Genomic Instability in Kidney Cancer: Etiologies and Treatment Opportunities

Genomic instability is a hallmark of cancer, allowing for cancer initiation, proliferation, and progression through the accumulation of driver mutations. This instability seen in cancer arises due to a variety of factors in the cancer cell itself as well as in the cell’s environment, including endogenous and exogenous stressors leading to DNA damage in the setting of deficiency in DNA damage response (DDR). While genomic instability is beneficial to cancer cell growth and survival, it also creates targetable vulnerabilities in the cell. Kidney cancer displays low to moderate genomic instability, yet does not have frequent mutations in canonical DDR genes and is not typically responsive to DNA damaging therapies. In this review, the etiology of genomic instability in kidney cancer, with a primary focus on clear cell renal cell carcinoma (ccRCC) histology, is discussed; and, pre-clinical data supporting the use of agents targeting DDR in ccRCC is summarized with associated progress towards clinical applications.

A Review of Papillary Renal Cell Carcinoma and MET Inhibitors

Papillary renal cell carcinoma (PRCC) is a subtype of renal cell carcinoma (RCC) accounting for approximately 15–20% of cases and further divided into Type 1 and Type 2. Type 1 PRCC tends to have more alterations in the MET tyrosine kinase receptor than Type 2 PRCC. Treatment for RCC patients is based on studies with minimal participation from patients with PRCC; consequently, conventional therapies tend to be less effective for RCC patients with a subtype other than ccRCC (non-ccRCC). Since MET is a known alteration in PRCC, it is potential target for directed therapy. There have been many attempts to develop MET inhibitors for use in solid tumors including PRCC. The following review will discuss the current research regarding MET-targeted therapy, MET inhibitors in clinical trials, and future directions for MET inhibitors in PRCC.

Double Immune Checkpoint Blockade in Renal Cell Carcinoma

Long considered an immunogenic tumour, immunotherapy has been the cornerstone of systemic treatment in renal cell carcinoma (RCC) for decades, since the introduction of interleukin 2 and interferon-alfa in the 1980s to the more recently approved immune checkpoint inhibitors. Moreover, on the basis that anti-CTLA-4 and anti-PD-1/PD-L1 intrinsic mechanisms are different, double checkpoint inhibition was proposed to further improve anti-tumor immune response. The first trial to assess double checkpoint inhibition was Checkmate 016 (nivolumab and ipilimumab). It showed acceptable safety and promising antitumor activity that led to the first phase III trial with combination immunotherapy in RCC, Checkmate 214. This trial showed superior overall survival and response rate of the combination immunotherapy (nivolumab and ipilimumab) versus sunitinib in intermediate- and poor-risk advanced RCC, leading to its approval in this setting. Despite these advances, there is still room for improvement. In this context, cytokines and T-cell costimulatory molecules are currently under investigation. This review summarizes the principles of immunotherapy and its role in RCC, provides an update on double checkpoint blockade and discusses the major challenges with double checkpoint blockade.

Targeted Therapies Following First-Line Immune Checkpoint Inhibitor Combination in Metastatic Renal Cell Carcinoma: A Single Center Experience

 Background: Both late and early phase immune checkpoint inhibitor (CPI) combination trials indicate an impending role of combinations in the first-line treatment of metastatic renal cell carcinoma (mRCC). Sequencing the options following failure of CPI combinations is an emerging conundrum. Objective: To present our single-center clinical experience with targeted therapies (TT) following first-line CPI combinations. Methods: mRCC patients who received TT following failure of a combination regimen with CPI were identified from an institutional database. Clinical information including tumor characteristics, survival outcomes, and adverse events was retrieved from medical records. Descriptive statistics and Kaplan-Meier survival functions were performed. Results: Of 11 patients identified, median age was 63 (31–79) and 8 (73%) patients were male. First-line treatment was a CPI and TT combination in 7 (64%) patients while the rest received combination of two CPIs. The majority of patients (82%) were intermediate risk category at the initiation of targeted therapies. TTs utilized included cabozantinib (46%), lenvatinib and everolimus (27%), sunitinib (18%), and temsirolimus (9%). Best response was stable disease for 10 (91%) and partial response for 1 (9%) patient. In a median follow up of 9.1 months (range, 4.9–34.1), median progression free survival was 7.7 (95% CI 4.6–10.8) months. Progression has occurred in 7 patients, and 3 patients remain on treatment. One patient discontinued treatment due to toxicity. Conclusions: In our report, TTs demonstrate effective disease control and safety. Further exploration in prospective setting is warranted.

