Michael Birrer, MD, PhD, professor of medicine, Harvard Medical School, director, Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, explains how the endpoints of progression-free survival (PFS) and overall survival (OS) are holding back the approval of drugs for patients with ovarian cancer.

Fortunately, patients with ovarian cancer demonstrate an initial response rate of 75% to 80% with a long duration of disease-free survival, Birrer says. Unfortunately, 75% to 80% of women with advanced-stage ovarian cancer eventually recur, develop drug resistance disease, and die.

Birrer says in order to test drugs upfront, pharmaceutical companies spend up to hundreds of millions of dollars on a phase III clinical trial. Ascertaining an endpoint of OS generally takes 6-7 years and is generally reached with confounding variables, such as crossover. Because of this, PFS is an attractive endpoint for drug development in this space, since it requires less time to fulfill.

Bevacizumab, which has not been approved in the United States to treat ovarian cancer, has been tested in 8,000 women around the world in various randomized phase IIItrials. Birrer says the results of those trials have all shown a positive primary endpoint of PFS but OS has not yet been shown. Researchers believe this occurs because of interactions between bevacizumab and other drugs or as the result of inadequate administration duration.

Birrer believes that bevacizumab should be considered an effective treatment for patients with advanced-stage ovarian cancer. The ideal indication for bevacizumab, Birrer believes, is in the frontline setting before patients become unfit for treatment.

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Dr. Birrer on the Approval Process in Ovarian Cancer

Michael J. Birrer, MD, PhD, director, Massachusetts General Hospital Cancer Center, gynecologic medical oncology, discusses the overall survival (OS) concerns surrounding the GOG0218 and the ICON7 trials that investigated bevacizumab (Avastin) in women with ovarian cancer.

Birrer does not believe these trials will demonstrate an OS benefit because many of the patients received bevacizumab after coming off the trial. Receiving the therapy at a later point contaminates the trial, since the OS benefit needs time to mature. As a result the full impact of the agent may not be realized.

The idea of using bevacizumab to treat recurrent ovarian cancer alone may result in some patients, which have aggressive tumors or are sick, from receiving the agent. Delaying recurrence provides relief from anxiety and lowers psychosocial concerns. Even without an OS benefit some patients feel that progression-free survival is sufficient.

Dr. Michael Birrer from Massachusetts General Hospital Cancer Center on the Ovarian Cancer Avastin OS Benefit

Dr. Birrer on the Ovarian Cancer Avastin OS Benefit

Michael J. Birrer, MD, PhD, director, Massachusetts General Hospital Cancer Center, gynecologic medical oncology, discusses the GOG0218 and the ICON7 trials, which added bevacizumab to standard chemotherapy in the first-line and maintenance setting for patients with ovarian cancer. These trials were recently published in the 

 and have caused controversy in regards to the efficacy of bevacizumab (Avastin) to treat ovarian cancer.

These studies concluded that the addition of bevacizumab prolonged progression-free survival (PFS) but did not significantly extend overall survival (OS). GOG0218 was an 1873-patient study that demonstrated an improvement in PFS of 3.8 months. ICON7 enrolled 1528 women with a 1.5-month increase in PFS.

The time needed to accurately calculated OS has not yet been reach for these trials, but early indications show that they did not significantly improve OS. Birrer notes that the FDA has made it clear that they will not approve new drugs for ovarian cancer based on PFS alone. An OS benefit must be demonstrated to gain approval, which he believes neither of these trials will demonstrate, due in part to the design of the trials.

In the GOG0218 trial Birrer estimates the crossover rate to be higher than 30-50%. Out of the patients that received placebo many did not receive bevacizumab until they had progressed. This high-level of crossover makes the OS endpoint difficult to achieve, which was the secondary endpoint for this trial.

The ICON7 trial is easier to gauge because it was conducted in Europe, where bevacizumab is difficult to receive outside of trials, this made crossover more difficult. OS was the primary endpoint in this trial, which cannot be accurately calculated until 2013.

Avastin Increases PFS in Patients With Ovarian Cancer

Dr. Michael Birrer, from Massachusetts General Hospital Cancer Center, Discusses the GOG0218 and ICON7 Trials

Dr. Birrer Discusses the GOG0218 and ICON7 Trials

Michael J. Birrer, MD, PhD, director, Massachusetts General Hospital Cancer Center, gynecologic medical oncology, discusses the 3 main treatment options available for women with platinum sensitive recurrent ovarian cancer, which he defines as having recurred greater than 6 months after their last platinum treatment.

The current standard of care for platinum sensitive ovarian cancer includes 1 of 3 platinum doublets, each demonstrating a survival benefit in randomized trial.

The first doublet contains a combination of carboplatin and paclitaxel (Taxol), this was investigated in the ICON4 trial, which demonstrated a median 13 month progression-free survival (PFS) and a 29 month overall survival (OS).

The second doublet contains a combination of carboplatin and gemcitabine. This was demonstrated in the AGO-OVAR study with a median PFS of 8.6 months, which was the primary endpoint. The OS benefit was not deemed statistically significant.

The third doublet is the most recently discovered; it contains a combination of carboplatin and Doxil. This study demonstrated a survival benefit that was similar to the carboplatin and Taxol combination. This new combination therapy is preferred because it is less toxic than the other doublets. Once the Doxil shortage is resolved it will most likely become the favored standard of care for many physicians.

Dr. Michael Birrer, from Massaschusetts General Hospital Cancer Center, Discusses Recurrent Ovarian Cancer Treatment

Michael J. Birrer, MD, PhD, University of Arkansas Medical Center

Articles

Dr. Birrer on the Approval Process in Ovarian Cancer

Dr. Birrer on the Ovarian Cancer Avastin OS Benefit

Dr. Birrer Discusses the GOG0218 and ICON7 Trials

Dr. Birrer Discusses Recurrent Ovarian Cancer Treatment