Abstract
Background
Sites of metastasis have prognostic significance in advanced urothelial carcinoma
(aUC), but more information is needed regarding outcomes based on metastatic sites
in patients treated with immune checkpoint inhibitors (ICI). We hypothesized that
presence of liver/bone metastases would be associated with worse outcomes with ICI.
Methods
We identified a retrospective cohort of patients with aUC across 26 institutions,
collecting demographics, clinicopathological, treatment, and outcomes information.
Outcomes were compared with logistic (observed response rate; ORR) and Cox (progression-free
survival; PFS, overall survival; OS) regression between patients with/without metastasis
beyond lymph nodes (LN) and those with/without bone/liver/lung metastasis. Analysis
was stratified by 1st or 2nd+ line.
Results
We identified 917 ICI-treated patients: in the 1st line, bone/liver metastases were
associated with shorter PFS (Hazard ratio; HR: 1.65 and 2.54), OS (HR: 1.60 and 2.35,
respectively) and lower ORR (OR: 0.48 and 0.31). In the 2nd+ line, bone/liver metastases were associated with shorter PFS (HR: 1.71 and 1.62),
OS (HR: 1.76 and 1.56) and, for bone-only metastases, lower ORR (OR: 0.29). In the
1st line, LN-confined metastasis was associated with longer PFS (HR: 0.53), OS (HR:0.49)
and higher ORR (OR: 2.97). In the 2nd+ line, LN-confined metastasis was associated with longer PFS (HR: 0.47), OS (HR: 0.54),
and higher ORR (OR: 2.79); all associations were significant.
Conclusion
Bone and/or liver metastases were associated with worse, while LN-confined metastases
were associated with better outcomes in patients with aUC receiving ICI. These findings
in a large population treated outside clinical trials corroborate data from trial
subset analyses.
Keywords
Abbreviations:
aUC (advanced urothelial carcinoma), ICI (immune checkpoint inhibitors), IRAEs (immune related adverse effects), LN (lymph node), MIBC (muscle-invasive bladder cancer), PDL1 (programmed death ligand 1), TME (tumor microenvironment)To read this article in full you will need to make a payment
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References
- Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook.Ther Clin Risk Manag. 2018; 14 (Published 2018 Jun 5): 1019-1040https://doi.org/10.2147/TCRM.S158753
- Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma.N Engl J Med. 2020; 383: 1218-1230https://doi.org/10.1056/NEJMoa2002788
- Enfortumab vedotin in previously treated advanced urothelial carcinoma.N Engl J Med. 2021; 384: 1125-1135https://doi.org/10.1056/NEJMoa2035807
- Erdafitinib in locally advanced or metastatic urothelial carcinoma.N Engl J Med. 2019; 381: 338-348https://doi.org/10.1056/NEJMoa1817323
- 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: 2474-2485https://doi.org/10.1200/JCO.20.03489
- Prognostic model for predicting survival of patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy.J Natl Cancer Inst. 2013; 105: 499-503https://doi.org/10.1093/jnci/djt015
- 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: 1850-1855https://doi.org/10.1200/JCO.2009.25.4599
- Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy.J Clin Oncol. 1999; 17: 3173-3181https://doi.org/10.1200/JCO.1999.17.10.3173
- Five-factor prognostic model for survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-L1 inhibitors [published correction appears in J Urol. 2021 Mar;205(3):942].J Urol. 2020; 204: 1173-1179https://doi.org/10.1097/JU.0000000000001199
- A new prognostic model in patients with advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors.Eur Urol Oncol. 2021; 4: 464-472https://doi.org/10.1016/j.euo.2020.12.006
- A model combining clinical and genomic factors to predict response to PD-1/PD-L1 blockade in advanced urothelial carcinoma.Br J Cancer. 2020; 122: 555-563https://doi.org/10.1038/s41416-019-0686-0
Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. The Lancet. 2017;389:67-76. doi:10.1016/S0140-6736(16)32455-2.
- First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study.Lancet Oncol. 2017; 18: 1483-1492https://doi.org/10.1016/S1470-2045(17)30616-2
- Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.Ann Oncol. 2019; 30: 970-976https://doi.org/10.1093/annonc/mdz127
Nelson AA, Cronk RJ, Lemke EA, et al. Early bone metastases are associated with worse outcomes in metastatic urothelial carcinoma. Bladder Cancer. 2021;7:33-42. doi:10.3233/BLC-200377.
