The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory?
Abstract
:1. Introduction
2. Main Histological Subtypes
2.1. Papillary RCC
2.2. Chromophobe RCC
2.3. RCC with Sarcomatoid/Rhabdoid Features
2.4. Collecting Duct RCC
2.5. MiT Family Translocation RCC
2.6. Renal Medullary Carcinoma
3. Molecular Targets
3.1. VEGF Axis Pathway
3.2. mTOR Pathway
3.3. MET Pathway
Trials | Histologies | Drug | Setting | N. of Patients | ORR (%) | mOS (Months) | mPFS (Months) |
---|---|---|---|---|---|---|---|
SWOG 1500/PAPMET (phase II) [92] | pRCC | -cabozantinib -sunitinib -savolitinib -crizotinib | First or second line | −44 −46 −29 −28 | −23 −4 −3 −0 | −20.4 −16.4 −11.7 −19.9 | 9.0 −5.6 −3.0 −2.8 |
SAVOIR (phase III) [96] | pRCC | -savolitinib -sunitinib | First or later line | −33 −27 | −27 −7 | -NR −13.2 | −7.0 −5.6 |
SUPAP (phase II) [65] | pRCC: -type 1 -type 2 | -sunitinib | First line | −15 −46 | −13 −11 | −17.8 −12.4 | −6.6 −5.5 |
CREATE (phase II) [98] | pRCC: -type 1 -MET-driven type1 -MET-independent type1 | -crizotinib | First or later line | −23 −4 −19 | −17 −50 −11 | −30.5 -NA −14.5 | −5.8 -NA −3.0 |
SWOG S1107 (phase II) [100] | pRCC | -tivantinib -tivantinib + erlotinib | First or second line | −25 −25 | −0 −0 | −10.3 −11.3 | −2.0 −3.9 |
NCT00726323 (phase II) [99] | pRCC | -foretinib | First or second line | 74 | 13.5 | NA | 9.3 |
NCT02127710 (phase II) | -pRCC -MET-driven pRCC -MET-independent pRCC | -savolitinib | First or later line | −109 −44 −65 | −7 −18 −0 | -NA -NA -NA | -NA −6.2 −1.4 |
4. Immunotherapy and New Therapeutic Perspectives in nccRCC
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Histotype | Frequency (% of All RCCs) | Cytogenetic Mutations | Genes Altered |
---|---|---|---|
Type 1 papillary RCC | 10–15% (considering all pRCCs) | +3q, +7, +8q, +12q, + 16p, +17, +20, −9p, −Y | MET, CUL3, NFR2, TERT, CDKN2A/B, EGFR |
Type 2 papillary RCC | 10–15% (considering all pRCCs) | +7, +8q, +12, +16, +17, −1p, −9p, CpG island methylator phenotype, chromothripsis | CDKN2A silencing, SETD2, NF2, CUL3, TERT promoter, fumarate hydratase (FH) |
Chromophobe RCC | 5% | −1, −2, −6, −7, −10, −13, −17, −21 | TP53, PTEN, hypodiploidy KIT |
Oncocytoma | 3–7% | Diploid karyotype, loss of chromosome 1 or Y, or rearrangement of 11q13. | Mitochondrial genes (COX1, COX2, MTND4, MTCYB). The 11q13 rearrangement may affect the CCND1 gene. |
Collecting duct carcinoma (also known as Bellini’s carcinoma) | 1% | −1q, −8p, −9p, −16p, +13q | NF2, SETD2, SMARCB1, FH, CDKN2A |
Medullary RCC | 1% | ABL/BCR (rare), SMARCB1/ALK (rare), monosomy 11 | Not defined |
MiT family translocation RCC | 1% | Recurrent translocations involving Xp11.2 (TFE3) or 6p21 (TFEB) | Not defined |
Multilocular cystic renal neoplasm of low malignant potential | <1% | Not defined | Not defined |
Hereditary leiomyomatosis with RCC | <1% | Not defined | FH |
Succinate dehydrogenase-deficient RCC | <1% | Not defined | SDH (double hit inactivation) |
Acquired cystic kidney disease-associated RCC | <1% | +3, +7, +17, −Y | Not defined |
Unclassified RCC | about 5% | Not defined | Not defined |
Clinical Trial (phase) | Experimental Arm | Histology | Setting | Primary Endpoint |
---|---|---|---|---|
KEYNOTE 427 (phase II) [110] | Pembrolizumab | pRCC type 1 and 2, chRCC, unclassified nccRCC | Previously untreated metastatic ccRCC (cohort A) and nccRCC (cohort B) | ORR (26.7% in the overall nccRCC population) |
NCT03635892 (phase II) [111] | Nivolumab + cabozantinib | pRCC type 1 and 2, chRCC, MiT family translocation RCC, unclassified nccRCC | Previously untreated or treated with a prior VEGF-R TKI/mTORi metastatic pRCC, MiT family translocation RCC, unclassified RCC (cohort 1) and chRCC (cohort 2) | ORR (48% in cohort 1, 0% in cohort 2) |
