The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 12-4 recommending approval of neratinib (Nerlynx) for the extended adjuvant treatment of patients with early stage, HER2-positive breast cancer following postoperative trastuzumab (Herceptin).UPDATE 7/17/2017: FDA Approves Neratinib for HER2+ Breast Cancer
ODAC based its recommendation on data from the phase III ExteNET trial and the phase II CONTROL trial. In the primary analysis of the ExteNET trial, the invasive disease-free survival (iDFS) rate at 2 years was 94.2% with neratinib versus 91.9% with placebo (stratified hazard ratio [HR], 0.66; 95% CI, 0.49-0.90; stratified log-rank P
-value [two-sided] =.008).
The results indicated that the benefit may vary based on hormone receptor (HR) status. An exploratory subgroup analysis indicated that neratinib lowered the risk of recurrence by 51% (HR, 0.49; 95% CI, 0.31-0.75) in HR-positive patients, compared with 7% in HR-negative patients (HR, 0.93; 95% CI, 0.60-1.43).
Diarrhea was the primary safety concern with neratinib considered by the panel, as 95% of patients in the ExteNET trial who received the tyrosine kinase inhibitor experienced the adverse event (AE), including grade 3 diarrhea in 40% of patients. Diarrhea led to study discontinuation for 16.8% of patients. However, results from the ongoing phase II CONTROL trial suggest that antidiarrheal prophylaxis can control the occurrence and severity of diarrhea among patients receiving neratinib.
Beyond safety, another concern addressed by ODAC were the numerous amendments to the ExteNet study protocol, the effects of which included enriching the study population with high-risk patients; reducing the trial follow-up interval from 5 years to 2 years—changing the assessment from event-driven to time driven; and implementing a reconsent process to increase follow-up to 5 years after randomization. However, despite the amendments, data from sensitivity analyses were enough to assure the panel that neratinib had a positive effect in this patient population.
The FDA will now make its final decision on neratinib. The agency is not required to follow the ODAC recommendation.
Explaining his “yes” vote, panelist Andrew D. Seidman, MD, said, “The results look durable…[and] I’m reassured by the rigorous statistical analyses that were applied, given the changes in study design along the evolution of the trial.”
“I think that physicians will select patients very carefully when using [neratinib],” added Seidman, an attending physician in the Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, and a professor of medicine at Weill Cornell Medical College.
In the ExteNET study, 2840 patients who remained disease-free following 1 year of treatment with adjuvant trastuzumab and chemotherapy were randomized to neratinib (n = 1420) or placebo (n = 1420). Neratinib was administered for 12 months at 240 mg per day. In the final study amendment, the primary endpoint was iDFS at 2 years and 28 days from randomization.
The median age of patients in the study was 52 years and approximately 24% had node negative disease, with 47% of patients having 1 to 3 positive nodes and 30% having ≥4 positive nodes. Anthracyclines were administered as adjuvant chemotherapy in the majority (77%) of patients. Appropriate endocrine therapy was administered to 94% of patients with HR-positive breast cancer.
Beyond the primary analysis data, additional follow-up data from 2 to 5 years post randomization were submitted from an exploratory iDFS analyses that occurred after the implementation of a reconsent process.
Overall, 2117 (74.5%) of the 2840 primary analysis patients reconsented, including 1028 patients in the neratinib cohort and 1089 patients on the placebo arm. Baseline characteristics were similar between the reconsented and primary analysis populations, as well as between the 2 cohorts in the reconsent analysis.
In the updated analysis, the 2-year iDFS was 94.3% in the neratinib arm versus 91.7% in the placebo group. The 5-yeasr iDFS rates were 90.2% and 87.7%, respectively. The stratified hazard ratio was 0.73 (95% CI, 0.57-0.92; stratified log-rank P
-value [two-sided] =.008).
The safety analysis for the primary ExteNET data review was based on 1408 patients from the neratinib arm and 1408 patients from the placebo arm. The median duration of exposure to neratinib and placebo was 11.6 months and 11.8 months, respectively.
In the neratinib arm, grade 3/4 AEs occurred in 50% of patients and led to treatment discontinuation in 28% of patients. The most common AEs leading to neratinib discontinuation were diarrhea (16.8%), vomiting (3.8%), and nausea (2.8%). In the neratinib arm, 7.3% of patients experienced non-fatal serious AEs, the most frequent being diarrhea in 22 patients versus 1 patient in the placebo arm.
Although patients in the ExteNET study were not required to receive antidiarrheal prophylaxis, the ongoing, open-label phase II CONTROL trial examined the preventative measure in HER2-positive patients who received neratinib for 1 year along with antidiarrheal prophylaxis given during the first two 28-day treatment cycles.
At the January 13, 2017, data cutoff, 137 patients had received prophylaxis with loperamide alone, 64 patients had received loperamide plus budesonide, and 10 patients had received loperamide plus colestipol. The median duration of neratinib treatment for the 3 cohorts was 9.07 months, 2.83 months, and 0.56 months, respectively.
Comparing the loperamide-alone CONTROL cohort to the safety data cohort from the ExteNET trial (n = 1408), the incidence of all-grade diarrhea was 77% versus 95%, respectively. The rates of grade 3 diarrhea were 31% versus 40%, respectively.
The rate of dose reductions (7.3% vs 26.4%) and holds (13.9% vs 33.9%) due to diarrhea were lower in the patients who received loperamide. However, the rate of discontinuation due to diarrhea was higher in the loperamide cohort at 20.4% versus 16.8% with neratinib alone.