Improving the efficacy of immunotherapy in patients with advanced or metastatic urothelial carcinoma: a new role for tyrosine kinase inhibitors in the treatment paradigm?

Platinum-based combination chemotherapy has been for more than 30 years the only effective systemic therapy for advanced urothelial carcinoma (aUC) (1). Since 2016, five immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) (pembrolizumab, atezolizumab, nivolumab, avelumab, durvalumab) have been Food and Drug Administration and European Medicines Agency approved for 1st-line treatment or treatment following progression after platinum-based chemotherapy, because they produced prolongation of survival versus chemotherapy (2,3). More recently, the approval of avelumab maintenance therapy in patients with no progression on platinum-based chemotherapy (4) and of front-line chemotherapy/ICI combination gemcitabine/cisplatin/nivolumab (5) expanded the role of ICIs in 1st-line management of aUC. Nevertheless, not all patients benefit, with only about 20% of patients achieving long-term remission (6). Patients who do not respond to ICIs experience rapid progression of disease with obvious detrimental effects on prognosis and quality of life. Antibody-drug conjugates (ADCs) represent an effective option for these patients (7), while erdafitinib, a FGFR2/3 inhibitor can be used in the few patients with relevant alterations of this receptor (8). Further improvement in the prognosis of patients with aUC has also been achieved by the introduction of the ADC enfortumab vedotin with pembrolizumab as 1st-line treatment (9). In spite of these advances, still most patients with aUC will succumb to their disease. It is, therefore, important to develop more therapeutic options for these patients.

In a recent issue of Eur Urol Oncol, Msaouel et al. describe the efficacy and safety of a combination of an anti-PD-1 ICI, nivolumab with sitravatinib, a tyrosine kinase inhibitor (TKI) that targets TAM receptors (TYRO3, AXL, and MERTK) and vascular endothelial growth factor receptor 2 (VEGFR2) (10). Nivolumab is an effective agent in aUC and is approved both in 2nd line as well as adjuvant therapy after cystectomy for those patients with non-metastatic urothelial carcinoma, whose tumors highly express PD-L1 (11). The theoretical basis for this combination is the potential reversal of resistance to ICIs by using sitravatinib. TAM receptors reduce immune response in the tumor microenvironment (TME) by increasing immunosuppressive M2 macrophages, while regulatory T cells and myeloid-derived suppressor cells expand under the influence of VEGFR2-driven angiogenesis. Thus, inhibition of TAM receptors and VEGFR2 may restore the immune competence of TME and potentiate the effect of ICIs. The design of the study was realistic, since it included the whole therapeutic spectrum for patients with aUC, previously treated with platinum-based chemotherapy. Importantly, it also included patients previously treated with all approved agents, i.e., chemotherapy, ICIs and ADCs, a group with the highest need for effective options. Objective response rate (ORR) was the primary end point and 30% and 40% were chosen as indicators of efficacy in ICI refractory and ICI naïve cohorts, respectively.

In the paper by Msaouel et al. results were presented separately according to receipt of prior chemotherapy. In both cases, they fell short of the statistical hypotheses of the study. Among patients who received prior chemotherapy, ICI-pre-treated patients showed 14.9% ORR, while ICI-naïve 32.1%. Heavily pre-treated patients with chemotherapy, ICI and ADC showed a 5.4% ORR. Median progression-free survival (PFS) was similar across all groups (3.9, 3.9, and 3.7 months), while respective median overall survival (OS) was 8.6, 13.4 and 9 months. Among patients who did not receive prior chemotherapy, patients who had previously received ICI plus another IO (including but not limited to anti-CTLA-4, anti-OX40, or anti-CD137) or ADC (enfortumab vedotin or sacituzumab govitecan) showed no objective responses. On the contrary, ICI-naïve patients or patients who had received only one line of CPI showed ORRs of 33.3% and 21.7%, respectively. Importantly, complete response rates in these two groups were remarkable: 14.8% and 13%, respectively. Median PFS was 5.4 and 7.8 months, while respective median OS was not estimable and 15.6 months. Treatment-related adverse events (TRAEs) were effectively observed in 95.1% of patients, while more than 50% experienced at least one grade 3 TRAE. The percentages of patients who required dose reduction or interruption were also high: 132 (54.1%) and 187 (76.6%), respectively.