CONTACT-03 (phase III) | Atezolizumab + cabozantinib | All non-clear cell subtypes | Locally advanced or metastatic RCC in PD during or after one ICI-based regimen | PFS and OS (no results posted, recruiting underway) |
COSMIC-021 (phase Ib/II) [114] | Atezolizumab + cabozantinib | All non-clear cell subtypes | Previously untreated locally advanced, metastatic, or recurrent solid tumors (including ccRCC and nccRCC) | ORR (no results posted) |
COSMIC-313 (phase III) [115] | Nivolumab + ipilimumab + cabozantinib | All non-clear cell subtypes | Previously untreated IMDC intermediate-/poor-risk metastatic RCC (including ccRCC and nccRCC) | PFS (no results posted) |
UNISoN (phase II) | Nivolumab (for a maximum of 12 months), then nivolumab + ipilimumab (4 cycles) and lastly maintenance with nivolumab single agent | pRCC type 1 and type 2, chRCC, S RCC, Xp11 translocation RCC, unclassified nccRCC | Metastatic nccRCC previously untreated or treated with a VEGF-R TKI or another systemic therapy | ORR (no results posted) |
SUNIFORECAST (phase II) | Nivolumab + ipilimumab | All non-clear cell subtypes | Previously untreated locally advanced or metastatic nccRCC | OS (no results posted) |
CALYPSO (phase Ib/II) [113] | Savolitinib + durvalumab | pRCC type 1 and type 2 | Previously untreated metastatic ccRCC (cohort A) and nccRCC (cohort B) | DLT, ORR (no results posted) |
NCT02724878 (phase II) [112] | Atezolizumab + bevacizumab | All non-clear cell subtypes | Previously untreated locally advanced or metastatic nccRCC | ORR (33% in the experimental group) |
KEYNOTE-B61 (phase II) [116] | Pembrolizumab + lenvatinib | All non-clear cell subtypes | Previously untreated locally advanced or metastatic nccRCC | ORR (no results posted, recruiting underway) |
CheckMate 9ER [122] | KEYNOTE 426 [121] | Javelin RENAL 101 [119] | CheckMate 214 [118] | |
---|---|---|---|---|
Experimental arm | Nivolumab + cabozantinib | Pembrolizumab + axitinib | Avelumab + axitinib | Nivolumab + ipilimumab |
mOS (months) | NR (95% CI, 22.8–NE) HR 0.36 (95% CI, 0.17–0.79) | NR HR 0.58 (95% CI, 0.21–1.59) | Data unavailable | NR (95% CI, 25.2–NE) HR 0.45 (95% CI, 0.30–0.70) |
mPFS (months) | 10.3 (95% CI, 5.6–19.4) HR 0.42 (95% CI, 0.23–0.74) | NR HR 0.54 (95% CI, 0.29–1.00) | 7.0 (95% CI, 5.3–13.8) HR 0.57 (95% CI, 0.325–1.003) | 26.5 HR 0.54 (95% CI, 0.33–0.86) |
ORR (CR) | 55.9% (CR unavailable) | 58.8% (13%) | 46.8% (4.3%) | 60.8% (18.9%) |
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Marchetti, A.; Rosellini, M.; Mollica, V.; Rizzo, A.; Tassinari, E.; Nuvola, G.; Cimadamore, A.; Santoni, M.; Fiorentino, M.; Montironi, R.; et al. The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory? Int. J. Mol. Sci. 2021, 22, 6237. https://doi.org/10.3390/ijms22126237
Marchetti A, Rosellini M, Mollica V, Rizzo A, Tassinari E, Nuvola G, Cimadamore A, Santoni M, Fiorentino M, Montironi R, et al. The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory? International Journal of Molecular Sciences. 2021; 22(12):6237. https://doi.org/10.3390/ijms22126237
Chicago/Turabian StyleMarchetti, Andrea, Matteo Rosellini, Veronica Mollica, Alessandro Rizzo, Elisa Tassinari, Giacomo Nuvola, Alessia Cimadamore, Matteo Santoni, Michelangelo Fiorentino, Rodolfo Montironi, and et al. 2021. "The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory?" International Journal of Molecular Sciences 22, no. 12: 6237. https://doi.org/10.3390/ijms22126237