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Expert Critique

FROM THE ASCO Reading Room

Rosana Gnanajothy, MD Hematology-Medical Oncology Attending Physician; Part-time Assistant Professor of Medicine Columbia University, NY; Bassett Medical Center, Mary Imogene Bassett Hospital

Neratinib was approved in 2017, after the ExteNET trial had shown improvement in invasive disease-free survival (iDFS), when used for 1 year after standard adjuvant trastuzumab. The 2-year iDFS rate was 93.9% in the neratinib arm versus 91.6% in the placebo arm (HR 0.67, 95% CI 0.49-0.90, P=0.0091). However, increased rates of grade 3 diarrhea (40% of treated patients), treatment-related hepatoxicity, and increased costs for a relatively small benefit, had led to resistance in adopting neratinib as a standard part of anti-HER2 adjuvant therapy.

The recent report at this year's ESMO congress of the updated 5-year preplanned data analysis from the ExteNET study showed slightly more benefit, with iDFS rates reported to be 90.2% in the neratinib arm and 87.7% in the placebo arm (HR 0.73, 95% CI 0.57-0.92, P=0.008). Interestingly, the beneficial effect was observed in the hormone receptor (HR)-positive subgroup and not the HR-negative subgroup. Experts believe this difference could be attributed to bidirectional signaling between ER and HER2 receptors, resulting in more anti-tumor activity when HR and HER2 receptor blockade is used simultaneously. Also a report on health-related quality-of-life (HRQol) scores between the neratinib and placebo groups showed a mild transient decrease in HRQol at the 1-month time point but no clinically significant difference at all other subsequent time points (months 3, 6, 9, and 12). This decline at month 1 was thought to be related to neratinib-associated diarrhea, which can be controlled with the current recommendation of diarrhea prophylaxis.

In summary, with the 5-year update of the ExteNET study showing moderate benefit and no significant decline in quality-of-life scores after 1 month, there may be a role for extended adjuvant neratinib in high-risk HR+/HER2-positive patients. The overall survival data expected in 2019 may shed more light on the benefit with extended anti-HER2-based adjuvant therapy.

Full Critique

Neratinib received approval from the U.S. Food and Drug Administration in July 2017 for the extended adjuvant treatment of adults with early-stage HER2-overexpressed/amplified breast cancer previously treated with adjuvant trastuzumab-based therapy.

The approval was based on the , a multicenter, randomized, double-blind, placebo-controlled phase III trial of neratinib following adjuvant trastuzumab. In the trial, 2,840 women with early-stage HER2-positive breast cancer who had completed adjuvant trastuzumab within 2 years were randomized in a 1:1 ratio to receive either neratinib or placebo for 1 year.

After 2 years, the rate of invasive disease-free survival (iDFS), the primary efficacy endpoint, was 93.9% in patients treated with neratinib compared with 91.6% in those receiving placebo (HR 0.67, 95% CI 0.49-0.90, P=0.0091).

Despite the use of trastuzumab-based therapy, up to 20% of breast cancer patients have recurrences after a median of 10 years. New adjuvant therapeutic options are therefore needed in this population, but the approval of neratinib for this indication proved controversial given the high rate of grade 3 diarrhea and the cost of additional therapy for just a small improvement in iDFS. About 40% of neratinib-treated patients had grade 3 diarrhea, and diarrhea led to discontinuation of neratinib in about 17% of patients; similarly, hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib-treated patients.

According to the approval, the FDA mandates that anti-diarrheal prophylaxis be initiated with the first neratinib dose and continued during the first two cycles (56 days) of treatment and as needed thereafter.

In an attempt to shed further light on the potential value of neratinib, investigators led by Miguel Martin, MD, head of Medical Oncology at the Hospital General Universitario Gregorio Marañón in Madrid, presented efficacy findings at the 2017 European Society for Medical Oncology (ESMO) congress from a preplanned 5-year analysis of data from ExteNET.

In addition, Suzette Delaloge, MD, of Institut Gustave Roussy in Villejuif, France, presented findings from a longitudinal evaluation of health-related quality of life (HRQoL), an exploratory endpoint of the ExteNET trial.

The findings from both studies suggest that a significant improvement in the rates of iDFS in patients with early-stage HER2-positive breast cancer who were treated with extended adjuvant neratinib came at the expense of a transient deterioration in HRQoL.

The preplanned 5-year analysis had been scrapped by the second study sponsor but was restored with a change in the sponsor. A total of 53 patients died during the initial 2-year follow-up, and 2,117 (76%) patients re-consented to additional data collection evenly distributed between neratinib and placebo.

