Results from the randomized, phase 3 placebo-controlled ExteNET clinical trial led to the approval of neratinib as extended adjuvant therapy after trastuzumab-based adjuvant therapy in women with early-stage HER2-positive breast cancer. The trial showed that a 1-year course of neratinib significantly improved invasive disease-free survival (iDFS) after a median follow-up of 2 years. Patients have now been followed through to 5 years, and analysis shows that iDFS improvements with neratinib were sustained and remained statistically significant compared with placebo.
In the trial, the rate of patient dropout varied among groups, with more patients in the neratinib group ending treatment early (≤3 months), mainly because of adverse events (most often diarrhea) occurring during treatment.
“What we’ve been looking at is tolerability, and the main toxicity of neratinib is diarrhea,” said Dr Bryce. “The ExteNET trial did not have prophylaxis for diarrhea, so we wanted to know the effect that had on early discontinuation.”
This exploratory analysis used the 5-year data set from ExteNET. The researchers conducted the analysis by dividing patients into 2 cohorts: those who discontinued early (≤3 months) versus patients who stayed on the study for ≥11 months or had a qualifying event (ie, progression within 11 months).
The US label (intent-to-treat [ITT]) population comprised 2840 patients: neratinib for ≤3 months (N = 391) and neratinib for ≥11 months (N = 872). The EU label population (hormone receptor–positive and prior trastuzumab therapy ≤1 year) comprised 603 patients: neratinib for ≤3 months (N = 201) and neratinib for ≥11 months (N = 402). The 5-year iDFS rates by duration of neratinib therapy in the ITT and EU label populations revealed an absolute difference at 5 years of 3.3% with neratinib (91.0%) versus placebo (87.7%), compared with a 0.7% absolute difference in patients who discontinued treatment before 3 months: 88.4% with neratinib and 87.7% with placebo.
In the hormone receptor–positive group (EU label), the absolute difference in outcomes at 5 years was even greater: 7.4% for patients who stayed on adjuvant treatment for ≥11 months versus 0.2% for patients who discontinued treatment early. “We were able to show that if patients discontinued early, that had a significant negative effect on outcomes versus those patients who managed to stay on treatment for 11 months or longer,” said Dr Bryce. “The whole crux of this research is, stay on treatment longer and you’re obviously going to get a better benefit. And this is the first time we’ve quantifiably shown what that benefit was.”
To reduce the risk of disease recurrences in this patient population, the investigators concluded that early management is needed to allow patients to stay on neratinib therapy.
The phase 2 CONTROL clinical trial (results to be published soon) has investigated several strategies to improve neratinib tolerability, and data show that tolerability is improved with preemptive prophylaxis or neratinib dose escalation. Using these strategies, treatment discontinuations have been reduced since ExteNET was completed, allowing patients the potential benefit of a full year of extended adjuvant neratinib therapy.
Dr Bryce noted that when the ExteNET trial began in 2011, there was no prophylaxis against diarrhea available.
“But now, a number of mechanisms—particularly data from the CONTROL study—will show that using either dose escalation of neratinib or loperamide as prophylaxis will actually get these women through the 3 months, and hopefully, enable them to complete the year of treatment,” Dr Bryce said. “The whole basis is, stay on longer and you get a much better treatment effect than discontinuing early.”