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C-Reactive Protein-Albumin Ratio Predicts Objective Response to Enfortumab Vedotin in Metastatic Urothelial Carcinoma

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Abstract

Background

Enfortumab vedotin (EV), an antibody-drug conjugate that targets Nectin-4, is used for patients with metastatic urothelial carcinoma who have experienced progression on platinum-based chemotherapy and checkpoint inhibitors. Despite the widespread use of the drug, evidence remains scarce regarding clinical indicators that can predict the response to EV treatment.

Objective

We aimed to explore the predictive value of clinical indicators derived from peripheral blood tests for treatment responses to EV.

Methods

We utilized records of 109 patients with metastatic urothelial carcinoma treated by EV from our multi-institutional dataset. Receiver operating characteristic curve analyses for predicting objective responses including several indicators from blood examinations, such as C-reactive protein-albumin ratio (CAR), hemoglobin, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and lactate dehydrogenase, were performed. The optimal cutoff points were determined by the Youden index. Logistic regression analyses for achieving objective responses to EV treatment were performed among these indicators.

Results

The median age of the cohort was 74 years, and the median follow-up duration was 10 months for the entire group. Median overall survival and progression-free survival from the initiation of EV were 12 and 6 months, respectively. The objective response rate and disease control rate were 48% and 70%, respectively. The receiver operating characteristic curve analysis aimed at predicting the achievement of an objective response to EV showed that the concordant index for the CAR was 0.774, significantly surpassing other indicators such as hemoglobin level, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and serum lactate dehydrogenase. The Youden index identified an optimal cutoff value of 1 for CAR (mg/L for C-reactive protein and g/dL for serum albumin level) in predicting the objective response to EV treatment. Using the cutoff value for the CAR, the cohort was divided into 32 patients (29%) with lower CAR and 77 patients (71%) with higher CAR. The objective response rate was observed to be 84% in the lower CAR group and 32% in the higher CAR group (p < 0.0001). A logistic regression analysis revealed that an Eastern Cooperative Oncology Group Performance Status ≥1 (p = 0.04) and a CAR ≥1 (p < 0.001) were identified as independent predictors for the objective response to EV.

Conclusions

The evaluation of the CAR from a concise blood examination at the initiation of EV could effectively predict the treatment response to EV in patients with metastatic urothelial carcinoma after the progression of platinum-based chemotherapy and checkpoint inhibitors.

Plain Language Summary

Enfortumab vedotin, an antibody-drug conjugate that targets Nectin-4, is currently used for patients with metastatic urothelial carcinoma who no longer respond to checkpoint inhibitors. In the present report, we investigated which clinical indicators can predict achieving an objective response to enfortumab vedotin at the initiation of treatment. Among the blood-based putative indicators, the C-reactive protein-albumin ratio showed the highest value for predicting the treatment response to enfortumab vedotin. As the C-reactive protein-albumin ratio can be easily assessed from blood tests, physicians can consider evaluating it at the start of the EV treatment.

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References

  1. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–77.

    Article  PubMed  Google Scholar 

  2. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381(4):338–48.

    Article  CAS  PubMed  Google Scholar 

  5. Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Duran I, Lee JL, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sidaway P. Sacituzumab govitecan is safe and effective. Nat Rev Clin Oncol. 2021;18(7):400.

    PubMed  Google Scholar 

  7. Fukuokaya W, Koike Y, Yata Y, Komura K, Uchimoto T, Tsu**o T, et al. Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: a multicenter observational study. Int J Urol. 2024;31(4):342–7.

    Article  CAS  PubMed  Google Scholar 

  8. Hirasawa Y, Adachi T, Hashimoto T, Fukuokaya W, Koike Y, Yata Y, et al. Comparison of the efficacy of enfortumab vedotin between patients with metastatic urothelial carcinoma who were treated with avelumab or pembrolizumab: real-world data from a multi-institutional study in Japan. J Cancer Res Clin Oncol. 2024;150(4):182.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Uchimoto T, Tsuchida S, Komura K, Fukuokaya W, Adachi T, Hirasawa Y, et al. Durable response to enfortumab vedotin compared to re-challenging chemotherapy in metastatic urothelial carcinoma after checkpoint inhibitors. Target Oncol. 2024;19(3):401-10.

