American Society of Clinical Oncology 2012: Show Me the Overall Survival Data!
It was reported that T-DM1 met its co-primary endpoint of PFS back in March 2012, but the overall survival endpoint is what’s really critical to obtaining T-DM1’s regulatory approval. This data is promising so far, but less definitive. Data from the first interim overall survival analysis showed that patients treated with T-DM1 had higher 1- and 2- year survival rates (84.7% and 65.4% respectively) than patients treated with Tykerb plus Xeloda, who had 1- and 2- year survival rates of 77% and 47.5% respectively. Although there is a trend that shows that T-DM1 improves overall survival, this data is not yet mature, and cannot be considered statistically significant, as the hazard ratio for overall survival has not passed the pre-determined stopping boundary for this study. The final data analysis is expected to take place in 2014, but Roche and Genentech plan to file for regulatory approval in the US and EU in H2 2012.
While GlobalData believes that T-DM1 will ultimately offer an overall survival benefit, it remains to be seen whether this data will be available prior to regulatory filing. The companies seem confident that the current data is adequate to support filing, and they may get lucky; the trends in current data do imply that T-DM1 will confer a survival benefit to a population of patients who are nearly out of treatment options, and side effects associated with T-DM1 are less severe than the current standard of care. However, even if T-DM1 is approved without data showing statistically significant benefits in overall survival, the drug will inevitably have a tough time getting the thumbs-up from pricing watchdogs such as the UK’s National Institute for Health and Clinical Excellence until that data is available. This will hinder Roche and Genentech’s ability to demand premium pricing.
We were also anxious to hear new data on Johnson & Johnson’s Zytiga (abiraterone acetate), another drug spotlighted at this year’s ASCO meeting. Zytiga is already approved for the treatment of chemotherapy-refractory metastatic castration-resistant prostate cancer (mCRPC), but Johnson & Johnson plans to seek approval for Zytiga plus prednisone in the chemotherapy–naïve mCRPC population. The Phase III COU-AA-302 trial evaluating the efficacy of Zytiga plus prednisone in chemotherapy - naïve mCRPC patients compared to placebo plus prednisone - was stopped prematurely, in response to the Independent Data Review Committee recommendation that the trial be unblinded and all patients offered Zytiga. This initially seems positive for the drug – except that with the trial ending early, overall survival data showing a clear survival advantage of Zytiga over a placebo was not yet mature, and the median overall survival in the Zytiga arm was not reached.
While it would have been questionable ethically to deny placebo patients access to treatment that could prolong their lives, data from COU-AA-302 will now never be able to definitively support an overall survival benefit for Zytiga in the chemotherapy–naïve mCRPC population. However, data from COU-AA-302 showed that Zytiga dramatically increased the median radiological PFS of patients compared to a placebo. The median PFS was not yet reached in the Zytiga arm, compared to 8.3 months in the placebo arm with a hazard ratio of 0.43 and an impressive p-value of less than 0.0001. This PFS benefit was observed throughout all patient demographics. In addition, the trial met all secondary endpoints including time to chemotherapy initiation, time to PSA progression, and PSA decline of 50% or greater. The safety profile of Zytiga within this new population was consistent with previous data, despite the fact that the median exposure time of 15 cycles was significantly longer than in previous studies.
Taking all this into consideration, GlobalData still expects Zytiga to obtain regulatory approval when Johnson & Johnson files FDA and EMA applications later this year, even without an undisputable overall survival benefit. This is largely due to the fact that Zytiga is already approved globally for the treatment of prostate cancer, and the safety profile is good. Without a demonstrated overall safety benefit, it is possible that Zytiga may face issues with reimbursement and market access. However, this is less likely to be a problem for Zytiga than for T-DM1, as Zytiga has already been approved by pricing agencies and is successfully marketed for the prostate cancer indication with 2012 Q1 global sales reported as $200 million.
It remains to be seen whether regulatory approval without overall survival data becomes a trend in oncology pharmaceuticals. In Zytiga’s case, the lack of overall survival data is understandable and perhaps commendable from a humanitarian standpoint, although critics maintain that continuing the COU-AA-302 trial would have better served the prostate cancer population. However, it is debatable whether Roche and Genentech’s rush to file for approval of T-DM1 without definitive overall survival data is motivated by a desire to help underserved patients, or the desire to establish T-DM1 in the breast cancer treatment algorithm before Herceptin’s patents expire. Regardless, GlobalData hopes that data presented at ASCO 2012 encourages pharmaceutical companies to continually critique their clinical trial designs and regulatory submissions, in order to provide cancer patients with new therapies that deliver the greatest benefits.
*ASCO 2012: Show Me the Overall Survival Data!
This expert insight was written by GlobalData’s oncology and infectious diseases analyst, Dr. Cheryl Strelko. If you would like an analyst comment or to arrange an interview, please contact us on the details below.
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