Revolutionizing Triple-Negative Breast Cancer Treatment: A Safer Path Forward

Triple-negative breast cancer (TNBC) is a notoriously aggressive form of cancer, often requiring intense and highly toxic treatment regimens. The current standard of care frequently involves anthracyclines, a class of chemotherapy drugs known for their severe adverse effects, including secondary blood cancers like leukemia and irreversible heart failure. This urgent unmet need for effective yet less toxic treatment options for early TNBC is driving innovative research.

In an interview with Targeted Oncology, Rachel Ableman, MD, a medical oncologist at Mass General Cancer Center and an instructor of medicine at Harvard Medical School, discussed her team's recent study, which aims to address these critical issues.

Targeted Oncology: What was the rationale for your study?

Rachel Abelman, MD: Triple-negative breast cancer is an aggressive, extremely time-intensive regimen with a lot of toxicity and notably includes an anthracycline. Anthracyclines are notorious for having a relatively higher rate of causing secondary blood cancer like leukemia, as well as cardiac toxicity, including potentially irreversible heart failure. And so, for that reason, the need to develop an effective treatment regimen for early triple-negative breast cancer with less toxicity than our current standard of care is urgent and would be highly impactful. We know that triple-negative breast cancer, when it recurs or becomes metastatic, has fewer effective treatment options, and the survival at that point is relatively short in most patients. So, we’re eager to optimize early treatment of triple-negative breast cancer to minimize the risk of recurrence and minimize toxicity as well.

Could you summarize the objectives and methodology of your study?

The study involved the use of an antibody-drug conjugate [ADC]. This is a novel form of chemotherapy that involves an antibody targeted against a tumor-associated antigen paired with a potent chemotherapy-like payload. The goal of these ADCs is to deliver chemotherapy in a targeted fashion, to select cells, rather than traditional chemotherapy, which delivers chemotherapy to all cells, which is why there's more off-target toxicity.

The agent that we used was sacituzumab govitecan [SG; Trodelvy], which is a Trop-2–directed ADC with a topoisomerase 1 inhibitor payload. This is approved for use in both metastatic triple-negative breast cancer and some metastatic hormone receptor-positive, HER2-negative breast cancer in some settings but is not approved for use in early triple-negative breast cancer. This was paired with the immunotherapy pembrolizumab [Keytruda], which is an anti–PD-1 antibody that's used to essentially stimulate the immune system and help the body synergize with chemo[therapy] or ADCs to help fight against cancer and maximize response to therapy. Pembrolizumab is approved for both metastatic triple-negative breast cancer and early breast cancer as part of the standard-of-care KEYNOTE-522 [NCT03036488] regimen.

So, the question is, really, can we find an agent or agents that pair with pembrolizumab to provide similar effectiveness while minimizing some of the toxicity of the standard chemotherapy backbone? Our primary end point was pathologic complete response [pCR] after SG and pembrolizumab alone.

In the trial regimen, we gave patients 4 cycles of SG and pembrolizumab, and then patients underwent posttreatment imaging if there was residual disease suspected, and they then underwent research biopsy and, if positive, received additional neoadjuvant chemotherapy that was considered not pCR per the study protocol. Only patients who had no residual disease suspected after the 4 cycles of SG and pembrolizumab had imaging and went straight to surgery.

Could you summarize your findings?

There were several important findings. The primary end point was pathologic complete response to SG and pembrolizumab alone. The pCR rate in the study was 32%, or 16 patients of our 50 enrolled experienced pCR after SG and pembrolizumab alone.

There are many important secondary end points. The radiographic response rate was 66%, so after the trial, there was either a partial or complete response. So basically, two-thirds of the cohort experienced radiographic response prior to either additional chemotherapy or surgery. Also notably, there were several patients who got additional chemo that was not anthracycline prior to surgery and then experienced pCR at surgery. Nine of 9 additional patients, out of the 50, met those criteria. At surgery, 25 of 50 patients did not have any residual disease seen, but 9 of those had already received additional neoadjuvant chemotherapy.

Based on these findings, what would you say are the main takeaways for clinicians?

The first takeaway is there were no new or unexpected safety signals seen. So, this regimen, I think, is safe and effective. The question is just efficacy compared to the standard of care KEYNOTE regimen. There really is a lot of daylight between the number of agents used in the standard-of-care KEYNOTE regimen and the trial regimen of SG/pembrolizumab alone. We found that in the large part of our cohort who got additional chemotherapy that was not anthracycline based after the trial regimen before surgery, many of those patients had experienced pCR without the use of an anthracycline. So taken together, 50% of our cohort did not have residual disease at surgery. None of those patients had gotten anthracycline. So, I think the day-after question is, can we optimize a presurgery regimen that incorporates ADCs but minimizes use of anthracyclines to maximize efficacy and spare patients off-target toxicity, particularly the anthracycline toxicities of secondary leukemia and heart dysfunction?

Moving forward, what do you see as the next step in this research?

We're just starting our translational portion of this research. As part of the trial, we took blood and tissue samples pre- and posttreatment. We're seeking to analyze response to treatment based on pretreatment tissue samples and also looking at response as well. We have a lot of interesting analyses planned, including single-cell sequencing, spatial transcriptomics, and looking at biomarkers associated with response and resistance to therapy.

I think we're hoping to design future trials looking at potentially SG and pembrolizumab paired with nonanthracycline chemotherapies to, hopefully, have similar rates of response to compare it to, compared to the KEYNOTE regimen.

This is a really active space. The trial was designed before the standard-of-care regimen was approved. One of the challenges in our trials in general is that the standard of care is evolving so quickly that it can often make interpretation a little challenging, because there have been so many new approvals since the study started, even when they're relatively quick studies. But I think we do, as a field, have an urgent mission to try to maximize efficacy and minimize toxicity as much as possible. And I'm really motivated, as a clinician as well as an investigator, to find ways that we can do this.

REFERENCE:

Abelman A, McLaughlin S, Fell G, et al. A phase 2 study of response-guided neoadjuvant sacituzumab govitecan and pembrolizumab (SG/P) in patients with early-stage triple-negative breast cancer: Results from the NeoSTAR trial. J Clin Oncol. 511-511(2025). DOI:10.1200/JCO.2025.43.16_suppl.51