Novel Tyrosine Kinase Targets in Urothelial Carcinoma.

Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.

Tyrosine Kinase Receptors in Oncology.

Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments.

Among the most common molecular alterations detected in non-small-cell lung cancer (NSCLC) are mutations in Kristen Rat Sarcoma viral oncogene homolog (KRAS). KRAS mutant NSCLC is a heterogenous group of diseases, different from other oncogene-driven tumors in terms of biology and response to therapies. Despite efforts to develop drugs aimed at inhibiting KRAS or its signaling pathways, KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region of KRASG12C has revolutionized the treatment of KRASG12C-mutated NSCLC patients. Sotorasib and adagrasib, direct KRASG12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treated KRASG12C-mutated NSCLC, and these advances have become practice changing. However, first-line treatment in KRASG12C-mutated NSCLC does not differ from NSCLC without actionable driver genomic alterations. Treatment with KRASG12C inhibitors is not curative and patients develop progressive disease, so understanding associated mechanisms of drug resistance is key. New KRASG12C inhibitors and several combination therapy strategies, including with immune checkpoint inhibitors, are being studied in clinical trials. The aim of this review is to explore the clinical impact of KRAS, and outline different treatment approaches, focusing on the novel treatment of KRASG12C-mutated NSCLC.

Current and Future Landscape of Perioperative Treatment for Muscle-Invasive Bladder Cancer.

Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the current standard of care for muscle-invasive bladder cancer (MIBC). However, less than half of patients are candidates for this treatment, and 50% will develop metastatic disease. Adjuvant chemotherapy could be offered if neoadjuvant treatment has not been administered for suitable patients. It is important to reduce the risk of systemic recurrence and improve the prognosis of localized MIBC. Systemic therapy for metastatic urothelial carcinoma has evolved in recent years. Immune checkpoint inhibitors and targeted agents, such as antibody-drug conjugates or FGFR inhibitors, are new therapeutic alternatives and have shown their benefit in advanced disease. Currently, several clinical trials are investigating the role of these drugs, as monotherapy and in combination with chemotherapy, in the neoadjuvant and adjuvant settings with promising outcomes. In addition, the development of predictive biomarkers could predict responses to neoadjuvant therapies.

Meta-analysis of perioperative immunotherapy in renal cell carcinoma: Available, but the jury is still out.

INTRODUCTION: While surgical management of renal cell carcinoma (RCC) is curative for many patients, others may relapse and could benefit from adjuvant treatments. Immune checkpoint inhibitors (ICI) have been proposed as a potential adjuvant therapy for improving survival in these patients, but the benefit/risk ratio of ICI in the perioperative setting remains unclear. METHODS: A systematic review and a meta-analysis of phase III trials of perioperative ICI (anti PD1/PD-L1 alone or in combination with anti-CTLA4 agents) in RCC was conducted. RESULTS: The analysis included results from 4 phase III trials, comprising 3,407 patients. ICI did not show a significant increase in disease-free survival (Hazard Ratio [HR] 0.85; 95% confidence interval [CI] 0.69-1.04; p: 0.11) or overall survival [OS] (HR 0.73; 95% CI 0.40-1.34; p: 0.31). High-grade adverse events were more frequent in the immunotherapy arm (OR 2.65; 95% CI 1.53-4.59; p: <0.001), and high-grade treatment-related adverse events were 8 times more frequent in the experimental arm (OR: 8.07; 95% CI: 3.14-20.75; p: <0.001). Subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR: 0.71; 95 CI 0.55-0.92; p: 0.009), in sarcomatoid differentiation (HR: 0.60 95% CI 0.41-0.89; p: 0.01), and PD-L1 positive tumors (HR HR: 0.74; 95% CI 0.61-0.90; p: 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs. M0 patients). CONCLUSION: Our comprehensive meta-analysis generally suggests that immunotherapy does not confer a survival advantage in the perioperative setting for RCC, with the exception of one positive study. While the overall results are not statistically significant, individual patient factors and other variables may play a role in determining who benefits from immunotherapy. Therefore, despite the mixed findings, immunotherapy may still be a viable treatment option for certain patients, and further studies are needed to determine which patient subgroups would be most likely to benefit.

Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma.

Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.

Precision Medicine in Metastatic Colorectal Cancer: Targeting ERBB2 (HER-2) Oncogene.

Colorectal cancer (CRC) is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. The treatment of metastatic CRC (mCRC) is based on the use of chemotherapy, anti-vascular endothelial growth factor (VEGF), and anti-epidermal growth factor receptor (EGFR) for RAS wild-type tumors. Precision medicine tries to identify molecular alterations that could be treated with targeted therapies. ERBB2 amplification (also known as HER-2) has been identified in 2-3% of patients with mCRC, but there are currently no approved ERBB2-targeted therapies for mCRC. The purpose of this review is to describe the molecular structure of ERBB2, clinical features of these patients, diagnosis of ERBB2 alterations, and the most relevant clinical trials with ERBB2-targeted therapies in mCRC.

Local Treatments in the Unresectable Patient with Colorectal Cancer Metastasis: A Review from the Point of View of the Medical Oncologist.

For patients with isolated liver metastases from colorectal cancer who are not candidates for potentially curative resections, non-surgical local treatments may be useful. Non-surgical local treatments are classified according to how the treatment is administered. Local treatments are applied directly on hepatic parenchyma, such as radiofrequency, microwave hyperthermia and cryotherapy. Locoregional therapies are delivered through the hepatic artery, such as chemoinfusion, chemoembolization or selective internal radiation with Yttrium 90 radioembolization. The purpose of this review is to describe the different interventional therapies that are available for these patients in routine clinical practice, the most important clinical trials that have tried to demonstrate the effectiveness of each therapy and recommendations from principal medical oncologic societies.