ADCs, CDK4/6 Inhibitors, and SERDs Broaden HR+ and Triple-Negative Breast Cancer Treatment Paradigms

Heather McArthur, MD

Novel data with fam-trastuzumab deruxtecan-nxki (Enhertu), sacituzumab govitecan-hziy (Trodelvy), and ribociclib (Kisqali) have demonstrated an influx of overall survival (OS) advantages compared with standard-of-care (SOC) regimens across breast cancer patient subsets, including HER2-positive, hormone receptor (HR)–positive, and triple-negative disease, according to Heather McArthur, MD.

“We’re seeing unprecedented improvements in all settings, and it’s an exciting time to be treating patients with breast cancer,” McArthur said in an interview following an OncLive^® State of the Science Summit^™ on breast cancer, which she chaired.

In the interview, McArthur highlighted key points shared at the meeting, including the evolution of treatment sequencing with trastuzumab deruxtecan and sacituzumab govitecan; key findings with ribociclib in patients with node-negative, HR-positive, HER2-negative early breast cancer; and future directions with novel oral selective estrogen receptor degraders (SERDs).

Primary results from the phase 3 NATALEE trial (NCT03701334) indicated an invasive disease-free survival (IDFS) benefit with ribociclib plus endocrine therapy vs endocrine therapy alone in patients with HR-positive, HER2-negative early breast cancer, with 3-year IDFS rates of 90.4% vs 87.1% (hazard ratio, 0.748; 95% CI, 0.618-0.906; P = .0014).¹ McArthur discussed the unique features of this trial and the potential implications of an FDA approval of ribociclib based on these findings.

Additionally, she spotlighted updated data from the phase 3 TROPiCS-02 trial (NCT03901339), in which sacituzumab govitecan led to an OS improvement vs treatment of physician’s choice, with a median OS of 14.5 months vs 11.2 months (hazard ratio, 0.79; 95% CI, 0.65-0.95; nominal P = .01).²

McArthur is the Komen Distinguished Chair in Clinical Breast Cancer Research, as well as an associate professor in the Department of Internal Medicine and a member of the Division of Hematology and Oncology at UT Southwestern Medical Center in Dallas. She is also clinical director of the Breast Cancer Program at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center.

OncLive: How have the DESTINY-Breast trials clarified the appropriate treatment settings for trastuzumab deruxtecan in patients with breast cancer?

McArthur: The [phase 2] DESTINY-Breast01 trial [NCT03248492] first demonstrated that the novel antibody-drug conjugate [(ADC) trastuzumab deruxtecan], which is targeted to HER2, would be effective in HER2-positive disease. One of the notable adverse effects with that drug is interstitial lung disease. That requires close monitoring.

Subsequent studies investigating [trastuzumab deruxtecan] in HER2-positive disease included the [phase 2] DESTINY-Breast02 [NCT03523585] and [phase 3] DESTINY-Breast03 [NCT03529110] trials, where this drug moved earlier in the course of treatment. In DESTINY-Breast03, [trastuzumab deruxtecan] went head-to-head with SOC second-line treatment in the form of ado-trastuzumab emtansine [Kadcyla] and demonstrated a significant improvement in progression-free survival [PFS], as well as an advantage in OS.

One of the more interesting trials [of 2022] was the [phase 3] DESTINY-Breast04 trial [NCT03734029], which was presented by Shanu Modi, MD, [of Memorial Sloan Kettering Cancer Center in New York, New York] at the 2022 ASCO Annual Meeting. This trial investigated the HER2-directed ADC in patients with advanced HER2-low disease. [In total], 88.7% of patients had HR-positive disease, and 11.3% had [HR-negative disease] by conventional characteristics. This speaks to the intersection of this new arena of HER2-low disease across conventional subtypes.

When compared against physician’s choice of chemotherapy, trastuzumab deruxtecan conferred PFS and OS advantages in the intention-to-treat population. [This advantage] was significant in the HR-positive population. Although only 11.3% of patients in that trial had HR-negative disease, [trastuzumab deruxtecan] seemed to confer similar benefits in that population. [This is an] exciting time to be treating [patients with] HER2-positive [disease as well as] this new category of HER2-low [disease].

