Research ArticleClinical Studies

Site-specific Response to Nivolumab in Renal Cell Carcinoma

TAKAHITO NEGISHI, NOBUKI FURUBAYASHI, TOHRU NAKAGAWA, NAOTAKA NISHIYAMA, HIROSHI KITAMURA, YOSHIFUMI HORI, KENTAROU KUROIWA, YUHYON SON, NARIHITO SEKI, TOSHIHISA TOMODA, EIJIRO OKAJIMA and MOTONOBU NAKAMURA
Anticancer Research March 2021, 41 (3) 1539-1545; DOI: https://doi.org/10.21873/anticanres.14913

Abstract

Background/Aim: Nivolumab monotherapy for advanced/metastatic renal cell carcinoma (RCC) shows a survival benefit. The purpose of this study was to evaluate tumor responses to nivolumab in various metastatic and primary sites in patients with RCC. Patients and Methods: We retrospectively reviewed 68 patients who underwent nivolumab monotherapy after one or more regimens of targeted therapy for advanced/metastatic RCC. The site-specific response was evaluated and progression-free survival was estimated. Results: The site-specific overall response rates (ORRs) were as follows: lung (36%), bone (5%), lymph node (33%), liver (50%), adrenal gland (29%), pancreas (33%), and brain (0%). The ORR of bone metastasis was significantly worse in comparison to lung and liver metastases (p=0.017, 0.008). The site-specific median progression-free survival times were as follows: lung (5.1 months), bone (not reached), lymph node (not reached), and liver (17.5 months). Conclusion: Responses to nivolumab may vary depending on metastasized organs.

Key Words:

In 2018, more than 400,000 new cases of renal cell carcinoma (RCC) are diagnosed and 175,000 patients die from the disease worldwide (1). It is reported that 30% of newly diagnosed RCC cases present with metastases, and up to 30% of patients with locally limited RCC relapse after curative treatment (1). For the treatment of unresectable advanced/metastatic RCC, systemic therapies including targeted therapies and immune checkpoint inhibitors (ICIs) are administered. Since the development of targeted therapies in the 2000s, the prognosis of advanced/metastatic RCC has improved significantly (2). Recently, nivolumab [an anti-programmed death 1 (PD-1) antibody] after treatment with targeted therapies, and first-line therapy with nivolumab plus ipilimumab [an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody] were reported to achieve superior overall survival (OS) in comparison to targeted therapy (3, 4).

Although ICIs achieve a good response and long-term survival benefit, the overall response rate (ORR) to nivolumab monotherapy is only 25% (3). It is necessary to clarify the characteristics of patients in whom ICIs can be expected to be effective, as <50% of patients benefit from ICIs. Some predictors [e.g., the International Metastatic RCC Database Consortium (IMDC) criteria (5)], of the effects of targeted therapy have been reported; however, their applicability to ICIs is unknown.

In melanoma, non-small cell lung cancer, and hepatocellular carcinoma, responses to ICIs are reported to vary depending on the tumor site (6-8). The impact on the response to ICIs was mainly attributed to the tumor microenvironment (9), which includes tissue-resident immune cells, fibroblasts, endothelial cells and neurons, together with blood-derived cells that are recruited to the tumor site upon cancer progression (10). The tumor microenvironment differs between the primary organ and sites of metastasis, and there are differences among sites of metastasis (9, 11). These differences are expected to lead to the varied responses to ICIs.

In RCC, tumor responses in different organs have not been reported; however, this would help for selecting treatment or predicting the effectiveness of ICIs. We herein evaluated the tumor response to nivolumab in various organs and primary sites in patients with advanced/metastatic RCC.

Patients and Methods

Enrollment of patients. We retrospectively reviewed 68 patients who received nivolumab monotherapy with the standard dose of 240 mg/body every 2 weeks as a beyond first-line regimen following ≥1 targeted therapy regimens for advanced/metastatic RCC in 7 hospitals between October 2016 and June 2020. The key inclusion criteria were histologically diagnosed RCC and a measurable metastatic or primary site on computed tomography (CT) or magnetic resonance imaging (MRI) (defined below) at the initiation of nivolumab. The key exclusion criteria were prior immune checkpoint therapy before nivolumab and no radiographic examination after the initiation of nivolumab treatment. This study was approved by the institutional review board of National Hospital Organization Kyushu Cancer Center (approval no. 2020-4) and respective institutions. Obtaining additional informed consent from patients was not required by the Institutional Review Board of National Hospital Organization Kyushu Cancer Center for this retrospective study.

