Sailaja Darisipudi

In the phase 3 EMERALD trial (NCT03778931), treatment with elacestrant compared to standard-of-care endocrine therapy achieved improvement in progression-free survival (PFS) improvement, in patients with ER-positive/HER-2 negative metastatic breast cancer who had been previously treated with CDK4/6 inhibitors.


These results, which were presented at the 2022 San Antonio Breast Cancer Symposium, also demonstrated that the length of prior treatment with CDK4/6 inhibitors was associated with longer PFS.


“Most of (the) benefit is in the ESR1-mutated tumors,” explained Virginia Kaklamani, MD from The University of Texas Health Sciences Center in San Antonio, in a presentation of this data. “ESR1 mutation status will be important.”


Kaklamani explained that the trial enrolled men and postmenopausal women from 17 different countries with advanced or metastatic ER-positive/HER-negative breast cancer. The patients were randomized to receive either 400 mg of elacestrant daily or standard-of-care endocrine therapy consisting of either fulvestrant (Faslodex), anastrozole (Arimidex), letrozole (Femara) or exemestane (Aromasin) (SOC).

A total of 233 women and 6 men were given elacestrant and 238 women and 1 man were given SOC. The patients in the elacestrant arm ranged from 24 to 89 years old, with a median age of 63 years. The patients in the SOC arm ranged from 32 to 83 years old, with a median age of 63 years. Fourty-eight percent of the patients in the elacestrant arm had an ESR1 mutation (n=115) while 47% of the patients in the SOC group had an ESR1 mutation (n=113).

Among patients who had completed at least six months of treatment with CDK4/6 inhibitors (87.5% of trial participants), there was a 31.2% increase in PFS for patients who were given elacestrant compared to SOC (HR, .688). The median PFS for patients in this group was 2.79 months in the elacestrant arm and 1.91 months in the SOC arm.

Among patients who had undergone at least 12 months of treatment with CDK4/6 inhibitors (66.7%), there was a 38.7% increase in PFS for patients who were given elacestrant compared to SOC (HR, .613). The median PFS for patients in this group was 3.78and 1.91 months in the elacestrant and SOC arms, respectively.


Among patients who had undergone at least 18 months of treatment with CDK4/6 inhibitors (46.7%), there was a 29.7% increase in PFS for patients who were given elacestrant compared to SOC (HR, .703). Median PFS for patients in this group was 5.45 months in the elacestrant arm , and 3.29 in the SOC arm..

For patients with an ESR1 mutation, PFS benefit was even more significant for patients given elacestrant.

Among patients with an ESR1 mutation and who underwent at least six months of treatment with CDK4/6 inhibitors (92.3% of all participants with the mutation), there was a 48.3% increase in PFS for patients who were given elacestrant compared to SOC (HR, .517). The median PFS for patients in this group was 4.14 months for patients who were treated with elacestrant while it was 1.87 months for patients treated with SOC.

For patients with ESR1-mutant disease who underwent 12 months or more of CDK4/6 inhibitor treatment, (71.6%), there was a 59% increase in PFS for patients who were given elacestrant compared to SOC (HR, .410). The median PFS for patients in this group was 8.61 months for patients who were treated with elacestrant and 1.91 months for patients treated with SOC.

Among patients with an ESR1 mutation who had received at least 18 months of treatment with CDK4/6 inhibitors (50.0%), there was a 53.4% increase in PFS for patients who were given elacestrant compared to SOC (HR, .466). Median PFS for patients in this group was 8.61 and 2.10 months for patients in the elacestrant and SOC arms, respectively.

According to Kaklamani, only 3.4% of the patients who received elacestrant and .9 % of patients who received SOC needed to discontinue the trial due to treatment-related adverse events (TRAE). The most common TRAEs were grade 1 and 2 nausea, and there were no treatment-related deaths in either arm.