    Article  PubMed  Google Scholar 

  10. Komura K, Hashimoto T, Tsu**o T, Muraoka R, Tsutsumi T, Satake N, et al. The CANLPH score, an integrative model of systemic inflammation and nutrition status (SINS), predicts clinical outcomes after surgery in renal cell carcinoma: data from a multicenter cohort in Japan. Ann Surg Oncol. 2019;26(9):2994–3004.

    Article  PubMed  Google Scholar 

  11. Uchimoto T, Komura K, Fujiwara Y, Saito K, Tanda N, Matsunaga T, et al. Prognostic impact of C-reactive protein-albumin ratio for the lethality in castration-resistant prostate cancer. Med Oncol. 2019;37(1):9.

    Article  PubMed  Google Scholar 

  12. Tsu**o T, Komura K, Matsunaga T, Yoshikawa Y, Takai T, Uchimoto T, et al. Preoperative measurement of the Modified Glasgow Prognostic Score predicts patient survival in non-metastatic renal cell carcinoma prior to nephrectomy. Ann Surg Oncol. 2017;24(9):2787–93.

    Article  PubMed  Google Scholar 

  13. Tsu**o T, Komura K, Hashimoto T, Muraoka R, Satake N, Matsunaga T, et al. C-reactive protein-albumin ratio as a prognostic factor in renal cell carcinoma: a data from multi-institutional study in Japan. Urol Oncol. 2019;37(11):812.e1-8.

    Article  CAS  PubMed  Google Scholar 

  14. Guo Y, Cai K, Mao S, Zhang J, Wang L, Zhang Z, et al. Preoperative C-reactive protein/albumin ratio is a significant predictor of survival in bladder cancer patients after radical cystectomy: a retrospective study. Cancer Manag Res. 2018;10:4789–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kunizaki M, Tominaga T, Wakata K, Miyazaki T, Matsumoto K, Sumida Y, et al. Clinical significance of the C-reactive protein-to-albumin ratio for the prognosis of patients with esophageal squamous cell carcinoma. Mol Clin Oncol. 2018;8(2):370–4.

    CAS  PubMed  Google Scholar 

  16. Kuboki A, Kanaya H, Nakayama T, Konno W, Goto K, Nakajima I, et al. Prognostic value of C-reactive protein/albumin ratio for patients with hypopharyngeal and laryngeal cancer undergoing invasive surgery involving laryngectomy. Head Neck. 2019;41(5):1342–50.

    Article  PubMed  Google Scholar 

  17. Koh YW, Lee HW. Prognostic impact of C-reactive protein/albumin ratio on the overall survival of patients with advanced nonsmall cell lung cancers receiving palliative chemotherapy. Medicine (Baltimore). 2017;96(19): e6848.

    Article  CAS  PubMed  Google Scholar 

  18. Wu M, Zhou Y, Chen Q, Yu Z, Gu H, Lin P, et al. Prognostic role of pretreatment C-reactive protein to albumin ratio in urological cancers: a systematic review and meta-analysis. Front Oncol. 2022;12: 879803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou Q, He Q, He W, Wang C, Liu G, Wang K, et al. Clinical value of folate receptor-positive circulating tumor cells in patients with esophageal squamous cell carcinomas: a retrospective study. BMC Cancer. 2023;23(1):1171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gandevia B, Tovell A. Declaration of Helsinki. Med J Aust. 1964;2:320–1.

    Article  CAS  PubMed  Google Scholar 

  21. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

    Article  CAS  PubMed  Google Scholar 

  22. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143–52.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32–5.

    Article  CAS  PubMed  Google Scholar 

  24. Dumontet C, Reichert JM, Senter PD, Lambert JM, Beck A. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov. 2023;22(8):641–61.