The [phase 3] DESTINY-Breast06 trial [(NCT04494425) is investigating trastuzumab deruxtecan] and is including a population with ultra-low HER2-expressing breast cancer. It will be interesting to see whether the application of this drug becomes HER2 agnostic.

What data inform your treatment sequencing decisions with ADCs for patients with triple-negative breast cancer (TNBC) or HR-positive disease?

When I consider conventional categories of TNBC and HER2-low TNBC, I think about a TROP2-directed ADC, sacituzumab govitecan. That was evaluated in the [phase 3] ASCENT trial [NCT02574455], which demonstrated PFS and OS advantages [with the agent] compared with conventional chemotherapy. [Sacituzumab govitecan was] subsequently FDA approved for patients with TNBC. An exploratory subset analysis of ASCENT investigated the activity [of sacituzumab govitecan] in patients with HER2-low TNBC and showed similar efficacy compared with [the efficacy of the agent in] those with HER2-0 disease by conventional definitions.

Because we have phase 3 randomized data for TNBC specifically, I typically give sacituzumab govitecan before I give trastuzumab deruxtecan. In DESTINY-Breast04, only 11.3% of the patients had HR-negative disease. It wasn’t a triple-negative–dedicated trial.

For HR-positive disease, I typically consider trastuzumab deruxtecan before sacituzumab govitecan. Sacituzumab govitecan was evaluated in HR-positive disease in a heavily pretreated population and conferred a 1.5-month median PFS advantage [vs treatment of physician’s choice] in TROPiCS-02. That translated to an OS advantage that was presented at the 2023 ASCO Annual Meeting. I typically consider trastuzumab deruxtecan followed by sacituzumab govitecan largely because of the differences in the patient populations and the number of prior treatments permitted in [TROPiCS-02 and DESTINY-Breast04].

Ongoing efforts through the cooperative groups are investigating the sequencing of these ADCs in both HR-positive and triple-negative populations. None of the patients in these ADC studies have received prior ADCs. We don’t know, beyond extrapolating from the existing data, what the optimal sequence is. It may be that 1 ADC biologically changes the environment in a way that might be significant for serial downstream treatment administration. Those studies are planned.

Based on the presentation given by your colleague, Joyce O’Shaughnessy, MD, of Texas Oncology-Baylor Charles A. Sammons Cancer Center in Dallas, how do data from the NATALEE trial build on those from the phase 3 monarchE trial (NCT03155997)?

The monarchE trial investigated 2 years of adjuvant abemaciclib [Verzenio], a CDK4/6 inhibitor, in a very high-risk, node-positive population with a cohort of patients [with HR-positive, HER2-negative early breast cancer] who were also defined by Ki-67 levels of 20% or greater. Abemaciclib with hormone therapy vs endocrine therapy alone reduced the risk of relapse, [generating] a 33.6% reduction in IDFS in favor of abemaciclib.

This subsequently became a SOC for patients with very high-risk, node-positive disease. Originally, the FDA approval endorsed using Ki-67 levels for decision making regarding abemaciclib and later updated the approval to be Ki-67 agnostic, so [abemaciclib plus hormone therapy is] currently approved for high-risk, node-positive disease.

NATALEE was highly anticipated. In NATALEE, patients with high-risk, HR-positive breast cancer, stage II or III, were randomly assigned to receive a nonsteroidal aromatase inhibitor [AI] with or without ribociclib. A few unique features distinguished [NATALEE] from monarchE. [NATALEE] allowed patients with no nodal disease. We’re looking for a signal of an advantage with CDK4/6 inhibition in that lower-risk population. [Additionally, in NATALEE], ribociclib was administered at 400 mg daily, 3 weeks on and 1 week off, which is a lower dose than is approved in the metastatic setting. The hope in giving a lower dose was that we could potentially mitigate the need for serial electrocardiogram monitoring that looks for QTC prolongation.

