FDA Offers Guidance for Neoadjuvant Trials

A common definition for pathologic complete response will boost studies in early-stage breast cancer.

Neoadjuvant clinical trials of experimental cancer drugs, which test the drugs before initial surgery rather than after a tumor recurs, are on the rise for patients with breast cancer, driven by success stories such as I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2). Now the U.S. Food and Drug Administration (FDA) has given a stamp of approval.

On May 30, the FDA issued draft guidance that defines criteria for pathologic complete response (pCR) as an intermediate endpoint for breast cancer treatment and outlines trial design considerations. (Pathologists assess pCR by examining tissue removed after surgery for signs of cancer.)

The guidance is “an effort to harmonize what everyone is doing in neoadjuvant trials,” says Tatiana Prowell, MD, senior clinical reviewer at the FDA Breast Oncology Group in Silver Spring, MD, and assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD.

“This is a very attractive approach because you can learn a lot about an individual's tumor while it's still in place, as opposed to giving a treatment and guessing and hoping but not really knowing that it's working until the disease either does or does not recur down the line,” Prowell notes.

Researchers commonly employ pCR as an intermediate endpoint for these trials. However, different studies describe pCR differently, so the FDA has come up with a standard definition: the absence of residual invasive cancer on standard hematoxylin and eosin evaluation of the resected specimen and all sampled ipsilateral lymph nodes, after therapy and surgery.

Additionally, the FDA draft guidance reviews best practices for such trials, including restricting patient selection to those with triple-negative breast cancer or other high-risk conditions, making sure that all patients continue to get standard-of-care treatment regardless of pCR status, and tracking recurrence in patients over multiple years.

The neoadjuvant concept “can provide patients who are at a very high risk of recurrence with an opportunity to receive promising drugs at an earlier time point and on a more widespread basis,” Prowell says. “It also provides industry with an incentive to develop these drugs in these patient populations, because suddenly there's a path to approval that does not take a decade to travel.”

“The FDA is tiptoeing into this, but it's the right step forward,” comments Lisa Carey, MD, associate director for clinical research at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“We're running out of ways to do clinical trials effectively in breast cancer,” Carey explains. “We've got a lot of great ideas but there's a limit on the number of clinical trials we can run, in an era when cancers are being subsetted biologically. You can't do a 5,000-patient trial in triple-negative breast cancer. We need more nimble approaches, and the neoadjuvant setting has proven to give a very good readout on cancer behavior in terms of responsiveness.”

An international working group known as Collaborative Trials in Neoadjuvant Breast Cancer is performing a meta-analysis on the relationship between pCR, disease-free survival, and overall survival, examining data from more than 12,000 patients enrolled in published trials. This study, whose results are expected to appear next year, will help to match up subgroups of breast cancer types, such as triple-negative or HER2 positive, with how likely pCR is to occur and how well it predicts long-term outcomes.

Carey expects that other intermediate measures, such as the Preoperative Endocrine Prognostic Index, also will evolve and be validated in neoadjuvant trials.

Neoadjuvant trials “are here to stay, and there would be more and more of them even without the [draft] guidance,” says Prowell. “But I think the guidance will increase the pace and motivate companies to consider it as a really promising pathway to get drugs to patients years earlier than under the old approach.”