    Article  CAS  PubMed  Google Scholar 

  25. Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Flechon A, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhu J, Wang D, Liu C, Huang R, Gao F, Feng X, et al. Development and validation of a new prognostic immune-inflammatory-nutritional score for predicting outcomes after curative resection for intrahepatic cholangiocarcinoma: a multicenter study. Front Immunol. 2023;14:1165510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao Z, Yin XN, Wang J, Chen X, Cai ZL, Zhang B. Prognostic significance of hemoglobin, albumin, lymphocyte, platelet in gastrointestinal stromal tumors: a propensity matched retrospective cohort study. World J Gastroenterol. 2022;28(27):3476–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zakosek M, Bulatovic D, Pavlovic V, Filipovic A, Igic A, Galun D, et al. Prognostic Nutritional Index (PNI) and neutrophil to lymphocyte ratio (NLR) as predictors of short-term survival in patients with advanced malignant biliary obstruction treated with percutaneous transhepatic biliary drainage. J Clin Med. 2022;11(23):7055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yanagisawa T, Mori K, Katayama S, Mostafaei H, Quhal F, Laukhtina E, et al. Pretreatment clinical and hematologic prognostic factors of metastatic urothelial carcinoma treated with pembrolizumab: a systematic review and meta-analysis. Int J Clin Oncol. 2022;27(1):59–71.

    Article  CAS  PubMed  Google Scholar 

  30. Pond GR, Agarwal N, Bellmunt J, Choueiri TK, Qu A, Fougeray R, et al. A nomogram including baseline prognostic factors to estimate the activity of second-line therapy for advanced urothelial carcinoma. BJU Int. 2014;113(5b):E137–43.

    Article  CAS  PubMed  Google Scholar 

  31. Viers BR, Boorjian SA, Frank I, Tarrell RF, Thapa P, Karnes RJ, et al. Pretreatment neutrophil-to-lymphocyte ratio is associated with advanced pathologic tumor stage and increased cancer-specific mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy. Eur Urol. 2014;66(6):1157–64.

    Article  PubMed  Google Scholar 

  32. Bellmunt J, Choueiri TK, Fougeray R, Schutz FA, Salhi Y, Winquist E, et al. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol. 2010;28(11):1850–5.

    Article  PubMed  Google Scholar 

  33. Uchimoto T, Nakamura K, Komura K, Fukuokaya W, Yano Y, Nishimura K, et al. Prognostic value of the fluctuation in the neutrophil-lymphocyte ratio at 6 weeks of pembrolizumab treatment is specific to the clinical response in metastatic urothelial carcinoma. Urol Oncol. 2022;40(7):344 (e11–7).

    Article  Google Scholar 

  34. Uchimoto T, Komura K, Fukuokaya W, Kimura T, Takahashi K, Yano Y, et al. Risk classification for overall survival by the neutrophil-lymphocyte ratio and the number of metastatic sites in patients treated with pembrolizumab: a multicenter collaborative study in Japan. Cancers (Basel). 2021;13(14):3554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Heath EI, Rosenberg JE. The biology and rationale of targeting nectin-4 in urothelial carcinoma. Nat Rev Urol. 2021;18(2):93–103.

    Article  PubMed  Google Scholar 

  36. Qiu S, Zhang J, Wang Z, Lan H, Hou J, Zhang N, et al. Targeting Trop-2 in cancer: recent research progress and clinical application. Biochim Biophys Acta Rev Cancer. 2023;1878(4): 188902.

    Article  CAS  PubMed  Google Scholar 

  37. Nishimura K, Nishio K, Hirosuna K, Komura K, Hayashi T, Fukuokaya W, et al. Efficacy of pembrolizumab and comprehensive CD274/PD-L1 profiles in patients previously treated with chemoradiation therapy as radical treatment in bladder cancer. J Immunother Cancer. 2022;10(1): e003868.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Komura K, Hirosuna K, Tokushige S, Tsu**o T, Nishimura K, Ishida M, et al. The impact of FGFR3 alterations on the tumor microenvironment and the efficacy of immune checkpoint inhibitors in bladder cancer. Mol Cancer. 2023;22(1):185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. Taizo Uchimoto and Takuya Matsuda contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan

    Taizo Uchimoto, Takuya Matsuda, Kazumasa Komura, Takuya Higashio, Shuya Tsuchida, Kazuki Nishimura, Takuya Tsu**o, Ko Nakamura, Tatsuo Fukushima, Kyosuke Nishio, Teruo Inamoto & Haruhito Azuma

  2. Department of Urology, The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan

    Wataru Fukuokaya, Shutaro Yamamoto, Kosuke Iwatani, Fumihiko Urabe, Keiichiro Mori, Takafumi Yanagisawa, Shunsuke Tsuduki, Jun Miki & Takahiro Kimura