Collecting Duct Carcinoma of the Kidney: Analysis of Our Experience at the SPANISH ‘Grupo Centro’ of Genitourinary Tumors

Introduction: Collecting duct carcinomas (CDC), also known as Bellini’s tumors, are a rare and aggressive subtype of renal cell carcinoma. Therefore, there are very few data about their management, and there is no standard therapy for this malignancy. We report the outcome of CDC patients treated on institutions belonging to the ‘Grupo Centro’ of Genitourinary Tumors, a novel networking cooperative group in Spain. Material and Methods: Patients with CDC diagnosed between 1995 and 2015 were included. They had to have an appropriate follow-up, as well as available tissue for further correlative studies. Demographic baseline features and therapy outcomes were collected in a retrospective fashion. Approval for this data collection was obtained from a central ethical committee. Results: A total of 43 patients were analysed, with a median overall survival (OS) of 14 months (95% CI: 9.2–18.8 months). 29 of them (67.4%) were diagnosed as localized disease, and 14 (32.6%) as metastatic disease. For the subgroup of patients diagnosed without metastases, median relapse-free survival (RFS) is 22 months (95% CI: 12.4–35.6 months), and median OS, 53 months (95% CI: 35.5–84.3 months). For the subgroup of patients with metastatic disease, median OS is 6 months (95% CI: 4.1–7.8 months). 16 patients (55.2%) with stage IV disease received systemic therapy, mainly platinum-based chemotherapy, with a response rate of 12.5% and a median progression-free survival (PFS) of 2 months. Conclusions: CDC of the kidney is a malignancy with poor prognosis and few responses to therapy. Median OS of our group in the metastatic setting is similar to what has been observed in previous series. There is a clear need to improve the armamentarium we have for the systemic approach of patients with advanced CDC.

Current Trends in Partial Nephrectomy After Guideline Release: Health Disparity for Small Renal Mass

Background: Renal masses can be surgically treated by partial nephrectomy (PN) or radical nephrectomy (RN); however, in 2009 guidelines recommended PN as the standard of care for cT1a renal masses. Objective: To evaluate national trends of surgically appropriate patients using the National Cancer Database (NCDB) for utilization of PN focusing on guideline release, evaluating underlying health disparity. Methods: We identified 99,035 patients from 2004–2015 that underwent surgical resection of cT1a renal masses. We evaluated treatment proportions over time of patients treated with PN or RN. Logistic regression was utilized for multivariable analysis. Results: PN increased from 40.2% in 2004 to 71.3% in 2015 (p  < 0.001). Older patients were more likely to be treated with RN (OR 1.018, p  < 0.001), as were those with Charlson score 2 or 3+ (OR 1.288 and 2.074, p  < 0.001). Patients with lower income were more likely to be treated with RN (OR 1.186, p  < 0.001) as were uninsured patients (OR 1.108, p  = 0.018) and low volume centers (OR 1.063, p  < 0.001). Females were more likely to undergo RN (OR 1.123, p  < 0.001) as were black patients (OR 1.339, p  < 0.001). While these demographic trends persisted after the release of the guidelines, all associations decreased except for Charlson score and race. Black patients became more likely to undergo RN (pre-guideline OR 1.248 vs post-guideline OR 1.474, p  < 0.001). Patients treated with RN had worsened mortality (17.4% vs. 7.3%, p  < 0.001). Conclusions: Although use of PN in surgically appropriate patients for cT1a renal masses has increased over time, 30% of patients underwent RN in 2015. Socioeconomic disparities affect treatment decisions and require additional research.

Evolving Epidemiologic Trends of Renal Cell Cancer by Histologic Subtype: An Updated Analysis of the California Cancer Registry

Background: While most renal cell carcinomas (RCC) are of the clear cell subtype, other histologic subtypes are well described and have distinct clinical behavior. This study seeks to evaluate survival of clear and non-clear cell RCC retrospectively from a large, population-based cancer registry. Objectives: The key objectives of this study were to determine cancer-specific survival (CSS) and overall survival (OS) of RCC by histologic subtype and to examine survival by histologic subtype since the advent of anti-angiogenesis therapy in 2006. Methods: Within the California Cancer Registry (CCR), we used multivariable Cox proportional hazards models to assess the association of histologic subtype with CSS and OS, adjusted for sociodemographic and clinical factors. Results: In the CCR, 33,539 RCC patients were diagnosed between 2004 and 2014. The most common subtype, clear cell RCC, comprised 82.6% (n  = 27,717) of cases. The next most common subtypes were papillary (8.8%, 2,948) and chromophobe (5.2%, 1,759). RCC was more common in men (62.9%, 21,097) compared to women (37.1%, 12,442). Across histologic subtypes, patients with low neighborhood socioeconomic status had lower CSS (HR = 1.07, 95% CI 1.02–1.13, p  = 0.011) and OS (HR = 1.14, 95% CI: 1.10–1.19, p  < 0.001). On multivariate analysis, we observed an interaction between histologic subtype and CSS, finding that patients in the anti-angiogenesis treatment era with clear cell had a significant improvement in CSS (HR: 0.87, 95% CI: 0.82–0.92, p  < 0.001) as did patients with collecting duct subtype (HR: 0.25, 95% CI: 0.12–0.51, p  < 0.001), while there were no differences in outcomes over time among patients with chromophobe or papillary subtypes. After 2006, compared to clear cell subtype, patients with chromophobe subtype had a better CSS (HR = 0.40, 95% CI: 0.30–0.53, p  < 0.001), while those with collecting duct carcinomas had a poorer CSS (HR = 1.83, 95% CI: 1.29–2.59, p  = 0.001). Conclusions: In the era following anti-angiogenesis therapy development, patients with chromophobe subtype RCC continue to have a better prognosis compared with clear cell RCC, and patients with collecting duct subtype continue to have a significantly worse prognosis, with more advanced disease at diagnosis. There have been improvements in CSS in patients with clear cell and collecting duct subtypes since the advent of anti-angiogenesis therapy.

