"Trodelvy for TNBC secures evidence for expanded indication"

Professor Yeon Hee Park at Samsung Medical Center ·Professor Joohyuk Sohn at Yonsei Cancer Center

Improvement in Overall Survival (OS) despite the allowance of crossover…patient-centric design garners attention

"Meaningful achievement as a first-line treatment for PD-L1 negative patient group, where no new treatment options have emerged in the past 20 years"

The therapeutic paradigm for Triple-Negative Breast Cancer (TNBC) is entering a new phase.

 

Gilead's Trodelvy (sacituzumab govitecan), a Trop-2 targeted Antibody-Drug Conjugate (ADC), demonstrated significant results in the Phase 3 ASCENT-03 study, which evaluated the efficacy of this drug as a first-line monotherapy.

 

The study proves Trodelvy's potential to expand beyond its current second-line indication.

 

DailyPharm met with the authors for the ASCENT-03 trial conducted in South Korea, Professor Joohyuk Sohn (Division of Medical Oncology at Yonsei Cancer Center) and Professor Yeon Hee Park (Department of Hematology- Oncology at Samsung Medical Center), to discuss the evolving TNBC treatment landscape and the clinical value of Trodelvy.

 

(from left) Professor Yeon Hee Park of the Department of Hematology- Oncology at Samsung Medical Center , Professor Joohyuk Sohn of the Division of Medical Oncology at Yonsei Cancer Center

At the European Society for Medical Oncology (ESMO 2025) Annual Congress held last month in Berlin, the Phase 3 study evaluating Trodelvy's efficacy was unveiled.

 

The trial enrolled patients with unresectable locally advanced or metastatic TNBC who were either PD-L1 negative (CPS below 10) or PD-L1 positive (CPS over 10) but ineligible for immune checkpoint inhibitor therapy.

 

In the trial, Trodelvy recorded a median Progression-Free Survival (PFS) of 9.7 months, which was significantly longer than the 6.9 months with chemotherapy.

 

Furthermore, Trodelvy reduced the risk of disease progression or death by 38% compared to the control group.

 

While Overall Survival (OS) data were not yet mature at the time of the primary analysis, the widening gap in PFS2 (time from randomization to second progression) between the treatment and control groups suggests a potential for future OS improvement.

 

There has been lack of distinct first-line options in untreated metastatic TNBC, besides the immune checkpoint inhibitor 'Keytruda (pembrolizumab)'.

 

Notably, for the PD-L1 negative patient group who are ineligible for pembrolizumab, no viable alternatives to conventional chemotherapy existed.

 

This is why analysis indicates the potential for greater use of Trodelvy.

 

A particularly noteworthy aspect of this study was the design for allowance of crossover from the control group.

 

Control patients whose cancer progressed during the trial were permitted to receive Trodelvy as a salvage chemotherapy.

 

Offering crossover to an agent already proven to improve OS in a subsequent-line setting typically makes it statistically much harder to demonstrate a difference in OS for the primary outcome.

 

Despite this challenge, the investigators chose this patient-centric design, which was evaluated at ESMO as 'a decision reflecting confidence in the drug's efficacy and the study results.' Experts assert that these results reaffirm the clinical value of Trop-2 targeted ADCs, anticipating this will be a pivotal turning point that significantly expands treatment options in the previously limited TNBC space.

 

Q.

 

What was the first-line treatment landscape for TNBC like before the introduction of ADCs? Prof.

 

Park: TNBC is characterized by a lack of traditional targets, and treatment typically stratifies based on PD-L1 expression.

 

In the PD-L1 positive patient group, immune checkpoint inhibitors combined with chemotherapy have shown good results and become the standard of care, leading to PFS improvement, despiting having been less than a year.

 

In contrast, the PD-L1 negative patient group, which comprises the majority (about 60%) has seen virtually no new treatment options for the past 20 years.

