"The expected probability of a clinical cure for TNBC"…Keytruda

Perioperative treatment has been established as a comprehensive strategy…"Stage 2A cancer can be treated aggressively"

Confirmed OS improvement…not only inhibiting recurrence but also carries significance of extended survival

Although triple-negative breast cancer (TNBC) accounts for approximately 15 to 20% of all breast cancer cases, it is recognized as a highly aggressive subtype with a significant risk of recurrence.

Due to the lack of hormone receptors (HR) or HER2 expression, targeted therapies cannot be used, leaving patients with relatively limited treatment options. It has been classified as a high-risk breast cancer, particularly due to the high risk of recurrence and mortality within five years of diagnosis.

TNBC carries a high risk of recurrence even in relatively early stages (Stages I and II), and recurrence is highly likely to manifest as distant metastasis. Notably, the T2N0 patient population, characterized by a tumor size of 2 to 5 cm and node-negative status, has recently regarded as a high-risk subgroup requiring aggressive therapeutic intervention.

Amid this therapeutic landscape, analysis suggests that a perioperative treatment strategy based on the cancer immunotherapy 'Keytruda (pembrolizumab)' is leading a paradigm shift in the management of early-stage TNBC.

Professor Hee Kyung Ahn, Department of Hematology-Oncology, Samsung Medical Center

Keytruda received regulatory approval from the Ministry of Food and Drug Safety (MFDS) in July 2022 for the perioperative treatment of high-risk early-stage TNBC.

Based on the KEYNOTE-522 clinical study, Keytruda demonstrated significant improvements not only in pathological complete response (pCR) but also in event-free survival (EFS) and overall survival (OS). Consequently, it is drawing attention as a therapeutic strategy aimed at increasing the probability of a clinical cure rather than merely delaying disease recurrence.

As a result, an integrated therapeutic approach encompassing neoadjuvant chemotherapy, definitive surgery, and subsequent adjuvant therapy is increasingly well established in real-world clinical practice.

DailyPharm met with Professor Hee Kyung Ahn of the Department of Hematology-Oncology at Samsung Medical Center to discuss the shifting treatment paradigms in early-stage TNBC and the clinical implications of Keytruda-based perioperative therapy.

Q. What are the changes in clinical practices since Keytruda was approved for early-stage TNBC?

The therapeutic landscape has transformed significantly over the past few years, and Keytruda is now widely used in clinical settings.

Today, we no longer proceed to surgery first, even for node-negative Stage IIA patients. Instead, neoadjuvant therapy with Keytruda is used, followed by a risk-based adjuvant regimen regardless of whether the patient achieves pCR post-surgery. Because robust clinical trial data have demonstrated survival benefits with this strategy, proactive clinical interest and adoption have risen substantially.

Based on the KEYNOTE-522 clinical data, the pCR rate was 64.8% in the Keytruda arm compared to 51.2% in the control arm, representing an absolute improvement of approximately 13.6 percentage points. Furthermore, EFS improved by roughly 8 percentage points, and the overall survival rate improved by about 5 percentage points. Demonstrating these absolute benefit margins underscores a major breakthrough in therapeutic outcomes, making it a highly clinically meaningful finding.

Q. Why is the T2N0 patient cohort frequently highlighted in discussions regarding TNBC?

T2N0 defines a case where the tumor size spans 2 to 5 cm with node-negative status. Patients often feel reassured because it is classified as Stage IIA, a relatively early stage. However, even within the same clinical stage, TNBC carries a profoundly higher risk of recurrence compared to other subtypes, such as hormone receptor-positive breast cancer.

While the stage of the cancer is important, TNBC carries the risk of a poor prognosis and aggressive biological phenotype that even Stage IIA patients are classified into a high-risk group with an elevated risk of recurrence. Consequently, formulating an aggressive treatment strategy is essential

Q. How do you evaluate the clinical significance of Keytruda demonstrating an OS benefit?

Demonstrating an OS benefit in early-stage curative settings is incredibly difficult. It requires proving that a therapy extends actual patient survival, rather than merely delaying disease recurrence.

