Locally Advanced High Risk and Metastaic Renal Cell Carcinoma
ADJUVANT AND METASTATIC TREATMENTS
The first targeted therapy, sorafenib (Nexavar) was approved in 2005 as an orally available TKi after being shown to roughly double PFS in mRCC. (25) Not long after, sunitinib (Sutent) was approved as a VEGFi and shown to significantly increase PFS and showed a trend for imrpvoed OS in mRCC. (26,27)
A 2018 Urology article suggested that based on current data, patients with high risk locoregional clear cell kidney cancer may be offered the option of adjuvant sunitinib for 1 year following surgery in the context of known risk of side effects and there is no role in adjuvant immunotherapy (2). More recent data showed the combination of avelumab (Bavencio) and axitinib (Inlyta) doubled objective response rates (ORRs) and significantly improved progression-free survival (PFS) compared with sunitinib (Sutent) in patients with treatment-naïve advanced renal cell carcinoma (RCC) regardless of PD-L1 expression, according to findings from the phase III JAVELIN Renal 101 trial presented at the 2018 ESMO Congress. (22)
On April 19, 2019 FDA approved 1st line pembrolizumab plus axitinib based on the KEYNOTE‑426 which showed the 12-month overall survival rate was 90% with pembrolizumab plus axitinib and 78% with sunitinib. The median progression-free survival was 15.1 and 11.1 months for those receiving pembrolizumab plus axitinib vs. sunitinib, respectively. (33)
Adjuvant research:
Recist criteria defines progression.
A retrospective review of patients from 2000-2014 showed positive margins in 15.9% of local tumor bed recurrences compared with 3% of control. Median time between detection of local recurrence was 23 months. Multiple tumors and solitary kidney were associated with local recurrence. (16)
The first targeted therapy, sorafenib (Nexavar) was approved in 2005 as an orally available TKi after being shown to roughly double PFS in mRCC. (25) Not long after, sunitinib (Sutent) was approved as a VEGFi and shown to significantly increase PFS and showed a trend for imrpvoed OS in mRCC. (26,27)
A 2018 Urology article suggested that based on current data, patients with high risk locoregional clear cell kidney cancer may be offered the option of adjuvant sunitinib for 1 year following surgery in the context of known risk of side effects and there is no role in adjuvant immunotherapy (2). More recent data showed the combination of avelumab (Bavencio) and axitinib (Inlyta) doubled objective response rates (ORRs) and significantly improved progression-free survival (PFS) compared with sunitinib (Sutent) in patients with treatment-naïve advanced renal cell carcinoma (RCC) regardless of PD-L1 expression, according to findings from the phase III JAVELIN Renal 101 trial presented at the 2018 ESMO Congress. (22)
On April 19, 2019 FDA approved 1st line pembrolizumab plus axitinib based on the KEYNOTE‑426 which showed the 12-month overall survival rate was 90% with pembrolizumab plus axitinib and 78% with sunitinib. The median progression-free survival was 15.1 and 11.1 months for those receiving pembrolizumab plus axitinib vs. sunitinib, respectively. (33)
Adjuvant research:
- Traditional immunotherapy - high dose IL-2 has 5-10% response rate in mRCC in appropriately selected patients, but has many side effects (capillary leak and cytokine release syndrome) (1) Adjuvant therapy for RCC that has not metastasized yet with traditional immunotherapy has not been shown to increase DFS or OS and has many side effects and is not recommended (2)
- Inhibitors of VEGF (sorafenib, sunitinib, Lenvatinib, Pazopanib)
- Sorafenib and sunitinib approved in 2005, 2006 are TK inhibitors bind and inhibit VEGF and platelet derived GF on endothelial cells. (3) Both became 1st line therapy for mRCC by improve response rates, progression free survival and OS in mRCC. (4,5,6) Patient selection may be a more important factor than potentially small differences in specific VEGF inhibitors. (2)
- Lenvatinib combined with everiolims is FDA approved for mRCC use after one anti-angiogenic therapy (14)
- Pazopanib may have better response than temsirolimus for intermediate risk clear cell RCC and is a 1st line in favorable risk IMDC metastatic patient per NCCN. (15,18)
- mTOR inhibitors (everolimus, temsirolimus)
- Are approved for first line therapy for mRCC, but not as good initial response as other modern immunotherapy (9) or new targeted agents such as cabozantinib. (10) 20% of mRCC patients respond to everolimus or temsirolimus and they are the standard of care in pretreated patients. (11,12) There is a case report in JCCN about a patient who responded exceptionally to temsirolimus after progression with sorafenib and sunitinib. There is the possibility of the response being linked to a specific mutation (13).
