ADCs Are Poised to Transform the Metastatic TNBC Treatment Arsenal

Nerea Lopetegui-Lia, MD

Triple-negative breast cancer (TNBC) management is becoming increasingly individualized through the expansion of the clinical applications for immunotherapy agents and the increasingly selective varieties of PARP inhibitors and antibody-drug conjugates (ADCs) that are in development, according to Nerea Lopetegui-Lia, MD.

In an interview with OncLive®, Lopetegui-Lia discussed the evolving role of adjuvant pembrolizumab (Keytruda) for patients with early-stage TNBC who achieve pathologic complete response (pCR) following neoadjuvant therapy and surgery, ongoing clinical trials that may help clarify treatment options for patients with residual disease, and investigational ADCs that are shaking up the metastatic setting.

She explained the prevalence of TNBC, associated risk factors, and considerations for broadening the range of therapies for the management of early-stage disease in another article.

Lopetegui-Lia is a breast medical oncologist and assistant professor at The Ohio State University Comprehensive Cancer Center—James in Columbus.

OncLive: How do patients’ responses to neoadjuvant therapy help guide treatment decision-making in the adjuvant setting?

Lopetegui-Lia: One of the questions we oftentimes get is: What do we do in the post-neoadjuvant setting? Is [adjuvant] pembrolizumab necessary in cases of pCR [with neoadjuvant therapy]? There is a challenge in distinguishing between the few high-risk patients who need treatment intensification vs those who are at risk for overtreatment because of their favorable outcomes. Patients with pCR or residual cancer burden of 0 or 1 [have been shown to have] similar rates of recurrence [regardless of whether they] received [adjuvant] pembrolizumab. The ongoing phase 3 randomized OptimICEpCR study [NCT05812807] is evaluating pembrolizumab vs observation [in patients with early-stage TNBC who have received neoadjuvant pembrolizumab followed by surgery]. [This study has] a noninferiority margin of 3% for 3-year recurrence-free survival.1

Another area of high unmet need is what to do in patients with early-stage, high-risk TNBC who receive neoadjuvant chemoimmunotherapy and then have residual disease at the time of surgery. We tend to consider 2 different agents [in this setting]. [We use] capecitabine for patients who do not harbor a BRCA1 or BRCA2 mutation, and olaparib [Lynparza] in those who have a BRCA mutation. Those [decisions] are based on findings from the phase 3 CREATE-X [UMIN000000843] and OlympiA [NCT02032823] studies, respectively.

CREATE-X was a phase 3 trial of capecitabine vs observation in patients with residual disease after neoadjuvant therapy. Importantly, [at the time of this trial, the] phase 3 KEYNOTE-522 trial [NCT03036488] regimen had not been FDA approved yet, so these patients had not received [neoadjuvant] immunotherapy, but they received neoadjuvant chemotherapy. The 5-year disease-free survival [DFS] rates were 69.8% vs 56.1% [among patients with TNBC] in the capecitabine vs observation arms, respectively.2 Overall survival [OS] outcomes were also statistically significant [favoring] the capecitabine arm. Therefore if [a patient has] residual disease, I typically use a combination of pembrolizumab plus capecitabine, and that seems to be safe, although, again, because it wasn't studied in [patients who received neoadjuvant chemoimmunotherapy], we don't have efficacy data [in that setting].

The OlympiA study evaluated 1 year of olaparib —a PARP inhibitor—or placebo in patients with HER2-negative, high-risk early breast cancer with a germline pathogenic or likely pathogenic BRCA1 or BRCA2 mutation. Therefore, in patients with residual disease who have BRCA1 or BRCA2 mutations, I tend to combine pembrolizumab and olaparib. There is debate about whether we should give [these agents] concurrently or sequentially. Preclinical studies have shown that [these drugs] have a synergistic effect and that the combination seems to be safe. However, there are no clear data [showing the effects of] combining both these agents.

Many of us were excited about the 10-year update from the OlympiA trial, which was presented at the 2024 San Antonio Breast Cancer Symposium. OlympiA was the study that led to the FDA approval of olaparib in the adjuvant TNBC setting. At a median follow-up of 6.1 years, the trial showed that the benefits of olaparib [vs placebo] in terms of invasive DFS, distant DFS, and OS were maintained. More interestingly, there was no increase in [the rates of developing] myelodysplastic syndromes, acute myeloid leukemia, or new primary malignancies—including breast, ovarian or fallopian tube, and pancreas cancers—compared with placebo. These data are reassuring because [the risk of developing new primary malignancies] was a concern that was raised with PARP inhibitors. 