  3. Department of Urology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan

    Takahiro Adachi, Yosuke Hirasawa, Takeshi Hashimoto & Yoshio Ohno

  4. Department of Urology, Fujita-Health University School of Medicine, Kutsukake, Toyoake, Aichi Nagoya, Japan

    Atsuhiko Yoshizawa, Masanobu Saruta, Kiyoshi Takahara & Ryoichi Shiroki

  5. Department of Urology, Faculty of Medicine, Kindai University, Osakasayama, Osaka, Japan

    Mamoru Hashimoto, Kazutoshi Fujita & Hirotsugu Uemura

  6. Division of Translational Research, Department of Urology, Osaka Medical and Pharmaceutical University, Daigaku-machi 2-7, Takatsuki, Japan

    Kazumasa Komura

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  1. Taizo Uchimoto
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Corresponding authors

Correspondence to Kazumasa Komura or Takahiro Kimura.

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Funding

Kazumasa Komura was partially supported by Grant-in-Aid No. 21H03070 (Japan Society for the Promotion of Science), the Kenzo Suzuki Memorial Foundation, the SGH Foundation, the Naito Memorial Foundation, and the Cancer Translational Research Foundation of Japanese Urological Association.

Conflicts of Interest/Competing Interests

Taizo Uchimoto, Takuya Matsuda, Kazumasa Komura, Wataru Fukuokaya, Takahiro Adachi, Yosuke Hirasawa, Takeshi Hashimoto, Atsuhiko Yoshizawa, Masanobu Saruta, Mamoru Hashimoto, Takuya Higashio, Shuya Tsuchida, Kazuki Nishimura, Takuya Tsu**o, Ko Nakamura, Tatsuo Fukushima, Kyosuke Nishio, Shutaro Yamamoto, Kosuke Iwatani, Fumihiko Urabe, Keiichiro Mori, Takafumi Yanagisawa, Shunsuke Tsuduki, Kiyoshi Takahara, Teruo Inamoto, Jun Miki, Kazutoshi Fujita, Takahiro Kimura, Yoshio Ohno, Ryoichi Shiroki, Hirotsugu Uemura, and Haruhito Azuma have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

This study was approved by the Institutional Review Board of Osaka Medical and Pharmaceutical University (approval number: RIN-750-2571, approved on 24 January, 2020). This observational study adhered to ethical principles aligned with the Declaration of Helsinki, the International Conference on Harmonisation’s Good Clinical Practice guidelines, Good Pharmacoepidemiology Practices, and relevant laws for non-interventional and observational studies.

Consent to Participate

All patients provided written informed consent prior to data collection for the study.

Consent for Publication

Not applicable.

Availability of Data and Material

The data from this study can be accessed by academic and commercial partners upon a reasonable request, subject to institutional review board approval and a data use agreement. For further details or to reanalyze the study’s data, contact the Lead Contact at kazumasa.komura@ompu.ac.jp.

Code Availability

Not applicable.

Authors’ Contributions

TU: conceptualization, data curation, analysis, investigation, methodology, software, visualization, writing original draft, supervision. TM: data curation, analysis, investigation, methodology, software, visualization. KK: data curation, investigation, investigation, writing the original draft, supervision. WF: investigation, data curation, validation. AA: validation, methodology. YH: methodology, validation. TH: methodology, validation. AY: data curation. MS: data curation. MH: analysis. TH: data curation, analysis. ST: investigation. KN: data curation. TT: methodology, data curation. KN: investigation. TF: data curation, analysis. KN: validation. SY: data curation. KI: investigation, supervision. FU: investigation, validation, supervision. KM: methodology, data analysis. TY: investigation. ST: writing original draft, review. KT: editing, supervision. TI: data curation. JM: data curation, analysis. KF: review and editing, supervision. TK: investigation, validation, supervision. YO: supervision. RS: supervision. HU: supervision. HA: supervision.

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Uchimoto, T., Matsuda, T., Komura, K. et al. C-Reactive Protein-Albumin Ratio Predicts Objective Response to Enfortumab Vedotin in Metastatic Urothelial Carcinoma. Targ Oncol 19, 635–644 (2024). https://doi.org/10.1007/s11523-024-01068-7

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