Sacituzumab Tirumotecan Plus Pembrolizumab Is Set to Be Evaluated in TNBC

The novel antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT; formerly SKB264/MK-2870) demonstrated encouraging efficacy and safety data in the phase 3 OptiTROP-Breast01 trial (NCT05347134),which has informed an impetus to investigate the agent in combination with pembrolizumab (Keytruda) for the treatment of patients with triple-negative breast cancer (TNBC) who previously received neoadjuvant therapy and did not have a patho- logic complete response at surgery in the phase 3 TroFuse-012 trial (NCT06393374).1

“ADCs have changed the way we treat [patients with] breast cancer across essentially all subtypes, and we’ve seen tremendous activ- ity in the metastatic setting. Whenever we see promising strategies in the metastatic setting, we typically move those into the curative-intent setting, and that’s what TroFuse-012 aims to do,” Heather McArthur, MD, MPH, FASCO, said in
an interview with OncologyLive. “TROP2 is ubiquitously expressed, [specifically with an] expression of [approximately] 80% in TNBC, and is associated with a poor prognosis. Sac-TMT is an ADC that targets the TROP2 antigen and has a unique linker technology that links with a topoisomerase I payload. [Patients with] high-risk residual TNBC after neoadjuvant therapy
are the patients who are at the highest risk, so this study aims to improve on those outcomes.”

McArthur is the clinical director of breast cancer and the Komen Distinguished Chair in Clinical Breast Cancer Research at The University of Texas Southwestern Medical Center in Dallas.

OptiTROP-Breast01 trial Data Support Current Evaluation of Sac-TMT With Pembrolizumab

OptiTROP-Breast01 assessed the efficacy and safety of sac-TMT compared with physician’s choice of chemotherapy, including eribulin, capecitabine (Xeloda), gemcitabine, or vinorelbine, for the treatment of patients aged 18 to 75 years with histologically and/or cytologically confirmed unresectable locally advanced or metastatic TNBC who had previously received at least 2 lines of standard-of-care regimens.2,3

Patients were also required to have previously received taxanes for at least 1 cycle, have at least 1 measurable lesion per RECIST v1.1 criteria, and have an ECOG performance status of 0 or 1. Patients were stratified based on lines of prior therapy (2-3 vs > 3) and presence of liver metastases (yes vs no).2

Patients were randomly assigned 1:1 to receive intravenous sac-TMT at 5 mg/kg once every 2 weeks or physician’s choice of chemotherapy until disease progression, unacceptable toxicity, or other reasons for discontinuation. The primary end point was progression-free survival (PFS) by blinded independent central review. Secondary end points included overall survival (OS), PFS by investigator assessment, overall response rate (ORR), duration of response (DOR), and safety.

Prior data from the study revealed that sac-TMT significantly improved PFS compared with chemotherapy, with a 69% lower risk of disease progression or death in patients with previously treated locally recurrent or metastatic TNBC. Specifically, at the data cutoff of June 21, 2023, the median PFS was 5.7 months (95% CI, 4.3-7.2) compared with 2.3 months (95% CI, 1.6-2.7) in the sac-TMT (n = 130) and chemotherapy (n = 133) arms, respectively (HR, 0.31; 95% CI, 0.22-0.45; P < .00001).

Among patients with high TROP2 expression (H-score > 200), the median PFS was 8.3 months (95% CI, 5.6-9.4) compared with 2.3 months (95% CI, 1.6-2.9) in the sac-TMT (n = 73) and chemotherapy (n = 74) arms, respec- tively (HR, 0.29; 95% CI, 0.19-0.46). Those with low/medium TROP2 expression (H-score ≤ 200) achieved a median PFS of 5.7 months (95% CI, 4.3-7.2) in the investigational arm (n = 53) vs 2.6 months (95% CI, 1.5-2.8) in the control arm (n = 48; HR, 0.35; 95% CI, 0.21-0.56). Furthermore, sac-TMT demonstrated a signif- icant improvement in OS compared with chemotherapy, displaying a 47% lower risk of death. Notably, the median OS was not reached (95% CI, 11.2-not estimable) in the sac-TMT arm vs 9.4 months (95% CI, 8.5-11.7) in the chemother- apy arm (HR, 0.53; 95% CI, 0.36-0.78; P = .0005). The 12-month OS rates in the respective arms were 57.8% and 35.2%.

Additionally, in the overall popu- lation, the ORR was 45.4% in the sac-TMT arm vs 12.0% in the chemotherapy arm, demonstrating a 33.1% difference in ORR (95% CI, 23.0%-43.2%; P < .00001). In patients with high TROP2 expres- sion, 52.1% achieved a response in the sac-TMT arm compared with 10.8% in the chemotherapy arm. In a similar trend, 39.6% vs 14.6% of patients with low/medium TROP2 expression experienced a response in the respective arms. The median DORs in the overall populations were 7.1 months and 3.0 months, respectively (HR, 0.50; 95% CI, 0.22-1.13).