Radiography. Radiographic examinations, including CT/MRI, were performed every 4-12 weeks. The response of the entire cohort was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (12). Site-specific responses were evaluated according to modified RECIST 1.1 (12) and immune-related RECIST (13), which were previously reported (7). In each organ system, including the primary site, measurable lesions were defined as lesions of ≥1.0 cm (longest diameter) and lymph nodes of ≥1.5 cm (short axis diameter). At baseline, a maximum of 5 lesions were identified as target lesions in each organ. Tumor burden was defined as the sum of the long axis for all non-lymph nodes target lesions plus the short axis of all lymph nodes target lesions measured. The site-specific response was determined for each site. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to the rate of change in the organ size. The cut-off values for the rate of change used to classify the response were in accordance with RECIST1.1 (12). A new lesion did not define PD; measurements were included in the sum of measurements (7, 13). The ORR was defined as the sum of the CR and PR rates, and disease control rate (DCR) was defined as the sum of the CR, PR, and SD rates.

Statistical analysis. The ORR and DCR were compared between tumor sites using Fisher’s exact test. OS was calculated using Kaplan–Meier method from the initiation of nivolumab to death. Patients who were lost to follow-up or no death was experienced were censored at the last date known to be alive. Progression-free survival (PFS) was calculated using Kaplan–Meier method from the initiation of nivolumab until tumor progression according to the above-mentioned criteria or death due to any reason, whichever occurred first. Patients were still alive and having no progression were censored at the last follow-up date. Waterfall plots were used to evaluate the best percentage changes in the tumor burden of each patient relative to baseline in each site. p-Values of <0.05 were considered to indicate statistical significance. All analyses were performed using the JMP® Pro software package (version 15.1.0; SAS Institute, Cary, NC, USA, Inc.).

Results

Patient characteristics. The patient characteristics are presented in Table I. The median follow-up period after the initiation of nivolumab was 13.4 months (range=1.0-42.7 month). Fifteen of the 68 patients (22%) patients with non-clear cell carcinoma were included. Thirteen (19%), 36 (53%) and 17 (25%) patients had favorable, intermediate, and poor-risk IMDC classifications, respectively. Sixty (88%) patients underwent nephrectomy. Thirty-six (53%) and 32 (47%) patients received nivolumab as second-line and beyond first-line therapy, respectively. The sites of metastasis at the initiation of nivolumab were as follows: lung (n=32; 47%), bone (n=21; 30%), lymph node (n=15; 22%), liver (n=10; 15%), adrenal gland (n=7; 10%), pancreas (n=4; 6%) and brain metastasis (n=2; 3%).

View this table:
Table I.

Characteristics of the patients.

Treatment efficacy in the entire cohort. The CR, PR, SD, and PD rates in the entire cohort were 2%, 26%, 38%, and 34% respectively. Kaplan–Meier curves for PFS and OS are shown in Figure 1. The median PFS was 7.5 months and the median OS was 31.9 months.

Figure 1.
Figure 1.

Progression-free survival and overall survival in the entire cohort.

Site-specific overall response. The overall responses for each metastatic site were as follows lung (36%), bone (5%), lymph node (33%), liver (50%), adrenal gland (29%), pancreas (33%), and brain (0%) (Table II). The ORR for bone metastasis was significantly worse in comparison to those for lung and liver metastases (p=0.017, 0.008. Table III). The ORR varied among tumor sites, however the DCR was comparatively consistent, ranging from 49% in the lung to 100% in the brain. The primary site ORR was only 13%, whereas the DCR was 100%. Only one pancreatic lesion showed a CR.

View this table:
Table II.

Average change in target lesions and site-specific responses.

View this table:
Table III.

