Dramatic Changes on Horizon in Renal Cell Carcinoma.

The optimal frontline treatment strategy for patients with metastatic renal cell carcinoma (RCC) could look dramatically different in the next few years, as studies assess combination strategies and predictive biomarkers for immunotherapy and targeted therapies, according to Sumanta Kumar Pal, MD.

For the past decade, VEGF-targeted therapies were considered the optimal frontline treatment for patients with metastatic clear cell RCC, Pal said during a presentation at the 2016 GU Cancers Symposium. However, this paradigm could be disrupted by the recent wave of immuno-oncology agents, which are gaining approval across indications for patients with cancer.

“There’s a lot of hope here for perhaps the best of both worlds, with higher response rates and longer progression-free survival with VEGF therapy combined with more durable responses with the PD-1 and PD-L1 directed agents,” said Pal, co-director of the Kidney Cancer Program at City of Hope in Duarte, California.

In November 2015, the first immune checkpoint inhibitor, nivolumab (Opdivo), was approved as a second-line therapy for advanced RCC. This decision was based on the CheckMate-025 study, which showed a median overall survival (OS) of 25.0 months with nivolumab compared with 19.6 months for everolimus (HR, 0.73; P = .002).1

“There is a subset of patients who seem to derive an exceptional response. I think we need to find out who these exceptional responders are. There has been an emerging body of evidence to characterize these individuals,” said Pal. “I don’t think nivolumab in the frontline setting is appropriate at this point.”

Anecdotal findings suggest that neoantigens are associated with better responses to immunotherapy, providing a potential tool for tailoring therapy. A correlation between mutational load and responses has also been observed. However, both of these observations still need to be vetted in larger trials, explained Pal.

The need for an effective biomarker also exists for VEGF therapies. A number of studies have hinted at markers of response with various agents, although one indicator has not yet conclusively emerged. Currently, early data suggest KDM5C alterations could be associated with long and durable responses to VEGF-targeted therapy, although these findings still need to be validated.

Tyrosine Kinase Inhibition

The leading frontline VEGF tyrosine kinase inhibitors (TKIs) currently used for RCC are sunitinib (Sutent) and pazopanib (Votrient). These therapies were compared in the phase III 1110-patient COMPARZ trial, which demonstrated similarity between the two agents.2 In the study, pazopanib was shown to be noninferior to sunitinib for progression-free survival (PFS; HR, 1.05; 95% CI, 0.90-1.22) and OS (HR, 0.91; 95% CI, 0.76-1.08).

In addition to established therapies, new agents have recently entered the RCC arena. Although not yet approved, the multikinase inhibitor cabozantinib (Cometriq) demonstrated superiority to everolimus in the phase III METEOR study.3 A rolling submission of data from this trial was completed in December 2015, with a decision from the FDA expected within the next 6 to 8 months.

After a minimum of 11 months of follow-up in the METEOR study, median PFS with cabozantinib was 7.4 months compared with 3.8 months with everolimus (HR, 0.58; 95% CI, 0.45-0.75; P <.001). At the interim analysis, a trend toward improvement in OS was observed; however, this did not yet pass a high bar for statistical significance (HR, 0.67; 95% CI, 0.51-0.89; P = .005).

The ongoing phase II CABOSUN trial is comparing frontline cabozantinib with sunitinib for patients with clear cell RCC. The study enrolled 150 participants to assess the dual primary endpoints of OS and PFS. Early data from this study are anticipated later this year.

Combination Strategies Under Exploration

Early-phase clinical trials exploring VEGF TKIs in combination with anti–PD-1 agents have shown prohibitive hepatic and gastrointestinal toxicity, explained Pal. These studies looked at nivolumab with sunitinib or pazopanib or at the PD-1 inhibitor pembrolizumab (Keytruda) with pazopanib.

Despite these setbacks, promising data were seen for the combination of the VEGF TKI axitinib (Inlyta) and pembrolizumab in a small, 11 patient study.4 In this trial, the most common grade 3/4 adverse events were hypertension (27.3%), and diarrhea and increased alanine transaminase (9.1% each).

In addition to a manageable toxicity profile, axitinib plus pembrolizumab demonstrated sustained and prolonged responses. Overall,  6 patients had confirmed partial responses and 5 patients had stable disease with tumor shrinkage.

“This bodes well for a clinical trial that is currently under way exploring axitinib and avelumab,” said Pal, referring to an emerging PD-L1 inhibitor. “This particular trial has already inspired a phase III trial that will randomized patients to either sunitinib or axitinib and avelumab. We are very excited to see how that study turns out.”