- ASSURE, S-TRAC, SORCE, ATLAS, EVEREST, PROTECT are all studies looking at adjuvant therapy for VEGF and mTOR inhibitors
- vaccines and antibody dependent cytotoxic agent
- VACCINES
- Autologous tumor cell vaccine admixed with BCG vaccine showed no improvement in DFS or OS (7)
- Other studies looking into vitespen (HSP dreived from patient' nephrectomy specimen) showed no benefit
- ANTIBODY DEPENDENT CYTOTOXIC AGENT
- ARISER (Adjuvant Rencarex) - 6mo girentuximab (MAB targeting CAIX, a cell surface recempter expressed in clear cell and correlated w/ poor prognosis) found no benefit, although in patients <65 with higher CAIX expression, with ECOG of 0, with lower grade tumor (grade 1 or 2) there was disease free survival improvement (8)
- VACCINES
- immune checkpoint inhibitors - Nivolumab approved in US for 2nd line treatment after 1 or 2 TK inhibitors failed
- CHECKMATE025 - nivolumab vs. Evirolimus: Nivolumab has 5.4mo OS advantage.
- PROSPER, INMOTION025 are also underway
- CHECKMATE214 - Nivolumab plus Ipilimumab performed better than Sunitinib in intermediate and poor risk patients w/ previously untreated advanced RCC (17)
- autologous cellular transplationations - Small amount of research has shown some promise however not much has progressed since the NEJM 2000 article. (35)
Recist criteria defines progression.
A retrospective review of patients from 2000-2014 showed positive margins in 15.9% of local tumor bed recurrences compared with 3% of control. Median time between detection of local recurrence was 23 months. Multiple tumors and solitary kidney were associated with local recurrence. (16)
CYTOREDUCTIVE NEPHRECTOMY
2001 were first studies that showed benefit for cytoreductive nephrectomy (CN) in metastatic patients when SWOG 8949 trial showed surgery + interferon alpha improved OS to 11.1mo from 8.1 mo with interferon alpha alone. (23) EORTC 30947 showed similar results that year. (24)
As targeted therapy became available observational studies and large data analysis seemed to support CN in certain patients. (28,29,30) The largest of these is the IDMC which showed CN gave a 40% reduction in death compared with systemic therapy alone, however this was retrospective and therefore limited by selection bias and appeared to benefit only those with 3 or less IMDC prognostic factors. (28)
Then CARMENA, a large RCT found CN + Sunitinib (13.9mo OS) is inferior to Sunitinib alone (18.4mo OS) in intermediate and poor risk patient with mRCC. These patients had no brain mets or had received surgery or RT for brain mets without corticosteroids and with no progression for 6wks. (19) One criticism of this study was patients were perhaps more poor risk, reflected by the fact that OS was shorter than other studies of mRCC (ie CHECKMATE214 median OS 26mo despite 38% patients classified as poor risk IMDC (17), CABOSUN OS 21.8 w/ 19% poor risk IMDC (32)) Furthermore, thhe CARMENA patients had significant metastatic tumor burden with average primary tumor was 8cm and overall burden 14cm, meaning 40% of overall burden was metastatic. (19) Thus, since patients with metastatic favorable risk disease were excluded, care should be taken when considering CARMENA results in these patients.