 

When clinical trials succeeded for the first time in PD-L1 positive patients, we had patients requesting the combination, but the evidence was lacking for the negative group.

 

Patients with aggressive progression, young age, or recurrence within a year of early-stage adjuvant therapy had to rely on chemotherapy, despite its toxicity.

 

Professor Joohyuk Sohn of the Division of Medical Oncology at Yonsei Cancer Center

Prof.

 

Sohn: From an oncologist's view, TNBC is challenging.

 

For nearly 20 years, standard treatment has been limited to conventional chemotherapy agents like taxanes or Xeloda (capecitabine).

 

It is concerning because this cancer has a higher incidence in younger patients, and the restricted options have been a constant source of clinical difficulty.

 

The prognosis for TNBC is notoriously poor.

 

Patients who appear healthy at initial diagnosis can unfortunately pass away in as little as 18 months, a devastating reality.

 

While the introduction of immunotherapies and targeted agents has been helpful, their use is restricted to specific patient groups, underscoring the desperate need for better options.

 

Q.

 

Please elaborate on the key results and significance of the ASCENT-03 study.. Prof.

 

Sohn: PD-L1 This study is highly encouraging because it demonstrated a statistically and clinically meaningful extension of PFS compared with standard-of-care chemotherapy in the first-line treatment of PD-L1-negative TNBC.

 

We anticipate these results will position Trodelvy as a new standard of care in first-line TNBC, offering tangible benefits to many patients.

 

Prof.

 

Park: ASCENT-03 garnered significant attention for presenting the first data in the first-line PD-L1-negative TNBC setting in approximately 20 years.

 

Presenting a new possibility for this patient group makes the results highly meaningful.

 

The primary endpoint of ASCENT-03 was PFS.

 

While the control group, despite utilizing best efforts with existing standard treatments, only achieved 6.9 months, the Trodelvy group reached 9.7 months, which is highly encouraging.

 

Q.

 

What were the unique aspects of the study design?

Professor Yeon Hee Park of the Department of Hematology- Oncology at Samsung Medical Center

Prof.

 

Park: Several points make this study design stand out.

 

First, the control group included not only single-agent chemotherapies (paclitaxel, albumin-bound paclitaxel) but also combination chemotherapy (gemcitabine-carboplatin).

 

Second, the study registered a significant proportion of patients with a relatively poor prognosis.

 

Trials typically exclude patients who relapse within one year of completing adjuvant therapy.

 

This study, however, included patients who relapsed between 6 and 12 months after adjuvant therapy.

 

Furthermore, some patients had previously received adjuvant immunotherapy.

 

These are patients for whom selecting treatment choices are tough after relapse and metastasis.

 

The most notable feature was the allowance for crossover from the control group.

 

Trodelvy has already demonstrated OS improvement in the subsequent-line setting and is used in clinical practice.

 

It is rare for a new trial to permit crossover to an agent with known survival benefits for ethical and statistical reasons, as it complicates OS analysis and makes it difficult to prove the drug's effect.

 

This was essentially a high-stakes decision, reflecting the research team's confidence in the drug's efficacy.

 

The choice to prioritize the patient perspective by allowing crossover, despite the statistical risk, was highly evaluated.

 

While OS data are incomplete, the study showed a significant effect in the surrogate endpoint, PFS2.

 

Even with the crossover allowance in the control group, the PFS2 was markedly longer in the Trodelvy treatment group.

 

This result clearly demonstrates the critical impact of the initial treatment choice on the patient's overall therapeutic course.

 

The study successfully achieved both meticulous design and uncompromising evidence of efficacy.

 

Q.

 

On the day of presentation of ASCENT-03 data, TROPION-Breast02 data for the competing drug Dato-DXd have also been presented.

 

How do you project the OS outcome for ASCENT-03, given the incomplete data? Prof.

 

Park: ESMO 2025 was a major stage for breast cancer research.

