Neratinib Extends Invasive DFS in HER2-Positive Early-Stage Breast Cancer

Neratinib Extends Invasive DFS in HER2-Positive Early-Stage Breast Cancer

One year of neratinib improved the rate of invasive disease–free survival (iDFS) compared to placebo in patients with HER2-positive, early-stage breast cancer who had undergone prior adjuvant therapy with chemotherapy and trastuzumab, according to results of a randomized phase III trial (Abstract 508).

Dr. Arlene Chan

Arlene Chan, MD, of the Breast Cancer Research Centre at Western Australia and Curtin University, Australia, presented results of the ExteNET study during the “Breast Cancer—HER2/ER” Oral Abstract Session on Monday, June 1.

“Despite the survival gains that have been achieved with the administration of adjuvant trastuzumab and chemotherapy… up to one-quarter thus treated will still experience a breast cancer event,” Dr. Chan said. “To date, no treatment strategies have been shown to reduce this relapse rate.”

Neratinib, an oral tyrosine-kinase inhibitor of HER1, HER2, and HER4, showed promise in this patient population in a phase II trial. In the phase III study presented by Dr. Chan, 2,840 women with HER2-positive breast cancer and prior adjuvant trastuzumab and chemotherapy were randomly assigned to receive either 240 mg/day of neratinib for 1 year or placebo (1,420 patients in each arm).


Click to Expand.


The primary endpoint was iDFS. At 24 months, patients who received neratinib had an iDFS rate of 93.9% compared to 91.6% in the placebo group (hazard ratio [HR] 0.67, 95% CI [0.50, 0.91]; p = 0.009). Dr. Chan said it is too early to assess the cohort for overall survival benefits.

There were a total of 109 iDFS events in the placebo group, compared with 70 events in the neratinib group. There were 73 distant recurrences (5.1%) in the placebo group, and 52 (3.7%) in the neratinib group. The results were confirmed in analyses of two prespecified subpopulations, including a higher-risk group and a centrally confirmed HER2-positive group.

The secondary endpoint of DFS including occurrence of DCIS was also significantly in favor of neratinib at 93.9% compared with 91.0% for placebo (HR 0.63, 95% CI [0.46, 0.84]; p = 0.002).

Dr. Shanu Modi
 “Patients with hormone receptor–positive disease were observed to derive an even greater benefit with neratinib therapy,” Dr. Chan said. In that group, iDFS rates were 95.4% for neratinib and 91.2% for placebo (p = 0.001). There was no significant difference in the patients with hormone receptor–negative disease (92.0% vs. 92.2%). 

Diarrhea was the most common adverse event with neratinib; grade 3/4 diarrhea occurred in 39.9% of patients compared with 1.6% of patients who received placebo. Dr. Chan said that grade 3 diarrhea could be reduced to between 0% and 17% with intensive loperamide prophylaxis.

Discussant Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, addressed why this trial showed a 33% decreased risk of recurrence when other attempts, such as those in the HERA and ALTTO trials, were not successful. Possible reasons include the crossover to a drug with a different mechanism of action and that neratinib was given to patients after all chemotherapy and trastuzumab had been completed. She said that overall survival data are still needed before neratinib could be considered a new standard, and questions remain about which populations will benefit from this therapy.

Watch the session: Visit the ASCO Virtual Meeting website.