Regarding safety, treatment-related adverse effects (TRAEs) were observed in 100% and 96.2% of patients from the sac-TMT and chemotherapy arms, respectively. Grade 3 or greater TRAEs were reported in 57.7% and 56.8% of patients; serious TRAEs were reported in 20.8% and 12.9% of patients. The most common any-grade TRAEs observed in at least 30% of patients included anemia (sac-TMT, 80%; chemotherapy, 54%), decreased neutrophil count (74%; 74%), decreased white blood cell count (74%; 77%), stomatitis (44%; 5%), decreased platelet count (41%; 26%), nausea (35%; 19%), rash (31%; 0%), increased alanine aminotransferase level (25%; 36%), and increased aspartate aminotransferase level (18%; 48%).

Diving Into the TroFuse-012 Trial

Findings from the OptiTROP-Breast01 study have emphasized the use of sac-TMT in the TNBC setting, in which TroFuse-012 aims to take a step further by combining sac-TMT with pembrolizumab in patients with previously treated TNBC (Figure)1,4

TroFuse-012 is enroll- ing patients 18 years or older with centrally confirmed TNBC defined by the updated American Society of Clinical Oncology/College of American Pathologists guidelines, no evidence of locore- gional or distant relapse, and previous receipt of neoadjuvant treatment based on the phase 3 KEYNOTE-522 trial (NCT03036488) regimen of pembrolizumab plus carboplatin/taxanes and pembrolizumab plus anthracycline-based chemo- therapy.

Moreover, patients will be randomly assigned within 16 weeks of definitive surgery, have received adjuvant radiation therapy that is completed before being randomly assigned, have provision of a tumor sample for assessment of TROP2 expression, have adequate organ function, and have an ECOG performance status of 0 or 1.1 Patients will be stratified based on residual tumor and lymph node status, TROP2 expression, and intention to use capecitabine (yes vs no).

“Notably, patients with germline BRCA mutations who are candidates for olaparib [Lynparza], where olaparib is approved and available, are not eligible [for the TroFuse-012 study],” McArthur noted.

Patients will be randomly assigned 1:1 to receive either pembrolizumab at 400 mg once every 6 weeks for 5 doses plus sac-TMT at 4 mg/kg once every 2 weeks for 12 doses (arm A) or pembrolizumab at 400 mg once every 6 weeks for 5 doses or pembrolizumab at the same dose level plus capecitabine at 1000 to 1250 mg/m2 twice a day on days 1 to 14 and days 22 to 35 in every 6-week cycle for 4 cycles (2 weeks on, 1 week off; arm B).

The primary end point is inva- sive disease–free survival (iDFS). Secondary end points include OS, distant recurrence-free survival, and safety.

“With a primary end point of iDFS, the study is open globally and is enrolling very quickly. We hope to see those data sooner rather than later, and the sponsor recently announced that they’ve even moved this strategy into the neoad- juvant setting and therefore have plans to enroll in that setting as well,” McArthur said. “[This is] highly anticipated, and we hope this is the strat- egy that pushes the needle forward and further improves cure rates for our [patients with] high-risk TNBC.”

Furthermore, the study will involve disease and adverse effect (AE) assessments. In particu- lar, the disease assessment will be determined by the local investigator every 6 weeks from random assignment through the end of treatment, in which patients whose disease recurs before the end of treatment will be assessed until week 24 before entering long-term follow-up. Patients who complete the intervention period and those who discontinue treatment for reasons beyond distant recurrence will enter long-term follow-up, which will occur from the date of random assign- ment at every 3-month interval for month 9 to year 2, at every 6-month interval for years 2 to 5, and then annually for years 6 to 10.

Additionally, AEs will be assessed through 30 days following the end of study treatment, including 90 days for serious AEs or 30 days if the patient begins a new anticancer therapy. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Enrollment for the study began in June 2024 and is planned across 18 countries at 280 sites.

“It’s an incredibly exciting time to be treating breast cancer—it’s an era of hope and optimism,” McArthur said. “We’ve seen unprecedented, rapid drug development; successful drug development that has led to improvements in cure rates in the curative-intent setting; and improvements in OS in the metastatic setting.”

References

1. McArthur HL, Dent RA, Hui R, et al. A phase 3, randomized study of adjuvant sacituzumab tirumotecan plus pembrolizumab vs treatment of physician’s choice in participants with triple- negative breast cancer who received neoadjuvant therapy and did not achieve a pathologic complete response at surgery. J Clin Oncol. 2025;43(suppl 16):TPS616. doi:10.1200/JCO.2025.43.16_suppl.TPS616
2. Xu B, Yin Y, Fan Y, et al. Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): results from the phase III OptiTROP-Breast01 study. J Clin Oncol. 2024;42(suppl 16):104. doi:10.1200/JCO.2024.42.16_ suppl.104
3. SKB264 injection vs investigator selected regimens to treat locally advanced, recurrent or metastatic triple-negative breast cancer. ClinicalTrials.gov. Updated December 12, 2024. Accessed July 22, 2025. https://clinicaltrials.gov/study/NCT05347134
4. Sacituzumab tirumotecan (MK-2870) plus pembrolizumab versus TPC in TNBC who did not achieve pCR (MK-2870-012). ClinicalTrials.gov. Updated July 20, 2025. Accessed July 22, 2025. https://www.clinicaltrials.gov/study/NCT06393374