Ongoing Research Aims to Unveil the Optimal Use of Neoadjuvant and Adjuvant Therapies in TNBC

Linda T. Vahdat, MD

A host of clinical trials are comparing standard adjuvant regimens and introducing novel agents for the treatment of patients with triple-negative breast cancer (TNBC) with residual disease after upfront chemoimmunotherapy, according to Linda T. Vahdat, MD.

In an interview with OncLive^®, Vahdat discussed ongoing research investigating the use of immunotherapy, antibody-drug conjugates, and targeted agents in patients with TNBC who have residual disease following first-line chemoimmunotherapy, as well as potential lessons to be learned from clinical trials investigating adjuvant immunotherapy in this disease that failed to meet their primary end point.

Vahdat provided additional insights on the management of TNBC in another article.

Vahdat is the section chief of Medical Oncology, interim section chief of Hematology, and a professor of medicine at the Geisel School of Medicine at Dartmouth Health in Lebanon, New Hampshire.

OncLive: What research may inform the future treatment of patients with TNBC who have residual disease after first-line chemoimmunotherapy?

Vahdat: A lot of clinical trials are investigating what to do with patients after they receive upfront chemoimmunotherapy. There are clinical trials evaluating what to do with patients who have a pathologic complete response [pCR] and patients who have a non-pCR. [Regarding] trials that are available and actively accruing, the [phase 3] SCARLET trial [NCT05929768] is comparing the [phase 3] KEYNOTE-522 trial [NCT03036488] and [phase 2] NeoPACT [trial (NCT03639948) regimens]. Unfortunately, [patients in this trial have the option to receive adjuvant] pembrolizumab [Keytruda], but [the trial is still] going to give us a good idea of how these 2 therapeutic [regimens] stack up against each other.

For patients who have a pCR [with chemoimmunotherapy], there’s a trial called the [phase 3] OptimICE-PCR trial [NCT05812807], in which patients are randomly assigned to receive pembrolizumab or undergo observation after they achieve a pCR [following neoadjuvant chemotherapy with pembrolizumab]. [This trial will] give us a sense [of whether these patients] need adjuvant immunotherapy. Additionally, the [phase 3] ASCENT-05 trial [NCT05633654] is evaluating adjuvant sacituzumab govitecan-hziy [Trodelvy] plus pembrolizumab vs treatment of physician’s choice, which can either be pembrolizumab by itself or pembrolizumab plus capecitabine.

The [phase 3] TROPION-Breast03 trial [NCT05629585] is investigating datopotamab deruxtecan [Dato-DXd] plus durvalumab [Imfinzi]. There are 3 arms in that study [that include] patients who have non-pCRs: Dato-DXd plus durvalumab, Dato-DXd by itself, and treatment of physician’s choice.

Finally, there’s the [phase 2] PERSEVERE trial [NCT04849364], which is a little different [from the other trials] in that it screens patients not only according to whether they have residual disease at the time of surgery, but also by whether they’re circulating tumor DNA [ctDNA] positive. If patients are ctDNA positive, they will receive a genomically-directed therapy. The 2 [genomically-directed agents currently available] include inavolisib, an agent targeting the PI3K pathway,[which is being combined with] capecitabine plus or minus pembrolizumab, and talazoparib [(Talzenna), which targets] the DNA repair pathway, [and is being combined with] capecitabine plus or minus pembrolizumab. [The control arm is] treatment of physician’s choice, which is capecitabine plus or minus pembrolizumab. In the next couple years, we’ll get a lot of good information about what might be the optimal standard-of-care adjuvant therapy for patients with residual disease, and hopefully that will push the survival curves out.

What has been seen regarding the activity of adjuvant immunotherapy in patients with TNBC?

At the 2024 ASCO Annual Meeting, [findings from] 2 studies were reported [regarding the use of] adjuvant immunotherapy [in patients with TNBC]. There was no benefit in disease-free survival [DFS] in either of those studies. One was the [phase 3] IMpassion030/ALEXANDRA trial [NCT03498716]. In that trial, 2,300 patients were randomly assigned to receive paclitaxel followed by dose-dense anthracycline plus cyclophosphamide with atezolizumab [Tecentriq] vs the same [regimen] without atezolizumab. [The DFS] curves completely overlapped, so [there was] no benefit [with the addition of atezolizumab.

The second trial was the [phase 3] A-BRAVE trial [(NCT02926196), findings from which were] presented by Pier Franco Conte, MD, [of the Istituto Oncologico Veneto in Padova, Italy]. That trial included 2 cohorts of patients: those treated in the adjuvant setting and those in the neoadjuvant [setting with] residual disease. Patients were randomly assigned to receive avelumab [Bavencio] vs undergo observation.

For the entire cohort, there was no [DFS] advantage with avelumab. However, interestingly, it looked like there might be a survival benefit in the [patients who received] avelumab. This needs more study, [but was] interesting. We look forward to hearing these [survival data]. [Overall, regarding] adjuvant immunotherapy, the results we’re seeing were predicted by the preclinical models, so they are not a surprise.

How might TNBC subtyping evolve in the coming years?

The management of TNBC, whether it’s in the early stage or in the metastatic stage, is evolving. The next [development] we’re going to see is subtyping within TNBC. [The phase 3 CIBOMA trial (NCT00130533), findings from which were] presented at the 2024 ASCO Annual Meeting, evaluated the utility of capecitabine in non-basal TNBC. We’re going to start seeing subtypes of subtypes. It’s important to stay up to date so you can offer patients the latest and greatest [therapies].