Neratinib Promising for Early-Stage HER2+ Breast Cancer, But Has Caveats

Mohammed Rahman, MD

The pan-HER TKI neratinib (Nerlynx) demonstrates efficacy as an adjuvant therapy for patients with HER2-positive breast cancer; however, the associated adverse events (AEs) provide some patient selection challenges, explained Mohammed Rahman, MD.

“I think all-in-all, it’s an attractive treatment. The only downside of it is gastrointestinal toxicity—the diarrhea rate in the ExteNET trial was almost 90%, but more importantly, grade 3 diarrhea was close to 39% or 40%,” said Rahman. “However, if doctors are very aggressive with antidiarrheal management, these [events] can be managed easily and effectively. We can actually get the numbers down with various remedies to maybe single-digit figures in terms of grade 3 diarrhea toxicity.”

The FDA approved neratinib (Nerlynx) in July 2017 to prevent recurrence in patients with early-stage HER2-positive breast cancer who had completed at least 1 year of adjuvant therapy with trastuzumab (Herceptin).

The regulatory decision was based on data from the multicenter, double-blind, phase III ExteNET trial, which enrolled 2840 women with early-stage HER2-positive breast cancer who within 2 years of completing adjuvant trastuzumab, were randomized to receive either neratinib (n = 1420) or placebo (n = 1420) for the duration of 1 year.

The primary outcome for the trial was invasive disease-free survival (iDFS), which was defined as time between randomization date to the first occurrence of invasive recurrence, distant recurrence, or death from any cause within 2 years and 28 days of follow-up. After 2 years, investigators reported a 94.2% iDFS in patients who received neratinib versus 91.9% in patients who received placebo (HR, 0.66; 95% CI, 0.49-0.90; P = .008). Five-year follow-up data showed an iDFS rate with neratinib of 90.2% (95% CI, 88.3-91.8) versus 87.7% (95% CI, 85.7-89.4) with placebo.

Patients who received neratinib were also more likely to experience severe diarrhea compared with those who received placebo; diarrhea was the most common AE that led to discontinuation of treatment. Due to the high rate of AEs among other factors, patient selectivity is key, Rahman added.

OncLive: What are the key findings from the ExteNET trial?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Rahman discussed ongoing efforts to optimize the use of neratinib in patients with HER2-positive breast cancer.Rahman: Neratinib is a pan-HER TKI, which blocks pan HER domains on the cancer cells—specifically, HER2, HER1/EGFR, and HER4.

What it showed was the use of neratinib after completion of trastuzumab in the adjuvant setting. If we extend it by 12 months, the iDFS is extended by an absolute 2.4%. Now, if you look at subgroup analyses, if the patients were hormone receptor (HR)—positive, their iDFS showed an absolute difference of almost 4.4%.

It was interesting that further subclassification showed that if neratinib was started as early as possible in a fit patient with HER2-positive, estrogen receptor (ER)—positive breast cancer, who has not shown evidence of progression of disease and who has had their HER2 testing done at a central location, the absolute benefit from this treatment was more than 7%. In the setting of adjuvant HER2-positive breast cancer—which is a disease that still has about a 26% recurrence in the first 10 years—that is a very provocative result and oncologists in the United States should take that seriously.

Is neratinib’s use in the adjuvant setting impacted at all by pertuzumab’s indication in both the neoadjuvant and adjuvant settings?

The other important thing that is coming out of the neratinib data—not just in the ExteNET trial, but other trials, such as I-SPY 2 or NEfERT-T—is [that it penetrates] the central nervous system (CNS). As this is a small molecule TKI, it seems to be very effective, and there is a 50% reduction in the formation of CNS metastases.That is an open question because neratinib and pertuzumab have similar toxicity profiles; they both cause diarrhea. Therefore, it is very difficult for patients to complete pertuzumab and then you tell them, “Well, I’m going to give you a drug that’s going to cause diarrhea.”

But, it goes back to residual disease burden. If you have a very high-grade tumor that was large at outset, and after neoadjuvant trastuzumab, trastuzumab/pertuzumab, or trastuzumab/pertuzumab/chemotherapy, there’s still a large tumor remaining in the breast or there are several positive nodes, then that is the definition of residual disease burden and it becomes a high disease burden. In those patients, you know that they are not going to do as well, so you want to do the best and most for them. That is when neratinib will come into the equation—when a disease burden is high.

Is there anything else that you want to emphasize in terms of patient selection and what the trial informs?

The other thing about neratinib that we saw was that it needs to be started sooner rather than later; the patients who started much later after 1 year or 2, didn’t seem to benefit. The ER-positive patients will benefit, and obviously, so will the HER2-positive patients. Starting it as soon as possible will benefit them. Overall, I believe that the pertuzumab and neratinib relationship will pan out as more data come out.The patient selection was based upon HER2 positivity in high-risk patients. Again, it goes back to residual disease at the time of surgery. The other important question that somebody asked me was, “What about genomic profiling?” We are still using clinical criteria. What about the genomic criteria? What about next-generation sequencing?

That is kind of a whole new arena that we may have to venture into because not only do we want to make decisions on the basis of clinical high risk, but we need to make decisions on genomic high risk.

What would you like to remind physicians working in the space?

One of the things that attracts me is the CNS penetration. In some of the recent trials, it shows that instances of brain metastases may be reduced as low as 50% with neratinib; that’s very attractive for us in terms of recurrent HER2-positive breast cancer because these patients are living long. Hence, the natural disease has changed, and they are developing brain metastases in the later part of their disease process. Therefore, a drug that does penetrate CNS and takes care of brain metastases would be a very attractive proposal.We need to look out for the HER2-positive, ER-positive patients with a lot of disease burden. In those patients, it will be easy to influence them and present these data. As I mentioned in my presentation, we took anthracycline on board for an absolute benefit difference of just over 2%, and taxanes were [a benefit of] around 2%.

Here comes a drug that has 2.4% in all-comers, 4.4% in a HR-positive cohort, and then it goes up to over 7% if you get a central HER2 testing and start the drug earlier rather than later. The 7.4% is sellable as long as physicians are very diligent about treating the diarrhea and helping patients get through their treatment.

What is sitting at the crux of subsequent progress in patients with early-stage HER2-positive breast cancer?

Again, the diarrhea comes as a tsunami; they say in the first 24 hours to the first week, and then tails off over a period of 30 days. However, [patients should be treated] upfront with loperamide and add colestipol, because then the rate of grade 3 diarrhea goes down to 11%. Then, there’s budesonide, which is an oral, nonabsorbable steroid, which is available. Therefore, if you had a plan in place, this drug can be quite easily given.We are evolving. The secret lies in the genomic profiling of these tumors. Does neratinib save all the patients? It doesn’t. That means you are still missing patients who need more potent treatment. I believe it comes down to mutations at a subcellular level of genomics; that’s where we are going to get the most “bang for our buck.”

Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9.