A Wealth of Clinical Trials Expands Potential Breast Cancer Treatment Options

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Joyce O’Shaughnessy, MD, highlights key data from the 2022 San Antonio Breast Cancer Symposium, explains how trastuzumab deruxtecan and CDK4/6 inhibitors are altering the treatment landscape, and discusses novel data on steroid receptor expression in triple-negative breast cancer.

Joyce O’Shaughnessy, MD

Joyce O’Shaughnessy, MD

Across breast cancer subsets, the armamentarium is swiftly expanding to include additional indications for agents like antibody-drug conjugates and CDK4/6 inhibitors, with fam-trastuzumab deruxtecan-nxki (Enhertu) and ribociclib (Kisqali) demonstrating encouraging efficacy in both metastatic and nonmetastatic disease, according to Joyce O’Shaughnessy, MD.

“Trastuzumab deruxtecan can clearly benefit patients with active and progressing brain metastases and leptomeningeal disease, [which is] exciting,” O’Shaughnessy said in an interview with OncLive® following an OncLive® State of the Science Summit™ on breast cancer, which she chaired.

In the interview, O’Shaughnessy highlighted key data from the 2022 San Antonio Breast Cancer Symposium (SABCS), explained how trastuzumab deruxtecan and CDK4/6 inhibitors are altering the treatment landscape, and discussed novel data on steroid receptor expression in triple-negative breast cancer (TNBC).

O’Shaughnessy is co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at the Texas Oncology Baylor-Sammons Cancer Center, as well as a member of the Scientific Advisory Board for the US Oncology Research Network, both in Dallas.

OncLive®: What research has further solidified the role of HER2-directed therapy in patients with HER2-positive disease with and without metastases? What other updates are important to note in this population?

O’Shaughnessy: The [phase 3] APHINITY trial [NCT01358877] published 8-year data [in July 2022] showing a continued statistically significant improvement in invasive disease-free survival in patients with node-positive disease.

With longer follow-up, the systemic outcomes in the [phase 2] APT [NCT00542451] and ATEMPT [NCT01853748] trials remain fantastic. [Distant recurrences occurred in] 7 of 36 patients [with invasive disease-free survival (IDFS) events] in APT and 3 of 11 patients [with IDFS events] in ATEMPT. [These patients achieved] outstanding long-term benefit with weekly paclitaxel and trastuzumab [Herceptin] in APT and ado-trastuzumab emtansine [Kadcyla] in ATEMPT.

The [phase 3] DESTINY-Breast02 [NCT03523585] trial investigated trastuzumab deruxtecan in patients previously treated with trastuzumab emtansine who were randomized to capecitabine [Xeloda] with trastuzumab or lapatinib [Tykerb]. [This trial demonstrated] an improvement in progression-free survival [PFS] and a statistically significant improvement in overall survival [OS]. This was a later-line trial, so there were 2 deaths from interstitial lung disease [ILD].

The [phase 3] DESTINY-Breast03 trial [NCT03529110] was [a second-line trial in patients] who had progressed on a taxane plus trastuzumab with or without pertuzumab [Perjeta]. It was a head-to-head comparison [of trastuzumab deruxtecan] vs trastuzumab emtansine in patients with HER2-positive disease. [Trastuzumab deruxtecan demonstrated] a median PFS of 28.8 months, the longest median PFS we’ve seen in [this population], vs 6.8 months with trastuzumab emtansine. This median PFS was 10.1 months longer than that seen [with pertuzumab, trastuzumab, and docetaxel] in the first-line [phase 3] CLEOPATRA trial [NCT00567190], [which showed a median PFS of] 18.7 months.

In DESTINY-Breast03, there were no deaths from ILD. The incidence of ILD went from 10.5% in the original presentation [of the data] to 15.2% because patients had been on [trastuzumab deruxtecan] longer. ILD tends to happen within the first 12 months [of treatment], but it can happen [throughout the first] 2 years. We need to regularly look for ILD clinically and perhaps with chest computed tomography scans.

Data from the [phase 2] TUXEDO-1 trial [NCT04752059] were published in [August 2022 in] Nature Medicine with trastuzumab deruxtecan in patients with active, untreated brain metastasis. A total of 11 of 15 patients responded.

In the ROSET-BM trial [UMIN000044995] heavily pretreated patients with active or progressing brain metastases or leptomeningeal disease also benefited from trastuzumab deruxtecan. In total, [55.7% of patients had an objective response].

[At SABCS, there was also] an update on the [phase 2] HER2CLIMB trial [NCT02614794] data from the Flatiron Database showing that physicians were using the tucatinib [Tukysa]/capecitabine/trastuzumab triplet in either the first or second lines for patients with brain metastases. The PFS and OS data in that real-world evidence mirrored the HER2CLIMB data. That was reassuring because tucatinib provides a survival advantage in patients with active brain metastases. In May 2022, ASCO updated their guidelines to say that asymptomatic patients with active brain metastases can receive the tucatinib triplet and forego or postpone radiation therapy.

How have trials investigating ribociclib in the HER2-negative, hormone receptor (HR)–positive population supported the use of CDK4/6 inhibitors in the frontline setting?

