"'바카라사이트 벳무브 + Keytruda' combination set to redefine paradigm of first-line treatment for triple-negative breast cancer"

[by Lee, Young Sung] Gilead Sciences' antibody-drug conjugate (ADC) '바카라사이트 벳무브 (sacituzumab govitecan)' has shown significant therapeutic efficacy as a first-line treatment for metastatic triple-negative breast cancer (TNBC), suggesting the potential for a paradigm shift in its treatment.

TNBC is the most aggressive form of breast cancer, accounting for approximately 15% of all breast cancer cases. Unlike other subtypes, TNBC is characterized by markedly limited 바카라사이트 벳무브 options and a significantly higher risk of recurrence and metastasis compared to other types of breast cancer. The median time to metastatic recurrence for TNBC is approximately 2.6 years, notably shorter than the average of 5 years observed in other breast cancer types. The five-year survival rate for TNBC remains relatively much lower in comparison.

바카라사이트 벳무브 exerts its therapeutic effect by selectively targeting Trop-2, a protein overexpressed on the surface of cancer cells. Through this mechanism, it delivers cytotoxic agents directly into cancer cells while minimizing off-target effects on normal tissues. The drug was developed from the outset to enhance therapeutic efficacy and reduce systemic toxicity.

The Phase 3 clinical trial (ASCENT-04) results evaluating the combination therapy of Trodelvy and the immune checkpoint inhibitor 'Keytruda (pembrolizumab)' were recently presented at the American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, USA. The study targeted patients with locally advanced or metastatic, unresectable TNBC who tested positive for PD-L1 (CPS≥10).

According to the study findings, the '바카라사이트 벳무브 + Keytruda' combination therapy achieved a median progression-free survival (mPFS) of 11.2 months (95% confidence interval: 9.3-16.7), outperforming the current 'standard therapy (Keytruda + chemotherapy),' which reported an mPFS of 7.8 months (95% confidence interval: 7.3-9.3). This difference was statistically significant, demonstrating a clear improvement in PFS and successfully meeting the primary endpoint. Reflecting the significance of these results, the study was selected as a 'Late Breaking Abstract' at the ASCO Annual Meeting.

The PFS benefit observed was generally consistent across key predefined subgroups. Furthermore, the 바카라사이트 벳무브 + Keytruda combination therapy (n=221) demonstrated a statistically significant and clinically meaningful 35% reduction in the risk of disease progression or death (HR: 0.65; p<0.001) compared to the Keytruda + chemotherapy combination (n=222).

The Trodelvy + Keytruda combination demonstrated a superior objective response rate (ORR) compared to the Keytruda + chemotherapy combination [60% (95% CI: 52.9–66.3) vs. 53% (95% CI: 46.4–59.9)]. The complete response (CR) rate was also higher in the Trodelvy + Keytruda group, with 13%, relative to the Keytruda + chemotherapy group, with 8%. Notably, the duration of response (DoR) was significantly longer in the 'Trodelvy + Keytruda' combination group [16.5 months (95% CI: 12.7–19.5) vs. 9.2 months (95% CI: 7.6–11.3)].

An encouraging trend toward improved overall Survival (OS) was also observed with the 바카라사이트 벳무브 combination therapy. However, the OS data remained immature at the time of the primary PFS analysis. Importantly, the safety profiles of 바카라사이트 벳무브 and Keytruda in this study were consistent with their previously established safety characteristics.

Professor Im Seock-ah, from the Department of Hemato Oncology at Seoul National University Hospital and a member of the clinical trial research team, commented in an interview with <THE BIO> at the ASCO conference site, "At 12 months, nearly half of the patients (48%) remained progression-free, and the median PFS (mPFS) was 11.2 months." She further stated, "It is a very encouraging result that half of the patients are alive without cancer progression after one year, and it holds significant meaning from the patient's perspective."

"Trodelvy has long been anticipated to exert a complementary effect when used in combination with the immunotherapy agent Keytruda," Im emphasized. "As the ADC releases cytotoxic substances inside cancer cells, an immunomodulatory effect is induced. In this context, combining it with Keytruda, which inherently possesses immunoregulatory properties, is expected to yield a synergistic therapeutic effect."

According to Professor Kim Sung-bae of the Department of Oncology at Seoul Asan Medical Center, also a member of the clinical trial research team, the study design allowed treatment crossover for patients in the control group. Specifically, patients receiving Keytruda + chemotherapy were allowed to switch to an alternative therapy upon cancer progression. As a result, 43% of patients in the 'Keytruda + chemotherapy' group subsequently received 바카라사이트 벳무브 as part of their follow-up treatment.

"In other words, 81% of patients who received second-line treatment continued treatment with Trodelvy monotherapy. Nevertheless, an improving trend of OS improvement is being observed in the 'Trodelvy + Keytruda' combination therapy. This effect is expected to become more clearly evident with extended long-term follow-up," Kim further noted.