Certain therapies may successfully prolong the time to recurrence, but once the disease recurs, the biological characteristics of the tumor can shift aggressively, preventing extended patient survival. In those situations, an OS benefit is absent.

In contrast, the validation of an OS benefit implies that early-intervention treatment successfully translates into a potential cure for a substantial proportion of patients, or at the very least, prolongs overall life expectancy even if the disease eventually recurs.

Because cancer directly threatens life, the absolute benchmark and ultimate objective of all oncology treatments is to extend survival as much as possible. Thus, improving overall survival holds significance, demonstrating that the therapy has successfully achieved the gold standard goal of oncological intervention.

Q. What do you consider to be the most noteworthy findings from the subgroup analysis?

The fact that consistent outcomes were demonstrated across nearly all subgroups is highly meaningful. An especially intriguing aspect is the divergence between metastatic TNBC and early-stage TNBC data.

In the metastatic setting, Keytruda's efficacy was confirmed exclusively in PD-L1-positive patients. However, in early-stage TNBC, pCR and EFS improvements were achieved regardless of PD-L1 expression status.

This means that early-stage TNBC may possess distinct immunological profiles compared to the metastatic stage, suggesting that Keytruda-based regimens function more effectively when deployed early in the disease stage.

Q. Why is the integrated therapeutic approach of continuing perioperative adjuvant therapy so crucial in early-stage TNBC?

Previously, if a patient achieved pCR following neoadjuvant chemotherapy, further post-operative systemic treatment was frequently omitted. However, the KEYNOTE-522 study design mandated that even patients achieving pCR continue receiving adjuvant Keytruda post-surgery. Driven by these data, current guidelines recommend maintaining therapy unless precluded by significant adverse events.

Notably, highly meaningful outcomes were confirmed in the non-pCR cohort. While this subpopulation historically carries a dismal prognosis, the inclusion of Keytruda demonstrated a trend toward improved survival outcomes. This strongly suggests that maintaining adjuvant therapy plays a critical role in managing residual disease burdens and mitigating the risk of recurrence.

Keytruda's ability to fundamentally transform treatment outcomes across the entire TNBC continuum (from early-stage to metastatic disease) is significant. The observable decline in recurring patients compared to the past directly translates to lives saved, which is why its clinical value is so deeply felt on the ground.

Q. How do you view the current reimbursement landscape and the challenges ahead?

Currently, Keytruda is not reimbursed for this indication; partial reimbursement is restricted only to the backbone cytotoxic chemotherapies used in the combination regimen. While this alleviates a fraction of the cost, the out-of-pocket financial burden on patients remains substantial.

The crucial factor we must not overlook is the societal and economic value of a clinical cure. Achieving a cure goes beyond the mere eradication of cancer cells; it represents returning a patient fully to society. When a patient is cured, it eliminates the massive future medical expenditures and drug costs associated with recurrence, while preserving the economic and social productivity that would otherwise be lost.

In South Korea, a stringent threshold demand high standard for OS data for early-stage indications due to fiscal constraints. However, capturing definitive OS data requires an extended timeline, and while waiting for those results, a significant number of patients miss their critical window for a cure.

While managing metastatic disease is vital, I personally believe that curative-intent treatment in the early-stage setting should take precedence. This is particularly justifiable because therapies deployed in the neoadjuvant setting have a fixed number of treatment cycles, allowing total healthcare expenditures to be capped and predicted in advance.

Therefore, as a realistic alternative, if budget impact is the primary hurdle delaying full reimbursement, health authorities should actively explore mechanisms to enhance patient access, such as implementing partial reimbursement structure or adjusting patient co-payment tiers to a realistically affordable level.

Allowing regulatory and institutional flexibility by taking into account the manageable financial thresholds for individuals confronting critical illnesses will serve as a practical solution to improve market access and patient drug availability for cancer patients.