What ongoing research is evaluating optimal treatments for patients with residual TNBC?

One ongoing trial is the phase 3 ASCENT-05/​AFT-65/OptimICE-RD/​NSABP B-63 trial [NCT05633654], which is investigating sacituzumab govitecan-hziy [Trodelvy] plus pembrolizumab vs pembrolizumab with or without capecitabine in patients with early-stage TNBC with residual disease. Sacituzumab govitecan is a highly selective TROP2-directed ADC. Its payload is SN-38. SN-38 is more potent than its parent compound, which is irinotecan. [Sacituzumab govitecan has] a high drug-to-antibody ratio of 7.6.

Additionally, the phase 3 TROPION-Breast03 trial [NCT05629585] is investigating datopotamab deruxtecan [Dato-DXd; Datroway] with or without durvalumab [(Imfinzi) in patients with residual TNBC]. Dato-DXd is also an ADC. It's a humanized anti-TROP2 IgG1 monoclonal antibody that uses a topoisomerase I inhibitor payload. It's an exatecan derivative, and the drug-to-antibody ratio is 4. [Dato-DXd] has a high-stability linker, which limits the systemic exposure—or nontargeted delivery—of the payload.

Lastly, there's adjuvant sacituzumab tirumotecan [sac-TMT] plus pembrolizumab vs treatment of physician's choice that's being evaluated [in the adjuvant setting in a phase 3 trial (NCT06393374) in patients with TNBC who have received neoadjuvant therapy and did not achieve a pCR at the time of surgery].

What does the treatment paradigm currently look like for patients with metastatic TNBC?

Unfortunately, we don't have a lot of great options here. The phase 3 KEYNOTE-355 trial [NCT02819518] investigated the addition of immune-oncology [IO] to chemotherapy in patients with [advancedTNBC with] a PD-L1 CPS of 10 or higher. [In this trial], chemotherapy plus pembrolizumab generated significantly prolonged progression-free survival [PFS] and overall survival [OS] compared with chemotherapy alone. However, [only approximately] 40% of patients with TNBC have PD-L1–positive disease [at a level that makes them] eligible for IO. There's still a big unmet need in this setting for which [there are] a few ongoing trials that are exciting.

[For patients with] metastatic TNBC, first, I usually check their PD-L1 status. If they have a PD-L1 CPS of 10 or greater, I use a combination of chemotherapy plus pembrolizumab. If their PD-L1 CPS is less than 10, and if there's no germline BRCA1 or BRCA2 mutation, then I usually use systemic chemotherapy.

If patients do have a germline BRCA1 or BRCA2 mutation, then [I consider] PARP inhibitors, such as olaparib or talazoparib [Talzenna]. Those agents were FDA approved based on findings from the OlympiA and phase 3 EMBRACA [NCT01945775] trials, respectively. However, notably, as presented at the 2024 ASCO Annual Meeting, [EMBRACA evaluated patient populations with several] breast cancer subtypes. Expansion cohorts evaluated patients with germline PALB2 mutations or somatic BRCA1 mutations to see whether these patients would benefit from PARP inhibitors. There's going to be more to come on that topic.

Speaking of PARP inhibitors, there is a first-in-class PARP1-selective inhibitor called saruparib [AZD5305]. This [agent was investigated in] the phase 1/2a PETRA study [NCT04644068] that showed promising safety, pharmacokinetics, pharmacodynamics, and efficacy with the agent [in the cohort of patients with advanced breast cancer harboring BRCA1/2, PALB2, or RAD51C/D mutations]. That is another exciting trial.

Single-agent chemotherapy has been the mainstay of treatment for metastatic TNBC for many years, with limited treatment options for patients who are not candidates for PD-L1 therapy. Some of the ADCs that are approved in this setting are sacituzumab govitecan—a first-in-class TROP2-directed ADC, which was [FDA approved for this population] based on findings from the phase 3 ASCENT trial [NCT02574455], where it was compared with treatment of physician's choice.

Similarly, the phase 3 DESTINY-Breast04 trial [NCT03734029] evaluated fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] vs treatment of physician's choice [in patients with HER2-low metastatic or unresectable breast cancer]. T-DXd is an anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab. It has a topoisomerase I inhibitor payload deruxtecan, and it has a high drug-to-antibody ratio of 8.

DESTINY-Breast04 included 58 patients with HER2-low TNBC. An exploratory analysis [in this cohort] found that T-DXd led to numerical improvements in PFS and OS vs treatment of physician's choice. However, the analysis of the efficacy of T-DXd in this population was not a prespecified end point of the trial, so no formal comparison was conducted, and no P-value was provided for this analysis.