Im also conveyed optimism regarding 바카라사이트 벳무브 outcomes.

Im anticipated that the adoption of the '바카라사이트 벳무브 + Keytruda' combination as a first-line treatment would accelerate the release of additional OS data in the future.

"The confirmation of a significant difference of more than three months in mPFS serves as an important indicator that this could also translate into an improvement in OS, so I believe that the 'Trodelvy + Keytruda' combination therapy is likely to become the future standard for first-line treatment," Im emphasized. "This trend is expected to be particularly evident in the subgroup of patients with high PD-L1 expression (CPS≥10)."

Presented below is a question-and-answer (Q&A) with 바카라사이트 벳무브 Kim Sung-bae and 바카라사이트 벳무브 Im Seock-ah.

Q: Based on the results of the ASCENT-04 study, do you believe the '바카라사이트 벳무브 + Keytruda' combination therapy will shift the current treatment paradigm for triple-negative breast cancer? How do you anticipate it will be implemented in actual clinical practice?

▶ (Professor Im) 바카라사이트 벳무브 has already demonstrated superior efficacy over conventional chemotherapy in patients with secondary or higher metastatic triple-negative breast cancer who have undergone multiple prior treatments. Moreover, 바카라사이트 벳무브 can be administered as monotherapy, which significantly simplifies the treatment regimen. From the patient's perspective, this represents a substantial advantage, as it eliminates the burden of managing multiple chemotherapeutic agents typically required in standard combination therapies.

In the ASCENT-04 study, the '바카라사이트 벳무브 + Keytruda' combination therapy demonstrated a significant extension of PFS compared to the existing first-line standard regimen of Keytruda + chemotherapy combination, marking a highly noteworthy advancement. In particular, nearly half of patients (48%) remained progression-free at 12 months, with a median PFS (mPFS) of 11.2 months. Achieving an mPFS exceeding one year is particularly challenging in triple-negative breast cancer. However, among the subgroup of patients who experienced disease recurrence more than one year after completing adjuvant chemotherapy, the PFS reached 16.6 months. In this context, the finding that half of the patients were alive without disease progression after one year is especially encouraging and holds significant meaning from the patient's perspective.

Furthermore, the objective response rate (ORR) in the '바카라사이트 벳무브 + Keytruda' combination group reached 60%, surpassing the 53% observed in the control group, with the therapeutic response appearing rapidly. This rapid onset of efficacy is particularly meaningful for patients experiencing symptomatic internal organ metastases, such as dyspnea, as it contributed to an improvement in the patient's quality of life. Provided that adverse events, particularly neutropenia, are effectively managed, the '바카라사이트 벳무브 + Keytruda' combination therapy is anticipated to become the standard first-line treatment for metastatic triple-negative breast cancer.

However, in Korea, the current standard first-line treatment, 'Keytruda + chemotherapy' combination therapy, is not yet reimbursed under the insurance system. As a result, it is likely that the '바카라사이트 벳무브 + Keytruda' combination therapy will require additional time before it can be established as the practical standard of care in clinical settings.

If additional overall survival (OS) data becomes available in the future, the adoption of the 'Trodelvy + Keytruda' combination as the first-line treatment is expected to accelerate further. Although the current OS data are considered immature due to a relatively short follow-up period, the existing evidence already demonstrates a clear divergence in survival curves within 2-3 years. The confirmation of a more than three-month improvement in mPFS serves as a critical indicator of the potential for OS benefit. Therefore, the likelihood that the 'Trodelvy + Keytruda' combination will become the new standard in first-line treatment for TNBC is high, especially in patients with high PD-L1 expression (CPS≥10), where this trend is expected to be more evident.

Q: What is your expectation regarding the extent of m바카라사이트 벳무브 improvement in the ASCENT-04 study?

▶ (Professor Im) Personally, I expect, and hope, that the mOS will exceed two years. In fact, there are already cases in which patients have been treated with the '바카라사이트 벳무브 + Keytruda' combination therapy for over two years without any particular issue. Nevertheless, formal OS data will require continued follow-up observation.

▶ (Professor Kim) Given the observed trend of improved OS, it is anticipated that this effect will become more pronounced with extended long-term follow-up. While the ORR was 60% in the '바카라사이트 벳무브 + Keytruda' combination group compared to the 53% in the control group, a difference that may initially appear modest, the median duration of response (mDOR) was nearly twice as long, with 16.5 months versus 9.2 months, respectively. This indicates that responses were sustained longer in the '바카라사이트 벳무브 + Keytruda' combination therapy group. Such findings are believed to reflect the distinct mechanism of action of 바카라사이트 벳무브. The synergy between the ADC and the immune checkpoint inhibitor likely contributed not only to tumor size reduction but also to disease stabilization.