Comparison of overall response rate between tumor sites using Fisher’s exact test.

Change in tumor burden. The best percentage changes in the tumor burden of each patient relative to baseline in the lung, bone, lymph node, liver, and primary site are shown in Figure 2, which shows the analysis of primary tumor sites that were present in >10 patients. The average change in each metastasis site was as follows: lung (29%), bone (26%), lymph node (7%), liver (20%), adrenal gland (2%), pancreas (-46%), and brain (-5%) (Table II). In 2 patients with lung metastasis, tumors enlarged >200% in the 8 weeks after the initiation of nivolumab. They met the definition for hyperprogressive disease (HPD) (14). In addition to lung metastasis, one of these patients had bone metastasis; the other had liver metastasis. The patient with bone metastasis achieved SD; the patient with liver metastasis achieved PD after the initiation of nivolumab. At the primary site, the change in tumor size was not large and there was no great variation among patients.

Figure 2.
Figure 2.

Best percentage change over time (from baseline) in tumor burden in various tumor sites.

Site-specific progression-free survival. Kaplan–Meier curves for PFS in each tumor site are shown in Figure 3; the analysis of tumor sites included >10 patients. The median PFS was as follows: lung (5.1 months), bone (not reached), lymph node (not reached), and liver (17.5 months). The Kaplan–Meier curves for liver, bone, and lymph node metastasis stopped falling approximately 5 months after the initiation of nivolumab, whereas the curves for lung metastasis continued to fall consistently. Regarding the primary site, PFS was 21.5 months. The Kaplan–Meier curves flattened at 5 months after the initiation of nivolumab and continued for 16 months.

Figure 3.
Figure 3.

Progression-free survival in various tumor sites.

Discussion

Although a low response rate requires predictive factors to determine patients who should be treated with nivolumab, there are currently no such predictors for RCC In melanoma, non-small cell lung cancer, and hepatocellular carcinoma, the responses to ICIs were reported to vary depending on the site of metastasis (6-8). The impact on the response to ICIs was mainly attributed to the tumor microenvironment (9), which differs between the primary organ and sites of metastasis, and there are differences among sites of metastasis (9, 11). These differences are expected to lead to the varied responses to ICIs.

The site-specific ORR of bone metastasis was significantly worse in comparison to lung and liver metastases. Bone tissue provides a good environment for metastatic tumor cells, is rich in hematopoietic cells, bone cells, and growth factors (15), and is an active and fertile ground for the development of bone metastasis. Thus, targeted therapy or immune checkpoint inhibitor monotherapy had limited effects on bone metastasis (15, 16). Combined therapy should be considered to improve the efficacy of nivolumab in such cases. The concomitant use of denosumab (a monoclonal antibody against receptor activator for nuclear factor-kappa B ligand) and an PD-1 antibody, showed promising efficacy for bone metastasis from melanoma (17). Moreover, radiotherapy with systemic therapy including TKI or ICIs achieved a superior radiographic response to systemic therapy without radiotherapy (16). These modalities should be used with nivolumab for bone metastasis from RCC.

The ORR of lung metastasis was comparable to that of other tumor sites; however, PFS was shorter in comparison to other organs. Lung metastasis is reported to have a more immunogenic environment with higher lymphocytic infiltration and myeloid dendritic cells than brain, bone, and liver metastases, regardless of tumor origin, whereas lung metastasis showed high PD-L1 and CTLA-4 gene expression levels (18), implying that nivolumab monotherapy is inadequate for lung metastasis and that combination with an anti-CTLA-4 antibody is more suitable. Moreover, anti-CTLA-4 antibodies, which are reported to enhance CD8+ T-cell memory formation (19), possibly prolong the duration of response and improve PFS.

There were two cases with lung metastasis in which the tumor size increased >200% in 2 months (14), satisfying the definition of HPD [clinically defined by the unexpected acceleration of cancer evolution on initiation of immunotherapy, and more accurately defined by a >200% increase in tumor growth kinetics with <2 months to treatment failure (14)]. These cases had no reported risk factors for HPD (i.e., age>65 years; >2 metastatic sites) (20). The biological mechanism underlying the development of HPD is unknown (14), and it is not clear whether the tumor site is associated with HPD.

