Introduction: A case of multiple liver metastases of clear cell RCC with a significant response to sunitinib as the fifth line after nivolumab is reported.
Case presentation: The patient was a 65-year-old man who underwent open nephrectomy for RCC. After the nephrectomy, he had recurrences several times, and metastasectomy had been performed for each recurrence. At 13 years after the nephrectomy, multiple liver, and lung metastases appeared. The treatment was switched to axitinib, followed by cabozantinib, then nivolumab. The best response was PR, SD, and PD for these three drugs, and treatment duration was 14, 3, and 3 months, respectively. As the fifth line, sunitinib was administered, with significant shrinkage of the multiple liver metastases, and PR has been maintained for 34 months.
Conclusion: Sunitinib after an IO-drug showed a significant effect in spite of only slight efficacy with other VEGFR-TKIs, which may have occurred through the alteration of the immunological microenvironment

Daizumoto, Kei

Fukawa, Tomoya

Kanayama, Hiro-omi

Kusuhara, Yoshito

Tada, Kouki

Takahashi, Masayuki

Tsuda, Megumi

Uehara, Hisanori

Yamaguchi, Kunihisa

Yamamoto, Yasuyo

English

Tokushima University Institutional Repository

Case ReportRecurrent multiple liver metastases of clear cell renal cell carcinomawith a significant response to sunitinib after nivolumab treatmentKouki Tada,1 Kei Daizumoto,1 Masayuki Takahashi,1 Hisanori Uehara,2 Megumi Tsuda,1Yoshito Kusuhara,1 Tomoya Fukawa,1 Yasuyo Yamamoto,1 Kunihisa Yamaguchi1 andHiro-omi Kanayama11Department of Urology, Tokushima University Graduate School of Biomedical Sciences, and 2Division of Pathology, TokushimaUniversity Hospital, Tokushima, JapanAbbreviations & AcronymsAE = adverse eventIO-drug = Immuno-OncologydrugPD = progressive diseasePDGFR = platelet-derivedgrowth factor receptorPR = partial responseRCC = renal cell carcinomaSD = stable diseaseVATS = video-assisted thoracicsurgeryVEGFR-TKI = vascularendothelial growth factorreceptor-tyrosine kinase inhibitorCorrespondence: MasayukiTakahashi, M.D., Ph.D., Departmentof Urology, Tokushima UniversityGraduate School of BiomedicalSciences, 3-18-15 Kuramoto-cho,Tokushima, Tokushima 770-8503,Japan. Email:takahashi.masayuki@tokushima-u.ac.jpHow to cite this article: Tada K,Daizumoto K, Takahashi M et al.Recurrent multiple liver metastasesof clear cell renal cell carcinomawith a significant response tosunitinib after nivolumab treatment.IJU Case Rep. 2023; 6: 41–44.This is an open access article underthe terms of the Creative CommonsAttribution-NonCommercial-NoDerivs License, which permitsuse and distribution in any medium,provided the original work isproperly cited, the use is non-commercial and no modifications oradaptations are made.Received 28 March 2022; accepted30 September 2022.Online publication 18 October 2022Introduction: A case of multiple liver metastases of clear cell RCC with a significantresponse to sunitinib as the fifth line after nivolumab is reported.Case presentation: The patient was a 65-year-old man who underwent opennephrectomy for RCC. After the nephrectomy, he had recurrences several times, andmetastasectomy had been performed for each recurrence. At 13 years after thenephrectomy, multiple liver, and lung metastases appeared. The treatment was switchedto axitinib, followed by cabozantinib, then nivolumab. The best response was PR, SD,and PD for these three drugs, and treatment duration was 14, 3, and 3 months,respectively. As the fifth line, sunitinib was administered, with significant shrinkage of themultiple liver metastases, and PR has been maintained for 34 months.Conclusion: Sunitinib after an IO-drug showed a significant effect in spite of only slightefficacy with other VEGFR-TKIs, which may have occurred through the alteration of theimmunological microenvironment.Key words: molecular-targeted therapy, nivolumab, renal cell carcinoma, sunitinib.Keynote messageIn this case, sunitinib administered as the fifth line after nivolumab demonstrated the remark-able tumor reduction for multiple liver metastases of RCC, which is considered to be an unfa-vorable factor for VEGFR-TKIs. A VEGFR-TKI may have been effective due to thealteration of tumor immunological microenvironment after IO-drug treatment although differ-ent mechanisms of action exist among the VEGFR-TKIs.IntroductionThe advent of IO-drugs as the monotherapy in the subsequent