Nerlynx (neratinib) is an extended adjuvant treatment for patients with HER2-positive early-stage breast cancer. It was developed to reduce the rate of breast cancer recurrence in patients who are at risk of recurrence even after using trastuzumab as post-surgical adjuvant therapy. It was approved in Korea in October 2022 and recently attracted attention as Korean pharmaceutical company Boryung agreed with Bixink Therapeutics to co-market the treatment.
Nerlynx's first real-world data (RWD) reflecting treatment patterns for HER2-positive early-stage breast cancer was unveiled at the 50th Annual Meeting of the Korean Cancer Association and the 10th International Cancer Conference, held in Seoul on June 20-21.
The study included 44 patients with hormone-positive/HER2-positive early-stage breast cancer. These patients started Nerlynx treatment within one year of completing post-operative adjuvant therapy with trastuzumab, with a median age of 50 years (37-66 years). Of the patients, 79.5 percent had T stage 2 or higher and 70.5 percent had N stage 1 or higher, with the majority receiving TCHP prior chemotherapy (chemotherapy plus trastuzumab plus Perjeta).
The results showed that 10 patients (34.6 percent) achieved a complete response (pCR). The most commonly reported adverse event (AE) was diarrhea (88.6 percent), followed by fatigue (29.5 percent) and skin reactions (20.5 percent). However, most AEs were mild (grade 1 or 2) and there were no treatment discontinuations due to AEs.
Nerlynx was well-tolerated and safe, especially in patients receiving Perjeta (pertuzumab) or Kadcyla (trastuzumab emtansine), with the majority of patients completing the full year of treatment.
Korea Biomedical Review spoke to Professor Moon Yong-wha of the Department of Hematology/Oncology at CHA Bundang Hospital, the lead author of the RWD study, to learn more about the role Nerlynx could play in the treatment of HER2-positive early breast cancer patients in Korea and what the Nerlynx RWD means for them.
Question: Nerlynx's first real-world data was presented at the 50th Annual Meeting of the Korean Cancer Association and the 10th International Cancer Conference. Can you explain what this data means?
Answer: The use of HER2-targeted therapies as adjuvant therapy in HER2-positive early breast cancer is currently the standard of care. Recently, many HER2-targeted agents have been used as adjuvant therapy. Trastuzumab and the recently approved Perjeta and Kadcyla are used as adjuvant therapies, but they are not 100 percent cures, so extended adjuvant therapies like Nerlynx are used.
Although Nerlynx has been on the market for several years, it is still underutilized, in part because there is no clinical data on its use after Perjeta or Kadcyla. When the phase 3 ExteNET study of Nerlynx tablets as extended adjuvant therapy in early breast cancer was initiated, only trastuzumab was approved, and both Perjeta and Kadcyla were yet to be approved.
Therefore, this study is significant in compiling national data on the use of Nerlynx in patients who received Perjeta or Kadcyla.
Q: How do you think the results of this RWD study will impact the perception of extended adjuvant therapy with Nerlynx in the future?
A: Historically, physicians have been hesitant to use Nerlynx after Perjeta or Kadcyla for two reasons. The first is the lack of clinical data on the use of Nerlynx after Perjeta or Kadcyla. Second, there were concerns about the safety and tolerability of Nerlynx.
When I ask my fellow doctors, not many physicians have much experience prescribing extended adjuvant therapy. The results of this study should give a positive impression of the tolerability and safety of using Nerlynx after Perjeta or Kadcyla. However, the question of effectiveness cannot be fully answered based on the current data. The number of patients is small and the data accrual period is short. We are currently collecting data on relapsed patients, but it will take more time before we have sufficient results.
Q: I'm curious about the extent to which the case for extended adjuvant therapy in the treatment of HER2-positive early breast cancer has been made.