Kaklamani claimed that this data shows that elacestrant can become an important oral endocrine monotherapy agent in the second- and third-line setting as an alternative to other therapies, which may cause other toxicities.

“If you look at the outcomes, not just in this trial but of others in patients whose CDK4/6 (inhibitor therapy) is less than six months” Kaklamani explained, “it gives you the idea that there are resistant tumors that need to move on to either chemotherapy or potentially combination endocrine therapy, but those treatments are toxic to our patients…”

In her presentation, Kaklamani stressed that this data reflects a need for patients to find out if their tumors are endocrine-resistant or not.

“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. Abstract GS3-01.

Articles

Patients with ER-positive/HER2-negative metastatic breast cancer demonstrated improvement in  progression-free survival when administered elacestrant vs standard of endocrine therapy.

Elacestrant Outperforms SOC in Terms of PFS in ER+/HER2– mBC

Results from the phase 3 DESTINY-Breast02 trial (NCT03523585) showed that trastuzumab deruxtecan (T-DXd) led to a 34% reduction in death and a 13-month increase in overall survival (OS) for patients with advanced HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1; Kadcyla) compared with treatment of physician’s choice (TPC).

These results, 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 T-DXd as a viable treatment for patients with HER2-positive breast cancer and led to the accelerated approval of T-DXd for patients with metastatic or unresectable breast cancer.

“(The findings from) the phase 3 DESTINY-Breast02 trial demonstrated a statistically significant and clinically meaningful improvement in both progression-free and overall survival compared to treatment of physicians choice in the post-T-DM1 setting,” study author Ian Krop, MD, PhD, a chief clinical research officer at the Yale Cancer Center, said in a presentation of this data. “DESTINY-Breast02 confirms the favorable benefit-risk ratio of T-DXd in patients with advanced HER2-positive breast cancer.”


In the trial, 608 patients with metastatic breast cancer who had previously received 2 lines of T-DM1 treatment were randomized to receive either T-DXd (n = 406) or a physician-recommended combination of capecitabine with either trastuzumab (Herceptin) or lapatinib (Tykerb; n= 202).

The patients who received T-Dxd had a median age of 54.2 years and a median treatment time of 11.3 months. The patients who received TPC had a median age of 54.2 years and a median treatment time of approximately 4.5 months.

The objective response rate for the T-DXd arm was 69.7%, compared to 29.2% in the TPC arm.


Krop also explained that the median progression-free survival (PFS) was 17.8 months for patients with T-DXd while it was 6.9 months for patients with TPC (HR, 0.3589), demonstrating a 64% reduction in the risk of disease progression or death.

Krop also shared that 42% of patients who received T-DXd were progression-free after two years, compared to 13.9% for the patients who received TPC.

After one year, 89.4% of patients who received T-DXd were alive, compared with 74.7% of patients who received TPC.


Regarding OS, median OS was 39 months and 26.5 months in the T-DXd and TPC arms, respectively (HR,0.66), indicating a 34% reduction in the risk of death with T-DXd compared to TPC.


Krop also shared that the percentage of patients who had to discontinue therapy because of an adverse reaction to the drug was 14% with T-Dxd versus 5% with TPC. He noted that most of these patients had to discontinue due to interstitial lung disease or pneumonitis.


Krop emphasized that even though this trial studied T-DXd as the third line of therapy, these results should not be used to change any current practices of using T-DXd as a second-line of therapy because oncologists “generally don’t hold back” the superior therapy for patients with cancer.

“T-DXd should still be used in the second line setting in virtually all patients (with advanced HER2-positive breast cancer),” he 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. Abstract GS2-01.

Patients with advanced HER2-positive breast cancer had better progression-free and overall survival outcomes when given trastuzumab deruxtecan versus capecitabin-based treatment.

Sailaja Darisipudi | Authors

Articles

Elacestrant Outperforms SOC in Terms of PFS in ER+/HER2– mBC

T-DXd Improves Survival in HER2-Positive BC Versus Capecitabine-Based Regimens