Ribociclib, in addition to a nonsteroidal AI, conferred a benefit for preventing invasive events. The IDFS hazard ratio was 0.748, [translating to] a 25.2% reduction in the risk of recurrence, including improvement in distant disease-free survival and a [potential] improvement in OS. The benefit seems to be consistent across all patient subgroups, although notably, in the node-negative subset, a minority population, the confidence intervals overlapped. It’s unclear whether there’s an absolute benefit in that population, but [these data indicate] that in selected patients with high-risk, node-negative disease, this might be a likely strategy.

This approach is not yet FDA approved, but may be approved later in 2023, and will be an appropriate option for high-risk, node-negative patient populations. [NATALEE used] a different duration of therapy [than monarchE]. [In NATALEE, patients were treated] for 3 years with [ribociclib], whereas [the duration of therapy was] 2 years in monarchE with abemaciclib.

What ongoing research may broaden the application of oral SERDs across breast cancer subtypes?

Elacestrant [Orserdu] was evaluated in the phase 3 EMERALD trial [NCT03778931]. Patients with ER-positive disease were enrolled. All patients needed to have received a prior CDK4/6 inhibitor. That made EMERALD unique. Patients were randomly assigned to receive elacestrant vs physician’s choice of hormone therapy: fulvestrant [Faslodex], anastrozole, letrozole, or exemestane.

[Elacestrant] improved PFS, a benefit that was consistent when considering prior exposure to CDK4/6 inhibitors. An interesting analysis investigated [elacestrant] exposure for at least 6 months vs 12 months [and showed] consistent benefits [with elacestrant]. That became a SOC for patients with ESR1-mutated breast cancers. That mutation is acquired in response to palliative AI therapy. On progression after AI therapy, we should do genomic assays to recheck to see whether an ESR1 mutation has been acquired.

Many other oral SERDs have been evaluated, and we have some data. Camizestrant [AZD9833] has been compared with fulvestrant in the [phase 2] SERENA-2 trial [NCT04214288], which allowed for prior CDK4/6 inhibition but did not require it. Early data indicate a PFS benefit with [camizestrant], but we await long-term follow-up.

Imlunestrant [LY3484356] is another [oral SERD] being evaluated with or without abemaciclib in the [phase 3] EMBER 3 trial [NCT04975308]. Those data are forthcoming. Interestingly, that trial allows men with estrogen receptor [ER]–positive advanced breast cancer.

[There is much] more to come. [There has been] 1 FDA approval of elacestrant for patients with ESR1-mutated, advanced, HR-positive breast cancer, but [there is] more in the pipeline.

What data from the 2023 ASCO Annual Meeting may be practice changing going forward?

The NATALEE findings will potentially be practice changing; we’re awaiting FDA approval based on those data. There was also an interesting analysis from monarchE of older patients who participated in the study. Dose reductions were not explored optimally in that patient population. [Older patients] were more likely to come off the study, but they seemed to derive as much benefit [from ribociclib as the overall population]. This underscores the importance of exploring dose reductions prior to taking older patients off potentially life-extending and cure-[inducing] therapy.

[Another important presentation] was the update from TROPiCS-02 [that] reported an OS of 11.2 months vs 14.5 months in favor of [sacituzumab govitecan], with a hazard ratio of 0.79. [This translated to] a 21% reduction in the risk of death in favor of the ADC.

What is your main message for colleagues regarding updates in the breast cancer treatment paradigm?

It’s an incredibly exciting time to be treating patients with breast cancer. We’ve had an unprecedented number of FDA approvals in past years that have dramatically changed outcomes for patients with breast cancer. We’re seeing OS advantages in patients with advanced breast cancer, so we’re extending life. We’re seeing reductions in toxicity that confer extended survival. In the curative-intent setting, we’re seeing improvements in cure rates, some that are unprecedented. [With] immunotherapy, for example, [patients with] TNBC [achieved] an approximately 8% improvement in IDFS in that setting. 

References

1. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(suppl 17):LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500
2. Tolaney SM, Bardia A, Marmé F, et al. Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC). J Clin Oncol. 2023;41(suppl 16):1003. doi:10.1200/JCO.2023.41.16_suppl.1003