therapy or the combination ther-apy in the first line of treatment has dramatically changed the treatment landscape for metastaticRCC. However, the efficacy of drugs used in very late line is limited. We present an interestingcase where sunitinib administered as the fifth line after nivolumab was very effective.Case presentationThe patient was a 65-year-old man. The progress is also shown in the figure (Fig. 1).He had undergone open nephrectomy for left RCC (clear cell carcinoma, Fuhrman Grade3, INFb, pT2, v+, pN0, RM0) in X year. Interferon alfa-2b was given as adjuvant therapy.During the adjuvant therapy with interferon alfa-2b, a lung metastasis appeared 1 year laterand was resected by VATS. Ten years after the nephrectomy, the patient had a recurrence ofsplenic metastasis and underwent a splenectomy. Two years later, recurrent metastasisappeared in the left retroperitoneum, and combined resection of the retroperitoneal mass andtail of the pancreas was performed. One year later, multiple liver and lung metastasesappeared and the patient was referred to our department.© 2022 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association. 41IJU Case Reports (2023) 6, 41--44 doi: 10.1002/iju5.12545Chest and abdominal pelvic contrast-enhanced CT demon-strated multiple lung metastases in both lungs, and multiplemetastatic foci with a ring-shaped contrast effect were seen inthe liver (Fig. 2). The patient was started on axitinib as thesecond-line therapy. After 5 months of treatment, the tumorshrank by 36.1% and a PR had been achieved. After14 months, axitinib was discontinued due to PD.The patient was started on cabozantinib as the third-line ther-apy. At 3 months after starting cabozantinib, gastroschisis andperforated abscesses were observed. In addition to these AEs,the disease was progressive and cabozantinib was discontinued.After the gastroschisis subsided, nivolumab was started as thefourth-line therapy. After 3 months, nivolumab was discontin-ued due to a marked increase in liver metastases.Sunitinib at 25 mg was started as the fifth-line therapy.Sunitinib was temporarily interrupted with AEs requiring hos-pitalization, including fever, liver dysfunction, and worseningof general condition.After 2 weeks of interruption, sunitinib was re-started withno AEs, then, the dose was increased to 37.5 mg. Numbnessand pain in the arms and legs and decreased appetiteappeared gradually, the dose was again reduced to 25 mg. At5 months after the introduction of sunitinib, CT showed PRwith 55.5% shrinkage in target lesions of multiple livermetastases. Thereafter, because of the worsening of theretroperitoneal abscess, the dose of sunitinib was reduced to12.5 mg, which does not cause any major health problems,and PR is maintained 34 months after sunitinib initiation(Fig. 3).DiscussionAs the primary treatment for metastatic clear cell RCC,VEGFR-TKI monotherapy had been the mainstay of systemictherapy. Recently, international phase III trials such asCheckMate 214, KEYNOTE-426, JAVELIN Renal 101, andCheckMate 9-ER have shown the superiority of IO-IO com-bination or IO-drug plus VEGFR-TKI combination therapyover sunitinib.1–4 However, with regard to the subsequenttherapy, nivolumab has proved to be effective after VEGFR-TKI in the CheckMate 025 trial, but the efficacy of VEGFR-TKI therapy after IO-drug is still unclear.5In this case, sunitinib administered as the fifth line wasvery effective after nivolumab. It is important to consider theFig. 1 Clinical course from the onset of RCC tothe present.Fig. 2 Contrast-enhanced CT images of representative lung and liver metastases before starting Axitinib.42 © 2022 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.TADA ET AL 2577171x, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iju5.12545 by Tokushima University, Wiley Online Library on [05/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensereasons why fifth-line sunitinib has been so effective withlong-term PR. The first reason may be a specific characteris-tic of the therapeutic agent. The VEGFR-TKIs that areapproved for metastatic RCC include sorafenib, sunitinib,pazopanib, axitinib, and cabozantinib, and each drug inhibitsits own specific signaling pathways in addition to VEGFR.Sunitinib inhibits not only VEGFR, but also PDGFR andKIT, and it is possible that inhibition of PDGFR and KIT,which is not inhibited by axitinib or cabozantinib, resulted ina significant