Another RCT, SURTIME officially showed sunitinib prior to CN at 28wks did not improve PFS compared to upfront CN followed by sunitinib. However, this only had 99 patients, was underpowered and the median OS was actually 32.4mo in deferred CN vs. 15.1mo in upfront CN. (31)
A small retrospective study found 77% reduced risk of death with CN + immunotherapy vs. immunotherapy alone. (34)
The NCCN recommends to consider CN if good performance status and no brain mets (18).
PREINSUT
Changes in biomarkers may predict outcomes. Biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response); sVEGFR2 (PFS); and SDF‑1 and VEGFR1 (OS). Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. (20)
2001 were first studies that showed benefit for cytoreductive nephrectomy (CN) in metastatic patients when SWOG 8949 trial showed surgery + interferon alpha improved OS to 11.1mo from 8.1 mo with interferon alpha alone. (23) EORTC 30947 showed similar results that year. (24)
As targeted therapy became available observational studies and large data analysis seemed to support CN in certain patients. (28,29,30) The largest of these is the IDMC which showed CN gave a 40% reduction in death compared with systemic therapy alone, however this was retrospective and therefore limited by selection bias and appeared to benefit only those with 3 or less IMDC prognostic factors. (28)
Then CARMENA, a large RCT found CN + Sunitinib (13.9mo OS) is inferior to Sunitinib alone (18.4mo OS) in intermediate and poor risk patient with mRCC. These patients had no brain mets or had received surgery or RT for brain mets without corticosteroids and with no progression for 6wks. (19) One criticism of this study was patients were perhaps more poor risk, reflected by the fact that OS was shorter than other studies of mRCC (ie CHECKMATE214 median OS 26mo despite 38% patients classified as poor risk IMDC (17), CABOSUN OS 21.8 w/ 19% poor risk IMDC (32)) Furthermore, thhe CARMENA patients had significant metastatic tumor burden with average primary tumor was 8cm and overall burden 14cm, meaning 40% of overall burden was metastatic. (19) Thus, since patients with metastatic favorable risk disease were excluded, care should be taken when considering CARMENA results in these patients.
Another RCT, SURTIME officially showed sunitinib prior to CN at 28wks did not improve PFS compared to upfront CN followed by sunitinib. However, this only had 99 patients, was underpowered and the median OS was actually 32.4mo in deferred CN vs. 15.1mo in upfront CN. (31)
A small retrospective study found 77% reduced risk of death with CN + immunotherapy vs. immunotherapy alone. (34)
The NCCN recommends to consider CN if good performance status and no brain mets (18).
PREINSUT
Changes in biomarkers may predict outcomes. Biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response); sVEGFR2 (PFS); and SDF‑1 and VEGFR1 (OS). Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. (20)
- Allard, Christopher B., et al. "Contemporary trends in high-dose interleukin-2 use for metastatic renal cell carcinoma in the United States." Urologic Oncology: Seminars and Original Investigations. Vol. 33. No. 11. Elsevier, 2015.
- Lenis, Andrew T., et al. "Adjuvant therapy for high risk localized kidney cancer: emerging evidence and future clinical trials." The Journal of urology 199.1 (2018): 43-52.
- Rini, Brian I., Steven C. Campbell, and Bernard Escudier. "Renal cell carcinoma." The Lancet 373.9669 (2009): 1119-1132.
- Motzer, Robert J., et al. "Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma." Journal of Clinical Oncology24.1 (2006): 16-24.
- Motzer, Robert J., et al. "Sunitinib in patients with metastatic renal cell carcinoma." Jama 295.21 (2006): 2516-2524.
- Escudier, Bernard, et al. "Sorafenib in advanced clear-cell renal-cell carcinoma." New England Journal of Medicine 356.2 (2007): 125-134.
- Galligioni, Enzo, et al. "Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and Bacillus Calmette‐Guèrin: Five‐year results of a prospective randomized study." Cancer 77.12 (1996): 2560-2566.
- Chamie, Karim, et al. "Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: the ARISER randomized clinical trial." JAMA oncology 3.7 (2017): 913-920.
- Motzer, Robert J., et al. "Nivolumab versus everolimus in advanced renal-cell carcinoma." New England Journal of Medicine 373.19 (2015): 1803-1813.