A: That’s a good question. In the treatment of HER2-positive early breast cancer, a few cycles of TCHP followed by surgery may or may not result in a complete remission. If a complete remission is achieved, the rule of thumb is to continue with the original targeted therapy, such as trastuzumab or Perjeta. If a complete remission is not achieved after surgery, for example, if prior anti-cancer therapies have had limited benefit, it is common to switch to Kadcyla after surgery.
Studies have shown this treatment strategy to be very effective, so one might wonder why the concept of extended adjuvant therapy is necessary in this situation, and indeed, this is often questioned by physicians.
However, it is possible to ask this question. "Is there a 100 percent cure with the current standard of care?” - where 100 percent cure means no recurrence. However, the data shows that the three-year progression-free survival rate with standard treatment is about 90 percent. This means that about 10 percent of patients will relapse within three years. With longer follow-ups, more patients may relapse by the fifth year. Because current treatments are not perfect, some patients relapse and there is an unmet need. So there may be a need for extended adjuvant therapy.
Another compelling argument is that HER2-positive breast cancer has a high incidence of brain metastases. Data suggests that about 12 out of every 600 patients, or about 2.7 percent, will develop a first brain metastasis. This statistic refers to the first brain metastasis; metastasis to other sites and subsequent brain metastasis is another story.
With Nerlynx, the odds of brain metastasis are reduced by one-third. The ability of Nerlynx to reduce and prevent brain metastases explains the rationale for extended adjuvant therapy. Many HER2 breast cancer patients have a fear of brain metastases and would be willing to undergo treatment if there was a way to lower their chances.
Q: How many patients in Korea have access to Nerlynx?
A: The cost is high: the drug costs millions of won per month, and Nerlynx has to be used for a year. For those who can afford it, it's not a big deal, but for most patients, it's a big burden. In my experience with patients, many of them are privately insured for the actual medical cost. When they hear about extended supportive care, they say, "I'm going to use Nerlynx. If there is such an opportunity, it's definitely good to do it, and why not?" and often use it.
However, if they have to pay for it out of pocket, we explain it to them, but a lot of patients don't use it. It's up to the government to decide whether or not to give health insurance coverage, but we can explain that there are these issues.
Q: Are the side effects found in clinical trials, such as diarrhea and skin rashes, manageable?
A: According to statistics, 70-80 percent of patients experience diarrhea. To prevent this, an antidiarrheal agent is prescribed along with the drug. Another option is to adjust the dose. The Nerlynx dosing schedule is six pills a day, which can be difficult for patients. So the first week, the dose starts with three pills, the next week, increased to four pills, and in the third week, to six pills. In clinical trials, this has been shown to reduce diarrhea and improve tolerability, so I've followed that and most patients feel much better.
Some patients experience skin rashes. Real-world data shows that about 20 percent experience a skin rash, but it's not a big problem. The symptoms could be managed with medication without too much trouble. Most cases can be managed with proactive measures, and if side effects do occur, they can be managed with adjustments to the medication. I want to emphasize that patient longevity is the most important thing.
Q: Have there been any notable changes in the treatment of HER2-positive early breast cancer?
A: Antibody-drug conjugates (ADCs) have pretty much taken over the oncology market, and it all started with Enhertu. Enhertu has a large role in the treatment of HER2-positive metastatic breast cancer, and is covered by insurance in some indications. It is now entering the early breast cancer market. It is difficult to predict how the treatment paradigm will be reshaped in the future, but the emergence of new drugs and increased competition will have a positive impact on patients. With a wider range of drugs, patients will be able to choose the right drug for their condition, which is likely to improve survival.
Q: What could be improved to increase access to new drugs?
A: I'm not necessarily talking about Nerlynx. The government runs a program called “pre-screening.” This is a system that allows new drugs that are not covered by health insurance to be prescribed before they are officially approved. For example, a new drug called A is pre-applied for, but A must be used in combination with an existing standard of care called B to be effective. B is covered by health insurance. However, when a combination of A+B is used, B also becomes non-reimbursable. This is hard to understand. If A is non-reimbursable, B should remain covered. There's a lot of discussion about this, but it's a shame that it's not getting better.