Outside of TKIs, other opportunities for combination strategies exist as treatments for patients with advanced RCC. Historically, the VEGF-targeted antibody bevacizumab (Avastin) has paired well with other novel agents, according to Pal.

At this point, phase I trials have demonstrated sustained responses and tolerable safety for the combination of bevacizumab and the anti-PD-L1 agent atezolizumab (MPDL3280A), leading to the initiation of a phase III study comparing the combination with sunitinib. The current endpoint for the study is PFS and the targeted enrollment is 830 patients (NCT02420821).

Building on success in other areas, the combination of nivolumab and the CTLA-4 inhibitor ipilimumab (Yervoy) is also being assessed for patients with RCC (NCT02231749). In a phase I study exploring the combination, the objective response rate was between 43% and 48%, depending on the dose of each medication utilized.5 Additionally, these responses were durable, according to Pal.

In patients receiving a higher 3 mg/kg dose of ipilimumab and a 1 mg/kg dose of nivolumab, the adverse events associated with the combination were unacceptably high, noted Pal. However, when nivolumab was given at 3 mg/kg and ipilimumab was administered at 1 mg/kg, the combination was far more tolerable, he said.

“This is the dose that has made its way into the phase III experience comparing nivolumab and ipilimumab with sunitinib therapy,” according to Pal.

A number of studies are currently exploring various combination strategies. Among these studies are those assessing cabozantinib with ipilimumab plus nivolumab or nivolumab alone. Also, a study is examining bevacizumab with nivolumab for patients with RCC.

Role of Interleuken-2 Remains Unclear

As studies continue to assess novel immunotherapies as single-agents and in combination with VEGF-targeted therapy, the role for high-dose interleuken-2 (IL-2) grows increasingly unclear, noted Pal. Even in the absence of the latest explosion in immunotherapy for patients with RCC, IL-2 was a less common frontline option.

“Experts are always going to remain divided in their opinion on high-dose interleuken-2,” said Pal. “The criteria for selecting the appropriate high-dose interleuken-2 therapy will always remain inconsistent.”

The SELECT trial explored high-dose IL-2 in 120 patients with an ECOG performance status of 0 to 1, measurable and clearly progressive disease, and adequate organ function. By independent review, the objective response rate (ORR) was 25% with IL-2, which compares favorably with historical cohorts (14%).6

The complete response rate was 2.5% and the partial response rate was 22.5%. Importantly, 10.8% of patients in the study had a PFS time that lasted >3 years, which is the goal when using high-dose IL-2, said Pal.

The adverse events associated with high-dose IL-2 are hypotension, renal failure, and hyperbilirubinemia. There were two treatment-related mortalities in the study, which is important to keep in mind, cautioned Pal.

“What we saw in the context of SELECT is that clinical factors did not seem to predict outcomes to high-dose interleuken-2. In addition to that, biomarkers, such as carbonic anhydrase 9 (CA-9) and fibronectin, also did not predict clinical outcomes. This is an important lesson for us,” said Pal.

Interestingly, the SELECT trial did provide insight into PD-L1 and B7-H3 as biomarkers for immunotherapy. In those with PD-L1-positive tumors, the ORR with IL-2 was 50% compared with 19% in those with negative disease (P = .01). In the B7-H3–positive group, the ORR with IL-2 was 29% compared with 11% in the negative population (P = .08).6

“There were some interesting biomarker findings in SELECT. We see that PD-L1 was associated with a higher response rate, and this is quite striking given that data that we’ve seen with nivolumab therapy in the second- and third-line setting,” said Pal.

High-Dose IL-2 Utilization Trends in RCC

There are selection biases for utilizing high-dose IL-2, which are inherent with the adverse events associated with the medication, explained Pal. In general, clinicians with an established infrastructure and prior experience with the medication are most likely to consider using the agent.

“High-dose IL-2 remains confined to specialized centers, and I really wanted to go to these specialized centers and figure out what their opinions were of high-dose IL-2,” said Pal.

To achieve this goal, Pal conducted an electronic survey asking participants at large centers in the United States and Europe whether or not they used high-dose IL-2.7 Overall, 33% of respondents said they did not use the immunotherapy.

Those who used IL-2 (67%) identified clear characteristics for treatment selection. In general, IL-2 was considered most frequently for those who were young, had clear cell histology, a good performance status, and no comorbidities.

Interestingly, for young patients at good risk with lung-only metastases, a majority of the respondents (64%) said they would consider a clinical trial exploring a checkpoint inhibitor or VEGF-directed therapy rather than administer IL-2, according to the survey.