- Choueiri, Toni K., et al. "Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial." The Lancet Oncology17.7 (2016): 917-927.
- Motzer, Robert J., et al. "Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial." The lancet oncology 16.15 (2015): 1473-1482.
- Motzer, Robert J., et al. "Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma." The Lancet Oncology 17.1 (2016): e4-e5.
- Rodríguez-Moreno, Juan Francisco, et al. "Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel MTOR-Activating Mutation." Journal of the National Comprehensive Cancer Network 15.11 (2017): 1310-1315.
- https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501070.htm
- http://www.cancernetwork.com/renal-cell-carcinoma/pazopanib-tops-temsirolimus-intermediate-risk-clear-cell-rcc
- Wood, Erika L., et al. "Local tumor bed recurrence following partial nephrectomy in patients with small renal masses." The Journal of urology 199.2 (2018): 393-400.
- Motzer, Robert J., et al. "Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma." New England Journal of Medicine 378.14 (2018): 1277-1290.
- NCCN Kidney Cancer Guidelines. Accessed 8/14/2018
- Méjean, Arnaud, et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine (2018).
- Mauge, Laetitia, et al. "Sunitinib prior to planned nephrectomy in metastatic renal cell carcinoma: angiogenesis biomarkers predict clinical outcome in the prospective Phase 2 PREINSUT trial." Clinical Cancer Research (2018): clincanres-1045.
- Bhindi, Bimal, et al. "Comparative survival following initial cytoreductive nephrectomy versus initial targeted therapy for metastatic renal cell carcinoma." The Journal of urology (2018).
- https://www.onclive.com/conference-coverage/esmo-2018/avelumabaxitinib-nearly-doubles-pfs-orr-in-frontline-rcc. Accessed 10/23/18
- Flanigan, Robert C., et al. "Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer." New England Journal of Medicine 345.23 (2001): 1655-1659.
- Mickisch, G. H. J., et al. "Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial." The Lancet 358.9286 (2001): 966-970.
- Escudier, Bernard, et al. "Sorafenib in advanced clear-cell renal-cell carcinoma." New England Journal of Medicine 356.2 (2007): 125-134.
- Motzer, Robert J., et al. "Sunitinib versus interferon alfa in metastatic renal-cell carcinoma." New England Journal of Medicine 356.2 (2007): 115-124.
- Motzer, Robert J., et al. "Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma." Journal of clinical oncology27.22 (2009): 3584.
- Heng, Daniel YC, et al. "Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium." European urology 66.4 (2014): 704-710.
- García-Perdomo, Herney A., James A. Zapata-Copete, and Diego F. Castillo-Cobaleda. "Role of cytoreductive nephrectomy in the targeted therapy era: A systematic review and meta-analysis." Investigative and clinical urology 59.1 (2018): 2-9.
- Bhindi, Bimal, et al. "Comparative survival following initial cytoreductive nephrectomy versus initial targeted therapy for metastatic renal cell carcinoma." The Journal of urology(2018).
- Bex, A., et al. "LBA35Immediate versus deferred cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal cell carcinoma (mRCC) receiving sunitinib (EORTC 30073 SURTIME)." Annals of Oncology 28.suppl_5 (2017).
- Choueiri, Toni K., et al. "Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial." Journal of clinical oncology: official journal of the American Society of Clinical Oncology 35.6 (2017): 591-597.
- https://jnccn360.org/kidney/news/fda-approves-pembrolizumab-plus-axitinib/?utm_source=Email&utm_medium=Email&utm_campaign=JNCCN360%20Emails%203.9%20Ongoing&email=dcfe2ff5f691a3339ac24e5598fad86a2099a4ae7349d4e43fb36a56d03a99e2
- Singla N, Hutchinson R, Ghandour R, et al. Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: A national population-based analysis. Presented at the Society of Urologic Oncology 20th annual meeting held December 4 to 6 in Washington, DC. Poster 43.
- Childs, Richard, et al. "Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation." New England Journal of Medicine 343.11 (2000): 750-758.