Treatment with the oral selective estrogen receptor degrader (SERD) elacestrant following treatment with CDK4/6 inhibitors improved progression-free survival (PFS) outcomes vs standard care options in patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer according to findings from the phase 3 EMERALD study (NCT03778931). This benefit was more pronounced among those who had longer exposure to CDK4/6 inhibitors and among patients with 

Results presented during the 2022 San Antonio Breast Cancer Symposium showed that patients who received elacestrant at least 12 months of CDK4/6 inhibition (n = 150) had a median PFS of 3.78 months vs 1.91 months for those who received standard-of-care (SOC) hormonal therapy (n = 160; HR, 0.613; 95% CI, 0.453-0.828). The 6-, 12-, and 18-month PFS rates were 41.56%, 25.64%, and 19.34% with elacestrant vs 21.72%, 7.38%, and 3.69% with SOC.

Following at least 12 months of CDK4/6 inhibitor treatment patients with 

-mutant tumors had a median PFS was 8.61 months with elacestrant (n = 78) vs 1.91 months with SOC (n = 81) for a 59% reduction in the risk of progression or death (HR, 0.410; 95% CI, 0.262-0.634). The 6-, 12-, and 18-month PFS rates were 55.81%, 35.81%, and 28.49% with elacestrant vs 22.66%, 8.39%, and 0% with SOC. 

-mutated tumors,” Virginia Kaklamani, MD, professor of medicine in the Division of Hematology/Oncology at The University of Texas Health San Antonio and leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center said in a presentation of this data. “

The updated EMERALD analysis assessed PFS outcomes after at least 6, 12, and 18 months of CDK4/6 inhibition. EMERALD trial postmenopausal women and men from 17 different countries with advanced or metastatic ER-positive, HER-negative breast cancer. Patients were randomly assigned to receive 400 mg of elacestrant daily or SOC endocrine therapy of either fulvestrant (Faslodex), anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin).

The elacestrant arm had 239 patients, 115 of whom had an 

-mutant tumor and the SOC arm had 239 patients, 113 of whom had an 

-mutant tumor. The median age was 63 years (range, 24-89). In terms of prior therapy, 46% of patients in the elacestrant arm received 2 prior lines of therapy and 40.6% of patients in the SOC arm. Prior treatment with fulvestrant was reported in 29.3% and 31.4% of patients in the elacestrant and SOC arms, respectively, with prior chemotherapy reported among 20.1% and 24.7% of patients.

For patients who had at least 6 months of prior CDK4/6 inhibition (87.5% of the population), the median PFS for those in the elacestrant arm (n = 202) was 2.79 months vs 1.91 months in the SOC arm (n = 205; HR, 0.688; 95% CI, 0.535-0.884). The PFS rates at 6, 12, and 18 months for those who received elacestrant vs SOC were 34.40% vs 19.88%, 21.0% vs 6.42%, and 16.24% vs 3.21%, respectively.

-mutant cohort, the median PFS for those who received CDK4/6 inhibition for at least 6 months was 4.14 months vs 1.87 months among patients who received elacestrant (n = 103) and SOC (n = 102), respectively (HR, 0.517; 95% CI, 0.361-0.738). The PFS rates for patients who received elacestrant vs SOC at 6, 12, and 18 months were 42.43% vs 19.15%, 26.02% vs 6.45%, and 20.70% vs 0%, respectively.

Among patients who received CDK4/6 inhibition for at least 18 months in the overall cohort, the HR for disease progression or death for elacestrant vs SOC was 0.703 (95% CI, 0.482-1.019). The median PFS was 5.45 vs 3.29 months, respectively. The PFS rates at 6, 12, and 18 months were 44.72% vs 25.15%, 26.70% vs 8.23%, and 21.03% vs 4.11%, for elacestrant vs SOC, respectively.

-mutant tumors received CDK4/6 inhibition for at least 18 months. The median PFS was 8.61 months vs 2.10 months for those who received elacestrant (n = 55) vs SOC (n = 56; HR, 0.466; 95% CI, 0.270-0.791). The PFS rates at 6, 12, and 18 months were 58.57% vs 27.06%, 35.79% vs 7.73%, and 30.68% vs 0%, for elacestrant vs SOC, respectively.

An analysis of patients who received less than 6 months of CDK4/6 inhibition showed that those with 

-mutant disease has similar outcomes with elacestrant (n = 9) vs those who received SOC (n = 8; HR, 1.565; 95% CI, 0.424-5.769). The median PFS in both arms was 1.89 months. In the general population, the median PFS with elacestrant (n = 29) was 3.55 months vs 1.87 months with elacestrant (n = 29; HR, 0.709; 95% CI, 0.347-1.405).



