SABCS Generates Discussion Around SERDs, CDK4/6 Inhibitors, and ADCs in Breast Cancer

Neil Vasan, MD, PhD

From early phase 1/2 to pivotal phase 3 data, the 2021 San Antonio Breast Cancer Symposium (SABCS) was full of exciting research with selective estrogen receptor degraders (SERDs), CDK4/6 inhibitors, and antibody-drug conjugates (ADCs), faculty from an OncLive^® workshop moderated by Neil Vasan, MD, PhD, explained.

Vasan, an assistant professor at Columbia University Medical Center, was joined by fellow colleagues:

• Sarah Sammons, MD, assistant professor of medicine, Department of Medicine, Duke University School of Medicine, member, Duke Cancer Institute, Duke Health
• Marina Sharifi, MD, PhD, fellow, Medical Oncology, University of Wisconsin, Madison
• Laura Spring, MD, assistant professor of medicine, Harvard Medical School, Massachusetts General Hospital
• Niki Patel, MD, assistant professor of medicine, Department of Medical Oncology and Therapeutics Research; program director, Hematology and Medical Oncology Fellowship, City of Hope
• Tiffany Onger, MD, fellow, Hematology/Oncology, Cleveland Clinic
• Reva K. Basho, MD, assistant professor of medicine, codirector, Women’s Cancer Program, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center

During the workshop, the faculty reviewed data from several trials that were presented at the 2021 SABCS, including AMEERA-1 (NCT03284957), EMERALD (NCT03778931), TRINITI-1 (NCT02732119), MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), and MONALEESA-7 (NCT02278120), and TROPION-PanTumor01 (NCT03401385).

SERDs

First, Spring presented updated data from arm 2 of the ongoing phase 1/2 AMEERA-1 trial. The study enrolled postmenopausal women with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer with disease progression on at least 6 months of prior endocrine therapy in the advanced setting, or those who relapsed on adjuvant endocrine therapy after the first 2 years of treatment or within 12 months of completing adjuvant endocrine therapy.¹

Patients received 200 mg of amcenestrant once daily plus 125 mg of palbociclib (Ibrance) every 21 days of a 28-day cycle. At a median follow-up of 48.3 weeks in the response-evaluable population, the objective response rate (ORR) was 32.4% (n = 11/34; all partial responses). The 24-week clinical benefit rate (CBR) was 73.5% (n = 25/34).

In terms of safety, all-grade treatment-related adverse effects (TRAEs) with amcenestrant and palbociclib, respectively, occurred in 69.2% (n = 27/39) and 89.7% (n = 35/39) of patients; grade 3 or greater TRAEs occurred in 12.8% (n = 5/39) and 46.2% (n = 18/39) of patients, respectively.

“It seems like the combination continued to demonstrate encouraging activity, sustained clinical benefit, and a favorable safety profile overall. It’s becoming clearer that the combination of novel oral SERDs with CDK4/6 inhibitors will be more efficacious than using SERDs as single agents. A lot of oral SERDs are being explored and it remains to be seen where they will all fall, but we’ll continue to hear quite a bit in upcoming meetings,” Spring said.

“Something that I’m hopeful for as we continue to develop new therapies for our patients is that cost is kept in mind. Sometimes we have these new therapies but they’re outside of a price point that is realistic for some of our other patients. As we’re thinking about continuing to provide equitable care, I hope that this is kept in mind, so that [amcenestrant] is going to be accessible to everyone,” Onger said.

Turning next to the phase 3 EMERALD trial, Sammons explained that the study enrolled men and postmenopausal women with advanced or metastatic ER-positive, HER2-negative breast cancer that had progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor. Patients could not have received more than 1 line of chemotherapy for advanced disease.²

Patients were randomized 1:1 to 400 mg of elacestrant daily or investigator’s choice of fulvestrant (Faslodex), anastrozole, letrozole, or exemestane.

The median progression-free survival (PFS)in the intention-to-treat population was 2.79 months with amcenestrant vs 1.91 months with standard of care (HR, 0.697; 95% CI, 0.552-0.880; P = .0018). In the ESR1-mutant subgroup, the median PFS was 3.78 months vs 1.87 months, respectively (HR, 0.546; 95% CI, 0.387-0.768; P = .0005).

Additionally, elacestrant was well tolerated with a predictable and manageable safety profile, and treatment-emergent AEs leading to discontinuation with the oral SERD were infrequent at 6.3% vs 4.4% with standard of care.

“I think [these data are] enough to move the drug forward and blend itself to combination trials and probably move it earlier on in the metastatic and adjuvant settings,” Sammons said.

CDK4/6 Inhibitors

In looking at the investigational landscape of CDK4/6 inhibitors, Onger shared the schema of the TRINITI-1 trial, in which ribociclib (Kisqali), everolimus (Afinitor), and exemestane was evaluated in postmenopausal patients with endocrine refractory, hormone receptor–positive, HER2-negative advanced breast cancer who experienced disease progression on a CDK4/6 inhibitor.³

In the study, patients received 25 mg of oral exemestane once daily with 300 mg of ribociclib and 2.5 mg of everolimus (group 1) or 200 mg of ribociclib and 5 mg of everolimus (group 2).

