Earlier this year, neratinib (Nerlynx, Puma Biotechnology) was approved for extended adjuvant treatment of patients with early-stage human epidermal growth factor receptor–positive (HER2+) breast cancer who had already been treated with trastuzumab (Herceptin, Genentech/Roche).
But now that the drug is approved and available, which patients exactly should receive this new therapy?
This is the question addressed by Mariana Chavez-MacGregor, MD, and Elizabeth A. Mittendorf, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, writing in an editorial published online November 13 in the Lancet Oncology.
That editorial was prompted by the publication of a 5-year analysis of results from the ExteNET trial of neratinib, which was the pivotal study that led to the drug’s approval. These new results were not significantly different from the results at 3 years, presented in 2015, which were reported at that time by Medscape Medical News.
The ExteNET trial compared 1 year of treatment with neratinib vs placebo in patients with HER2+ early breast cancer who had already received trastuzumab for 1 year.
The 5-year results show that invasive disease-free survival (iDFS) was 90.2% for patients receiving neratinib vs 87.7% for patients in the placebo group (P = .0083). Previously reported 3-year iDFS rates were 90.5% and 88.6% for the neratinib and placebo groups, respectively (P = .023).
This is the benefit from taking neratinib for a year. But is this improvement in iDFS “worth the cost and side-effects associated with neratinib?” the editorialists ask.
The ExteNET researchers reported a 40% incidence of grade 3 diarrhea after neratinib treatment, so the drug’s approval came with a recommendation for antidiarrheal prophylaxis for the first two cycles of therapy (56 days).
The ExteNET authors indicate that emerging data from the phase 2 CONTROL/PUMA-NER-6201 study (NCT02400476) suggest that a prophylactic regimen of loperamide along with neratinib reduces the incidence, severity, and duration of neratinib-associated diarrhea.
The recommended dose of neratinib is 240 mg (six tablets) given orally once daily with food, continuously for 1 year.
In the United States, the estimated wholesale cost of a month’s supply of neratinib is reported to be $10,500 ($126,000 for a year).
There’s another observation that poses a riddle and is not consistent with findings seen with other HER2-targeted agents in the adjuvant/neoadjuvant setting.
In the ExteNET study, patients with hormone receptor (HR)–positive breast cancer benefited from extended adjuvant treatment with neratinib, whereas patients with HR-negative disease did not. This contrasts with previous findings from the neoadjuvant setting, in which HER2 blockade appears to have greater benefit in patients with HR-negative disease, the commentary indicates.
Where Does Neratinib Fit?
Neratinib’s manufacturer suggests that this drug is the next step in the progressive treatment of women with HER2+ early-stage breast cancer — neoadjuvant therapy, surgery, radiation, adjuvant therapy, and then neratinib. Advertisements for the drug show a woman stepping from adjuvant therapy into extended adjuvant therapy, having already navigated the steps of neoadjuvant therapy, surgery, and radiation.
However, a breast cancer expert approached for comment by Medscape Medical News, as well as the two editorialists, pointed out that extended neratinib is not needed for all patients with prior trastuzumab-based adjuvant therapy.
Lisa A. Carey, MD, professor of breast cancer research at the North Carolina Cancer Hospital, Chapel Hill, pointed out that even though neratinib was approved for a broad indication, the patient population in ExteNET predominantly had node-positive disease (about 77%), so the patient population fulfilled clinical high-risk criteria, but with a modest impact.
“There’s a lot of uncertainty about the best patient population for this indication,” she said. “Its greatest impact was in the highest-risk group with many involved lymph nodes,” she added.
But how, Dr Carey asked, does one better define a high-risk group of patients who would gain benefit from this drug? “We desperately need to have a better handle on what constitutes high-risk and targetable disease,” she added. “We need a better biomarker than lymph node positivity,” she said.
Patients in the ExteNET trial took trastuzumab for 1 year and then neratinib for another year, so they had a total of 2 years on HER2-targted therapy, she pointed out. “It’s not trivial. Patients are going through a lot for a little [benefit].”
A separate consideration is that neratinib is an oral drug, so with co-pays considerable financial toxicity may be passed on to the patient, she added.
