Case report: durable complete response to pembrolizumab plus lenvatinib in a metastatic upper tract urothelial carcinoma patient with high tumor mutational burden and an immune-active tumor microenvironment.
Journal
Anti-cancer drugs
ISSN: 1473-5741
Titre abrégé: Anticancer Drugs
Pays: England
ID NLM: 9100823
Informations de publication
Date de publication:
01 07 2023
01 07 2023
Historique:
medline:
15
5
2023
pubmed:
3
2
2023
entrez:
2
2
2023
Statut:
ppublish
Résumé
Immune checkpoint inhibitors (ICIs) have been approved as an emerging first-line treatment option for advanced and metastatic urothelial carcinoma whose tumors express programmed death-ligand 1 (PD-L1). However, the efficacy of immunotherapy in PD-L1-negative urothelial carcinoma patients remains unclear, and biomarkers beyond PD-L1 expression to predict response to immunotherapy need investigation. Here, we report a metastatic renal pelvis urothelial carcinoma patient with PD-L1 negative expression that responded dramatically to first-line pembrolizumab plus lenvatinib. By the recent follow-up in March 2022, the patient had a complete radiological response for 3.4 years, with no recurrence even during the 23-month drug-withdrawal period. The results of the next-generation sequencing using the tumor sample revealed a high tumor mutational burden (TMB), which may be independently driven by the pathogenic mutation in TP53 , TERT , NCOR1 , and TSC2 genes. Besides, the tumor microenvironment exhibited an immune-active signature with relatively abundant CD8+ cells and M1 tumor-associated macrophages but scarce regulatory T cells may also explain the great benefit of the combination therapy. Our case provides a direction for identifying biomarkers beyond PD-L1 expression to screen urothelial carcinoma patients who benefit from ICI as well as ICI-based therapy.
Identifiants
pubmed: 36729952
doi: 10.1097/CAD.0000000000001464
pii: 00001813-202307000-00010
doi:
Substances chimiques
pembrolizumab
DPT0O3T46P
B7-H1 Antigen
0
lenvatinib
EE083865G2
Biomarkers, Tumor
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
797-802Informations de copyright
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
Références
Tanaka MF, Sonpavde G. Diagnosis and management of urothelial carcinoma of the bladder. Postgrad Med 2011; 123:43–55.
Galsky MD, Arija JA, Bamias A, Davis ID, De Santis M, Kikuchi E, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (Imvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2020; 395:1547–1557.
Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II keynote-199 study. J Clin Oncol 2020; 38:395–405.
Boudadi K, Suzman DL, Anagnostou V, Fu W, Luber B, Wang H, et al. Ipilimumab plus nivolumab and DNA-repair defects in Ar-V7-expressing metastatic prostate cancer. Oncotarget 2018; 9:28561–28571.
Graff JN, Antonarakis ES, Hoimes CJ, Tagawa ST, Hwang C, Kilari D, et al. Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mcrpc): keynote-199 cohorts 4-5. J Clin Oncol 2020; 38(6_suppl):15.
Kolinsky MP, Gravis G, Mourey L, Piulats JM, Sridhar SS, Romano E, et al. Keynote-365 cohort B updated results: pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mcrpc). J Clin Oncol 2020; 38(6_suppl):103.
Rizzo A, Ricci AD. Biomarkers for breast cancer immunotherapy: PD-L1, TILs, and beyond. Expert Opin Investig Drugs 2022; 31:549–555.
Gunda V, Gigliotti B, Ashry T, Ndishabandi D, McCarthy M, Zhou Z, et al. Anti-PD-1/PD-L1 therapy augments lenvatinib’s efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer. Int J Cancer 2019; 144:2266–2278.
Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al.; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021; 384:1289–1300.
Kawazoe A, Fukuoka S, Nakamura Y, Kuboki Y, Wakabayashi M, Nomura S, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (Epoc1706): an open-label, single-arm, phase 2 trial. Lancet Oncol 2020; 21:1057–1065.
Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019; 20:711–718.
Taylor MH, Lee CH, Makker V, Rasco D, Dutcus CE, Wu J, et al. Phase Ib/Ii trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol 2020; 38:1154–1163.
Mandal R, Samstein RM, Lee KW, Havel JJ, Wang H, Krishna C, et al. Genetic diversity of tumors with mismatch repair deficiency influences anti-Pd-1 immunotherapy response. Science 2019; 364:485–491.
Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 keynote-158 study. Lancet Oncol 2020; 21:1353–1365.
Lee C-H, Rasco DW, Rao A, Taylor MH, Hsieh JJ, Pinto A, et al. Association between biomarkers and clinical outcomes of lenvatinib + pembrolizumab in advanced renal cell carcinoma (Rcc): results from study 111/keynote-146. J Clin Oncol 2022; 40(6_suppl):375–375.
Lin J, Yang X, Long J, Zhao S, Mao J, Wang D, et al. Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma. Hepatobiliary Surg Nutr 2020; 9:414–424.
Zhang Q, Liu X, Wei S, Zhang L, Tian Y, Gao Z, et al. Lenvatinib plus Pd-1 inhibitors as first-line treatment in patients with unresectable biliary tract cancer: a single-arm, open-label, phase II study. Front Oncol 2021; 11:751391.
Lin X, Wang L, Xie X, Qin Y, Xie Z, Ouyang M, et al. Prognostic biomarker Tp53 mutations for immune checkpoint blockade therapy and its association with tumor microenvironment of lung adenocarcinoma. Front Mol Biosci 2020; 7:602328.
Lyu H, Li M, Jiang Z, Liu Z, Wang X. Correlate the Tp53 mutation and the Hras mutation with immune signatures in head and neck squamous cell cancer. Comput Struct Biotechnol J 2019; 17:1020–1030.
Lyu Q, Lin A, Cao M, Xu A, Luo P, Zhang J. Alterations in Tp53 are a potential biomarker of bladder cancer patients who benefit from immune checkpoint inhibition. Cancer Control 2020; 27:1073274820976665.
Lin A, Qiu Z, Zhang J, Luo P. Effect of Ncor1 mutations on immune microenvironment and efficacy of immune checkpoint inhibitors in patient with bladder cancer. Front Immunol 2021; 12:630773.
Huang Q, Li F, Hu H, Fang Z, Gao Z, Xia G, et al. Loss of Tsc1/Tsc2 sensitizes immune checkpoint blockade in non-small cell lung cancer. Sci Adv 2022; 8:eabi9533.
Li H, Li J, Zhang C, Zhang C, Wang H. Tert mutations correlate with higher TMB value and unique tumor microenvironment and may be a potential biomarker for anti-Ctla4 treatment. Cancer Med 2020; 9:7151–7160.
Li F, Li C, Cai X, Xie Z, Zhou L, Cheng B, et al. The association between Cd8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: a systematic review and meta-analysis. EClinicalMedicine 2021; 41:101134.
Zeng D, Ye Z, Wu J, Zhou R, Fan X, Wang G, et al. Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer. Theranostics 2020; 10:7002–7014.
Liu Q, Du F, Huang W, Ding X, Wang Z, Yan F, et al. Epigenetic control of Foxp3 in intratumoral t-cells regulates growth of hepatocellular carcinoma. Aging (Albany NY) 2019; 11:2343–2351.
Beyer M, Schultze JL. Regulatory T cells in cancer. Blood 2006; 108:804–811.
Xiong H, Mittman S, Rodriguez R, Moskalenko M, Pacheco-Sanchez P, Yang Y, et al. Anti-PD-L1 treatment results in functional remodeling of the macrophage compartment. Cancer Res 2019; 79:1493–1506.
Kimura T, Kato Y, Ozawa Y, Kodama K, Ito J, Ichikawa K, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci 2018; 109:3993–4002.