Observed adverse effects (AEs) were consistent with previously reported findings from the EMERALD trial.

The most common grade 1/2 AE was nausea, with grade 3 nausea reported in 6 and 2 patients in the elacestrant and SOC arms, respectively. Three patients discontinued elacestrant due to nausea. No grade 4 treatment-emergent AEs were reported. Treatment discontinuation was reported among 3.4% of patients receiving elacestrant vs 0.9% of patients receiving SOC. No deaths were reported due to treatment in either arm.

Antiemetic use was reported among 8% of patients receiving elacestrant and among 10.3% of patients in the SOC arm who received an aromatase inhibitor and 1.3% of patients who received fulvestrant. Investigators noted that there was There was no incidence of bradycardia.

Kaklamani said these data show that elacestrant can become an important oral endocrine monotherapy agent in the second- and third-line setting. “If you look at the outcomes, not just in this trial but of others in patients whose CDK4/6 [inhibitor therapy] is less than 6 months, it gives you the idea that there are resistant tumors [and patients] need to move on to either chemotherapy or potentially combination endocrine therapy, but those treatments are toxic to our patients. Hopefully, [with this trial] we’ll have options for those patients,” she concluded.

Bardia A, Bidard FC, Neven P, et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. 

. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338

Articles

Treatment with the oral selective estrogen receptor degrader elacestrant following treatment with CDK4/6 inhibitors improved progression-free survival  outcomes vs standard care options in patients with estrogen receptor-positive, HER2-negative metastatic breast cancer.



Benefit of Elacestrant Improves With Longer Duration of CDK4/6 Inhibition in Patients With ER+/HER2– Metastatic Breast Cancer

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated a clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) compared with treatment of physician's choice (TPC) in patients with advanced HER2-positive unresectable and/or metastatic breast cancer who received prior treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla), according to the primary analysis of the phase 3 DESTINY-Breast02 trial (NCT03523585).

The median PFS by blinded independent central review (BICR) was 17.8 months (95% CI, 14.3-20.8) for patients who received trastuzumab deruxtecan (n = 406) compared with 6.9 months (95% CI, 5.5-8.4) with TPC (n = 202; HR, 0.3589; 95% CI, 0.2840-0.4535; 

 < .0000001), demonstrating a 64% reduction in the risk of disease progression or death.

A key secondary end point was OS. The median OS was 39.2 months (95% CI, 32.7-not evaluable [NE]) and 26.5 months in the trastuzumab deruxtecan and TPC arms, respectively (HR, 0.6575; 95% CI, 0.5023-0.8605; 

The findings, which were presented at the 

2022 San Antonio Breast Cancer Symposium (SABCS)

, are consistent with findings from the 2019 phase 2 DESTINY-Breast01 trial (NCT03248492), which demonstrated trastuzumab deruxtecan as a viable treatment for patients with HER2-positive breast cancer and led to its 

accelerated approval for patients with metastatic or unresectable breast cancer

 DESTINY-Breast02 is the confirmatory trial for the approval.

“[Findings from] the phase 3 DESTINY-Breast02 trial demonstrated a statistically significant and clinically meaningful improvement in both progression-free and OS compared [with] TPC in the post–T-DM1 setting,” study author Ian Krop, MD, PhD, a chief clinical research officer at the Yale Cancer Center in New Haven, Connecticut, said in a presentation of this data. “DESTINY-Breast02 confirms the favorable benefit-risk ratio of trastuzumab deruxtecan in patients with advanced HER2-positive breast cancer.”

The 12-month and 24-month PFS rates were 62.3% (95% CI, 57.0%-67.1%) and 42.2% (95% CI, 36.5%-47.8%) of patients who received trastuzumab deruxtecan. These rates were 27.2% 95% CI, 20.1%-34.8%) and 13.9% (95% CI, 7.9%-21.6%) for patients who received TPC.

 The PFS benefit was consistent across all subgroups.

The 12-month OS rate for patients who received trastuzumab deruxtecan was 89.4% vs 74.7% with TPC. The 24-month OS rates were 65.9% vs 54.3%, respectively.

In the trial, 608 patients with pathologically confirmed HER2-positive metastatic breast cancer who had previously received T-DM1 were randomly assigned to receive trastuzumab deruxtecan or a physician-recommended combination of capecitabine with either trastuzumab (Herceptin) or lapatinib (Tykerb).

