ADC option for HR+ breast cancer...'Datroway' garners attention

Professor Kyung Hwa Park of the Division of Medical Oncology at Korea University Anam Hospital

Treatment void following CDK4/6 inhibitor treatment…expected to improve the limitations of conventional chemotherapies

PFS 6.9 months·disease progression risk 37%↓…patients are confirmed to sustain treatments

Which therapeutic options to choose from following CDK4/6 inhibitor treatment in the course of hormone receptor-positive (HR+)/HER2-negative (HR-) metastatic breast cancer treatment is becoming a major issue.

The establishment of a combination therapy of endocrine therapy and a CDK4/6 inhibitor as the first-line standard therapy has significantly improved early-stage therapeutic outcomes and quality of life. However, therapeutic options that secure both therapeutic effects and tolerability are relatively limited when drug resistance occurs.

Professor Kyung Hwa Park of the Division of Medical Oncology at Korea University Anam Hospital 

In South Korea, due to limited follow-up endocrine-based therapeutic options, patients whose disease has progressed often move on to chemotherapy. Industry experts view this process as increasing patient burden, such as hair loss, accumulated toxicity, and daily life struggles.

'Datroway (datopotamab deruxtecan),' a TROP2-directed antibody-drug conjugate (ADC) recently approved in South Korea, is drawing attention as a novel treatment option distinct from conventional chemotherapy for patients with HR+/HER2- metastatic breast cancer.

In a recent interview with Daily Pharm, Professor Kyung Hwa Park of the Division of Medical Oncology at Korea University Anam Hospital stated, "Patients treated with CDK4/6 inhibitors have high expectations for maintaining a high quality of life and sustaining daily routines for a prolonged period," and added, "However, patients feel frustrated because there are not enough subsequent treatment options to continue that."

Professor Park continued, "In this situation, the approval of Datroway and availability of a new ADC treatment option is highly meaningful, as it allows patients to expect a relatively long progression-free survival (PFS) while maintaining their quality of life."

Shortened survival following CDK4/6 inhibitor use… Subsequent treatment is not available

For HR+/HER2- metastatic breast cancer, combination therapy of endocrine therapy and a CDK4/6 inhibitor is generally used as first-line treatment.

The issue arises after resistance develops. Among patients whose disease progressed after CDK4/6 inhibitor use, the median PFS is less than 4 months;. In comparison, median PFS with chemotherapy is 6.4 months in the first-line setting, but drops to about 4.1 months in the third-line setting. In practice, only 31% of all patients proceeded to third-line therapy.

Professor Park pointed out that this issue can be even more pronounced in Korea's domestic treatment landscape.

Professor Park stated, "In Korea, subsequent endocrine therapies that can realistically be used are limited to fulvestrant monotherapy or the combination of everolimus plus exemestane," adding, "For patients with ESR1 gene mutations, there are no available drugs, leaving them at a stage where they must consider participating in clinical trials."

Ultimately, a substantial number of patients transition to chemotherapy, but the reluctance felt by patients is considerable.

Professor Park added, "Rather than financial reasons, many patients who have maintained their daily lives while undergoing treatment with CDK4/6 inhibitors do not want to switch to chemotherapy, which causes hair loss and makes daily living difficult."

Datroway improves PFS… Safety is the benefit

Last March, Datroway was approved in Korea for the treatment of patients with HR+/HER2- metastatic breast cancer who have received prior endocrine-based therapy and systemic chemotherapy in the advanced setting.

In the TROPION-Breast01 study, the basis for approval, Datroway reduced the risk of disease progression or death by 37% compared with investigator's choice of chemotherapy.

The median PFS was 6.9 months in the Datroway group and 4.9 months in the control group, with a hazard ratio (HR) of 0.63. The objective response rates (ORR) were 36.4% and 22.9%, respectively.

The therapeutic effect demonstrated a consistent pattern regardless of prior lines of therapy, prior CDK4/6 inhibitor use, or HER2-low versus IHC 0 status.

Professor Park viewed this as a case where, rather than focusing solely on the absolute PFS difference of two months, one must consider the limitations of existing therapies alongside patient characteristics.