“There’s really no consensus at this point, after two decades of clinical research, regarding who the appropriate patient for high-dose IL-2 therapy actually is,” said Pal. “There is actually one question that did generate a consensus, and that was the question of whether there are appropriate biomarkers to identify ideal IL-2 patients. And here the answer was a resounding, ‘No.’”

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Rare kidney tumor provides insights on role of metabolic changes in cancer

Researchers in The Cancer Genome Atlas (TCGA) Network have made a number of new findings about the biology and development of a rare form of kidney cancer. They found that the disease – chromophobe renal cell carcinoma (ChRCC) – stems in part from alterations in genes in the mitochondria, the cell’s energy supplier. They also discovered that the tumor is characterized by genetic rearrangements near a gene important in DNA repair and in maintaining telomerase, the enzyme which determines a cell’s lifespan. Finally, investigators also found that ChRCC is a distinct disease and shares few genomic characteristics with other kidney cancers.

In the study – the most extensive genomic view of ChRCC to date – investigators led by Chad Creighton, Ph.D., Baylor College of Medicine, Houston, and Kimryn Rathmell, M.D., Ph.D., University of North Carolina, Chapel Hill, performed a complex array of analyses, including examining the entire genomes of 50 of the 66 ChRCC tumors studied, a high number for a rare cancer. The study revealed increased numbers of mitochondria as well as mutations in mitochondrial DNA. This led researchers to discover that ChRCC tumors favor a different energy-generating process than that used by the more common clear cell kidney cancer. In addition, their findings are the first to show specific alterations affecting the TERT gene that could affect cancer development, and might help explain its increased expression – and deregulation – in cancer. Overall, the findings provide new insights into the development of more common forms of kidney cancer, and shed light on the role of mitochondria and metabolic pathways in cancer. The results also support the growing realization that both the cancer’s genomic characteristics and cell of origin matter, as many cancers consist of several individual diseases that require specific therapies. TCGA is a collaboration jointly supported and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.Cancer Cell.

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Reduced Kidney Function Linked With Higher Risk Of Kidney And Urothelial Cancers.

Individuals with poor kidney function may require more intensive screening for these cancer types

Reduced kidney function may increase the risk of developing kidney and urothelial cancers, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN). The findings suggest that patients with kidney disease may benefit from more intensive screenings for these types of cancer.

Chronic kidney disease and cancer are both major and growing public health problems. “While multiple studies have observed higher risks of cancer in persons with end-stage renal disease, the association of less severe kidney disease with cancer remains poorly understood,” said Alan Go, MD (Kaiser Permanente Northern California).

To investigate, Dr. Go and his colleagues analyzed information from nearly 1.2 million adult members of Kaiser Permanente in Northern California who were at least 40 years of age and who had no history of cancer, dialysis, or kidney transplantation. Kidney function was measured by estimated glomerular filtration rate (eGFR), with normal kidney function being over 60 ml/min/1.73m2 and kidney failure being below 15 ml/min/1.73m2.

During more than 6 million person-years of follow-up, 72,875 individuals developed cancer. (A person-year is the number of years of follow-up multiplied by the number of people in the study.) Among the major findings during follow-up:

Individuals with an eGFR of 45 to 59 had a 39% increased risk of kidney cancer (or renal cell carcinoma).
Individuals with an eGFR of 30 to 44 had an 81% increased risk of kidney cancer.
Individuals with an eGFR below 30 had a 100% (or a 2-fold) increased risk of kidney cancer.
Individuals with an eGFR below 30 had a 48% increased risk of urothelial cancer, which includes tumors in the bladder and ureters.
There were no significant links between eGFR and other cancer types such as prostate, breast, lung, and colorectal cancers.

The researchers noted that various biologic mechanisms may help to explain the links observed in this study. For example, kidney dysfunction causes a state of chronic inflammation and oxidative stress. “These and other mechanisms deserve further study in order to better define the link between kidney function and site-specific cancer risk,” said lead author Will Lowrance, MD, MPH (University of Utah).

In an accompanying editorial, Jonathan Hofmann, PhD and Mark Purdue, PhD (National Cancer Institute) noted that the study is “an important step forward in characterizing the relationship between chronic kidney disease and risk of renal cell carcinoma and other malignancies. Studies such as this further support an etiologic role of impaired renal function in the development of renal cell carcinoma.”


Source: American Society of Nephrology


Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma.


Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.


We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.


Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand–foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons).


Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib

Source: NEJM

Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.

The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer.
METHODS: We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392.
FINDINGS: A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6.7 months with axitinib compared to 4.7 months with sorafenib (hazard ratio 0.665; 95% CI 0.544-0.812; one-sided p<0.0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm.
INTERPRETATION: Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma.

Source:Lancet Oncology