Clinical Trials Corner

PD-Inhibitor (Nivolumab) and Ipilimumab Followed by Nivolumab vs. VEGF TKI Cabozantinib With Nivolumab: A Phase III Trial in Metastatic Untreated Renal Cell Cancer [PDIGREE]

Status: Recruiting identifier: NCT03793166
Sponsor: National Cancer Institute (NCI)
Enrollment: 1046

Rationale: Based on the results of the CheckMate-214 trial, an overall survival (OS) advantage has been observed in patients with newly diagnosed metastatic RCC with intermediate- to poor-risk disease by International Metastatic RCC Database Consortium (IMDC) criteria when treated with nivolumab and ipilimumab as compared to sunitinib (OS not reached versus 26.0 months; hazard ratio (HR)= 0.63; p<0.001). The objective response rate (ORR) for the combination was 42%. Patients receiving nivolumab and ipilimumab receive 4 treatments with ipilimumab, after which, as long as there is no evidence of progressive disease (PD), they continue to receive nivolumab. Both the JAVELIN Renal 101 and KEYNOTE 426 trials demonstrated an advantage to combining a checkpoint inhibitor with axitinib as compared to treatment with sunitinib alone in Phase 3 trials, with some suggestion that ORR was higher with these combinations. An ongoing Phase 3 trial (CheckMate 9ER) is evaluating the combination of nivolumab plus cabozantinib versus sunitinib in patients with mRCC. It is unclear, after combination immune checkpoint inhibition, whether the combination of immune checkpoint inhibitor therapy and TKI is of benefit.

Study Design: This Phase 3 study enrolls patients with newly diagnosed IMDC intermediate or poor risk advanced or metastatic RCC, who have not previously received any systemic therapy for RCC, who have histologically confirmed predominantly clear cell subtype RCC; patients with clear cell disease with sarcomatoid features are also included. Patients will be randomized to two arms. In both arms, patients will be treated with induction immune checkpoint inhibitor therapy, involving nivolumab and ipilimumab every 21 days. In Arm A, after induction therapy, if there is evidence of PD, patients will be treated with cabozantinib continuously; all other patients will continue on nivolumab treatment every 28 days until progression or unacceptable toxicity. In Arm B, after induction therapy, patients who have PD will be treated cabozanitinib until further progression or toxicity. Patients who achieve a complete response (CR) will remain on nivolumab alone. Patients who are found to have a partial response or stable disease will receive a combination of nivolumab with cabozantinib until progression or unacceptable toxicity.

Endpoints: The primary endpoint of the trial is OS. The secondary endpoints include progression-free survival (PFS), CR at 12 months, ORR, and proportion of patients discontinuing protocol-directed treatment prior to 1 year. Incidence of adverse events will also be reported.

Comments: This multi-center trial brings us closer to understanding the role of combination of immune checkpoint inhibitor with TKI therapy. Ideally, a trial comparing dual immune checkpoint inhibition (nivolumab plus ipilimumab) to a checkpoint inhibitor with TKI (ie pembrolizumab plus axitinib) would help us to answer the question of optimal sequencing of therapy. However, such a trial would require large numbers of patients as well as extended follow-up, thus is likely not feasible in the short-term. As such, we currently have the option to treat patients with IMDC intermediate or poor risk mRCC with either nivolumab plus ipilimumab or a checkpoint inhibitor in combination with axitinib. For patients who are treated with nivolumab plus ipilimumab, this study will demonstrate the utility of incorporating cabozantinib in combination with checkpoint inhibitor before the time of overt progression. This will shed further light into the potential synergism of TKIs and immune checkpoint inhibitor, and may help guide sequencing therapy moving forward.