The present study was associated with several limitations. RCC after ICI treatment sometimes shows a histological CR after resection, even when a tumor is visible on CT (21). We only evaluated responses on images using the combined RECIST and immune-related RECIST according to a previous report (7), because it is not possible to remove or histologically evaluate all metastasis. RECIST and immune-related RECIST were properly validated (12, 13), and are reasonable methods for evaluating tumor response. Furthermore, the population was relatively small. The sample sizes of studies investigating site-specific responses to ICIs in melanoma, non-small cell lung cancer, and liver cancer (6-8) were 52, 75, and 140, respectively. Although the populations of the latter 2 studies were larger than this study, they included patients treated with various ICIs including anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies. Our study population is the largest to evaluate patients treated by nivolumab monotherapy.

The response to nivolumab differed according to tumor site, which was attributed to the microenvironment (7, 8). Improving the microenvironment, which may be achieved by combination therapy with an additional ICI, targeted therapy (22), or radiotherapy (23), is therefore necessary to overcome resistance. These modalities combined with PD-1 blockade exerted better cancer control than PD-1 blockade monotherapy (4, 24, 25). Clinical trials of various combination therapies are ongoing (26) and further improvement is expected.

Conclusion

Responses to nivolumab may vary depending on metastasized organs. Efficacy of nivolumab has a risk of limiting when treating RCC metastasis in specific sites. The mechanism underlying the differing responses among tumor sites remains to be elucidated. More evidence and the development of basic research will provide clues to clarify the phenomenon.

Footnotes

  • Authors’ Contributions

    T Negishi: Protocol/project development, Data collection and management, Data analysis, Manuscript writing; N Furubayashi: Data collection; T Nakagawa: Data collection, Manuscript revision; N Nishiyama: Data collection, Manuscript revision; H Kitamura: Data collection, Manuscript revision; Y Hori: Data collection; K Kuroiwa: Data collection; Y Son: Data collection; N Seki: Data collection; Tomoda: Data collection; E Okajima: Data collection, Manuscript revision; M Nakamura: Data management; All Authors read and approved the final manuscript.

  • Conflicts of Interest

    T Nakagawa has received research support from Ono Pharmaceutical. H Kitamura has received a speaker honorarium from Bristol-Myers Squibb. The other Authors declare that they have no competing interests.

  • Received January 28, 2021.
  • Revision received February 10, 2021.
  • Accepted February 11, 2021.

