FDA Panel Backs Novel Anti-HER2 Drug for Breast Cancer

WASHINGTON -- Another potential drug for HER2-positive breast cancer received strong numeric support from an FDA advisory committee, tempered by reservations about a broad indication, modest clinical benefit, and toxicity issues.

By a 12-4 vote, the Oncologic Drugs Advisory Committee (ODAC) supported FDA approval of the dual HER2/EGFR inhibitor neratinib for early HER2-positive breast cancer that relapses after trastuzumab (Herceptin) maintenance therapy.

Primary support for the approval bid came from the randomized phase III ExteNET Trial, which showed a 2-year disease-free survival (DFS) of 94.2% with neratinib and 91.9% with placebo. The difference represented a 34% reduction in the risk of recurrence with neratinib (95% CI 10%-51%, P=0.008).

A sensitivity analysis of 5-year results in the intention-to-treat population (n=2,840) supported the primary analysis, showing a 27% reduction in the DFS hazard in favor of neratinib. The analysis involved contacting patients to obtain consent for the extended follow-up (reconsent), and about three-fourths of the patients were included.

A prespecified subgroup analysis showed that patients with hormone receptor (HR)-positive disease derived greater benefit from neratinib, which drove the overall results (HR 0.49 versus placebo at 2 years, HR 0.60 at 5 years). In contrast, patients with HR-negative tumors did not derive a significant benefit from neratinib (HR 0.93, HR 0.95 at 2 and 5 years, respectively).

Similarly, patients who started neratinib ≤1 year after completing adjuvant trastuzumab (n=2,297) had a significant reduction in the DFS hazard (HR 0.63, HR 0.70 at 2 and 5 years), whereas patients who started neratinib later did not (HR 0.92, HR 1.00).

The proposed indication for neratinib does not specify patient selection by HR receptor status or time interval since the completion of adjuvant trastuzumab. Even ODAC members who voted in favor of neratinib approval acknowledged those issues, as well as a risk of potentially severe diarrhea without premedication.

"I have a lot of the same concerns that you've already heard," said Stanley Lipowitz, MD, PhD, of the Women's Malignancy Branch of the National Cancer Institute. "It clearly has efficacy in HER2-positive breast cancer, based on metastatic, neoadjuvant, and now this intention-to-treat analysis from a post-adjuvant study. There is clear benefit. There is an unmet need in patients who relapse after adjuvant therapy.

"There's clearly toxicity associated with this drug, and a significant number of patients won't continue it. That's something that is concerning, but as you heard, it can be managed ... There are some unknowns that concern me. There is a broad indication here, and as an oncologist, I would have some thoughts about which patients would I treat with it, and I don't think I would treat as broadly as the indication."

Lori M. Minasian, MD, also of the NCI Women's Malignancy Branch, voted in favor of approval, but called on the sponsor, Puma Biotechnology, to conduct more research aimed at identifying biomarkers of response, so as to reduce the chances of giving the drug to patients who won't benefit from it.

Harold Burstein, MD, of Dana Farber Cancer Institute in Boston, found the data for the HR-positive subgroup of patients compelling and acknowledged that the drug might provide substantial benefit to selected patients. Nonetheless, he voted against approval, citing the broadness of the proposed indication.

"I was not persuaded that there is a clinical signal of activity that would justify even modest side effects," said Burstein. "I appreciate that the point that these are generally reversible and the patients and their medical team can choose, but the effects were shown to affect quality of life somewhat adversely."

Existing data for the drug in the neoadjuvant and metastatic settings also failed to provide compelling evidence of activity, he added.

Two breast cancer specialists who participated in clinical trials of neratinib spoke to the panel as part of the sponsor's presentation. Hope Rugo, MD, of the University of California San Francisco, reviewed data to show that the risk of potentially severe diarrhea with neratinib was recognized early, and strategies were developed to ameliorate the problem. She pointed out that diarrhea is an expected on-target adverse effect of EGFR inhibitors.

In the phase III trial, 95% of neratinib-treated patients developed diarrhea, including a 40% incidence of grade 3/4 diarrhea. A fourth of patients had diarrhea that led to dose reduction, a third had dose holds or interruptions, and 17% of patients treated with neratinib discontinued treatment because of diarrhea. Aside from diarrhea, adverse events were uncommon with neratinib.

Ongoing studies are investigating premedication with loperamide and loperamide-based antidiarrheal combinations. Preliminary data from the studies have demonstrated reductions in the frequency and severity of diarrhea in patients treated with neratinib.

ExteNET investigator Joyce O'Shaughnessy, MD, of Baylor University Medical Center in Dallas, emphasized that relapse in the post-adjuvant setting of HER2-positive breast cancer represents a substantial unmet clinical need. No FDA-approved therapy has demonstrated improvement in benefits of trastuzumab in the adjuvant setting.

Neratinib demonstrated a statistically significant improvement in DFS in that setting. O'Shaughnessy said she witnessed the improvement in some of her own patients and that as a practicing oncologist, she would like to have the drug available as another option for her patients.

The FDA staff reported several amendments to the trial protocol that could have influenced the results: enrichment of the study population with high-risk patients; follow-up reduced from 2 to 5 years and the primary analysis from event driven to time driven; and use of a reconsent process to extend follow-up to 5 years post-randomization.

Comment