Professor Park noted, "While it is a difference of about two months, a PFS of approximately seven months is a considerably meaningful figure," adding, "Even when cytotoxic chemotherapies are effective, it can be difficult to maintain treatment for a long time due to cumulative toxicities such as peripheral neuropathy, hand-foot syndrome, and edema."

Professor Park further added, "A major advantage of ADCs is that patients can sustain treatment with a relatively lower burden of cumulative toxicity."

Considering both quality of life and Toxicity… "Maintaining daily life Is also a treatment outcome"

In TROPION-Breast01, differences from conventional chemotherapy were also confirmed in terms of patient-reported outcomes (PROs) and safety.

Analysis of time to confirmed deterioration showed a time to deterioration in quality of life of 9 months in the Datroway arm versus 4.8 months in the control group. Time to pain deterioration also differed, at 9 months versus 5.5 months, respectively.

The incidence of Grade 3 or higher treatment-related adverse events was 20.8% in the Datroway group and 44.7% in the control group. Neutropenia was recorded in 1.1% and 30.8% of patients, respectively.

Professor Park said, "Previsously, what mattered to metastatic cancer patients was how many more months they could live, but nowadays they ask whether they can travel abroad or go to a swimming pool during treatment," adding, "As more patients view cancer as a condition to live with while receiving treatment, maintaining quality of life and extending meaningful time have become essential."

While adverse events such as stomatitis and ocular toxicities can occur with Datroway treatment, Professor Park's view is that many of them are preventable and manageable.

Based on Professor Park's involvment in clinical trials, she explained, "There were low-grade cases of stomatitis that were managed using steroid mouthwashes, and patients with blurred vision were managed without major issues through appropriate ophthalmologic care and treatment," adding, "The incidence of high-grade adverse events that lead patients to visit hospitals or emergency rooms due to neutropenia or interstitial lung disease was very low."

Switching to an ADC considering tumor burden and comorbidities

Then, which HR+/HER2- patients should clinicians consider first for Datroway?

Professor Park identified patients whose disease progresses rapidly despite CDK4/6 inhibitors, or those unlikely to respond to subsequent endocrine therapy, as primary candidates.

She said, "Some patients experience disease progression within six months of using first-line therapies. For such patients, switching promptly to an ADC can be considered as the next treatment," adding, "The same applies to patients whose disease was controlled for a relatively long period with CDK4/6 inhibitors, but who have a high tumor burden or lack suitable subsequent endocrine therapy."

Switching to an ADC can also be considered when targeted therapies such as PI3K or AKT inhibitors are difficult to use because of the patient's physical condition or underlying comorbidities.

Patients with HER2 IHC (immunohistochemistry) 0 are also a population for whom Datroway can be considered. This is because they can leverage TROP2 as an independent target, even when existing HER2-targeted ADCs are restricted.

Professor Park suggested, "Datroway can be considered for patients with HER2 0 status, patients who have HER2-low disease but face difficulties using HER2 ADCs due to cardiac function or other comorbidities, and vulnerable patients for whom safety is paramount."

"Diversity of treatment options is crucial for patients"

However, the issue of insurance reimbursement remains to enhance real-world access to treatment in Korea.

Aside from clinical need, Professor Park anticipated that securing reimbursement for Datroway will not be simple. This is because evaluation standards have been raised as other ADCs demonstrated high clinical achievements and even improvements in overall survival (OS).

Nevertheless, Professor Park emphasized the need to secure treatment options with diverse mechanisms and modes of administration, as every patient differs in organ function, comorbidities, susceptibility to toxicity, and hospital accessibility.

Professor Park stated, "From a clinician's perspective, because each patient's condition, comorbidities, and organ function status are entirely different, it is essential to secure diversity in treatment options in terms of toxicity and tolerability."

In conclusion, Professor Park said, "Continuing treatment while maintaining quality of life is an extension of meaningful time that is hard to measure in monetary terms," emphasizing that "As patients with metastatic breast cancer can maintain their daily routines and sustain their roles in their families and society while undergoing treatment, such benefit must also be viewed as an important aspect of care."