The FDA ( U.S. Food and Drug Administration ) has approved 1 year of extended adjuvant Neratinib ( Nerlynx ) after chemotherapy and a year of Trastuzumab ( Herceptin ) for HER2-positive breast cancer on the basis of the ExteNET trial.
Many were surprised at the approval, since the evidence of benefit was slim and early, the toxicity severe, and the trial had been shortened and closed short of planned accrual ( presumably in despair ) by its first sponsor.
An extended analysis of the study out to 5 years was presented at the European Society for Medical Oncology ( ESMO ) 2017 Congress in Madrid.

Neratinib is an irreversible inhibitor of HER1, HER2, and HER4.
In a two-cohort phase II study, the drug produced a 56% response rate in patients with HER2-positive metastatic disease who had not received prior Trastuzumab and a 24% response rate in those who did get prior Trastuzumab.
Nausea, vomiting, and fatigue were common, but diarrhea was nearly universal ( 93% ) and severe in 21%. Diarrhea was worst in the first week of therapy, improved with Loperamide, which was recommended prophylactically, and 99% of patients could continue on the drug.

Neratinib increased the pathologic complete response rate by 23% when substituted for Trastuzumab and given with Paclitaxel in one arm of the I-SPY 2 trial.
Enthusiasm for the drug’s neoadjuvant development waned when ALTTO failed to confirm the adjuvant promise of Lapatinib ( Tykerb ) added to Trastuzumab based on a clearly improved rate of pathologic complete response in neoALTTO.

ExteNET was an attempt to show that extended Neratinib therapy after a year of Trastuzumab would prevent or delay metastatic disease and death.
When the Breast Cancer International Research Group ( BCIRG ) 006 trial showed that node-negative HER2-positive patients had a remarkably good prognosis with modern therapy, researchers acted to limit accrual of lower-risk ( node-negative ) patients to ExteNET, and also limited accrual to the first year after completion of Trastuzumab, since the relapse rate decreased over time.
Initially, entry was allowed up to 2 years after Trastuzumab completion.

In the ExteNET trial, Neratinib produced severe diarrhea ( grade 3 ) in 40% of those assigned to it, leading to dose reductions in 26% and treatment discontinuation in 17%. Perhaps as a result, accrual was stopped after 2,842 patients were enrolled ( of a planned 3,850 ) and shortened follow-up to 2 years.
The goal was presumably to limit monetary losses on a drug considered excessively toxic. Pfizer then sold the rights to Neratinib, first to Wyeth, then to the biotech start-up Puma, while retaining a small share of any ultimate profits if the drug ever achieved regulatory approval.

Puma, having no drugs on the market, decided to extend follow-up to 5 years in the patients who agreed to this ( 2,117 did so; 1,028 on Neratinib ).
The reconsented population had almost identical entry characteristics to the entire population.

The ExteNET results

Two-year survival free of invasive disease went from 91.6% for placebo to 93.9% for Neratinib ( hazard ratio [ HR ] = 0.67, P = 0.0091 ).
The initial analysis found most of the benefit in the hormone receptor–positive population ( HR = 0.51, P = 0.0013 ), with a hazard ratio of 0.93 ( P = 0.74 ) in the hormone receptor–negative patients ( P for interaction = 0.054 ).

No long-term toxicities were noted from Neratinib in the 5-year analysis.

The failure to significantly reduce distant metastases at 5 years in the entire study population suggests that Neratinib will not significantly reduce death in the entire population at 10 years, since the median survival after metastases appear is now almost 5 years if Pertuzumab ( Perjeta ) is used as part of initial metastatic therapy.
Thus, 5-year distant disease–free survival should predict 10-year overall survival.

In ExteNET, where no Loperamide prophylaxis was mandated or employed, 40% of patients had grade 3 or worse diarrhea ( greater than or equal to 7 stools per day or requiring hospitalization ). An additional 33% had grade 2 diarrhea ( 4–6 liquid stools per day ).
This was worst in the first month of therapy ( when about three-quarters of the grade 3 diarrhea occurred ).
There was still a 6% rate of grade 3 diarrhea after the third month, and grade 2 diarrhea had a frequency of 12% in month 12.

Dose reductions for diarrhea occurred in 26% of Neratinib patients, and 17% discontinued Neratinib for diarrhea at a median of 20 days after entry.
There was continued attrition from Neratinib therapy during the entire year of planned therapy.

In several small phase II studies sponsored by the neratinib manufacturer, with a month of prophylactic intensive-dose Loperamide starting with the first Neratinib dose of 240 mg, grade 3 diarrhea ranged from 10% to 17%. ( Xagena )

Source: ASCOPost, 2017