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Genomic Health Kidney Cancer Test Gauges Recurrence Risk in Study, Not Benefit to Pfizer's Sutent

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PARIS – A 16-gene expression test that Genomic Health developed in collaboration with Pfizer was able to determine in a validation study which clinically high-risk, stage III kidney cancer patients would experience recurrence following surgery.

However, the study did not confirm the test's ability to predict which patients would benefit from adjuvant treatment with Sutent (sunitinib), a drug Pfizer currently markets for advanced kidney cancer. Genomic Health said it will hold off commercializing the test until adjuvant treatments for kidney cancer come to market. Still, since the present study was underpowered to assess the test's predictive capabilities, the molecular diagnostic firm remains interested in further exploring the predictive aspects of the assay.

Genomic Health and Pfizer have been working together for nearly a decade to advance a molecular diagnostic that can be used to identify stage I-III renal cell cancer patients at risk of recurrence. The companies worked with Cleveland Clinic researchers to develop the 16-gene expression test, and published the first validation study in The Lancet Oncology in 2015, which showed that the test's recurrence score provided prognostic information on recurrence risk beyond clinicopathological factors. 

At an annual symposium in Paris on Tuesday, Jean-Francois Martini, senior director of translational oncology at Pfizer, presented data from a second validation study evaluating patients previously enrolled in the S-TRAC trial. That study has shown that kidney cancer patients determined to be high risk based on clinicopathological factors had longer disease-free survival when given adjuvant treatment with Pfizer's Sutent compared to those on placebo. 

However, there are currently no US Food and Drug Administration-approved therapies that kidney cancer patients can receive in the adjuvant setting after they have surgically removed their kidneys.

In using the gene expression test on patients' samples from the S-TRAC trial, Pfizer was interested in not only finding a new way of characterizing and stratifying recurrence risk in kidney cancer, but also whether the test could identify which patients would benefit from adjuvant treatment with Sutent, Martini said at the symposium hosted by Worldwide Innovative Networking (WIN) in Personalized Cancer Medicine. WIN is a nonprofit, nongovernmental entity involving 41 member organizations with the common goal of bringing precision oncology to patients globally.

Worldwide, 300,000 people are diagnosed with renal cell carcinoma, and less than one-fifth have stage III or locoregional disease. The five-year survival rate for patients with stage III disease is 53 percent, and around 30 percent of patients experience a relapse after surgically removing their kidneys. Since adjuvant treatment strategies using radiotherapy, cytokine therapy, or hormone therapy haven't shown to successfully reduce the rate of relapse, researchers have turned their attention to anti-angiogenic treatments, such as Sutent and Bayer's Nexavar (sorafenib), given their efficacy in metastatic kidney cancer.

After a study called ASSURE found that adjuvant treatment with neither Sutent nor Nexavar benefitted kidney cancer patients compared to placebo, Pfizer funded the S-TRAC trial. In this study involving more than 600 stage III, high-risk, clear cell kidney cancer patients, those receiving adjuvant treatment with Sutent lived a median of 6.8 years without experiencing a relapse compared to 5.6 years in the placebo group. Although Sutent-treated patients had significantly longer disease-free survival compared to the placebo group, they also experienced more toxicities and needed more dose reductions.

The read out from S-TRAC enabled Pfizer to further evaluate the prognostic and predictive aspects of the gene expression test in a subset of kidney cancer patients who have poor outcomes. Genomic Health was a logical partner to work with since the firm already markets gene-expression recurrence risk tests under its Oncotype DX brand for breast, prostate, and colorectal cancer. The 21-gene expression risk score for breast cancer is also recommended in treatment guidelines as a tool that can be used to predict whether an early-stage patient is likely to benefit from chemotherapy.

The development of the kidney cancer test began with 732 genes that based on published data and their biological function were important in clear-cell, renal cell carcinoma. Of these, 516 genes were found to be associated with recurrence-free survival, and researchers homed in on 16 genes ― 11 selected based on additional statistical analyses plus five reference genes ― with which to develop the recurrence score algorithm.

A recurrence score of less than 32 was considered to be low risk for recurrence, while a score above 44 was considered high risk. Kidney cancer patients with a score of between 32 and 44 are considered at intermediate risk for recurrence.

In the S-TRAC analysis, researchers had recurrence scores on 193 high-risk, stage III patients. The test was able to assess time-to-recurrence and disease-free survival for patients treated with Sutent and receiving placebo. Martini noted that "the risk score strongly predicted the risk of recurrence in the placebo arm." He further highlighted that, overall, the gene expression test identified 20 percent of patients as low risk even though they were considered at high risk of by clinical factors.

However, the interaction between the risk score and treatment with Sutent didn't reach statistical significance. One reason for that could be due to the fact that only 63 patients out of 193 experienced recurrence, which reduced the power for an interaction test. "It is important to note that this study was primarily powered to validate the test as prognostic and under-powered to test for prediction," a Genomic Health spokesperson said.

While this analysis supports the 16-gene expression signature's prognostic value in kidney cancer, and enables "new ways of quantifying tumor biology … it didn't have a predictive value," Martini said. Based on this data, he didn't believe this test wouldn't qualify as a companion diagnostic for Sutent in the adjuvant setting, but perhaps it could be used to inform treatment strategy as a complementary diagnostic.

"The recurrence score may help identify patients with clear cell, stage III high-risk kidney cancer who could derive higher absolute benefit from adjuvant therapy, but so far there are no therapies approved in this setting," Martini concluded.

Genomic Health attributed its decision to hold-off commercializing the 16-gene expression test to the lack of approved adjuvant treatments in kidney cancer. "With our maturing urology channel and as treatments are approved, we are well positioned to bring a test forward to help bring precision medicine to kidney cancer care," the spokesperson said.

At the symposium, Brian Leyland-Jones from the Avera Cancer Institute Center for Precision Oncology in Sioux Falls, South Dakota, suggested that Pfizer and Genomic Health go back to the 11 active genes in the algorithm, reanalyze their contribution in the disease setting, and further refine the predictive aspects of the signature. However, because the assay is already analytically validated, it would be difficult to refine it at this point, Martini said.

Given the rarity of renal cell cancer, he noted that the development program has already taken 10 years. "Genomic Health wouldn't have much of an appetite” for reanalyzing the biomarker algorithm, Martini said, "unless there was an approved treatment in the adjuvant setting." Meanwhile, he added that Pfizer is considering looking at other signatures that have shown to be predictive of treatment response in this context.

In the second quarter of 2016, Genomic Health reported $88,000 in contract revenues from its collaboration with Pfizer in renal cell carcinoma. Genomic Health is evaluating the next steps in terms of its collaboration with Pfizer, the spokesperson said. "Looking ahead, we would be quite interested in future opportunities for studies that can rigorously validate the test for prediction given its strong prognostic performance in the S-TRAC study."

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