Three-fourths of the overall study population had node-positive disease. In the re-consented population, 41% and 44% of patients in the neratinib and placebo arms, respectively, were hormone receptor (HR)-negative.

At 5 years, any iDFS event occurred in 8.2% of patients assigned to neratinib and 11.5% assigned to placebo. Reductions in the risk of distant recurrence (6.4% versus 7.8%), local/regional invasive recurrence (0.8% versus 2.5%) and invasive contralateral breast cancer (0.3% versus 0.8%) were observed in neratinib-treated patients compared with placebo. After a median follow-up of 5.2 years, the iDFS rates were 90.2% in the neratinib arm and 87.7% in the placebo arm (HR 0.73, 95% CI 0.57-0.92, P=0.008).

By HR status, neratinib demonstrated a benefit in the HR-positive subgroup. In this subset, the iDFS rate was 91.2% in the neratinib arm versus 86.8% in the placebo arm (HR 0.60, 95% CI 0.43-0.83, P=0.002). There was no significant difference in the rate of iDFS between study arms in the HR-negative subgroup, Martin reported: "The curves are almost super-imposable at the end of 5 years [in the HR-negative group]."

After treatment discontinuation, there was no evidence of long-term toxicity with neratinib versus placebo or late-term consequences from neratinib-associated diarrhea, he added, noting that overall survival data are not yet mature and are expected in 2019.

Small Changes in HRQoL

The other study demonstrated small changes in HRQoL with neratinib relative to placebo. About 1,200 patients in each arm of the study completed the Functional Assessment of Cancer Therapy -- Breast Cancer (FACT-B) and the general HRQoL EQ-5D questionnaires at baseline and again at months 1, 3, 6, 9, and 12. Changes in scores from baseline were measured, and changes were considered to be clinically meaningful if greater than the minimal clinically important differences (MCIDs) reported in the literature.

A decrease in HRQoL scores occurred in the neratinib arm at 1 month compared with placebo. The adjusted mean difference between groups was -2.9 points in the FACT-B total and -0.02 in the EQ-5D index in neratinib-treated patients. Between-group differences diminished at later time points. Except for the FACT-B physical well-being subscale at 1 month (-2.4), all between-group differences were less than MCIDs.

Delaloge and co-authors suggested that the neratinib-related diarrhea was possibly associated with decreased HRQoL in physical well-being at month 1.

Implications

In HER2-positive disease, a number of datasets show that biology differs based on the expression of hormone receptors, said the discussant for the study at the meeting, Hope S. Rugo, director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center.

In HER2-positive disease, not only does the rate of pathologic complete response vary based on HR status but recurrence patterns differ as well. "Despite HER2 gene amplification or overexpression, we're still seeing that estrogen receptor [ER]-like biology where patients continue to relapse well after 5 years," she said. "In HR-positive patients, the number of patients that relapse over time -- after trastuzumab -- seems to increase, whereas there seems to be a plateau in patients with HR-negative disease."

ExteNET showed continued demonstration of clinically significant benefit, particularly in higher risk, HR-positive disease despite limitations due to the change in sponsor and the initial plan for only 2 years of follow-up, Rugo said.

Why should neratinib work better in ER-positive disease? She pointed to the bi-directional signaling between ER and HER2, and the activation of HER2 downstream that leads to ER activation and relative resistance to endocrine therapy. "If you block HER2, you increase the transcriptional activity of ER-related genes. The combination of an anti-estrogen with a HER2 inhibitor results in enhanced anti-tumor activity.

"Every time we think about adding a new drug we need to do a risk-versus-benefit analysis," Rugo continued. "Diarrhea is a limiting factor, but it can be reduced significantly with prophylaxis, which is a mandatory component of treatment. The diarrhea with neratinib occurs in the first month -- "so you can definitely tell which patient is going to be at higher risk. After adjuvant trastuzumab for 1 year, it's possible that we will want to take patients with HR-positive disease and use a risk-based paradigm to decide who we should offer neratinib to for 1 year."

Also commenting about the study, Alexandra Zimmer, MD, of the National Cancer Institute's Women's Malignancies Branch, said in an NCI news release that although the high rate of side effects and the modest reduction in the recurrence rate means that neratinib is not likely to be used widely in patients with HER2-positive breast cancer, the use of neratinib could be considered in patients with early-stage HER2-positive breast cancer and with clinical features that indicate a higher likelihood of relapse, such as larger tumors or cancer found in axillary lymph nodes.