PD-L1 expression | Negative prognostic factor. CheckMate 025 trial: median OS was 21.8 months in patients whose tumors were PD-L1-positive compared with 27.4 months in those whose tumors were PD-L1-negative. However the benefit offered by nivolumab was observed regardless of PD-L1 expression. CheckMate 214 trial: PD-L1 expression had a negative prognostic impact on survival for patients treated with sunitinib but not for those treated with nivolumab plus ipilimumab. | [13,25] |
Frameshift indel count | Positive predictive factor in patients treated with anti-PD-1 agents. | [43] |
High expression of T-effector gene signature | Better PFS and ORR among patients treated with atezolizumab plus bevacizumab. | [44] |
High myeloid inflammation gene expression pattern | Negative prognostic factor for PFS in patients treated with atezolizumab single-agent or atezolizumab combined with bevacizumab | [44] |
Mutations in bromodomain-containing genes | Long-lasting clinical benefit in two patients with tRCC treated with ICIs. | [38] |
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Lavacchi, D.; Pellegrini, E.; Palmieri, V.E.; Doni, L.; Mela, M.M.; Di Maida, F.; Amedei, A.; Pillozzi, S.; Carini, M.; Antonuzzo, L. Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective. Int. J. Mol. Sci. 2020, 21, 4691. https://doi.org/10.3390/ijms21134691
Lavacchi D, Pellegrini E, Palmieri VE, Doni L, Mela MM, Di Maida F, Amedei A, Pillozzi S, Carini M, Antonuzzo L. Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective. International Journal of Molecular Sciences. 2020; 21(13):4691. https://doi.org/10.3390/ijms21134691
Chicago/Turabian StyleLavacchi, Daniele, Elisa Pellegrini, Valeria Emma Palmieri, Laura Doni, Marinella Micol Mela, Fabrizio Di Maida, Amedeo Amedei, Serena Pillozzi, Marco Carini, and Lorenzo Antonuzzo. 2020. "Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective" International Journal of Molecular Sciences 21, no. 13: 4691. https://doi.org/10.3390/ijms21134691