Metastatic urothelial carcinoma

Discovery-driven research and clinical research have worked together to change the outcomes of many cancer patients. We choose urothelial carcinoma as an example to showcase how recent diagnostic and therapeutic innovations have re-shaped cancer clinical practice. Discovery-driven research and clinical research have worked together to change the outcomes of many cancer patients. We choose urothelial carcinoma as an example to showcase how recent diagnostic and therapeutic innovations have re-shaped cancer clinical practice. Compared to molecular features of non-muscle-invasive bladder cancer (NMIBC), those of metastatic tumors appear dauntingly complex. Many NMIBCs show limited copy number alterations and have clear mutated oncogenic drivers (e.g., FGFR3, PIK3CA) and a small repertoire of inactivated tumor suppressors. This contrasts dramatically with what we know of metastatic bladder cancer, where it can be difficult to identify critical drivers, highly complex branching evolution can be traced, many “private” mutations are present, and diversity between metastatic sites indicates ongoing independent evolution. In addition to genomic heterogeneity, there is also evidence of transcriptional heterogeneity and phenotypic plasticity within individual tumors. The features of metastatic tumors reflect the mutagenic and/or selective effects of therapies, that can be strongly influenced by distinct microenvironments at distant sites, and may no longer share therapeutic vulnerabilities with the primary tumor. The theoretical construct of two distinct genomic evolutionary pathways to NMIBC or muscle-invasive bladder cancer (MIBC) has long provided a framework within which to build knowledge. However, this can no longer accommodate all clinical observations or the complex molecular picture that has emerged. Not only solid MIBCs but also some papillary NMIBCs can become metastatic, indicating multiple evolutionary trajectories to metastasis. How to make progress in the face of such complexity? To understand the evolution and potential vulnerabilities of metastases at different sites, investment in analysis of related lesions over time from large numbers of patients will be key. Given the uniquely high frequency of chromatin modifier gene mutations in bladder cancer, it is predicted that epigenome analysis will pay important dividends in this tumor type. Significant progress has been made in our understanding of the biological framework, mutational and transcriptomic landscapes, tumor microenvironment, and molecular subtypes in urothelial carcinoma. However, it is surprising how limited the impact that our research has on clinical practice still is. One of the largest obstacles toward identifying robust biomarkers is the high degree of inter- and intra-tumor heterogeneity. We know that metastatic urothelial carcinoma shares genomic alterations with primary tumors, but large differences exist—also between different metastatic sites. This makes it challenging to use primary tumors as a proxy for determining the response of immunotherapy and chemotherapy, which are targeted toward the metastatic counterparts. Moving forward, we should focus on a combined approach where we delineate the biological framework of the primary tumor and simultaneously identify the biology of metastasized tumor cells directly from biopsies, or from analysis of blood samples (i.e., liquid biopsies). The liquid biopsy research in recent years has documented that blood-based analysis may reveal if the tumor has already metastasized at time of surgery, determine the level of metastatic tumor burden, and identify novel therapeutic targets. Importantly, longitudinal blood sampling through therapy may also be applied to monitor treatment efficacy and consequently to help informing treatment decisions. In my opinion, we are now at a point where our previous efforts should pave the way for next-generation clinical trials; tumor-centric and blood-based biomarker analysis should be included to monitor drug efficacy in biological context and ultimately used to guide treatment decisions. Until this past decade, there have been limited treatment options for patients with urothelial carcinoma, despite it being a major global health challenge. Immunotherapy, targeted inhibitors, and antibody-drug conjugates are welcome additions to the long-standing, predominantly chemotherapy-based armamentarium of treatments for metastatic disease. Enfortumab vedotin (EV), an antibody-drug conjugate targeting nectin-4, was approved in 2019 for the treatment of locally advanced and metastatic urothelial carcinoma. Additional testing for nectin-4 overexpression is not required before therapy, as it is known to be highly expressed in urothelial carcinomas. In pre-clinical studies, nectin-4 is significantly enriched in luminal subtypes of bladder cancer, and downregulation of nectin-4 may lead to resistance to EV. Identifying mechanisms of resistance remains important, especially as combination strategies are being evaluated in clinical trials. EV in combination with pembrolizumab was reported to have a high objective response rate of 73% and a disease control rate of 93% in cisplatin-ineligible patients as front-line therapy. These promising results may ultimately change the treatment landscape of metastatic urothelial carcinoma. However, clinicians need to pay attention to the rapidly evolving treatment options. A personalized plan according to the patient’s fitness to chemotherapy or specific FGFR mutation target therapy is a part of the new treatment paradigm. Moreover, early recognition of EV’s unique toxicities, including cutaneous adverse reactions as well as ocular abnormalities, is critical in successfully managing symptoms. Being prepared and informed on EV’s dose modifications and interruptions will ultimately result in improved patient care. After decades of paucity in effective therapeutics, the research of urothelial carcinoma (UC) biology and the development of immune checkpoint blockade (ICB) therapies have finally provided some effective treatments for our patients. Targeted therapies against FGFR or Nectin-4 are choices to be combined with ICB therapies or chemotherapies. The jury is still out for combined regimens, yet the approval of ICB therapy for UC monotherapy has not gone smoothly. While pembrolizumab showed level 1 evidence, atezolizumab and durvalumab indication was withdrawn for second-line therapy after several failed trials, dampening the initial enthusiasm from phase 1 and 2 trial positive results. Single-arm ICB therapy trials in the neoadjuvant space have shown some promises; however, controversy occurred in the adjuvant setting, where two trials with similar designs showed completely different outcomes (IMvigor010 and CheckMate 247). Fortunately, a second wave of hope came in the switch maintenance space after first-line chemotherapy, where avelumab plus best supportive care significantly prolonged overall survival among patients who had not progressed. More questions need to be answered: (1) What differs among the therapy regimens approved by the FDA? Are PD1/PD-L1 inhibitors really the same for patients with UC? (2) Chemo + ICB regiments don’t seem to work—will precision oncology help us refine the application scenarios? (3) Will there be a next therapy target as successful as FGFR? Finally, the hope is now on the use of antibody-drug conjugates to be combined with ICB. Clinical trials are exploring this approach in first- and second-line therapies. When I first began working over 20 years ago in the field of urothelial cancer, the initial excitement from the advent of cisplatin-based chemotherapy had subsided to a miasma of depression on the lack of progress beyond the therapeutic plateau first achieved with MVAC in 1986. Despite applying the serial alchemy of alphabet-soup chemotherapy combinations, from MVAC to CISCA, ITP, IAGem, GC, and GTP, we ultimately circled back to DDMVAC with the main benefit of reduced toxicity compared to MVAC. In a desperate bid to invoke immune responses that we had observed anecdotally as a means of impacting disease control, we even combined α-interferon with 5-FU and cisplatin and found evidence of clinical activity but increased toxicity. Our excitement has now returned beginning with the new class of agents, the checkpoint inhibitors. There are durable responses, albeit in small numbers of patients. My “Patient Number One,” the first patient I personally enrolled on combination checkpoint inhibition, remains alive and has been cancer-free for more than 7 years despite having been diagnosed with incurable cancer! We are building upon our understanding of mechanisms of response and resistance through combinations of newly approved targeted agents, including erdafitinib, antibody-drug conjugates like enfortumab vedotin, and promising early results of other combinations including lymphocyte proliferators like bempegaldesleukin, HER-2 targeting agents, and others that may enhance the immune response. Bladder cancer is no longer just one disease! The framework we are now developing will target each patient’s cancer to apply optimal combinations and sequences, extending the lives of all our patients.