- Impact of performance status on treatment outcomes: a real-world study of advanced urothelial cancer treated with immune checkpoint inhibitors.Cancer. 2020; 126: 1208-1216
- Histological subtypes and response to PD-1/PD-L1 blockade in advanced urothelial cancer: a retrospective study.J Urol. 2020; 204: 63-70
- Immune checkpoint inhibitors in advanced upper and lower tract urothelial carcinoma: a comparison of outcomes.BJU Int. 2021; 128: 196-205
- The REDCap consortium: building an international community of software platform partners.J Biomed Inform. 2019; 95103208https://doi.org/10.1016/j.jbi.2019.103208
- Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support.J Biomed Inform. 2009; 42: 377-381
- Efficacy of enfortumab vedotin in advanced urothelial cancer: analysis from the urothelial cancer network to investigate therapeutic experiences (UNITE) study [published online ahead of print, 2021 Dec 9].Cancer. 2021; (10.1002/cncr.34057)https://doi.org/10.1002/cncr.34057
- Role of bone metastases in patients receiving immunotherapy for pre-treated urothelial carcinoma: the multicentre, retrospective meet-URO-1 bone study [published online ahead of print, 2021 Dec 16].Clin Genitourin Cancer. 2021; (00238-X): S1558-S7673https://doi.org/10.1016/j.clgc.2021.12.008
- Clinical outcome after progressing to frontline and second-line Anti–PD-1/PD-L1 in advanced urothelial cancer.Eur Urol. 2020; 77: 269-276https://doi.org/10.1016/j.eururo.2019.10.004
- Characterization of outcomes in patients with advanced genitourinary malignancies treated with immune checkpoint inhibitors.Urol Oncol Semin Orig Investig. 2021; 39 (e1-437.e9): 437https://doi.org/10.1016/j.urolonc.2021.01.006
- The cancer immunogram as a framework for personalized immunotherapy in urothelial cancer.Eur Urol. 2019; 75: 435-444https://doi.org/10.1016/j.eururo.2018.09.022
- The cancer immunogram: a pledge for a comprehensive biomarker approach for personalized immunotherapy in urothelial cancer.Eur Urol. 2019; 75: 445-447https://doi.org/10.1016/j.eururo.2018.12.005
- Evolution of PD-1 and PD-L1 gene and protein expression in primary tumors and corresponding liver metastases of metastatic bladder cancer.Eur Urol. 2018; 74: 527-529https://doi.org/10.1016/j.eururo.2018.06.028
- Integrative clinical and genomic characterization of mtap-deficient metastatic urothelial cancer.Eur Urol Oncol. 2021; 14 (Published online November)https://doi.org/10.1016/j.euo.2021.10.006
- Clonal evolution of chemotherapy-resistant urothelial carcinoma.Nat Genet. 2016; 48: 1490-1499https://doi.org/10.1038/ng.3692
- Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV201): a multicentre, single-arm, phase 2 trial [published correction appears in Lancet Oncol. 2021 Jun;22(6):e239].Lancet Oncol. 2021; 22: 872-882https://doi.org/10.1016/S1470-2045(21)00094-2
- Making patient-specific treatment decisions using prognostic variables and utilities of clinical outcomes.Cancers. 2021; 13https://doi.org/10.3390/cancers13112741
- Systemic immunity in cancer.Nat Rev Cancer. 2021; 21: 345-359https://doi.org/10.1038/s41568-021-00347-z
- Current perspectives on immunotherapy in the perioperative setting of muscle-infiltrating bladder cancer.Front Oncol. 2020; 10 (Published 2020 Oct 21)568279https://doi.org/10.3389/fonc.2020.568279
- Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma.N Engl J Med. 2021; 384: 2102-2114https://doi.org/10.1056/NEJMoa2034442
- Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma.N Engl J Med. 2020; 383: 1218-1230https://doi.org/10.1056/NEJMoa2002788
- Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): a multicenter phase 2 trial.J Clin Oncol. 2021; 39 (4504): 4504https://doi.org/10.1200/JCO.2021.39.15_suppl.4504
- Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB trial.J Clin Oncol. 2020; 38 (542): 542https://doi.org/10.1200/JCO.2020.38.6_suppl.542
- Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial.Nat Med. 2020; 26: 1839-1844https://doi.org/10.1038/s41591-020-1085-z
- A phase Ib/II study of neoadjuvant pembrolizumab (pembro) and chemotherapy for locally advanced urothelial cancer (UC).Ann Oncol. 2018; 29: viii726https://doi.org/10.1093/annonc/mdy424.039
Article Info
Publication History
Published online: June 04, 2022
Accepted:
June 1,
2022
Received in revised form:
June 1,
2022
Received:
March 23,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