References

  1. ↵
    1. Attalla K,
    2. Weng S,
    3. Voss MH and
    4. Hakimi AA
    : Epidemiology, risk assessment, and biomarkers for patients with advanced renal cell carcinoma. Urol Clin North Am 47(3): 293-303, 2020. PMID: 32600532. DOI: 10.1016/j.ucl.2020.04.002
    OpenUrlCrossRefPubMed
  2. ↵
    1. Marchioni M,
    2. Bandini M,
    3. Pompe RS,
    4. Tian Z,
    5. Martel T,
    6. Kapoor A,
    7. Cindolo L,
    8. Berardinelli F,
    9. Briganti A,
    10. Shariat SF,
    11. Schips L and
    12. Karakiewicz PI
    : Survival of metastatic renal cell carcinoma patients continues to improve over time, even in targeted therapy era. Int Urol Nephrol 49(12): 2143-2149, 2017. PMID: 28932952. DOI: 10.1007/s11255-017-1703-y
    OpenUrlCrossRefPubMed
  3. ↵
    1. Motzer RJ,
    2. Escudier B,
    3. McDermott DF,
    4. George S,
    5. Hammers HJ,
    6. Srinivas S,
    7. Tykodi SS,
    8. Sosman JA,
    9. Procopio G,
    10. Plimack ER,
    11. Castellano D,
    12. Choueiri TK,
    13. Gurney H,
    14. Donskov F,
    15. Bono P,
    16. Wagstaff J,
    17. Gauler TC,
    18. Ueda T,
    19. Tomita Y,
    20. Schutz FA,
    21. Kollmannsberger C,
    22. Larkin J,
    23. Ravaud A,
    24. Simon JS,
    25. Xu LA,
    26. Waxman IM,
    27. Sharma P and CheckMate 025 Investigators.
    : Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19): 1803-1813, 2015. PMID: 26406148. DOI: 10.1056/NEJMoa1510665
    OpenUrlCrossRefPubMed
  4. ↵
    1. Motzer RJ,
    2. Tannir NM,
    3. McDermott DF,
    4. Arén Frontera O,
    5. Melichar B,
    6. Choueiri TK,
    7. Plimack ER,
    8. Barthélémy P,
    9. Porta C,
    10. George S,
    11. Powles T,
    12. Donskov F,
    13. Neiman V,
    14. Kollmannsberger CK,
    15. Salman P,
    16. Gurney H,
    17. Hawkins R,
    18. Ravaud A,
    19. Grimm MO,
    20. Bracarda S,
    21. Barrios CH,
    22. Tomita Y,
    23. Castellano D,
    24. Rini BI,
    25. Chen AC,
    26. Mekan S,
    27. McHenry MB,
    28. Wind-Rotolo M,
    29. Doan J,
    30. Sharma P,
    31. Hammers HJ,
    32. Escudier B and CheckMate 214 Investigators.
    : Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med 378(14): 1277-1290, 2018. PMID: 29562145. DOI: 10.1056/NEJMoa1712126
    OpenUrlCrossRefPubMed
  5. ↵
    1. Heng DY,
    2. Xie W,
    3. Regan MM,
    4. Warren MA,
    5. Golshayan AR,
    6. Sahi C,
    7. Eigl BJ,
    8. Ruether JD,
    9. Cheng T,
    10. North S,
    11. Venner P,
    12. Knox JJ,
    13. Chi KN,
    14. Kollmannsberger C,
    15. McDermott DF,
    16. Oh WK,
    17. Atkins MB,
    18. Bukowski RM,
    19. Rini BI and
    20. Choueiri TK
    : Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 27(34): 5794-5799, 2009. PMID: 19826129. DOI: 10.1200/JCO.2008.21.4809
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Pires da Silva I,
    2. Lo S,
    3. Quek C,
    4. Gonzalez M,
    5. Carlino MS,
    6. Long GV and
    7. Menzies AM
    : Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti-PD-1 therapy. Cancer 126(1): 86-97, 2020. PMID: 31584722. DOI: 10.1002/cncr.32522
    OpenUrlCrossRefPubMed
  7. ↵
    1. Lu LC,
    2. Hsu C,
    3. Shao YY,
    4. Chao Y,
    5. Yen CJ,
    6. Shih IL,
    7. Hung YP,
    8. Chang CJ,
    9. Shen YC,
    10. Guo JC,
    11. Liu TH,
    12. Hsu CH and
    13. Cheng AL
    : Differential organ-specific tumor response to immune checkpoint inhibitors in hepatocellular carcinoma. Liver Cancer 8(6): 480-490, 2019. PMID: 31799205. DOI: 10.1159/000501275
    OpenUrlCrossRefPubMed
  8. ↵
