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Pembrolizumab-Based Regimens Gain Ground in TNBC Management

Nerea Lopetegui-Lia, MD, discusses the prevalence of and risk factors for triple-negative breast cancer, and strategies that may improve survival outcomes.

Nerea Lopetegui-Lia, MD

Nerea Lopetegui-Lia, MD

Evolving early-stage triple-negative breast cancer (TNBC) treatment approaches underscore the importance of precision medicine and ongoing research to improve outcomes for patients with this malignancy, who have historically had poor prognoses, according to Nerea Lopetegui-Lia, MD.

“In general, despite significant progress in breast cancer research and treatment, TNBC remains a clinical challenge, which underscores the urgent need for innovative therapeutic approaches and precision medicine strategies,” Lopetegui-Lia said in an interview with OncLive®.

In the interview, Lopetegui-Lia, a breast medical oncologist and assistant professor at The Ohio State University Comprehensive Cancer Center—James in Columbus, discussed the prevalence of TNBC compared with other breast cancer subtypes, key risk factors associated with the development of this disease, and the need for additional treatment strategies to improve long-term survival rates.

Additionally, Lopetegui-Lia highlighted standard treatment strategies for patients with stage I to III disease, as well as questions that remain regarding optimal therapeutic decision-making for certain patients. She noted the role of perioperative pembrolizumab (Keytruda) in combination with neoadjuvant carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide, which was investigated in patients with previously untreated stage II or III TNBC in the phase 3 KEYNOTE-522 trial (NCT03036488). Findings from the primary interim analysis of this trial, which led to the 2021 FDA approval of the regimen in this population, showed that patients who received pembrolizumab plus chemotherapy (n = 401) achieved a pathologic complete response (pCR) rate of 64.8% vs 51.2% in those who received chemotherapy alone (n = 201; P = .00055).1

She also noted future directions in researching anthracycline-free regimens for patients with TNBC to build upon findings from the phase 2 NeoPACT trial (NCT03639948), in which patients who received neoadjuvant pembrolizumab plus carboplatin and docetaxel (n = 115) achieved a pCR rate of 58% (95% CI, 48%-67%) and a 3-year event-free survival (EFS) rate of 86% (95% CI, 77%-95%).3

OncLive: What is the prevalence of TNBC compared with other breast cancer subtypes?

Lopetegui-Lia: TNBC is a breast cancer subtype that accounts for approximately 15% to 20% of all newly diagnosed breast cancers. It is a complex, heterogeneous disease entity that is associated with unique therapeutic and diagnostic challenges. Typically, we think of TNBC as being more aggressive. It has a higher prevalence among young women, especially women of African ancestry, as well as in patients who carry a BRCA mutation. TNBC is less likely to be detected by mammography screening [compared with] other breast cancers; therefore, patients tend to present in more advanced stages and have a higher likelihood, unfortunately, of early metastases to distant organs, such as the lungs, liver, and brain. All of this contributes to this disease’s poor prognosis compared with other breast cancer subtypes.

What are some of the risk factors associated with TNBC development?

[This is] one of the questions I often get asked in the clinic. A systematic review and meta-analysis led by Nitya Kumar, PhD, [of the Royal College of Surgeons in Ireland at the Medical University of Bahrain], examined the association of established breast cancer risk factors with triple-negative [disease status]. They found that family history and higher breast density were both significantly associated with an increased risk for TNBC, as well as a longer duration of oral contraceptive use; [at least] 10 years of oral contraceptive use was associated with an approximate 30% increased risk of [developing] TNBC. On the other hand, protective factors against TNBC were later age at menarche, breastfeeding, and—in contrast with published associations with the overall [development of] breast cancer—later age at first [child] birth.

What are the biggest unmet needs for patients with this breast cancer subtype?

