Paulo Gustavo Bergerot

Tivozanib: Current status and future directions in the treatment of solid tumors

Introduction: Tivozanib is a novel tyrosine kinase inhibitor (TKI) which inhibits vascular endothelial growth factor (VEGF) receptors-1, -2, and -3 at nanomolar concentrations. Areas covered: A comprehensive MEDLINE and American Society of Clinical Oncology abstract search was performed to gather all relevant clinical and translational data related to tivozanib. We discuss pre-clinical studies associated with tivozanib, and the results of a Phase I assessment in advanced solid tumors. We highlight combination studies with tivozanib, including pairings of tivozanib with cytotoxic therapy in patients with colorectal cancer and breast cancer. A randomized discontinuation Phase II study and a randomized Phase III study assessing the activity of tivozanib in metastatic renal cell carcinoma (mRCC) are described in detail. Expert opinion: Tivozanib will face the challenge of entering an already crowded therapeutic space in mRCC—emerging combination studies and biomarker assessments may distinguish this agent among other VEGF-TKIs. The current review will outline the development pathway of tivozanib to date, and offer lessons learned and future opportunities.

Preoperative therapy for localized prostate cancer: A comprehensive overview

At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, two studies of preoperative systemic therapy for localized prostate cancer garnered significant attention. In the first, investigators evaluated various permutations of conventional hormonal therapies prior to prostatectomy, with detailed biomarker studies focused on tissue androgens. In the second, investigators assessed the novel CYP17 lyase inhibitor abiraterone prior to prostatectomy. Both studies provide a wealth of biological information, but the question remains - will preoperative systemic therapy ultimately be incorporated into clinical algorithms for prostate cancer? Herein, the existing literature for both preoperative hormonal and chemotherapeutic approaches is reviewed. We performed a MEDLINE search of published prospective and retrospective clinical studies assessing preoperative systemic therapy for prostate cancer from 1982 onwards, revealing a total of 75 publications meeting these criteria. Of these, 55 possessed a number of patients (i.e., greater than 10) deemed worth of the current analysis. Beyond outlining these datasets, we discuss the relevance of clinical and pathologic endpoints in assessing preoperative therapy.

The Role of Circulating Tumor DNA in Renal Cell Carcinoma

Opinion statementNext-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a novel technology that can complement tumor tissue NGS and has the potential to influence diagnosis and treatment of both localized and metastatic renal cell carcinoma (mRCC). ctDNA NGS is an attractive alternative to tumor tissue NGS because it circumvents the need for repeated, invasive tissue biopsies while providing a contemporary mutational profile of a patient’s tumors. While the role of ctDNA NGS in non-small cell lung cancer and colorectal cancer is well established, studies of ctDNA NGS in mRCC are only hypothesis-generating to date. In the localized RCC setting, ctDNA has demonstrated potential as a surveillance biomarker for disease recurrence. Earlier detection of mRCC, prior to the onset of symptoms, may lead to improved clinical outcomes. NGS of ctDNA in mRCC is even more promising in patients with metastatic disease. The majority of patients with mRCC have detectable ctDNA. Thus, ctDNA could be used to select patients for biomarker-guided clinical trials, such as savolitinib in MET-positive papillary RCC. Furthermore, studies have shown that the mutational profile of mRCC in ctDNA evolves after treatment progression. The most exciting potential role for ctDNA in mRCC is as a predictive biomarker for response to immunotherapy. Studies have shown that tumor mutational burden (TMB) is predictive of response to immune checkpoint inhibitors, and hypermutated ctDNA can act as a surrogate biomarker for TMB and response to immunotherapy. While studies of ctDNA in RCC are still in their infancy, there are many promising roles for ctDNA in localized and metastatic RCC.

Association of Circulating Tumor DNA (ctDNA) Detection in Metastatic Renal Cell Carcinoma (mRCC) with Tumor Burden

Background: In a series of 224 patients with advanced renal cell carcinoma (RCC), we have previously reported circulating tumor DNA (ctDNA) detection in 79% of patients. Clinical factors associated with detection are unknown. Methods: Data was obtained from patients with radiographically confirmed stage IV RCC who received ctDNA profiling as a part of routine clinical care using a CLIA-certified platform evaluating 73 genes. Detailed clinical annotation was performed, including assessment of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, previous and current treatments and calculation of tumor burden using scan data most proximal to ctDNA assessment. Tumor burden was equated to the sum of longest diameter (SLD) of all measurable lesions. Results: Thirty-four patients were assessed (18 male and 16 female) with a median age of 62 (range, 34–84). Twenty-six patients, 4 patients and 4 patients had clear cell, sarcomatoid and papillary histologies, respectively. IMDC risk was good, intermediate and poor in 14, 19 and 1 patient, respectively. ctDNA was detected in 18 patients (53%) with a median of 2 genomic alterations (GAs) per patient. No associations were found between IMDC risk, histology or treatment type and presence/absence of ctDNA. However, patients with detectable ctDNA had a higher SLD compared to patients with no detectable ctDNA (8.81 vs 4.49 cm; P = 0.04). Furthermore, when evaluated as a continuous variable, number of GAs was correlated with SLD (P = 0.01). Conclusions: With the caveat of a limited sample size, it appears that SLD (a surrogate for tumor burden) is higher in mRCC patients with detectable ctDNA. Confirmation of these findings in larger series is ongoing and may suggest a capability for ctDNA to either complement or supplant radiographic assessment.

