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Redesigning Studies: Pushing the Envelope

Don S. Dizon, MD, FACP

03 Jun 2012 8:09 PM

Being a session chair at the ASCO Annual Meeting is a huge honor, and one that I had wanted to do for quite some time. I finally had my chance this year, as co-chairman of the Gynecologic Cancer Oral Abstract Session, held on Saturday, June 2, 2012, alongside my colleague, Gottfried Konecny, from UCLA.

As in years past, the room was filled to capacity—a testament to the level of interest in gynecologic malignancies among ASCO attendees. Most of us expect the Scientific Program Committee to select the most intriguing abstracts related to gynecologic oncology, and this year was no exception. In addition, we expect our discussants to place the science and the findings of the studies in context, and again, this was wonderfully done this year. However, sometimes a speaker goes beyond expectations and delivers a talk of such magnitude that people are talking about it hours and days later. Such is the state of what happened at this session.

Following the presentation of the first three abstracts (clinical trials involving the agents erlotinib, olaparib, and bevacizumab in ovarian cancer) Dr. Michael Seiden from Fox Chase Cancer Center came to the podium as the discussant and what I thought was going to be a thoughtful and concise summary turned out to be a far more provocative talk.

Dr. Seiden went through each trial and its results—the lack of a benefit in survival with the use of erlotinib maintenance following adjuvant treatment, the positive progression-free survival (PFS) result of the olaparib plus chemotherapy study in platinum-sensitive ovarian cancer, and the impressive response and PFS results of the AURELIA bevacizumab study in platinum-resistant ovarian cancer—and explained that while each study in its own right were to be applauded and discussed, in the end we learned very little. He went so far as to predict that with further follow-up, both the olaparib and bevacizumab studies would not show a survival benefit.

He then went on to highlight a stark truth about ovarian cancer clinical trials—that our approach to targeted agents has yielded very little results. He explained how ovarian cancer is a genomically diverse disease, and that to date, there does not appear to be a driver mutation in ovarian cancer that applies to all women with ovarian cancer or even to a large subset of women with the disease. There was no HER-2/neu overexpression, no BCR-ABL translocation in ovarian cancer to date—the hallmarks of targeted treatment success that underlie the benefits of trastuzumab and imatinib in breast cancer and chronic myelogenous leukemia, respectively.

Ultimately he predicted that large trials of molecular targeted treatment in ovarian cancer were likely to be negative, without a reconsideration of the populations. Perhaps it was time to suspend the trials.

My eyebrows shot up at that suggestion and one could hear the collective gasp in the audience. At the end of his 15-minute talk, the audience appeared to be partially stunned and partially captivated. Because of our packed agenda in the session we had insufficient time to take questions and moved on to the rest of our agenda.

Although Dr. Seiden’s message might be considered by some to be a message of futility, I find myself still intrigued by it and still considering his presentation 24 hours later.

The task before us is to identify more active therapy. However, as our colleagues have done in other areas of oncology, like crizotinib in lung cancers (which targets the ALK translocation present in 2-7% of non-small cell lung cancers), it will take a closer look at the data coming from genomic studies to identify those patients who are more likely to benefit from targeted agents.

Instead of the randomized trial of all-comers we do now, his was a call to redesign studies informed by the science—it was a call to embrace personalized medicine.

I do believe the abstracts presented at this year's session taught us much; that EGFR inhibitors play a limited therapeutic role in this disease was confirmed in a phase III trial and AURELIA may establish the best place to use bevacizumab is in the setting of platinum-resistant ovarian cancer (because the benefits in response rate and progression free survival are likely to translate in to improvements in quality of life). I also believe that continuing phase III trials is important. But, I also believe the message about personalized medicine that Dr. Seiden has emphasized is just as important. As we begin to do so we begin to take the baby steps necessary for progress to occur. In so doing, with patience, time, and drive by the fortitude and passion of us all, we can learn to walk, run, and be rid of ovarian cancer once and for all.

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Don S. Dizon, MD, FACP