response.The second reason may be that IO treatment before suni-tinib altered the tumor immunological microenvironment. Anobservational study by Tomita et al. showed that the objectiveresponse rate of molecular targeted therapy after nivolumabor nivolumab plus ipilimumab combination therapy was 27%and 32%, respectively, in Japanese patients with mRCC.6 Inthe study by Nadal et al, the objective response rate ofVEGFR-TKI treatment after nivolumab or nivolumab plusipilimumab combination therapy was 36.2%, which is compa-rable to the study by Tomita.7 In the latest study, Bando et al.investigated the effectiveness of molecular targeted therapyafter nivolumab treatment for metastatic RCC, where TKItreatment after nivolumab showed a significant response withPR of 22.5% and SD of 45.0%.8 Several other studies havereported the efficacy of VEGFR-TKI therapy after IO therapy(Table 1).9,10 In the present case, as in those reports, the prioruse of nivolumab may have induced a significant antitumoreffect of sunitinib even in the fifth-line treatment. Such effi-cacy of chemotherapy after IO treatment has been reportednot only in metastatic RCC, but also in other malignan-cies.11,12 Also, NLR is thought to reflect the immunemicroenvironment of cancer patients, and in the study bySoda et al., the dynamics of NLR in the early stages of nivo-lumab treatment were inversely correlated with subsequenttreatment response.13 In the present case, the NLR beforenivolumab initiation was 2.61, while the NLR before sunitinibinitiation was 3.10, hardly any change, consistent with thepattern of the efficacy of the following treatment in this study.The patient also developed fever 4 weeks after starting suni-tinib, at which time the NLR temporarily increased, but afterthe fever resolved, the NLR was rather lower than before thefever. A reduction in NLR has also been reported to be asso-ciated with an improved prognosis with sunitinib, and it ispresumed that some immune response occurred in this caseand that sunitinib was also significantly effective.14Additionally, nivolumab alone did not show any responsein this case, but after discontinuation of nivolumab, immuno-logical effects may have continued afterward and a sort ofFig. 3 The course of liver metastases treated with sunitinib by contrast-enhanced CT. (a) Before starting Sunitinib (b) 5 months later: The ring contrast effect wasno longer seen and the tumor diameter markedly decreased. (c) 16 months later: Tumor had continued to shrink. (d) 22 months later: Tumor response was main-tained.Table 1 ORR of molecular targeted therapy after IO-drugs for metastatic renal cell carcinomaAuthor Prior drug Patients No. Subsequent drug ORR (%)Y. Tomita, et al Nivolumab 26 Sunitinib, Axitinib, Pazopanib, Everolimus 27Nivolumab + Ipilimumab 19 32R. Nadal, et al Nivolumab 32 Axitinib, Sunitinib, Pazopanib, Sorafenib 36.2Nivolumab + Ipilimumab 17Y. Bando, et al Nivolumab 40 Axitinib, Pazopanib, Sunitinib, Sorafenib 22.5P. C. Barata, et al Nivolumab + Ipilimumab 11 Axitinib, Cabozantinib, Pazopanib, Sunitinib 33A. Y. Shah, et al Atezolizumab/Nivolumab 12 Axitinib, Cabozantinib, Pazopanib, Sunitinib 50Nivolumab + Ipilimumab 32 43.8IO-drug, immuno oncology-drug; ORR, objective response rate.© 2022 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association. 43Significant response of sunitinib for RCC 2577171x, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iju5.12545 by Tokushima University, Wiley Online Library on [05/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensesynergistic effect of nivolumab and sunitinib may have pro-duced such anti-tumor effect for the liver metastases for along time.ConclusionA case of metastatic clear cell RCC that responded well tosunitinib as the fifth line after nivolumab treatment was pre-sented. The reasons for the significant response of sunitinibin late-stage therapy suggest differences in the target genes ofeach VEGFR-TKI and the use of IO-drug.AcknowledgmentWe would like to thank our patient for his cooperation.Author contributionsKouki Tada: Writing – original draft. Kei Daizumoto: Writing –review and editing. Masayuki Takahashi: Supervision. HisanoriUehara: Data curation. Megumi Tsuda: Writing – review andediting. Yoshito Kusuhara: Writing – review and editing.Tomoya Fukawa: Writing – review and editing. Yasuyo Yama-moto: Writing – review and editing. Kunihisa Yamaguchi:Writing – review and