TNBC has the worst prognosis among all breast cancer subtypes. Based on [data from] the SEER database, the 5-year overall survival [OS] rate for patients with TNBC is approximately 78% compared with approximately 92% to 95% [among patients with] hormone receptor [HR]–positive, HER2-negative breast cancers. More specifically, in stage IV disease, the 5-year OS rate is approximately 14.3% in patients with TNBC, which again is significantly lower than [that of patients with] metastatic HR-positive, HER2-negative breast cancers. Collaborative efforts among clinicians, researchers, biotech companies, pharmaceutical companies, [and others] will be essential to overcome these challenges and improve patient outcomes.

What comprises the treatment paradigm for patients with early-stage TNBC?

For [patients with] early-stage TNBC within stage I T1b, which are tumors that are between 6 mm and 1 cm, we typically consider a non-anthracycline chemotherapy regimen. Docetaxel plus cyclophosphamide for 4 cycles is usually our treatment choice.

For [patients with] T1c tumors, which are tumors between 1 cm and 2 cm, there’s a bit more controversy. I’ve seen a lot of different medical oncologists [each make different choices]. Many of us would choose dose-dense doxorubicin plus cyclophosphamide for 4 cycles, followed by either dose-dense paclitaxel for 4 cycles or weekly paclitaxel for 12 cycles. However, other options some medical oncologists may consider—depending on the patient’s performance status and comorbidities—are either doxorubicin plus cyclophosphamide for 4 cycles, or, even in some cases, the KEYNOTE-522 regimen.

There’s generally less controversy in stage II and III disease, where we typically consider the KEYNOTE-522 regimen. That is the gold standard, regardless of patients’ PD-L1 status. That’s carboplatin, paclitaxel, and pembrolizumab, followed by doxorubicin plus cyclophosphamide and pembrolizumab. That’s given in the neoadjuvant setting, and then patients are taken to surgery. Regardless of surgical pathology results—meaning regardless of whether patients have a pCR or residual disease [following surgery—the regimen then calls for adjuvant pembrolizumab to complete 1 year. This [regimen] was [FDA approved for patients with high-risk, early-stage TNBC] because there was a 13.6% improvement in pCR rate [with this regimen vs the placebo regimen], so patients who received chemoimmunotherapy had a pCR rate of 64.8% in comparison with those who received chemotherapy plus placebo, who had a pCR rate of 51.2%.

What might be the future role of anthracycline-free regimens for patients with early-stage TNBC?

[We typically] think of TNBC [as affecting primarily] younger patients, but older patients may also present with TNBC, and anthracycline use has been associated with cardiotoxicity. NeoPACT was a study that evaluated the efficacy of an anthracycline-free neoadjuvant regimen for patients with TNBC stages I to III. It was a single-arm, phase 2 trial using docetaxel plus carboplatin and pembrolizumab given every 3 weeks for 6 cycles.

[Importantly, this trial] enrolled 115 women, and 39% had node-positive disease. The pCR rates were encouraging, and the 3-year EFS rate was 86%. That has led to [the initiation of] the phase 3 randomized SCARLET study [NCT05929768] that’s comparing the NeoPACT regimen vs the KEYNOTE-522 regimen for early-stage TNBC. This will help us understand whether an anthracycline-free regimen is reasonable for patients with cardiac comorbidities or poorer performance status. This is an interesting study, and we are all awaiting the results.

References

  1. FDA approves KEYTRUDA (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as single agent as adjuvant treatment after surgery. News release. Merck. July 27, 2021. Accessed April 11, 2025. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/
  2. Schmid P, Cortés J, Dent R, et al. KEYNOTE-522: phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Ann Oncol. 2019;30(suppl 5):V853-V854. doi:10.1093/annonc/mdz394.003
  3. Sharma P, Stecklein SR, Yoder R, et al. Clinical and biomarker findings of neoadjuvant pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer: NeoPACT phase 2 clinical trial. JAMA Oncol. 2024;10(2):227-235. doi:10.1001/jamaoncol.2023.5033


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