Exceptional Response to Nivolumab Rechallenge in Metastatic Renal Cell Carcinoma with Parallel Changes in Genomic Profile

A 44-yr-old man was noted to have headaches, and computerized tomography imaging of the brain revealed a 1.6-cm frontal lesion. Complete staging revealed a 7.5-cm left-sided renal mass and extensive retroperitoneal adenopathy. The patient received a craniotomy and nephrectomy, with pathology from both procedures revealing clear cell renal cell carcinoma (RCC). The patient received high-dose interleukin-2 approximately 1 mo thereafter (Fig. 1), but progressed within a span of 2 mo. He then received pazopanib, which stabilized his disease for approximately 5 mo. The patient then received bevacizumab monotherapy but progressed within 2 mo. He then received nivolumab/ ipilimumab in a phase 1 clinical trial with a marked radiographic response in retroperitoneal nodes with no new findings on neuroimaging [1]. However, he developed grade 3 hepatoxicity requiring cessation of immunotherapy and initiation of chronic steroids, ultimately tapered after 6 mo. In the intervening period, while off of systemic therapy, the patient developed 14 new brain metastases which were treated with stereotactic radiosurgery. Eighteen months after initial receipt of nivolumab/ ipilimumab, the patient developed further systemic progression and was rechallenged with bevacizumab. He progressed on bevacizumab monotherapy after 4 mo and then received bevacizumab in combination with trebananib [2]. He progressed on this regimen within 4 mo and then received radiation to retroperitoneal lymph nodes. After 8 mo, the patient developed further progression and was started on an investigational antibody drug conjugate. The patient had relatively rapid progression on this with new brain metastases. After craniotomy and stereotactic radiosurgery to these new lesions, the patient was started on cabozantinib. While he had some stabilization of disease with cabozantinib, his disease ultimately progressed after 11 mo. He was then rechallenged with nivolumab and once again developed grade 3 hepatoxicity after just two doses. Nivolumab was discontinued. However, after 3 mo, the

Renal cell carcinoma: An update for the practicing urologist

Systemic therapy for metastatic renal cell carcinoma (mRCC) has evolved drastically, with agents targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) now representing a standard of care. The present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing. (1) Though observation remains a standard of care following resection of localized disease, multiple trials are underway to assess VEGF- and mTOR-directed therapies in this setting. (2) While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents, prospective data to support this approach is still forthcoming. (3) The first-line management of mRCC may change substantially with multiple studies exploring vaccines, immune checkpoint inhibitors, and novel targeted agents currently underway. In general, prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive nephrectomy. Over the same span of time, the current treatment paradigm for first-line therapy may evolve.

Sarcomatoid renal cell carcinoma: The apple doesn't fall far from the tree

The most comprehensive sequencing effort of sarcomatoid renal cell carcinoma (sRCC) to date reinforces the notion that the sarcomatoid component is closely related to the epithelial component of the cancer. This work also challenges the notion that sRCC evolves from low-grade RCC and identifies potential mediators of sarcomatoid differentiation. Clin Cancer Res; 23(21); 6381–3. ©2017 AACR. See related article by Wang et al., p. 6686

Case Discussion: Systemic Therapy for Metastatic Renal Cell Carcinoma

First-line systemic therapy for patients with metastatic renal cell carcinoma should largely entail the use of targeted agents. Depending on the clinical factors, VEGF- or mTOR-directed agents may be appropriate.

Assessment of distress and quality of life in rare cancers

Rare cancers are a heterogeneous group of conditions that can be associated with emotional and physical impairments. In view of the dearth of research in this area, we investigated the quality of life and prevalence of distress in a cohort of patients diagnosed with a rare cancer, classified by the RARECARE definition.

Advances in the Treatment of Metastatic Renal Cell Carcinoma

The treatment landscape for metastatic renal cell carcinoma has constantly been in flux. In 2005, with the advent of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy, the standard of care shifted to agents such as sunitinib and pazopanib. However, more recently there have been datasets, suggesting that next-generation TKIs such as cabozantinib may play an important role in therapy. Furthermore, immunotherapy has had resurgence with the FDA approval of nivolumab with ipilimumab. In the current chapter, we attempt to contextualize available frontline therapies for metastatic renal cell carcinoma with a focus on the CABOSUN and CheckMate 214 clinical trials.