The median age of patients in the trastuzumab deruxtecan arm was 54.2 years (range, 22.4-88.5) and 18.2% had brain metastases at baseline. The patients who received TPC had a median age of 54.2 years (range, 24.7-86.5) and 17.8% had baseline brain metastases. HER2 expression by immunohistochemistry (IHC) was mostly IHC 3+ (80.3% and 78.7%, respectively). More than half of patients in the trastuzumab deruxtecan (58.6%) and TPC (58.4%) arms had hormone receptor–positive disease. The median number of prior lines of therapy was 2 in both arms.

Objective response rate (ORR) was a secondary end point for the study. Patients in the trastuzumab deruxtecan arm has a confirmed ORR by BIRC of 69.7% (95% CI, 65.0%-74.1%) compared with 29.2% (95% CI, 23.0%-36.0%) in the TPC arm (

 <.0001). Among responders in the trastuzumab deruxtecan arm the confirmed complete response (CR) rate was 14% and the partial response (PR) rate was 55.7%. In the TPC arm, CR and PR rates were 5.0% and 24.3%, respectively. At data cutoff, 23.4% and 46.5% of patients had stable disease in the trastuzumab deruxtecan and TPC arms, respectively, with 4.7% and 12.9% of patients experiencing progressive disease.

The median duration of response was 19.6 months (95% CI, 15.9-NE) vs 8.3 months (95% CI, 5.8-9.5) in the trastuzumab deruxtecan and TPC arms, respectively.

Clinical benefit rate (CBR), investigator-assessed PFS, and time to second disease progression (PFS2) were exploratory end points for the study. The CBR with trastuzumab deruxtecan was 82.3% (95% CI, 78.2%-85.9%) and was 46.0% (95% CI, 39.0%-53.2%) with TPC. The median PFS by investigator was 16.7 months (95% CI, 14.3-19.6) vs 5.5 months (95% CI, 4.4-7.0). Finally, median PFS2 was 35.8 months (95% CI, 14.3-19.6) vs 15.8 (95% CI, 13.5-21.0).

Of note, in the TPC arms 140 patients (69.3%) received a new systemic anticancer treatment and 52 patients (25.7%) received trastuzumab deruxtecan in the posttrial setting.

In the safety analysis included 404 patients who received trastuzumab deruxtecan and 195 who received TPC. The percentage of patients who discontinued therapy due to a treatment-related adverse event (TRAE) to the drug was 14.4% with trastuzumab deruxtecan vs 5.1% with TPC. Krop noted that the most common noted that most common drug-related discontinuations associated with trastuzumab deruxtecan were pneumonitis (6.2%) and interstitial lung disease (ILD; 3.2%). Palmar-plantar erythrodysesthesia was attributed to discontinuation in 1.5% of patients who receive TPC.

Fewer grade 5 ILD events were observed in DESTINY-Breast02 (0.5%) compared with DESTINY-Breast01 (2.7%).

Another AE of special interest was left ventricular (LV) dysfunction. In the trastuzumab deruxtecan arm, 18 (4.5%) patients experienced an LV dysfunction event with 2 (0.5%) patients experiencing a grade 3 or higher event. In the TPC arm, 3 (1.5%) patients experienced an LV dysfunction, and 1 (0.5%) patient had a grade 3 or higher event. Other safety events were consistent with what were previously reported.

The median treatment duration was 11.3 months for patients who received trastuzumab deruxtecan and approximately 4.5 months for patients who received TPC.

“Trastuzumab deruxtecan should be used in the second-line setting in virtually all patients [with advanced HER2-positive breast cancer],” Krop concluded.

Krop, Ian et al T-DXd yields superior outcomes over chemotherapy-based regimens in patients previously treated with T-DM1 participating in the phase III DESTINY-Breast02 trial. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. News release. FDA. Updated December 23, 2019. Accessed December 7, 2022. bit.ly/3FDn2Yp

Trastuzumab deruxtecan demonstrated a 64% reduction in the risk of disease progression or death compared with physician's choice of treatment in patients with advanced HER2-positive unresectable and/or metastatic breast cancer who previously received ado-trastuzumab emtansine. 


Sailaja Darisipudi

Articles

Benefit of Elacestrant Improves With Longer Duration of CDK4/6 Inhibition in Patients With ER+/HER2– Metastatic Breast Cancer

Trastuzumab Deruxtecan Generates PFS, OS Benefit Vs Capecitabine-based Regimens in Pretreated HER2+ Breast Cancer