“Even though it is a positive study, neratinib’s role may be fairly limited,” she said. “We need a better clarity on who needs this drug and who will benefit from it,” she emphasized.
Alexandra Zimmer, MD, from the Women’s Malignancies Branch in the National Cancer Institute (NCI) Center for Cancer Research, agrees. In an NCI blog, she explained that despite the approval, several factors — the modest reduction in the recurrence rate, the fact that data on overall survival are not yet available, and the high rate of side effects — mean that neratinib is unlikely to be widely used.
“It’s important for patients to realize that FDA [US Food and Drug Administration] approval doesn’t mean the drug is now indicated for every HER2-positive breast cancer patient after one year of trastuzumab treatment,” Dr Zimmer wrote. “It’s another option for therapy that’s available, and patients should carefully discuss it with their doctors, to consider benefit versus side effects in every case.”
Dr Carey also pointed out that the patient population in ExteNET was heterogeneous. The impact of neratinib was seen more in patients from Asia, eastern Europe, and South America and less in patients from North America, Western Europe, Australia, and South Africa, she explained.
Of other HER2-based adjuvant approaches, data from APHINITY reported a significantly reduced risk for iDFS when pertuzumab (Perjeta, Roche/Genentech) was added onto trastuzumab and chemotherapy, compared with trastuzumab and chemotherapy in the adjuvant setting.
In their editorial, Dr Chavez-MacGregor and Dr Mittendorf ask whether dual antibody treatment with pertuzumab and trastuzumab followed by neratinib should now be considered in patients at high risk, even though whether neratinib offers additional benefit after pertuzumab benefit remains unknown. “It is unlikely that clinical trials will answer those questions,” they write.
Dr Carey agreed. She explained that because pertuzumab was approved in the neoadjuvant setting, clinicians have been prescribing it in the adjuvant setting based on recommendations from the National Comprehensive Cancer Network. “We do not know if there is a benefit of neratinib after pertuzumab,” she said.
“For now, we are left with the data and our clinical judgment,” Dr Chavez-MacGregor and Dr Mittendorf write.
They agree with Dr Carey and indicate that it is difficult to justify neratinib treatment for patients with node-negative disease who will have excellent outcomes with paclitaxel and trastuzumab.
For patients with node-positive disease, adding or extending adjuvant treatment will probably be based on individual patient risk — with some physicians being comfortable with extended adjuvant neratinib for patients with at least four positive lymph nodes or patients with HR-positive disease within 1 year of trastuzumab treatment.
“I will not consider it in patients with node-negative disease,” Dr Carey said. “I would consider it in patients with at least four or more positive lymph nodes and HR-positive disease,” she added.
Prescribing neratinib “will be a difficult balancing act — a shared decision-making process — in which we must balance the small benefit in outcomes with the not so minimal costs and side-effects,” Dr Chavez-MacGregor and Dr Mittendorf conclude.
No Data on Survival
The approval of neratinib was met with criticism from the breast cancer advocacy group Breast Cancer Action. Executive director of the group, Karuna Jaggar, noted the high cost of treatment, minimal clinical benefit from a surrogate endpoint (iDFS), and the absence of survival data. “A so-called ‘surrogate endpoint’ like invasive disease free survival that is not clinically significant may be useful in guiding the development of experimental treatments, but it cannot replace the outcome that patients and doctors ultimately care about: women actually living longer, or at least living better with fewer side effects,” she noted.
“With the approval of neratinib, the FDA has once again approved an experimental drug that has not been shown to lengthen or improve breast cancer patients’ lives — either by helping them live longer or live better, with fewer side effects,” she wrote. “It [the approval] means that thousands of cancer patients each year are exposed to expensive, toxic treatments that don’t actually help them live longer,” she said.
The ExteNET study was funded by Wyeth, Pfizer, and Puma Biotechnology. Most ExteNET authors have reported relevant financial relationships (grants, personal fees), which are listed at the end in the publication. In addition, several authors are employees of Puma Biotechnology. Dr Chavez-MacGregor, Dr Mittendorf, and Dr Carey have disclosed no relevant financial relationships.
Lancet Oncol. Published online November 13. Abstract, Comment
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