Q: This clinical trial also included Korean patient enrollment from Seoul National University H바카라사이트 벳무브pital and Seoul Asan Medical Center. What were the clinical outcomes observed specifically among the Korean patient cohort?

▶ (Professor Im) In this clinical trial, Korean patient participation was active, largely due to the opportunity to access standard 바카라사이트 벳무브s that are typically unavailable under the national insurance system in Korea. Even those assigned to the control group were able to receive therapies not ordinarily reimbursed. In fact, patients in the control group demonstrated more favorable prognoses compared to those undergoing conventional anticancer chemotherapy.

Among domestic patients, the '바카라사이트 벳무브 + Keytruda' combination therapy demonstrated superior clinical efficacy, with an mDOR of 16.5 months, compared to 9.2 months in the control group. Notably, several patients treated at Seoul National University Hospital experienced treatment responses persisting for over two years. Insights from the prior 'KEYNOTE-355' trial indicated that, within the control group, Asian patients with higher combined positive scores (CPS) tended to exhibit prolonged PFS and OS. These findings suggest that immune modulation may be more effective in Asian populations. A similar trend is anticipated in the ASCENT-04 trial, underscoring the value of conducting a subgroup analysis focused on Asian patients in future evaluations.

▶ (Professor Kim) At Seoul Asan Medical Center, a total of 16 patients were enrolled in the clinical trial, with three patients assigned to the 바카라사이트 벳무브 + Keytruda combination therapy group and 13 to the control group. Among the three patients in the combination group, one has maintained a sustained response for over two years. This patient has reported feeling more comfortable compared to their experience with previous chemotherapy regimens. They continue to attend outpatient visits, and each time they appear relaxed and free from pain, which is deeply rewarding to witness as a clinician.

In addition, 9 out of 13 patients in the control group transitioned to 바카라사이트 벳무브, and one of these patients continues to respond well. While administering the combination as a first-line treatment is ideal, these cases suggest that the 바카라사이트 벳무브 also demonstrates clinical benefit in the second-line treatment setting for certain patients.

Q: Given the positive outcomes of both the ASCENT-03 and ASCENT-04 studies, do you expect that these findings will significantly support Trodelvy’s incorporation into the first-line treatment?

▶ (Professor Im) Yes, I believe so. The ASCENT-03 trial evaluated 바카라사이트 벳무브 monotherapy in patients with a CPS score below 10, while ASCENT-04 assessed the '바카라사이트 벳무브 + Keytruda' combination therapy in patients with a CPS score of 10 or higher. As treatment selection between monotherapy and combination therapy depends on the CPS score, close collaboration with the pathology department will be essential in future clinical practice.

Q: What further research do you believe is necessary to facilitate the implementation of the '바카라사이트 벳무브 + Keytruda' combination therapy in actual clinical practice?

▶ (Professor Kim) In Korea, OS data are often considered a critical factor for determining insurance reimbursement, so it is likely that further implementation of the combination therapy will depend on the availability of mature OS results. However, as previously noted, the trial design allowed for treatment crossover in the control group, with a substantial proportion of patients eventually receiving 바카라사이트 벳무브, which may complicate the interpretation of OS outcomes. In addition, data on safety and patient quality of life will be essential and are expected to be clarified through ongoing follow-up studies. The final outcomes of the ASCENT-04 study are therefore highly anticipated.

▶ (Professor Im) Recently, T-DXd (trastuzumab deruxtecan) has demonstrated clinical efficacy in the second and third-line treatment of metastatic HER2-positive breast cancer, with encouraging results now emerging in the first-line setting as well. Similarly, Trodelvy has been shown to be effective as a first-line treatment for metastatic triple-negative breast cancer. Notably, at this year’s ASCO, the NeoSTAR study presented findings indicating that an ADC and immunotherapy combination therapy improved pathological complete response (pCR) rate by over 30% after just four cycles of preoperative neoadjuvant therapy. In contrast, the KEYNOTE-522 trial, which employed a Keytruda-based neoadjuvant regimen, reported substantial toxicity. Consequently, a new clinical trial is expected to launch soon to evaluate the substitution of part of the current neoadjuvant regimen with the 'Trodelvy + Keytruda' combination. Looking ahead, there will likely be increasing efforts to replace highly toxic conventional treatment with ADC-based therapeutic strategies.

Q: What aspects of the ASCENT-04 clinical study were considered disappointing or in need of further validation?

▶ (Professor Im) The results presented from the ASCENT-04 trial represent the first interim analysis for mPFS. Key outcomes such as OS, quality of life, and detailed subgroup analyses, as noted by Professor Kim Sung-bae, are all part of the predefined follow-up analyses outlined in the study protocol. Therefore, more detailed data will be released in phases through future analyses, allowing for a gradual and in-depth understanding of the trial’s results.