The 3 first-line ribociclib trials have [demonstrated] an OS advantage. We’re waiting on [survival data for the phase 3] MONARCH 3 trial [NCT02246621], which is [investigating] first-line abemaciclib [Verzenio]. Unfortunately, the [phase 3] PALOMA-2 trial [NCT01740427] with first-line palbociclib [Ibrance] was negative.

The [phase 2] RIGHT Choice trial [NCT03839823] was conducted in pre- and perimenopausal patients with mainly de novo metastatic disease. In total, [52% of patients had visceral crises, 68% had symptomatic, visceral metastases, and 14% had symptomatic, non-visceral disease]. These are patients for whom we might have considered first-line chemotherapy rather than a CDK4/6 inhibitor. They were randomized to combination chemotherapy vs a LHRH agonist, ribociclib, and an aromatase inhibitor [AI].

The median PFS [with ribociclib] was 24.0 months vs 12.3 months with combination chemotherapy. The time to treatment response was identical [between the 2 arms]. [There were also] fewer adverse effects with ribociclib. We should offer ribociclib [instead of combination chemotherapy] to pre- and perimenopausal patients, even those with aggressive de novo metastatic visceral crises.

To be eligible [for RIGHT Choice], patients needed to have a bilirubin level no higher than 1.5-fold the upper limit of normal. This trial wasn’t for patients in hepatic failure, although patients could have substantially elevated liver function tests. We should give CDK4/6 inhibitors [to patients who meet those criteria].

The [phase 2] MAINTAIN trial [NCT02632045] showed that switching from [an AI plus a CDK4/6 inhibitor] to fulvestrant [Faslodex] and ribociclib [upon progression on a CDK4/6 inhibitor] improved PFS compared with fulvestrant alone, with hazard ratios of [0.56 and 0.59, respectively]. We’re now giving patients more first-line ribociclib because of these survival data. If a patient is progressing on an AI plus ribociclib, you could switch to fulvestrant plus ribociclib.

In the [phase 2] PACE trial [NCT03147287], patients who progressed on an AI plus palbociclib were randomized to fulvestrant alone; fulvestrant plus continued palbociclib; or fulvestrant, palbociclib, and the PD-L1 inhibitor avelumab [Bavencio]. There was no PFS improvement [in the fulvestrant plus palbociclib arm]. Adding avelumab improved PFS, but that doesn’t change our practice. We shouldn’t continue palbociclib upon palbociclib progression.

We’re waiting for the FDA approval [of elacestrant, an oral selective estrogen receptor degrader, which] will change our practice. The [phase 3] EMERALD trial [NCT03778931] compared elacestrant with investigator's choice of endocrine therapy [and elicited] a statistically significant PFS improvement, both in the intent-to-treat [ITT] and ESR1-mutant populations. The longer patients had been on their antecedent-required CDK4/6 inhibitor, the better they did with elacestrant. Patients whose breast cancer is still endocrine therapy–sensitive will benefit the most from elacestrant. Patients with an ESR1 mutation who were on a CDK4/6 inhibitor for at least 1 year had an 8.61-month median PFS with elacestrant.

In the [phase 3] CAPItello-291 trial [NCT04305496], patients who had progressed on an AI were randomized to fulvestrant plus or minus capivasertib, an oral AKT inhibitor. The trial met its primary end point of PFS improvement in the ITT population, as well as in those who had a genomic alteration in the AKT pathway, [such as] a PIK3CA mutation, AKT mutation, or PTEN loss. We hope to see an FDA approval [in 2023] to have another option to inhibit that PI3K pathway in patients who progress on CDK4/6 inhibitors.

The POSITIVE trial [NCT02308085] was an important trial in the adjuvant setting. Premenopausal patients with stages I to III disease who had been on their adjuvant endocrine therapy for 18 to 30 months interrupted their therapy for up to 2 years to become pregnant, deliver a child, do fertility treatments, and/or potentially nurse.

Recurrences occurred on this trial. However, [these data were being compared with] what was expected from the [phase 3] SOFT [NCT00066690] and TEXT [NCT00066703] trials, in an age and stage-of-treatment–matched control group, and these findings were not worse than expected.

Patients should still take the least amount of time off [therapy] as possible, and it’s better for lower-risk patients to consider this. However, these were reassuring data. We couldn’t determine a big risk for interrupting endocrine therapy to become pregnant.

Could you share some details from research you’re currently conducting in TNBC?

At SABCS, we presented an interesting poster from the work I’m doing with my team at Baylor in collaboration with Emanuel F. Petricoin, PhD; Mariaelena Pierobon, MD, MPH; and Julia Wulfkulhe, PhD, all from George Mason University [in Fairfax, Virginia]. We described a subtype of early TNBCs with the steroid receptor signature. By reverse phase protein array, a sensitive proteomic evaluation of paraffin tissue in patients’ primary TNBCs and lymph node metastases, we showed that a small subset of TNBCs express [all 3 steroid receptors]: ERs, androgen receptors [ARs], and glucocorticoid receptors.

These steroid HRs lead to HER family transcription and activation. Some TNBCs express 2 of the 3, and that is also associated with HER1 and HER2 activation. We will corroborate these data in a larger dataset. We look forward to taking the next step, which is designing trials to block these steroid HRs with HER1 and HER2 inhibitors such as neratinib [Nerlynx]. Glucocorticoid receptors and ARs are positive in a subset of TNBCs, but this is the first time we’ve shown a group that expresses many of the HRs in these breast cancers.

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