 

Unlike Hormone Receptor-positive or HER2-positive breast cancers, where prognosis has rapidly improved, TNBC has lacked attention.

 

However, this year saw the release of significant data across all three subtypes, with ASCENT-03 and TROPION-Breast02 at the center.

 

There is a strong possibility of an OS improvement with Trodelvy in TNBC.

 

The basis for this is the PFS2 data.

 

Despite the fact that most patients (82%) in the control group who received subsequent therapy crossed over to Trodelvy, the difference in PFS2 between the Trodelvy-treated group and the control group continues to widen.

 

This trend suggests a positive OS outcome is anticipated.

 

A direct comparison between ASCENT-03 and TROPION-Breast02 is challenging due to entirely different trial designs.

 

First, the statistical design and analytical structure differ based on the primary and secondary endpoints.

 

ASCENT-03 set the primary endpoint to PFS alone, while TROPION-Breast02 set it to both PFS and OS.

 

Furthermore, ASCENT-03 allowed crossover to a standard treatment known to improve OS, making the interpretation of the results necessarily more complex.

 

Prof.

 

Sohn: Given the crossover design, there is a possibility that a statistically significant OS difference may not yield even with long-term follow-up.

 

However, since the primary endpoint, PFS, has already been met, there may not be any issues with regulatory approval or clinical use.

 

The fact that Dato-DXd achieved a significant improvement in OS is certainly encouraging.

 

However, direct comparison is difficult due to the design differences.

 

It's also inappropriate to definitively assess superiority or determine which drug is necessary in clinical practice solely on the basis of the presence or absence of OS data.

 

The important part is that both agents met their primary endpoints, diversifying the available first-line treatment options for TNBC.

 

Q.

 

We understand the ASCENT-04 study, evaluating the efficacy and safety of Trodelvy + Keytruda combination therapy, is also underway.

 

Can you share those clinical results? Prof.

 

Sohn: Similar to ASCENT-03, the PFS for patients treated with the Trodelvy + Keytruda combination was statistically significantly longer (11.2 months vs.

 

7.8 months) than for the chemotherapy + Keytruda combination group.

 

Taken together, these results indicate a high probability that Trodelvy will be established as a new standard of care in the first-line setting, regardless of PD-L1 expression.

 

Prof.

 

Park: This study was also conducted on a large scale.

 

The ability to enroll many patients stemmed from the opportunity for control group patients to access the Keytruda combination therapy, which is not covered by national health insurance.

 

The ASCENT-04 results are also highly encouraging, showing a PFS of nearly 1 year with the Trodelvy + Keytruda combination group.

 

Despite these significant results, the lack of FDA approval at this time is surprising.

 

Q.

 

Q.

 

What is your view on the positive performance of Trop-2 targeted ADCs recently? Prof.

 

Sohn: Oncology research often begins with breast cancer.

 

Breast cancer has the highest incidence among female cancers and carries significant symbolic weight.

 

Furthermore, most research is conducted using cell lines, and breast cancer cell lines have historically constituted the largest proportion.

 

The biological characteristics of breast cancer are well-understood, leading to active clinical trials for new drugs.

 

The high expression rate of Trop-2 in breast cancer makes it particularly responsive to Trop-2-targeted ADCs.

 

While research is ongoing in other cancer types, the response has not been as pronounced as in breast cancer.

 

Prof.

 

Park: The efficacy is due to the high Trop-2 expression in breast cancer, combined with the characteristics of ADCs, where the cytotoxic payload is broadly distributed within the tumor cell and has a sustained effect.

 

Trop-2 serves as the guide that helps direct the payload to the cancer cell.

 

ADCs enhance therapeutic effects by enabling targeted cancer cell killing while retaining the mechanisms and cytotoxicity of traditional chemotherapy.

 

While conventional chemotherapy is highly toxic and difficult to use long-term, ADCs can be regarded as a treatment option that can be used safely and stably for a relatively longer period.