This article has been corrected from a previous version that reported that the AXIS genomic substudy compared Pfizer's axitinib and Sutent. The AXIS trial is a head-to-head comparison between axitinib and Bayer Healthcare/Onyx's Nexavar.
By Turna Ray
In the search for markers that will help personalize therapy with anti-angiogenic drugs, researchers from Pfizer and elsewhere have found that kidney cancer patients whose tumors harbor certain VEGF-A SNPs live longer without their disease progressing when treated with the investigational VEGF inhibitor axitinib than patients treated with another drug in the same class, called Nexavar.
According to the results of a phase III substudy presented this week at the European Multidisciplinary Cancer Congress in Stockholm, the team identified three VEGF-A gene markers linked to response, suggesting "that specific SNPs might help to explain some of the observed interpatient variability in progression-free survival for renal cell carcinoma patients receiving axitinib therapy."
The researchers, led by Bernard Escudier of the Institute Gustave Roussy in France, concluded in their EMCC abstract that germline VEGF SNPs "might be important tools in the future to guide selection of VEGF inhibitors."
At the American Society of Clinical Oncology's annual meeting in June, Pfizer reported results from AXIS, a head-to-head comparison of axitinib and Bayer Healthcare/Onyx's Nexavar (sorafenib) as second-line treatments for metastatic renal cell carcinoma. In that study, patients experienced a median progression-free survival of 6.7 months while on axitinib compared with 4.7 months for those treated with Nexavar.
At EMCC this week, researchers from Pfizer, the Institute Gustave Roussy, Memorial Sloan Kettering, and elsewhere presented the results of a follow-on study that explored whether certain germline SNPs in the VEGF pathways of patients enrolled in AXIS impacted their cancer progression when treated with axitinib or Nexavar.
The researchers reported that the VEGF-A SNPs rs1570360, rs699947, and rs833061 were "potentially associated with progression-free survival" in axitinib-treated patients, but not for those treated with Nexavar. "For example, the median PFS for VEGF-A rs699947 A/A in axitinib-treated patients was 52 weeks (versus 28 weeks for other genotypes; adjusted P=0.16), while no difference in PFS among these genotypes was noted in sorafenib-treated patients (adjusted P=0.95)," researchers reported in the abstract.
For the PGx analysis, the researchers genotyped blood samples from 263 patients using Life Technologies' Taqman platform. They then assessed the association between PFS and VEGF pathway genes — VEGF-A, VEGFR1, VEGFR2, and HIF1α.
The team also explored the link between these variants and blood pressure-related endpoints, but found no association with axitinib-related hypertension or diastolic blood pressure.
Refining Patient Populations
By identifying best-responder populations for axitinib before it enters the market, Pfizer is laying the groundwork to potentially differentiate the patient population for the drug from Nexavar. Last year, Nexavar netted nearly a $1 billion in revenues as a treatment for unresectable liver cancer or advanced kidney cancer.
Although Pfizer is conducting early pharmacogenetic research with axitinib, the drug developer hasn't publicly announced any plans to gain approval for axatinib in a molecularly defined patient subset. The goal of the exploratory analysis presented at EMCC, according to Pfizer, was to explore potential associations between germline SNPs in VEGF pathway genes with progression-free survival and blood pressure-related endpoints.
"These exploratory analyses may merit further evaluation, and indicate that with additional research, germline SNPs may become important tools in the future to help guide selection of VEGF inhibitors at the outset of treatment," a Pfizer spokesperson told PGx Reporter. "However, because of the exploratory nature of this study, it is premature to draw broad conclusions."
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While Pfizer is conducting molecular analysis to identify best responders to axitinib, the company is also working with Genomic Health to advance a diagnostic that can help doctors determine whether patients' kidney cancer will recur based on the genomic measures. Based on that, physicians can then decide whether their patients should be treated aggressively with certain types of drugs or can receive less-aggressive forms of treatment.
As part of the company's broader efforts to develop new treatments for renal cancer and find biomarkers that may advance personalized medicine, "Pfizer has partnered with Genomic Health on the development of a genomic test to estimate the risk of recurrence following surgery for patients with clear cell renal cell carcinoma that has not spread to other parts of the body," the company spokesperson said.
The latest research by Escudier et al. on the VEGF-A SNPs associated with axitinib response is separate from Pfizer's work with Genomic Health. Pfizer also markets Sutent for the treatment of advanced kidney cancer.
While the exploratory SNP data presented by Escudier and colleagues may help further characterize the nature of biomarkers involved in angiogenesis, other data presented at EMCC suggest that researchers have a long road ahead in validating these markers before they can be developed into commercial tests.
Valid markers associated with patient response to anti-VEGF drugs have been elusive thus far, and researchers have been unable to find markers that are consistently similar for the class of drugs and across disease states.
Although this may be influenced by differences in sampling and storage of biological materials, experts believe that due to the complex nature of the angiogenic process, biomarker discovery is unlikely to be a straightforward affair.
Some of the markers identified in the Escudier et al. study have been linked to improved overall survival in patients enrolled in the E2100 trial — the pivotal study that led to the accelerated approval for Genentech's VEGF inhibitor Avastin (bevacizumab) for breast cancer. The same SNPs have been linked to response to GlaxoSmithKline's RCC VEGF-inhibitor Votrient (pazopanib).
Researchers haven't been able to validate the VEGF-A SNPs identified in the E2100 substudy in other Avastin breast cancer investigations, but subsequent studies have found plasma VEGF-A levels to be a potentially predictive biomarker in this setting. Data presented at EMCC, however, indicates that while varying levels of VEGF-A plasma appear to be associated with Avastin response in metastatic breast, gastric, and pancreatic cancers, the biomarker doesn't show the same effect on drug response in patients with kidney, non-small cell lung, and colorectal cancers (see related story, in this issue).
And although VEGF-A plasma levels were shown to be possibly associated with Avastin response in the metastatic breast cancer trial for Avastin, called AVADO, data from a retrospective VEGF SNP analysis in the same patient cohort presented at EMCC indicates only a "weak" association.
In this investigation, researchers from Genentech and various cancer centers analyzed patient blood samples using a PCR-based test to see whether any markers from a panel of 26 candidate SNPs involved in angiogenesis and tumorigenesis were significantly associated with progression-free survival or overall survival in patients receiving Avastin.
Researchers led by David Miles of the Mount Vernon Cancer Center found that there was an "indication" of improved treatment response associated with VEGF -2578 C/A in the Avastin arm, as well as a "non-significant treatment interaction" with the VEGF -1154 A/G marker.
Ultimately, however, "we observed only a weak correlation between the VEGF −2578 SNP and progression-free survival, driven by an effect in the placebo arm," Miles et al. concluded. "Thus, our analysis of germline DNA samples did not confirm findings from E2100. Likewise, our data do not confirm previous findings for VEGF and VEGFR-1 SNPs."
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