The development and approval of new cancer therapies, including immunotherapy, such as the immune checkpoint inhibitors nivolumab and pembrolizumab, and targeted therapies, such as osimertinib and alectinib, during the past decade have led the modern era of cancer treatment to be referred to as the “golden age of oncology.”¹ In fact, despite the unanticipated obstacles brought on by the COVID-19 global pandemic, the US Food and Drug Administration (FDA) approved more new cancer medicines during 2020 than in the prior year.² These cancer drug approvals have justifiably provided much hope and optimism to patients and the physicians and health care professionals caring for patients with cancer after a drought of several decades without new drug approvals for several cancers.^3,4

Bladder cancer accounts for nearly 200,000 deaths worldwide yearly. Urothelial carcinoma (UC) accounts for nearly 90% of cases of bladder cancer. Cisplatin-based chemotherapy has remained the mainstay of treatment in the first-line setting for locally advanced or metastatic UC. More recently, the treatment paradigm in the second-line setting was drastically altered with the approval of several immune checkpoint inhibitors (ICIs). Given that only a small subset of patients respond to ICI, further studies have been undertaken to understand potential resistance mechanisms to ICI. One potential resistance mechanism that has been identified in the setting of metastatic UC is the TGF-β signaling pathway. Several pre-clinical and ongoing clinical trials in multiple advanced tumor types have evaluated several therapies that target the TGF-β pathway. In addition, there are ongoing and planned clinical trials combining TGF-β inhibition with ICI, which may provide a promising therapeutic approach for patients with advanced and metastatic UC.

Background: Due to encouraging pre‐clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin‐converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer.We sought to investigate the anti‐cancer effects of drugs repurposed from cardiology or anti‐inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG‐CoA reductase inhibitors (statins), cyclo‐oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin‐converting enzyme inhibitors. We also included non‐steroidal anti‐inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer.Methods: We performed a systematic literature review using PubMed and Web of Science with search terms including “aspirin,” “NSAID,” “statin” (including specific statin drug names), “metformin,” “ACE inhibitors,” and “ARBs” (including specific anti‐hypertensive drug names) in combination with “cancer.” Searches were limited to human studies published between 2000 and 2023.Main Outcomes and Measures: The number and percentage of studies reported positive results and pooled estimates of overall survival, progression‐free survival, response, and disease‐free survival.Results: We reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non‐small‐cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first‐line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression‐free survival (86.1% of studies testing progression‐free survival) or in overall survival (94.3% of studies testing overall survival). Progression‐free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression‐free survival was worse in one study (2.8% of studies testing progression‐free survival).Conclusions and Relevance: Despite promising pre‐clinical and population‐based data, cardiovascular drugs and anti‐inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.

Non-small cell lung cancer (NSCLC) is a leading cause of death, but over the past decade, there has been tremendous progress in the field with new targeted therapies. The mesenchymal–epithelial transition factor (MET) proto-oncogene has been implicated in multiple solid tumors, including NSCLC, and dysregulation in NSCLC from MET can present most notably as MET exon 14 skipping mutation and amplification. From this, MET tyrosine kinase inhibitors (TKIs) have been developed to treat this dysregulation despite challenges with efficacy and reliable biomarkers. Capmatinib is a Type Ib MET TKI first discovered in 2011 and was FDA approved in August 2022 for advanced NSCLC with MET exon 14 skipping mutation. In this narrative review, we discuss preclinical and early-phase studies that led to the GEOMETRY mono-1 study, which showed beneficial efficacy in MET exon 14 skipping mutations, leading to FDA approval of capmatinib along with Foundation One CDx assay as its companion diagnostic assay. Current and future directions of capmatinib are focused on improving the efficacy, overcoming the resistance of capmatinib, and finding approaches for new indications of capmatinib such as acquired MET amplification from epidermal growth factor receptor (EGFR) TKI resistance. Clinical trials now involve combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy. Furthermore, new drug agents, particularly antibody–drug conjugates, are being developed to help treat patients with acquired resistance from capmatinib and other TKIs.

The treatment of metastatic urothelial carcinoma has dramatically changed over the past decade with the approval of several therapies from multiple drug classes including immune checkpoint inhibitors, targeted therapies, and antibody drug conjugates. Although next generation sequencing of urothelial carcinoma has revealed multiple recurring mutations, only one targeted therapy has been developed and approved to date. Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor, has been approved for treating patients with select FGFR2 and FGFR3 alterations and fusions since 2019. Since then, emerging data has demonstrated efficacy of combining erdafitinib with immunotherapy in treating FGFR-altered urothelial carcinoma. Ongoing trials are evaluating the use of erdafitinib in non-muscle invasive urothelial carcinoma as well as in combination with enfortumab vedotin in the metastatic setting, while other FGFR targeted agents such as infigratinib, AZD4547, rogaratinib and pemigatinib continue to be in development. Future challenges will include strategies to overcome FGFR acquired resistance and efficacy and safety of combination therapies with erdafitinib and other FGFR targeted agents.