    1. Schmid S,
    2. Diem S,
    3. Li Q,
    4. Krapf M,
    5. Flatz L,
    6. Leschka S,
    7. Desbiolles L,
    8. Klingbiel D,
    9. Jochum W and
    10. Früh M
    : Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC). Cancer Immunol Immunother 67(12): 1825-1832, 2018. PMID: 30171269. DOI: 10.1007/s00262-018-2239-4
    OpenUrlCrossRefPubMed
  9. ↵
    1. Oliver AJ,
    2. Lau PKH,
    3. Unsworth AS,
    4. Loi S,
    5. Darcy PK,
    6. Kershaw MH and
    7. Slaney CY
    : Tissue-dependent tumor microenvironments and their impact on immunotherapy responses. Front Immunol 9: 70, 2018. PMID: 29445373. DOI: 10.3389/fimmu.2018.00070
    OpenUrlCrossRefPubMed
  10. ↵
    1. Salmon H,
    2. Remark R,
    3. Gnjatic S and
    4. Merad M
    : Host tissue determinants of tumour immunity. Nat Rev Cancer 19(4): 215-227, 2019. PMID: 30867580. DOI: 10.1038/s41568-019-0125-9
    OpenUrlCrossRefPubMed
  11. ↵
    1. Jiménez-Sánchez A,
    2. Memon D,
    3. Pourpe S,
    4. Veeraraghavan H,
    5. Li Y,
    6. Vargas HA,
    7. Gill MB,
    8. Park KJ,
    9. Zivanovic O,
    10. Konner J,
    11. Ricca J,
    12. Zamarin D,
    13. Walther T,
    14. Aghajanian C,
    15. Wolchok JD,
    16. Sala E,
    17. Merghoub T,
    18. Snyder A and
    19. Miller ML
    : Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 170(5): 927-938.e20, 2017. PMID: 28841418. DOI: 10.1016/j.cell.2017.07.025
    OpenUrlCrossRefPubMed
  12. ↵
    1. Eisenhauer EA,
    2. Therasse P,
    3. Bogaerts J,
    4. Schwartz LH,
    5. Sargent D,
    6. Ford R,
    7. Dancey J,
    8. Arbuck S,
    9. Gwyther S,
    10. Mooney M,
    11. Rubinstein L,
    12. Shankar L,
    13. Dodd L,
    14. Kaplan R,
    15. Lacombe D and
    16. Verweij J
    : New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 228-247, 2009. PMID: 19097774. DOI: 10.1016/j.ejca.2008.10.026
    OpenUrlCrossRefPubMed
  13. ↵
    1. Nishino M,
    2. Giobbie-Hurder A,
    3. Gargano M,
    4. Suda M,
    5. Ramaiya NH and
    6. Hodi FS
    : Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res 19(14): 3936-3943, 2013. PMID: 23743568. DOI: 10.1158/1078-0432.CCR-13-0895
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Champiat S,
    2. Besse B and
    3. Marabelle A
    : Hyperprogression during immunotherapy: do we really want to know?. Ann Oncol 30(7): 1028-1031, 2019. PMID: 31173063. DOI: 10.1093/annonc/mdz184
    OpenUrlCrossRefPubMed
  15. ↵
    1. Turpin A,
    2. Duterque-Coquillaud M and
    3. Vieillard MH
    : Bone Metastasis: Current State of Play. Transl Oncol 13(2): 308-320, 2020. PMID: 31877463. DOI: 10.1016/j.tranon.2019.10.012
    OpenUrlCrossRefPubMed
  16. ↵
    1. Negishi T,
    2. Furubayashi N,
    3. Takamatsu D,
    4. Ieiri K,
    5. Nishiyama N,
    6. Kitamura H and
    7. Nakamura M
    : Radiographical efficacy of systemic treatment for bone metastasis from renal cell carcinoma. Oncol Lett 20(5): 267, 2020. PMID: 32989401. DOI: 10.3892/ol.2020.12130
    OpenUrlCrossRefPubMed
  17. ↵
    1. Angela Y,
    2. Haferkamp S,
    3. Weishaupt C,
    4. Ugurel S,
    5. Becker JC,
    6. Oberndörfer F,
    7. Alar V,
    8. Satzger I and
    9. Gutzmer R
    : Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases. Cancer Immunol Immunother 68(7): 1187-1194, 2019. PMID: 31187176. DOI: 10.1007/s00262-019-02353-5
    OpenUrlCrossRefPubMed
  18. ↵
    1. García-Mulero S,
    2. Alonso MH,
    3. Pardo J,
    4. Santos C,
    5. Sanjuan X,
    6. Salazar R,
    7. Moreno V,
    8. Piulats JM and
    9. Sanz-Pamplona R
