ADC and CDK4/6 Inhibitor Research Set to Refine TNBC and ER+ Breast Cancer Treatment Strategies

Emerging data from clinical trials in triple-negative and estrogen receptor (ER)–positive breast cancer underscore the importance of continuing research efforts to address treatment resistance, cost-effectiveness, and precision during therapeutic decision-making, according to Yuan Yuan, MD, PhD.

“With the shifting of our standards of care [SOCs, the needs of] our patient populations also shift,” Yuan summarized in an interview with OncLive® following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Yuan spotlighted recent advancements in breast cancer research, including benefit seen with the antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) in patients with metastatic triple-negative breast cancer (TNBC). She also outlined lingering questions regarding the use of CDK4/6 inhibitor/oral selective estrogen receptor degrader (SERD) combinations following prior CDK4/6 inhibitor progression in patients with ER-positive breast cancer.

Yuan is a professor, director of Breast Medical Oncology Medicine, and medical director of the Breast Oncology Disease Research Group at Cedars-Sinai Medical Center in California, as well as a health sciences clinical professor at the University of California, Los Angeles.

OncLive: What key findings from the phase 3 ASCENT-04 trial (NCT05382286) may influence future clinical practice for first-line metastatic TNBC?

Yuan: ASCENT-04 compared the ADC sacituzumab govitecan in combination with pembrolizumab [Keytruda] vs chemotherapy plus pembrolizumab in a subpopulation of patients with metastatic TNBC with PD-L1 positivity. The trial has possibly set a new SOC, and we’re waiting for the FDA approval of this [regimen]. There was a prominent median progression-free survival [(PFS) increase] of from 7.8 months [(95% CI, 7.3-9.3) in the chemotherapy arm] to 11.2 months [(95% CI, 9.3-16.7) in the sacituzumab govitecan arm].1

However, one challenge [in this population] would be the treatment-resistant cases we see after neoadjuvant chemoimmunotherapy. The SOC [for metastatic TNBC] in the United States [US] and European Union has changed since the FDA approval of chemotherapy plus [pembrolizumab]. Among patients who have relapsed disease, we have not seen a lot of persisting PD-L1 positivity. It’s a data-free zone. I would call for real-world data collection to understand that when these tumors recur, what is the percentage of the patients who remain PD-L1 positive? How [do we] apply the [ASCENT-04] data to that patient population?

What questions remain regarding the use of sacituzumab govitecan plus pembrolizumab in patients with TNBC?

The biggest challenge when treating these patients, especially after prior exposure to chemoimmunotherapy, is finding novel ways of activating immune-cold tumors that are PD-L1 negative, for example. How do we convert those tumors to be PD-L1 positive? How do we treat these immune-cold tumors with a lack of PD-L1 expression and then maybe use a novel immunotherapy to treat them effectively?

One [relevant] trial coming to the US is [investigating] a bispecific antibody targeting VEGF and PD-1. [This agent has] 2 warheads: 1 recognizes PD-1, and the other recognizes VEGF. At the 2024 ESMO Congress, [we saw data with] 2 promising drugs: one is BNT-327, and the other is ivonescimab [SMT112]. Both [agents have been evaluated in] early-phase clinical trials in China, which demonstrated the efficacy [of these agents in] combination with a taxane in PD-L1–negative patients. Now BNT-327 is [under exploration] in a phase 3 randomized trial.

How might data from the phase 3 SERENA-6 trial (NCT04964934) help refine the use of CDK4/6 inhibitors in ER-positive, HER2-negative breast cancer?

With the arrival of CDK4/6 inhibitors in the adjuvant setting, we are unanimously using them for high-risk [disease] defined by clinicopathological risk factors or genomic risk factors, especially T2, N0, ER-positive, HER2-negative disease. We now have ribociclib [Kisqali] in this setting. Some data [with that agent] give us lot of comfort. For example, one study tells us about the safety and efficacy of CDK4/6 inhibition in older adults.

The phase 3 SERENA-6 trial [NCT04964934] is a promising study in the early-phase, frontline, metastatic, ER-positive, HER2-negative disease. [This trial is exploring] circulating tumor DNA [ctDNA] detection and how to guide therapy. This trial had cohorts of patients who had detectable ctDNA but did not yet have imaging progression. They were randomly assigned to either continue their original aromatase inhibitor [AI] plus a CDK4/6 inhibitor or switch to a more effective oral selective estrogen receptor degrader [(SERD) camizestrant] in combination with a CDK4/6 inhibitor [following detection of an ESR1 mutation during first-line therapy.]

[The investigators] found a [6.8]-month PFS benefit [with camizestrant plus AI].2 This approach is interesting but difficult to interpret, because in the control arm, patients who continued AI plus the original CDK4/6 inhibitor had a median PFS of 9.2 months [95% CI, 7.2-9.5]. They could enjoy that extra 9.2 months without the need to switch [therapies].

What still needs to be learned about this treatment approach to effectively integrate it into clinical practice? Do you foresee any challenges with its incorporation?

[Using oral SERDs in this setting is not standard] practice in the US, although in the US, we have the single-agent oral SERD elacestrant [Orserdu] available. Should we compare PFS1 plus PFS2 for the control arm with PFS1 of the experimental switching arm? No one understands the caveats, because there are not a lot of data available. A longer follow-up is required. Are we just seeing this phenomenon due to the statistical lead time bias? That remains to be seen.

This is an interesting approach, and ctDNA is coming in either the early setting for disease monitoring or the late-stage setting. Maybe it will help us gauge when exactly to switch therapy. We can’t get away from these questions. [We are] looking forward to more data [showing] what to do and what exactly is most beneficial for the patients.

The other challenge is cost effectiveness. We had to screen [3325] patients to find the [315] patients who had ctDNA progression but not imaging progression. However, there were also several patients who did not qualify [for enrollment in the trial] because by the time of ctDNA progression or detection, they already had simultaneous imaging progression. Only approximately 10% of the [screened] patients [had the opportunity to] benefit from [the SERENA-6] approach, and the other approximately 90% of patients did not. We have to factor financial perspectives into these trials.

References

1. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109
2. Turner N, Mayer E, Park YH, et al. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. J Clin Oncol. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4