AstraZeneca and Daiichi Sankyo have revolutionized the treatment of HER2-positive metastatic breast and gastric cancer by co-developing the anticancer drug Enhertu (trastuzumab deruxtecan). Notably, the DESTINY-Breast03 phase 3 clinical trial, which compared the effectiveness of the drug with Roche's Kadcyla (trastuzumab emtansine or T-DM1), an existing second-line treatment for HER2-positive metastatic breast cancer, showed remarkable results.

Eighty-four patients at seven Korean medical institutions participated in the DESTINY-Breast03 trial, which involved 524 patients with HER2-positive metastatic breast cancer worldwide. However, despite the contributions of these domestic researchers and patients, there are still limitations to patient access as it is not yet covered by insurance.

Korea Biomedical Review spoke with Professor Seock-Ah Im of the Department of Hematology and Oncology at Seoul National University Hospital about the significance of the DESTINY-Breast03 study, the changes that Enhertu will bring to the treatment of HER2-positive metastatic breast cancer, and the solution between the government and patients ahead of the decision to reimburse the expensive new drug.

Professor Im is the director of the Seoul National University Cancer Research Institute and a member of the ESMO Clinical Practice Guidelines Committee. She also plays various roles in the field, including chairperson of the Korean Cancer Association International Committee, academic chair of the Korean Society of Medical Oncology (KSMO), and director of the Translational Research In Oncology (TRIO).

Im has been recognized as a Highly Cited Researcher (HCR) by Clarivate, a global academic information analytics company, for three consecutive years.

Question: Patient interest has been strong, as shown by a petition calling for the approval of Enhertu's reimbursement exceeding 50,000 signatures. In light of the results of the DESTINY-Breast03 study, which also included Korean patients, what are the implications of Enhertu in treating HER2-positive metastatic breast cancer?

Answer: The DESTINY-Breast03 study was a large phase 3 trial that directly compared the effectiveness of Enhertu against the second-line standard of care, T-DM1. In this study, Enhertu prolonged median progression-free survival (mPFS) compared to T-DM1 to 28.8 months vs. 6.8 months for T-DM1, a significant numerical difference. It is never easy to extend mPFS by more than four times.

I was on the clinical steering committee for DESTINY-Breast03. Even though we were videoconferencing due to Covid-19, when the first data from DESTINY-Breast03 came out, we were all so impressed with the hazard ratio (HR) of 0.28 that some of us were clapping and even shedding tears. Everyone was grateful to see an HR of this level in second-line treatment for metastatic breast cancer. Up until now, HRs of 0.7 were considered significant in metastatic breast cancer, so 0.28 was an incredible result.

And the 12-month progression-free survival (12-Mo PFS) is also quite different, with 75.8 percent for Enhertu and 34.1 percent for T-DM1. This means three out of four patients with Enhertu will remain disease-free one year after starting treatment, compared to one in three with T-DM1.

Considering that traditionally, patients with HER2-positive breast cancer have seen their cancer start to progress again within six to nine months of starting second-line treatment and often move on to third-line treatment, it is encouraging to see that more than 50 percent of patients remain on treatment for more than two years.

In addition, Enhertu achieved a partial response (PR) in most patients, with a reduction in tumor size of 30 percent or more and a disease progression rate (PD) of less than 5 percent after the first dose.

Q: Enhertu is yet to be on the reimbursement list. How is Enhertu treatment being conducted in the clinical field?

A: Before DESTINY-Breast03, we had a phase 1 study called DESTINY-Breast01. It targeted HER2-positive patients who had failed various standard therapies and included breast cancer in a multi-cancer cohort with an mPFS of 19.4 months.

Currently, few patients are using Enhertu as a second-line treatment, as in DESTINY-Breast03. Slightly more patients are using Enhertu when they have tried multiple therapies and have no other options, as in DESTINY-Breast01.

We also had phase 2 data from DESTINY-Breast02 that showed benefit in third-line treatment with Enhertu vs. capecitabine + trastuzumab or capecitabine + lapatinib, so there are quite a few patients who want to use T-DM1, which is covered, first, and then Enhertu as a third-line option when it gets coverage someday.

Not many patients can use Enhertu as a second-line treatment because it's not covered. They don't know when it will get coverage because taking it for a long time is a big financial burden. They would likely choose Enhertu as a second-line treatment if it were covered because it is more effective than T-DM1.

Of course, some patients have been using Enhertu as a second-line treatment since the end of last year, thinking that it will be covered someday, and many have already failed all other covered treatments and want to try Enhertu at least once while they remain alive.

Q: Are there any considerations when prescribing Enhertu?

A: About 10 percent of patients experience side effects of interstitial lung disease (ILD). Fortunately, there are currently no cases in Korea where patients have died from interstitial lung disease after using Enhertu. This is because Korean healthcare providers have done a good job of responding to the initial symptoms based on numerous clinical experiences by temporarily stopping the medication and resuming treatment after proper management. However, it may be difficult to recommend Enhertu to patients who have previously experienced interstitial lung disease.

Q: The first Pharmaceutical Reimbursement Review Committee (PRRC) meeting this year decided to rediscuss Enhertu, and the second PRRC meeting will be held on Feb. 1. As a physician, what direction would you like to see the discussion take?

A: In some ways, the long-established standard of a 5 percent co-payment rate for cancer patients further delays the reimbursement of newer drugs. The better the treatment by improving patient survival, the longer the treatment period and the higher the financial burden, so it will be difficult for the Health Insurance Review and Assessment Service (HIRA) to apply the benefit.

So, for example, a selective benefit method could be applied first by, for instance, allowing the government to pay about 70 percent of the health insurance and patients to shoulder the other 30 percent so that benefits can be implemented quickly and then supplement the system by reducing the patient to 5 percent later for some drugs. In this way, the barrier to entry to benefits will be lower than now, and it will be possible to apply benefits more broadly.

It is better to reimburse global standard therapies early, even if patients have to pay more than 5 percent out-of-pocket because trying to cover them according to the current standards makes patients wait too long for benefits.

In addition, if the global standard of care cannot surmount the domestic insurance barrier, it may limit the ability of domestic physicians to participate in future drug trials. Phase 3 studies must compare a new drug to a standard treatment. To close the gap with the global standard of care, it is necessary to reimburse drugs that have become the global standard of care.

Q: A new drug has appeared with superior efficacy. What would you say to breast cancer patients and their families who are staging a tough battle?

A: I would like them to think that they and medical professionals are one team aboard the same boat. Your doctor will recommend the right treatment for you based on your condition and the type of cancer you have. Patients need to communicate with their doctors and nurses so that they can make the best choice for them.

For instance, in HER2-positive breast cancer, there is no data yet to show that adding an immuno-oncology drug is effective. However, some patients have seen immuno-oncology used in other breast cancer types and have asked why they shouldn't be allowed to use it. Also, some patients have tried herbal remedies and experienced side effects such as hepatotoxicity.

The most important thing is to use treatments that are appropriate for the patient and have been clearly shown to prolong survival. Frequent transfers between treatment centers can also hurt patient prognosis, as it can lead to disruptions in care. Therefore, it is important to trust the medical staff at the hospital where you started treatment.