    : Lung metastases share common immune features regardless of primary tumor origin. J Immunother Cancer 8(1): e000491, 2020. PMID: 32591432. DOI: 10.1136/jitc-2019-000491
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Das R,
    2. Verma R,
    3. Sznol M,
    4. Boddupalli CS,
    5. Gettinger SN,
    6. Kluger H,
    7. Callahan M,
    8. Wolchok JD,
    9. Halaban R,
    10. Dhodapkar MV and
    11. Dhodapkar KM
    : Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol 194(3): 950-9, 2015. PMID: 25539810. DOI: 10.4049/jimmunol.1401686
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Popat S
    : Hyperprogression with immunotherapy: Is it real? Cancer 125(8): 1218-1220, 2019. PMID: 30768797. DOI: 10.1002/cncr.31997
    OpenUrlCrossRefPubMed
  21. ↵
    1. Shirotake S,
    2. Kaneko G,
    3. Nagata K,
    4. Oyama M and
    5. Nishimoto K
    : Histological complete response with nivolumab for renal cell carcinoma with multiple metastases: A case report. Mol Clin Oncol 10(2): 244-248, 2019. PMID: 30680202. DOI: 10.3892/mco.2018.1779
    OpenUrlCrossRefPubMed
  22. ↵
    1. George S,
    2. Rini BI and
    3. Hammers HJ
    : Emerging role of combination immunotherapy in the first-line treatment of advanced renal cell carcinoma: A review. JAMA Oncol 5(3): 411-421, 2019. PMID: 30476955. DOI: 10.1001/jamaoncol.2018.4604
    OpenUrlCrossRefPubMed
  23. ↵
    1. Trapani S,
    2. Manicone M,
    3. Sikokis A,
    4. D’Abbiero N,
    5. Salaroli F,
    6. Ceccon G and
    7. Buti S
    : Effectiveness and safety of “real” concurrent stereotactic radiotherapy and immunotherapy in metastatic solid tumors: a systematic review. Crit Rev Oncol Hematol 142: 9-15, 2019. PMID: 31325712. DOI: 10.1016/j.critrevonc.2019.07.006
    OpenUrlCrossRefPubMed
  24. ↵
    1. Rini BI,
    2. Plimack ER,
    3. Stus V,
    4. Gafanov R,
    5. Hawkins R,
    6. Nosov D,
    7. Pouliot F,
    8. Alekseev B,
    9. Soulières D,
    10. Melichar B,
    11. Vynnychenko I,
    12. Kryzhanivska A,
    13. Bondarenko I,
    14. Azevedo SJ,
    15. Borchiellini D,
    16. Szczylik C,
    17. Markus M,
    18. McDermott RS,
    19. Bedke J,
    20. Tartas S,
    21. Chang YH,
    22. Tamada S,
    23. Shou Q,
    24. Perini RF,
    25. Chen M,
    26. Atkins MB,
    27. Powles T and KEYNOTE-426 Investigators
    : Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 380(12): 1116-1127, 2019. PMID: 30779529. DOI: 10.1056/NEJMoa1816714
    OpenUrlCrossRefPubMed
  25. ↵
    1. Sun X,
    2. Gan L,
    3. Na A,
    4. Ge L,
    5. Chen B and
    6. Liu J
    : Combination with stereotactic body radiotherapy offers a promising strategy to overcome resistance to immunotherapy in advanced renal cell cancer. J Oncol 2019: 1483406, 2019. PMID: 31871454. DOI: 10.1155/2019/1483406
    OpenUrlCrossRefPubMed
  26. ↵
    1. Osawa T,
    2. Takeuchi A,
    3. Kojima T,
    4. Shinohara N,
    5. Eto M and
    6. Nishiyama H
    : Overview of current and future systemic therapy for metastatic renal cell carcinoma. Jpn J Clin Oncol 49(5): 395-403, 2019. PMID: 30722031. DOI: 10.1093/jjco/hyz013
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Site-specific Response to Nivolumab in Renal Cell Carcinoma
TAKAHITO NEGISHI, NOBUKI FURUBAYASHI, TOHRU NAKAGAWA, NAOTAKA NISHIYAMA, HIROSHI KITAMURA, YOSHIFUMI HORI, KENTAROU KUROIWA, YUHYON SON, NARIHITO SEKI, TOSHIHISA TOMODA, EIJIRO OKAJIMA, MOTONOBU NAKAMURA
Anticancer Research Mar 2021, 41 (3) 1539-1545; DOI: 10.21873/anticanres.14913
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords