The CLEOPATRA, BOLERO-2, and AVEREL trial results generated a lot of excitement (and confusion) in San Antonio at the annual Breast Cancer Symposium. Since the results were finally released, these trials have been hot topics. There’s good reason.

In the CLEOPATRA trial, the addition of pertuzumab to trastuzumab and docetaxel in previously untreated patients with HER2-positive metastatic breast cancer extended progression-free survival (PFS) by 6 months compared with trastuzumab and docetaxel alone. In BOLERO-2, the combination of everolimus and exemestane extended PFS by 4 months (local review) and by 7 months (central review) in women with ER-positive, HER2-negative breast cancer that is refractory to non-steroidal aromatase inhibitors. In AVEREL, the addition of bevacizumab to trastuzumab and docetaxel in women with HER2-positive, locally recurrent metastatic breast cancer also improved PFS — by 2.8 months (local assessment) and by 2.9 months (central assessment).

Image courtesy of NIH (public domain)

This is all great news but biomarkers to identify the patients who actually benefit the most from these new regimens would be even better news. All three presenters at one press conference — Dr. Luca Gianni, Dr. Gabriel Hortobaygi, and Dr. Jose Baselga — stressed the need for these tools. All three of these trials involved exploratory components to assess potential biomarkers to predict response.

“The common theme … of our three studies is that we have a challenge with the development of new drugs in identifying biomarkers that will determine which is the group that can be enriched and will derive the lion’s share of the benefit of adding drug X,” said Dr. Hortobaygi. “None of our new drugs in this panel has such a biomarker as yet. There is much work being done in all three studies to try to identify biomarkers that will help us to do that,” he said.

“That continues to be one of the major challenges for bevacizumab. We did not have a biomarker that can tell us that we can treat less than 100% of patients to observe the benefit. I think that most of us on this panel believe that most of these drugs provide benefit to a subset of patients and not to everybody. That is an ongoing challenge and we really need to invest in and redouble our efforts, so that we can develop those biomarkers,” he added.

Dr. Gianni told me that a biomarker for bevacizumab seriously could help with drug development. “If there was a biomarker, this combination could become very, very promising and would deserve analysis, head to head with other very active treatments in the case of HER2-positive disease.”

Dr. Howard A. Burris III told me that it makes sense based on what we already know that not every patient will benefit from the same treatments. “We know that not all ER-positive women are the same. The BOLERO-2 trial looked at adding the mTor inhibitor everolimus to exemestane in patients with ER-positive breast cancer. [However], you’ve got patients that have 10% ER overexpression and some that have 100%. Then you’ve got groups of patients who relapsed after the adjuvant therapy, so they didn’t have a long-lived response, and some that have had d great response in the metastatic setting. Those patients are not at all alike,” he said.

Image courtesy of NIH (public domain)

“I think we’re going to find that there isn’t this one size fits all and I think that the closer we get to this idea of having a panel — where you’re going to find out what the various overexpressions are for these patients — the clearer we’re going to be about who should get what.” Dr. Burris is the chief medical officer and the director of drug development at the Sarah Cannon Research Institute in Nashville.

“The primary toxicity, interestingly, for many of the new biologics is the financial toxicity. So it’s perfectly acceptable to give a relatively expensive therapy to the 10% of that it’s going to benefit greatly. The shame is that you can’t treat 10 patients to help that one patient who will benefit most. Somewhere in between is a societal decision,” Dr. Burris said.

“I think we’ve got to get closer to the idea that when a woman gets her original biopsy or surgery that you learn everything you can about that patient; then, at the time of relapse — if that’s unfortunate enough to occur –- if possible get a biopsy to see what’s changed; but if not, at least your first attempt in treating that relapse is going to be in the right direction. Identifying who’s the group at highest risk for relapse or who needs to stay on therapy longer are all going to be factors that are going to be important going forward,” said Dr. Burris.

Dr. Gianni noted that it’s easy to envision that these regimens potentially could be used earlier in the disease progression for women with breast cancer, who are identified by a biomarker to respond well to one of these regimens. It makes sense that these regimens could be used earlier for women identified by a biomarker to respond well to one of these regimen, he said.

— Kerri Wachter

SABCS: Paging Biomarkers STAT