editing. Hiro-omi Kanayama: Supervision.Conflict of interestHiro-omi Kanayama received an honorarium from TakedaPharmaceutical Company Limited and ONO PHARMACEU-TICAL CO., LTD.Masayuki Takahashi received an honorarium from MerckBiopharma Co., Ltd, Pfizer Inc, MSD K.K., Takeda Pharma-ceutical Company Limited, Novartis Pharma K.K., and ONOPHARMACEUTICAL CO., LTD.Approval of the research protocol byan Institutional Reviewer BoardThe ethical IRB number is 2004.Informed consentInformed consent was obtained from the patient included inthe study.Registry and the Registration No. ofthe study/trialNot applicable.References1 Motzer RJ, Tannir NM, McDermott DF et al. Nivolumab plus ipilimumabversus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 2018;378: 1277–90.2 Rini BI, Plimack ER, Stus V et al. Pembrolizumab plus axitinib versus suni-tinib for advanced renal-cell carcinoma. N. Engl. J. Med. 2019; 380:1116–27.3 Motzer RJ, Penkov K, Haanen J et al. Avelumab plus axitinib versus sunitinibfor advanced renal-cell carcinoma. N. Engl. J. Med. 2019; 380: 1103–15.4 Choueiri TK, Powles T, Burotto M et al. Nivolumab plus cabozantinib ver-sus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 2021; 384:829–41.5 Motzer RJ, Escudier B, McDermott DF. Nivolumab versus everolimus inadvanced renal-cell carcinoma. N. Engl. J. Med. 2015; 373: 1803–13.6 Tomita Y, Kimura G, Fukasawa S et al. Efficacy and safety of subsequentmolecular targeted therapy after immuno-checkpoint therapy, retrospectivestudy of Japanese patients with metastatic renal cell carcinoma (AFTER I-Ostudy). Jpn. J. Clin. Oncol. 2021; 51: 966–75.7 Nadal R, Amin A, Geynisman DM et al. Safety and clinical activity of vas-cular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitorsafter programmed cell death 1 inhibitor treatment in patients with metastaticclear cell renal cell carcinoma. Ann. Oncol. 2016; 27: 1304–11.8 Bando Y, Furukawa J, Terakawa T et al. Treatment outcomes of moleculartargeted therapy following nivolumab in metastatic renal cell carcinoma. Jpn.J. Clin. Oncol. 2021; 51: 1313–8.9 Barata PC, De Liano AG, Mendiratta P et al. The efficacy of VEGFR TKItherapy after progression on immune combination therapy in metastatic renalcell carcinoma. Br. J. Cancer 2018; 119: 160–3.10 Shah AY, Kotecha RR, Lemke EA et al. Outcomes of patients with meta-static clear-cell renal cell carcinoma treated with second-line VEGFR-TKIafter first-line immune checkpoint inhibitors. Eur. J. Cancer 2019; 114:67–75.11 Park SE, Lee SH, Ahn JS, Ahn MJ, Park K, Sun JM. Increased responserates to salvage chemotherapy administered after PD-1/PD-L1 inhibitors inpatients with non–small cell lung cancer. J. Thorac. Oncol. 2018; 13:106–11.12 Szabados B, van Dijk N, van der Heijden MS et al. Response rate tochemotherapy after immune checkpoint inhibition in metastatic urothelialcancer. Eur. Urol. 2018; 73: 149–52.13 Soda H, Ogawara D, Fukuda T et al. Dynamics of blood neutrophil-relatedindices during nivolumab treatment may be associated with response to sal-vage chemotherapy for non-small cell lung cancer: a hypothesis generatingstudy. Thorac. Cancer. 2019; 10: 341–6.14 Templeton AJ, Knox JJ, Lin X et al. Change in neutrophil-to-lymphocyteratio in response to targeted therapy for metastatic renal cell carcinoma as aprognosticator and biomarker of efficacy. Eur. Urol. 2016; 70: 358–64.Editorial CommentEditorial Comment on “Recurrent multiple liver metastases of clear cell renal cellcarcinoma with a significant response to sunitinib after nivolumab treatment: A casereport”The advent of tyrosine kinase inhibitors (TKIs) and immunecheckpoint inhibitors (ICIs) has increased treatment optionsfor metastatic renal cell carcinoma (mRCC). In this case, apatient with mRCC who received sunitinib as 5th line therapyThis is an open access article under the terms of the CreativeCommons Attribution License, which permits use, distribution andreproduction in any medium, provided the original work is properlycited.44 © 2022 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.TADA ET AL 2577171x, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iju5.12545 by Tokushima University, Wiley Online Library on [05/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Significant response of sunitinib for RCC

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Significant response of sunitinib for RCC

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