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FDA advisory committee largely supports neratinib approval for early-stage HER-2–positive breast cancer
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An FDA panel today largely expressed its support for the approval of neratinib in the adjuvant treatment of early-stage HER-2–positive breast cancer.
The Oncologic Drugs Advisory Committee (ODAC) voted 12-4 in favor of Puma Biotechnology’s new drug application for neratinib (Nerlynx, Puma Biotechnology).
Neratinib — an oral, irreversible pan-HER tyrosine kinase inhibitor that blocks signal transduction through epidermal growth factor receptors of HER-1–, HER-2– and HER-4–mutant tumors — is proposed for use as a single agent for extended adjuvant treatment of adults with early stage HER-2–positive breast cancer who have received adjuvant therapy with trastuzumab (Herceptin, Roche).
The panel reviewed data and modifications from the ExteNET study — a multicenter, randomized, double blind, placebo-controlled trial that compared neratinib with placebo in 2,840 women after adjuvant treatment with trastuzumab — as well as the drug’s safety profile and the risk–benefit ratio in this patient population.
Invasive DFS within 2 years and 28 days served as the study’s primary endpoints.
Patients treated with neratinib demonstrated an estimated 2.3% difference in invasive DFS at 2 years (94.2% vs. 91.9%; HR = 0.66; 95% CI, 0.49-0.9) compared with the placebo arm.
However, an exploratory subgroup analysis demonstrated a difference in the magnitude of benefit between those with hormone receptor–positive disease (HR = 0.49; 95% CI, 0.31-0.75) and hormone receptor–negative disease (HR = 0.93; 95% CI, 0.6-1.43).
“Although significant advances have been made in treating HER-2–positive breast cancer, patients remain at risk for recurrence and death after adjuvant trastuzumab,” said Joyce O’Shaughnessy, MD, medical director of Texas Oncology-Baylor Charles A. Sammons Cancer Center, who provided the clinical perspective on neratinib during the meeting on behalf of Puma Biotechnology. “Neratinib’s effectiveness in preventing disease recurrence greatly outweighs the risk. We need neratinib as another option for our patients.”
Extended follow-up after 5 years demonstrated an absolute difference of 2.5% between the neratinib arm (90.2% vs. 87.7%; HR = 0.73; 95% CI, 0.57-0.92) and the placebo arm.
Despite these data, the panel observed that trial researchers made amendments to the protocol and there were multiple changes of sponsor control throughout the trial. Changes specifically included that researchers enriched the study population with high-risk patients, shortened the study follow-up from 5 years to 2 years, changed the analysis from event driven to time driven, and introduced extended follow-up to 5 years in a reconsent process.
“These results demonstrated a consistent trend in favor of neratinib; however, given the degree of missing data, the true magnitude of benefit remains uncertain,” Amanda Walker, MD, medical officer for the FDA, said during the meeting.
Researchers evaluated safety data from 1,408 patients who received neratinib.
Diarrhea occurred in 95% of those evaluated, with 40% of patients reporting with severe diarrhea.
Other adverse reactions included nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite and muscle spasms.
Overall, 28% of patients discontinued treatment due to an adverse event.
An ongoing phase 2 study has suggested that loperamide, an antidiarrheal prophylaxis, may decrease the incidence and severity of diarrhea in this patient population.
“Neratinib-associated diarrhea typically occurs early and diminishes with time and is manageable with antidiarrheal prophylaxis and patient education,” Hope Rugo, MD, professor of breast oncology at University of California, San Francisco Medical Center, said during the applicant presentations. “Diarrhea is a common side effect of adjuvant therapies for HER-2–positive breast cancer; therefore, we have to manage diarrhea proactively because, more than any other side effect, it affects tolerability, which is important for adherence to therapy.”
The FDA is expected to make its final decision on neratinib by July 21, but the agency is not obligated to follow the opinion of ODAC. – by Kristie L. Kahl