The phase 1b/2 BEGONIA study [NCT03742102] examined Dato-DXd plus durvalumab as first-line treatment for patients with locally advanced or metastatic TNBC. This study confirmed that Dato-DXd plus durvalumab provided an ORR of 79% [95% CI, 66.8%-88.3%] with a median follow-up of 11.7 months.3 Importantly, 60% of patients had visceral metastases, and 87% of patients had low PD-L1 expression, which is interesting because responses to treatment were [observed] irrespective of PD-L1 expression level.4 The median PFS was 13.8 months [95% CI, 11.0-not calculable], and [the investigational combination had] a manageable safety profile with no safety signals reported.3,4

What ongoing research with ADCs may continue to shape the metastatic TNBC treatment paradigm?

The aim of the phase 3 TROPION-Breast02 [NCT05374512] trial is to evaluate the efficacy and safety of Dato-DXd vs investigator's choice of chemotherapy in patients with locally advanced or metastatic TNBC who are not candidates for PD-L1 or PD-1 inhibitor therapy. The phase 3 TROPION-Breast05 trial [NCT06103864] is also ongoing. This study is investigating Dato-DXd with or without durvalumab vs chemotherapy plus pembrolizumab in patients with PD-L1–positive, locally recurrent, inoperable or metastatic TNBC. Importantly, patients with active brain metastases will be excluded.

We're also eagerly awaiting [results from] the phase 3 ASCENT-04 trial [NCT05382286], which is evaluating the combination of sacituzumab govitecan plus pembrolizumab vs treatment of physician's choice plus pembrolizumab for PD-1–positive metastatic TNBC.

Additionally, the phase 3 OptiTROP-Breast01 trial [NCT05347134] is investigating sacituzumab tirumotecan, which is a novel ADC. [This ADC is] composed of an anti-TROP2 antibody that's coupled to a cytotoxic belotecan derivative via a novel linker. The average drug-to-antibody ratio is 7.4. This is a study of patients with locally recurrent or metastatic TNBC [who have previously been] treated with 2 or more lines of chemotherapy. They were randomly assigned to receive sacituzumab tirumotecan vs physician's choice of chemotherapy. [In this trial], sacituzumab tirumotecan alone improved PFS and OS vs chemotherapy in these patients who were already heavily pretreated with advanced TNBC. [There are] more [implications] to come [from that trial]. 

Lastly, patritumab deruxtecan [HER3-DXd] is a first-in-class, HER3-directed ADC composed of a fully human anti-HER3 IgG1 monoclonal antibody covalently linked to an exatecan derivative with a topoisomerase I inhibitor payload. HER3-DXd has shown promising activity across all breast cancer subtypes. [The phase 1/2 U31402-A-J101 study (NCT02980341)] evaluated [this ADC in] 53 patients with triple-negative disease; the ORR [with this agent] was 22.6% [95% CI, 12.3%-36.2%], and the median PFS was 5.5 months [95% CI, 3.9-6.8].5 Interestingly, objective responses were observed in tumors with HER3-high and HER3-low membrane expression.

References

1. Valenza C, Trapani D, Loibl S, et al. Optimizing postneoadjuvant treatment in patients with early breast cancer achieving pathologic complete response. J Clin Oncol. 2024;42(20):2372-2376. doi:10.1200/JCO.23.01935
2. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645
3. Datopotamab deruxtecan plus Imfinzi demonstrated robust and durable tumour responses in 1st-line treatment of patients with metastatic triple-negative breast cancer in BEGONIA phase Ib/II trial. News release. AstraZeneca. October 22, 2023. Accessed April 14, 2025. https://www.astrazeneca.com/media-centre/press-releases/2023/dato-dxd-plus-imfinzi-robust-durable-tumour-responses-1st-line-treatment-patients-metastatic-triple-negative-breast-cancer-begonia-phase-ibii-trial.html
4. Schmid P, Wysocki PJ, Ma CX, et al. Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase Ib/II study. Ann Oncol. 2024;34(suppl 2):S337. doi:10.1016/j.annonc.2023.09.556
5. Krop IE, Masuda N, Mukohara T, et al. patritumab deruxtecan (HER3-DXd), a human epidermal growth factor receptor 3-directed antibody-drug conjugate, in patients with previously treated human epidermal growth factor receptor 3-expressing metastatic breast cancer: a multicenter, phase I/II trial. J Clin Oncol. 2023;41(36):5550-5560. doi:10.1200/JCO.23.00882