Based on these results, no further development of the combination in aUC is planned. In spite of the negative results of this study, there are certain findings, that are worth discussing. First, the study included “platinum-ineligible” patients. In fact, they comprised 28% of the study population. Platinum-ineligible patients, i.e., patients not eligible for either cisplatin or carboplatin-based chemotherapy, represent an ill-defined population, which has been established for regulatory purposes in the USA, but it is not widely accepted in Europe and is not included in European Society for Medical Oncology guidelines (12). The percentage of this group in this study is high, suggesting that overidentifying such patients may have occurred. On the other hand, however, the inclusion of this population provided important information for patients who receive ICI in 1st-line. These patients are invariably cisplatin-ineligible (a much more clearly defined population) and include those who would be treated in Europe according to the current label for 1st-line immunotherapy in aUC: cis-ineligible and PD-L1 highly expressing tumors. The combination showed promising efficacy in this population regardless of previous exposure to CPIs. Unfortunately, there was no analysis according to PD-L1 status.

Rechallenges with ICIs have not been adequately studied in aUC. In a retrospective study, 13% of patients showed objective responses (13), a result very similar to that reported in this series, suggesting that the combination does not seem to substantially increase efficacy, which appears generally poor for this strategy.

The modest efficacy of the combination studied by Msaouel et al. does not come as a surprise. VEGFR-TKIs have not been proven efficient in aUC. Although the theoretical background of the combination used in this study is intriguing, due to the inhibition of other receptors apart from VEGFR by sitravatinib, this study confirms previous modest efficacy for this class of agents (14) as well as other targeted agents (15). Nevertheless, the median OS of 9 months, which was reported in the group of patients who had previously received chemotherapy, ICIs and ADCs is noteworthy. There is currently no approved agent in this setting and further study of sitravatinib as monotherapy may be worthwhile.

The authors should be commented for performing exploratory correlative analyses. They used biomarkers (Simpson clonality, peripheral clonal expansion), which indicate the state of the adaptive immune system (16). The strength of these analyses is weak, due to the low number of samples analyzed. In concert with previous studies (16,17), there was a suggestion that responders had higher baseline Simpson clonality than non-responders, while their repertoire turnover was significantly lower. Nevertheless, there were no significant changes during treatment. These results are similar to those reported for other biomarkers in aUC (18-21): they show promise, but they are not ready for prime time yet. Most data on biomarkers come from retrospective studies, while their role can only be clarified by prospective randomized trials, with biomarkers built in the study design. Such studies are currently in progress (22) and hopefully will lead to a new era of precision medicine in aUC.

