May 2012 Edition Vol.0, Issue 0

Kantar Health’s Top Picks: What’s Hot at ASCO 2012

Kantar Health’s Top Picks:

What’s Hot at ASCO 2012

By Mara Jeffress, Associate Consultant,  CancerMPact®, Kantar Health

Kantar Health has identified several pivotal clinical trials that will be presented at the upcoming American Society of Clinical Oncology (ASCO) conference, which have the potential to significantly alter the treatment paradigm in several tumor types. A brief synopsis of nine of those trials and an evaluation of the data expectations are discussed.

Zytiga (abiraterone acetate, Janssen Biotech/Johnson & Johnson) plus Prednisone in Chemotherapy-naive Castration Resistant Prostate Cancer (CPRC)
PRESENTATION: COU-AA-302, Abstract LBA4518, Saturday, June 2, 8:00 am

A mere four months after its approval in April 2011, Zytiga had captured approximately one-quarter of the patient share in the second-line CRPC market1,  and utilization has continued to grow. Although the approval of Zytiga was limited to patients previously treated with docetaxel, the National Comprehensive Cancer Network (NCCN) quickly adopted a recommendation (category 2B) for use of Zytiga in the first-line setting for patients with asymptomatic CRPC. This was based on early phase data, the safety profile of the drug, as well as the ongoing nature of a pivotal Phase 3 trial in this setting. 

COU-AA-302 is an international Phase 3 study of Zytiga plus prednisone versus placebo plus prednisone in 1,088 asymptomatic or minimally symptomatic, chemotherapy-naive CRPC patients. On March 8, 2012, Janssen announced that the Independent Data Monitoring Committee (IDMC) unanimously recommended unblinding the study and offering Zytiga to patients in the placebo arm. This recommendation was based on a planned interim analysis in which evidence of clinical benefit and favorable safety were determined.

The co-primary endpoints of the study are radiographic progression-free survival (PFS) and overall survival (OS). Results of either endpoint were not reported in the press release, but it was suggested that both endpoints were met, or at least with a strong trend to benefit. OS is the gold standard for regulatory approval in prostate cancer, and there is a failed history of using PFS as a basis for approval (ie, Xinlay [atrasentan; Abbott] and satraplatin [GPC Biotech/Spectrum Pharmaceuticals]), so demonstration of a survival signal is paramount to the success of  this study. 

While news of early unblinding is very promising, the subsequent patient cross-over may ultimately confound OS which could hamper the approval process down the road if a strong enough signal wasn’t already evident at the interim analysis. Zytiga produced a 4.6 month OS benefit in the post-docetaxel setting, and Provenge (sipuleucel-T; Dendreon) was approved in the asymptomatic setting with a 4.1 month OS benefit. Look for similar levels of benefit with Zytiga in the COU-AA-302 trial.

Zytiga is already utilized off-label in chemotherapy-naive patients, and these results with regulatory approval will spur even greater adoption. Although Zytiga will compete with Provenge in this setting, the simpler administration schedule, potentially lower cost of therapy, and strong physician’s enthusiasm for Zytiga, will give it a strong advantage over Provenge and potentially “pull in” patients who are otherwise untreated due to the lack of symptomatic disease.

Tivozanib (AV-951, AVEO/Astellas) vs Nexavar in First- or Second-line Renal Cell Carcinoma (RCC)
TIVO-1, Abstract 4501, Saturday, June 2, 3:15 pm

The large number of approved and emerging agents in advanced RCC makes it a very competitive field. Competitors can be grouped in two mechanistic classes: VEGF pathway inhibitors—Avastin [bevacizumab; Genentech/Roche], Inlyta [axitinib; Pfizer], Nexavar [sorafenib; Onyx/Bayer], Sutent [sunitinib; Pfizer], Votrient [pazopanib; GlaxoSmithKline], and potentially tivozanib—and mTOR pathway inhibitors—Afinitor [everolimus; Novartis] and Torisel [temsirolimus; Pfizer]. This results in competition for utilization both within a class and between classes. The increased level of competition now existing in RCC has raised the need for direct comparisons of agents in order to allow physicians to understand how best to treat RCC patients.

In January 2012, AVEO announced that tivozanib demonstrated superior PFS compared with Nexavar in TIVO-1, a global, randomized Phase 3 trial in patients with advanced RCC. TIVO-1 is the first registrational study in first-line RCC that is comparing an investigational agent against an approved VEGF-targeted therapy; Inlyta was compared head-to-head with Nexavar in the second-line setting in the AXIS trial, and Votrient is currently challenging Sutent in the Phase 3 COMPARZ trial. 

Top-line findings from TIVO-1 were released in January, showing a statistically significant 2.8 month improvement in PFS with tivozanib compared with Nexavar in the overall study population (11.9 mos vs 9.1 mos); the level of benefit was greater in the population of patients who were treatment naive (12.7 mos vs 9.1 mos). Patients in the Nexavar arm performed well compared with historical data, in which Nexavar has produced PFS of approximately 5 months. However, it should be noted that TIVO-1 eligibility criteria included only patients with clear cell RCC who had received prior nephrectomy, which generally represents a good prognosis population compared with those patients typically enrolled in RCC clinical trials. This may explain why Nexavar appears to have over-performed.

Although 12.7 months in first-line is higher than what has been observed in any other study, many expected the median PFS to be higher. Key data will be the shape of the Kaplan-Meier curves. Is the median PFS representative, or is there a greater level of benefit that can’t be appreciated at the median? Pay close attention as well to the patient characteristics in each arm, as well as any subgroup analysis when the full data are presented, since even seemingly minor details could prove highly influential in driving treatment decisions in such a competitive field as RCC.

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