The results showed an ORR of 6.5% in group 1 vs 9.4% in group 2. The 24-week CBR was 65.2% and 59.4% in groups 1 and 2, respectively. The median PFS was 8.0 months (95% CI, 3.8-14.5) in group 1 vs 4.7 months (95% CI, 2.0-12.7) in group 2 (HR, 0.740; 95% CI, 0.424-1.291). The median overall survival (OS) was 27.4 months and not estimable in groups 1 and 2, respectively.

The most common all-grade AEs were stomatitis (54.3%), infections (50.0%), neutropenia (43.5%), and fatigue (43.5%) in group 1, and infections (48.5%), nausea (42.4%), stomatitis (36.4%), and thrombocytopenia (36.4%) in group 2.

“I would be much more excited about seeing this triplet, as is going on in other studies, with the PI3 kinase inhibitors or AKT inhibitors, which seem to be more selective for patients who have alterations in the [PI3K] pathway because we know a number of patients treated with CDK4/6 inhibitors are going to acquire PIK3CA mutations and other alterations over the course of treatment,” Basho said.

“There is a subset where triplet therapy can really be helpful. Hopefully, further analysis from this study may identify some of the genomic correlates there. I don't think this is a regimen for all-comers, but for the right patient you can see some impressive results even after resistance to CDK4/6 inhibitors,” Spring said.

The next study, which was shared by Patel, comprised a correlative analysis of the phase 3 MONALEESA trials,⁴ in which investigators evaluated OS by intrinsic subtype in patients with hormone receptor–positive, HER2-negative advanced breast cancer treated with ribociclib and endocrine therapy.

A prior pooled analysis of patients in the MONALEESA trials demonstrated a significant PFS benefit with ribociclib plus endocrine therapy vs placebo plus endocrine therapy in the luminal A (HR, 0.63; P < .0001), luminal B (HR, 0.52; P < .0001), and HER2-enriched (HR, 0.39; P < .0001) subtypes.

Results from the OS analysis showed consistent OS benefit with ribociclib plus endocrine therapy in the luminal A (HR, 0.75; P =.021) luminal B (HR, 0.69; P = .023), and HER2-enriched (HR, 0.60; P = .018) subtypes and confirmed the prognostic value of the PAM50-based intrinsic subtype for OS in patients treated with ribociclib plus endocrine therapy and those treated with endocrine therapy alone.

“There’s a tremendous amount of potential here. I like this [study because] you’re looking at intrinsic subtypes and trying to find patterns within those subtypes. The methodology was important here,” Patel said.

“This multiplexing of correlative data is where the CDK4/6 inhibitor field needs to be heading. Hopefully, we are going to see more of these types of analyses in the future,” Vasan said.

ADCs

Shifting to another therapeutic class, Sharifi highlighted the results of the phase 1 TROPION-PanTumor01 trial, which enrolled patients with relapsed/refractory advanced or metastatic solid tumors. The cohort results presented at the 2021 SABCS included patients with triple-negative breast cancer who received the ADC at a dose of 8 mg/kg (n = 2) and 6 mg/kg (n = 42).⁵

The results reflected an ORR of 34% (n = 15), comprising a confirmed complete response (CR) rate of 32% (n = 14). Among patients who had not received prior topoisomerase I inhibitor–based ADC, the ORR was 52% (n = 14), with a CR rate of 48% (n = 13).

The most common AEs were nausea and stomatitis and were largely grade or 2. Additionally, a low frequency of hematologic toxicity and diarrhea were reported, and no cases of adjudicated drug-related interstitial lung disease were seen.

“As with [sacituzumab govitecan (Trodelvy)], there’s been a question about TROP2 tumor expression as a biomarker, which is going to be another interesting question. This was an unselected population, and I think the phase 3 trial is planned for that too. It’s an interesting drug, and it will be interesting to see how it evolves especially in this space,” Sharifi concluded.

References

1. Chandarlapaty S, Linden HM, Neven P, et al. Updated data from AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), combined with palbociclib in postmenopausal women with ER+/HER2- advanced breast cancer. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract P1-17-11.
2. Bardia A, Neven P, Streich G, et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: results of EMERALD phase 3 trial. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Session GS2-02.
3. Hurvitz SA, Clark AS, Rugo HS, et al. Ribociclib, everolimus, exemestane triplet therapy in HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: final efficacy, safety, and biomarker results from TRINITI-1. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract PD13-03.
4. Carey LA, Solovieff N, Andre F, et al. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Session GS2.
5. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan (Dato-DXd) in advanced/metastatic HER2 negative breast cancer: triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Session GS1.