Neratinib Reduced Recurrences, Diarrhea Problematic in Phase III ExteNET Study
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Treatment with neratinib immediately following adjuvant trastuzumab (Herceptin) plus chemotherapy modestly improved invasive disease-free survival (DFS) against placebo at the cost of low-grade diarrhea in almost all patients with HER2-positive early-stage breast cancer. Findings for neratinib from a 2-year analysis of the phase III ExteNET study were presented by Arlene Chan, MD, at the 2015 ASCO Annual Meeting. The 2-year invasive DFS rate was 93.9% in the neratinib arm versus 91.6% with placebo, representing a 33% reduction in the risk of recurrence (hazard ratio [HR] = 0.67; 95% CI, 0.50-0.91; P = .009). However, 95.4% of patients treated with neratinib experienced all-grade diarrhea (39.9% was grade 3/4). "The primary analysis that was reported at 2 years only provides early outcome results, and clearly longer benefit in the form of overall survival benefit will require longer follow-up," Chan, director of the Breast Cancer Clinical Trials Unit at Mount Hospital in Perth, said during her presentation. "As expected with this class of drug, diarrhea was by far the most common adverse event seen. It is noteworthy that at the time of the study design there was no protocol-mandated antidiarrhea prophylactics put in place." In the phase III 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. The median age of patients in the study was 52 years. Across both arms, trastuzumab and chemotherapy were administered concurrently in approximately 62% of patients, with 38% receiving the drugs sequentially. The interval between receiving trastuzumab and entering the trial was approximately 4.5 months. Approximately 23.8% of patients had node negative disease, 46.6% had 1 to 3 positive nodes, and 29.6% had ≥4 positive nodes. Anthracyclines were administered as adjuvant chemotherapy in the majority of patients (77%). Appropriate endocrine therapy was administered to 94% of patients with hormone receptor (HR)-positive breast cancer. The primary endpoint of the study was invasive DFS at 2 years. Secondary outcome measures focused on DFS in patients with DCIS, CNS recurrence incidence, and 5-year overall survival (OS). Treatment with neratinib benefited patients across all subgroups for invasive DFS. Trends toward a greater benefit were seen in patients who were <35 years old at randomization (n = 101; HR = 0.43; 95% CI, 0.14-1.17) and those who received sequential trastuzumab and chemotherapy (n = 1070; HR = 0.48; 95% CI, 0.28-0.81). In the neratinib arm, 3.7% of patients experienced distant recurrence compared with 5.1% in the placebo arm. Central nervous system (CNS) metastases were seen in 0.9% of patients in the neratinib versus 1.1% with placebo. "Patients receiving neratinib experienced fewer episodes of regional recurrence, contralateral breast cancer, and most importantly fewer episodes of distant metastatic recurrence, with a numerically lower incidence of CNS recurrence," Chan said. In patients with DCIS, the 2-year DFS rate was 93.9% with neratinib versus 91.0% (HR = 0.63; 95% CI, 0.46-0.84; P = .002). "This translates into a 2.9% absolute benefit at the 2-year mark," Chan noted. In patients with HR-positive breast cancer (n = 1631), the 2-year invasive DFS rate with neratinib was 95.4% compared with 91.2% with placebo (HR = 0.51; P = .001). In the HR-negative group (n = 1209) the 2-year invasive DFS rate was 92% with neratinib and 92.2% with placebo (HR = 0.93; P = .735). "Of great interest, patients with hormone receptor-positive disease were observed to derive an even greater benefit with neratinib therapy. This translated into an absolute benefit of 4.2% at the 2-year mark," Chan said. "The underlying crosstalk mechanism that may explain the observed greater benefit in the hormone receptor positive cohort clearly requires evaluation in further study." In high-risk patients, the 2-year DFS rate was 92.9% with neratinib and 89.8% with placebo (HR = 0.66; P = .01). In patients with centrally confirmed HER2-positive disease, the benefit with neratinib was 94.7% versus 90.6% with placebo (HR = 0.51; P = .002). In addition to the high-rates of diarrhea, other gastrointestinal-related side effects included nausea (43%), fatigue (27%), vomiting (26.2%), and abdominal pain (24.1%). In the placebo arm, 35.4% of patients had all-grade diarrhea, with a grade 3/4 incidence of just 1.6%. "Patients experiencing grade 2 or 3 diarrhea, largely experienced this within the first 30 days of treatment, which is essentially what is observed with neratinib," Chan said. "Studies have shown that intensive loperamide therapy can reduce diarrhea to between 0% and 17%." Other adverse events of special interest included QT prolongation, which was less common in the neratinib arm (3.5% vs 6.6%). Left ventricular ejection fraction abnormalities of grade ≥2 were 1.3% with neratinib versus 1.1% with placebo. "Cardiac toxicity was infrequent, generally asymptomatic, and there was no significant difference between the two arms," Chan said. Following the initiation of the study in April 2009, the trial underwent several protocol adjustments, including changes to the patient population, primary endpoints, and the number of patients enrolled. Throughout these various alterations, which were accompanied by new trial sponsors, the independent data monitoring committee remained the same. Additionally, all data collection was consistent throughout the investigation. "There may also be some concerns that there were potential biases as a result of all of the protocol amendments," Chan said. "However, there was no observed difference in attrition rates between the two arms throughout the study." Neratinib continues to be explored for other indications within HER2-positive breast cancer. Additionally, the drug is being explored in non–small cell lung cancer and other solid tumors with HER2 mutations. |
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