The introduction of ICIs to our armamentarium against aUC represents major progress in cancer therapy of the last decade. Their role will undoubtedly continue to evolve in the years to come. Attempts to improve their efficacy or reverse resistance, such as the one described in the paper of Msaouel et al., will be at the forefront of the efforts to improve the prognosis of patients suffering from this disease. Combining ICIs with other classes of agents (currently chemotherapy or ADCs has become the standard 1st-line treatment (4,9). The positive impact of the use of ADCs (enfortumab vedotin and sacituzumab govitecan), as salvage treatment after ICIs (7,23) has already been mentioned. Our knowledge regarding the mechanisms of resistance to ICIs is growing (24). Research in this area will lead to the development of novel drugs, which will prolong responses to therapy and hopefully will transform these long responses to long awaited cure for patients with aUC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-40/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-40/coif). R.Z. has received honoraria for presentations from IPSEN, JANSSEN, MERCK and support for attending meetings from ASTRAZENECA and IPSEN. A.B. reports research support from Astra Zeneca, BMS, Pfizer, Roche; honoraria for presentations at Congresses from BMS, MSD; and also served as an advisory board of Sensorion, MSD, Roche, BMS and member of the board of directors of Hellenic GU Cancer Group. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Bamias A, Tzannis K, Harshman LC, et al. Impact of contemporary patterns of chemotherapy utilization on survival in patients with advanced cancer of the urinary tract: a Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC). Ann Oncol 2018;29:361-9. [Crossref] [PubMed]
2. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer, Version 3. 2020.
3. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376:1015-26. [Crossref] [PubMed]
4. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020;383:1218-30. [Crossref] [PubMed]
5. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med 2023;389:1778-89. [Crossref] [PubMed]
6. Schmidt AL, Siefker-Radtke A, McConkey D, et al. Renal Cell and Urothelial Carcinoma: Biomarkers for New Treatments. Am Soc Clin Oncol Educ Book 2020;40:1-11. [Crossref] [PubMed]
7. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021;384:1125-35. [Crossref] [PubMed]
8. Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2023;389:1961-71. [Crossref] [PubMed]
9. Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 2024;390:875-88. [Crossref] [PubMed]
10. Msaouel P, Sweis RF, Bupathi M, et al. A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma. Eur Urol Oncol 2023; Epub ahead of print. [Crossref] [PubMed]
11. Opdivo: Summary of product characteristics. Available online: https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf (accessed April 7, 2024)
12. Powles T, Bellmunt J, Comperat E, et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol 2024;S0923-7534(24)00075-9.
13. Makrakis D, Bakaloudi DR, Talukder R, et al. Treatment Rechallenge With Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma. Clin Genitourin Cancer 2023;21:286-94. [Crossref] [PubMed]
14. Li XK, Wang WL. The role novel targeted agents in the treatment of previously treated patients with advanced urothelial carcinoma (UC): a meta-analysis. Eur Rev Med Pharmacol Sci 2018;22:5165-71. [PubMed]
15. Aragon-Ching JB, Trump DL. Targeted therapies in the treatment of urothelial cancers. Urol Oncol 2017;35:465-72. [Crossref] [PubMed]
16. Weir GM, Hrytsenko O, Quinton T, et al. Anti-PD-1 increases the clonality and activity of tumor infiltrating antigen specific T cells induced by a potent immune therapy consisting of vaccine and metronomic cyclophosphamide. J Immunother Cancer 2016;4:68. [Crossref] [PubMed]
17. Mahalingam D, Wilkinson GA, Eng KH, et al. Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study. Clin Cancer Res 2020;26:71-81. [Crossref] [PubMed]
18. Galsky MD, Guan X, Rishipathak D, et al. Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer. Cell Rep Med 2024;5:101393. [Crossref] [PubMed]
19. Kasi PM, Fehringer G, Taniguchi H, et al. Impact of Circulating Tumor DNA-Based Detection of Molecular Residual Disease on the Conduct and Design of Clinical Trials for Solid Tumors. JCO Precis Oncol 2022;6:e2100181. [Crossref] [PubMed]
20. Bellmunt J, de Wit R, Fradet Y, et al. Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials. Clin Cancer Res 2022;28:2050-60. [Crossref] [PubMed]
21. Rizzo A, Mollica V, Massari F. Expression of Programmed Cell Death Ligand 1 as a Predictive Biomarker in Metastatic Urothelial Carcinoma Patients Treated with First-line Immune Checkpoint Inhibitors Versus Chemotherapy: A Systematic Review and Meta-analysis. Eur Urol Focus 2022;8:152-9. [Crossref] [PubMed]
22. Jackson-Spence F, Toms C, O’Mahony LF, et al. IMvigor011: a study of adjuvant atezolizumab in patients with high-risk MIBC who are ctDNA+ post-surgery. Future Oncol 2023;19:509-15. [Crossref] [PubMed]
23. Tagawa ST, Balar AV, Petrylak DP, 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;39:2474-85. [Crossref] [PubMed]
24. Evans ST, Jani Y, Jansen CS, et al. Understanding and overcoming resistance to immunotherapy in genitourinary cancers. Cancer Biol Ther 2024;25:2342599. [Crossref] [PubMed]