Hope Rugo, MD, discusses how to balance the benefits and risks of neratinib, as well as unanswered questions regarding ExteNET, in patients with HER2-positive breast cancer.
Hope Rugo, MD
Neratinib immediately following adjuvant trastuzumab (Herceptin) plus chemotherapy resulted in a 33% reduction in the risk of disease recurrence in patients with early-stage, HER2-positive breast cancer, but the benefit comes with toxicities in nearly all patients.
In the phase III ExteNET study, 2840 patients who remained disease-free following 1 year of treatment with adjuvant trastuzumab and chemotherapy were randomized to receive either neratinib (n = 1420) or placebo (n = 1420).
A 2-year analysis of the trial found that the invasive disease-free survival (DFS) was 93.9% in the neratinib arm versus 91.6% in the placebo arm (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, with 39.9% experiencing grade 3 or 4. In the placebo arm, 35.4% of patients had all-grade diarrhea, with a grade 3/4 incidence of just 1.6%.
Other gastrointestinal-related side effects were also observed in the neratinib arm, including nausea (43%), fatigue (27%), vomiting (26.2%), and abdominal pain (24.1%).
To understand how to balance the benefits and risks of neratinib, as well as unanswered questions regarding ExteNET, OncLive spoke with Hope Rugo, MD, clinical professor, Department of Medicine (Hematology/Oncology), and director, Breast Oncology Clinical Trials Program, at UCSF Helen Diller Family Comprehensive Cancer Center.Dr Rugo: Neratinib has been met with some difficulty in the metastatic setting, mainly because of its tolerance. The drug was given without any preventive diarrheal therapy and it causes diarrhea in the majority of patients. Unlike some other drugs, including pertuzumab, it causes diarrhea right away. This causes patients to stop the drug early, hold treatment, or reduce the dose immediately. That is one of the reasons why the metastatic trials did not show as good of results as we thought they should have.
However, in the ExteNET trial, they treated a different group of patients. These are patients who completed 1 year of adjuvant trastuzumab and largely received anthracycline and taxane-based chemotherapy. They were randomized to receive either 1 year of neratinib or placebo. Part of the way through the study, a greater understanding of how to manage diarrhea was determined. That resulted in more effective management, even though they were not routinely prophylaxed, which is the standard right now. However, if you prophylax, the rate of diarrhea could go down in these patients. It could really make a big difference.For the first 700 or so patients included in the ExteNET trial, it was possible to have had a pathologic complete response (pCR) to neoadjuvant chemotherapy and to have stage I disease and node-negative disease and still be enrolled. After approximately 700 patients, they changed the trial to eliminate stage I patients who had node-negative disease and also those patients who had a pCR. That was a really important change because that meant that in the trial, which had over 2000 patients enrolled, the largest number of patients had at least stage II breast cancer and no pCR. That is very helpful.
Last year, it was announced that the patients who had received neratinib had a better 2-year DFS. It is important to think about this trial’s endpoint. The drug had not worked as well as they had hoped in the advanced setting, and I believe they changed the trial endpoint to not be a long-term one, but to basically say, “If we do not have a benefit of 2 years, we are done.” Therefore, the endpoint was decided to be 2 years. However, now they have extended that endpoint to 5 years. That long-term data will be important.We have finally seen the data from the ExteNET trial and there was no difference in what we expected in terms of toxicity, but there was an improvement in DFS at 2 years. However, the improvement is very small in the population as a whole. It may not be enough for oncologists to want to administer neratinib to patients when they will have to prophylax against diarrhea. For patients after 1 year of survival, they want to be done, and they feel like you have said to them, “You have HER2-positive disease, your chances of being cured are great.” But then, we say to them, “Now we want you to take a pill, you are still going to be a patient, have side effects, and need blood tests for a year” when the overall chance of DFS is small. It is something to think about when selecting patients.Researchers were able to look at the differential benefit in ER-positive versus ER-negative disease and they had a lot of patients in the ER-positive subset. In those patients, the difference was over 4% and that is considerable. It is a clinically meaningful difference for us.
If the drug is available to us, we should consider using neratinib in patients who have high-risk ER-positive breast cancer because that is a tough population for us. These are patients who relapse late, and if we could prevent that late relapse in these patients, that would be fabulous. Perhaps it is the overlap of neratinib and hormone therapy that is so critical in those patients.
However, I really think that there is a group of patients who have ER-positive, very high-risk HER2-positive disease where neratinib could really play a big role. I would like to tease out the group of patients who do not have a pCR and have ER-negative disease to know whether neratinib has the same impact in that group of patients. That is what is happening in the ER-positive group.Adding neratinib to pertuzumab and trastuzumab is a possibility. If the AFFINITY trial is positive, we are going to get pertuzumab now for a year. If we add neratinib, we could possibly further reduce risk of recurrence. This will need to be determined in a trial. It will be studied, we hope, in an I-SPY—type neoadjuvant trial along with chemotherapy. That will be fascinating.
If it turns out to be safe to give that triplet, my guess is that oncologists may start the neratinib early, so that they can shorten the duration of time patients receive the treatment.
Chan A, Delaloge S, Holmes FA, et al. Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). J Clin Oncol. 2015;33 (suppl; abstr 508).