Exploring New Approaches for ESR1 Mutations in Recent Trials and Future Directions

Research continues to evolve at a rapid pace for breast cancer, with clinical trials and novel therapeutic agents offering new hope for patients. Recent findings from the EMBER-3 trial (NCT04975308), the emergence of antibody-drug conjugates (ADCs), and the potential for new, practice-changing data from ongoing studies were discussed with Joyce O’Shaughnessy, MD, during an interview with Targeted Therapies in Oncology.

O’Shaughnessy, the Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, director, Breast Cancer Research Program, Texas Oncology, US Oncology, in Dallas, Texas, addressed the progress being made in treating hormone receptor (HR)–positive, HER2-negative, and HER2-positive breast cancer as well as the challenges and opportunities that lie ahead.

EMBER-3 Trial

The EMBER-3 trial¹ has emerged as a pivotal study in the treatment of HR-positive, HER2-negative breast cancer, particularly for patients who have developed resistance to endocrine therapy. The trial evaluated the efficacy of imlunestrant, an oral selective estrogen receptor degrader (SERD), compared with fulvestrant (Faslodex) in patients who had previously been treated with CDK4/6 inhibitors and aromatase inhibitors.

One of the key findings from the trial was the superior performance of imlunestrant in patients with ESR1 mutations, which are commonly associated with resistance to traditional endocrine therapies. The agent demonstrated enhanced efficacy in degrading the mutant estrogen receptor, offering a promising therapeutic option for this subset of patients. In patients without the ESR1 mutation, imlunestrant showed comparable efficacy to fulvestrant, suggesting it is a viable alternative across the board.

In the trial, patients were randomly assigned 1:1:1 to receive either imlunestrant, standard endocrine monotherapy, or the combination of imlunestrant and abemaciclib (Verzenio). The primary end points were investigator-assessed progression-free survival (PFS), comparing imlunestrant with standard therapy in patients with ESR1 mutations and in the overall population, as well as comparing the combination therapy with imlunestrant monotherapy among all patients who had undergone random assignment concurrently.

Among 256 patients with ESR1 mutations, the median PFS was 5.5 months with imlunestrant compared with 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% CI, 6.8-9.1) with imlunestrant and 5.4 months (95% CI, 4.6-6.2) with standard therapy (difference, 2.5 months; 95% CI, 1.2-3.9; P = .001).

In the overall population, the median PFS was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72-1.04; P = .12). Among 426 patients in the comparison arm of the combination vs imlunestrant alone, the median PFS was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44-0.73; P = .001).

Perhaps even more compelling was the combination of imlunestrant with the CDK4/6 inhibitor abemaciclib. This combination showed significant improvements in PFS across all patient groups, including those with prior CDK4/6 inhibitor exposure.

“The median PFS of 9.1 months in this heavily pretreated population is particularly noteworthy, underscoring the potential of this combination to become a new standard of care,” O’Shaughnessy said. She is also cochair of the upcoming 24th Annual International Congress on the Future of Breast Cancer® East, sponsored by Physicians’ Education Resource®, to be held July 11 to 12, 2025, in New York, New York.

The next drug development steps for imlunestrant include seeking FDA approval for monotherapy or for use in combination therapies. Additionally, the EMBER-4 trial (NCT05514054) is already underway. “Drug development is progressing quickly, with the possibility of the agent’s use in a curative setting,” O’Shaughnessy said.

ADCs Expand the HER2 Landscape

ADCs have revolutionized the treatment of HER2-positive breast cancer, and their versatility is now being explored in HER2-low disease and other subtypes. An ADC that shows promise is ARX788. This HER2-directed ADC features a microtubule inhibitor payload and has shown impressive activity in both HER2-amplified and HER2-low breast cancers. Early-phase data suggest that ARX788 is effective even in patients who are heavily pretreated, offering a potential approach for patients with limited options.

A phase 2 trial (NCT06224673) is evaluating the agent in patients with HER2-low, locally advanced unresectable or metastatic breast cancer.² Primary objectives are to determine the efficacy of ARX788 using duration of response, best overall response, and disease control rate.²

Similar to other ADCs, ARX788 is not without its challenges. Interstitial lung disease and ocular toxicity are notable adverse events (AEs), though the latter appears to be manageable with standard interventions. “The development plan for ARX788 is still being finalized, but its non–cross-resistant profile makes it a potential addition to the ADC arsenal,” O’Shaughnessy said.

A second-generation ADC, SYD985 (trastuzumab duocarmazine; T-Duo), was also undergoing evaluation.^3-5 The agent was evaluated in the phase 3 TULIP trial (NCT03262935), but the FDA suspended its decision to approve the agent.⁶

Managing ADC Toxicities: A Collaborative Approach

The ocular toxicities associated with ADCs, such as dry eye and stomatitis, require a proactive and collaborative approach to management. Oncologists are advised to prescribe preventive measures, such as over-the-counter moisturizing eye drops, and to consider dose reductions if necessary. In cases of severe toxicity, referral to an ophthalmologist is recommended.

The recent approval of datopotamab deruxtecan (Dato-DXd), a TROP2-directed ADC, has further emphasized the importance of managing these AEs.⁷ The agent was approved based on efficacy findings from the TROPION-Breast01 trial (NCT05104866).⁸ “Although Dato-DXd has shown efficacy in HR-positive, HER2-negative breast cancer, its unique toxicity profile necessitates close patient monitoring,” O’Shaughnessy said.

Upcoming Trials and Data Releases

Staying informed about the latest data and its practical applications is crucial. The upcoming 24th Annual International Congress on the Future of Breast Cancer East and West meetings will provide a comprehensive overview of the most significant developments over the past year. Key topics will include the integration of CDK4/6 inhibitors into HER2-positive breast cancer treatment, as demonstrated by the PATINA trial (NCT02947685), and the potential for ADCs to transform both metastatic and curative settings.

The next 6 to 8 months are poised to deliver several practice-changing trial results. Among the most anticipated is the DESTINY-Breast05 trial (NCT04622319), which evaluates the ADC trastuzumab deruxtecan (T-DXd) in the adjuvant setting for patients who have HER2-positive status with residual disease after neoadjuvant therapy. If successful, this trial could establish T-DXd as a superior alternative to the current standard therapy, ado-trastuzumab emtansine (T-DM1).

Another critical trial is the DESTINY-Breast09 trial (NCT04784715), comparing first-line T-DXd to the standard combination of taxane, trastuzumab, and pertuzumab (Perjeta) in HER2-positive breast cancer. “This study has the potential to redefine first-line treatment for this population,” O’Shaughnessy said.

In the HR-positive space, the SERENA-6 trial (NCT04964934) is exploring a novel approach to ESR1 mutation monitoring. Patients on first-line aromatase inhibitor and CDK4/6 inhibitor combination therapy will be screened for ESR1 mutations, and those with detectable mutations will be randomly assigned to continue their current regimen or switch to camizestrant, an oral SERD. This trial could pave the way for more personalized treatment strategies in endocrine-resistant breast cancer.

On the immunotherapy front, O’Shaughnessy is looking forward to findings from the SWOG S1418/KEYNOTE-242 trial (NCT02954874), which is investigating the use of pembrolizumab in patients with residual disease after neoadjuvant chemotherapy. The landscape of breast cancer treatment is undergoing a transformative shift. The future of breast cancer care is bright, and the coming months promise to deliver even more groundbreaking insights.

REFERENCES:

1. Jhaveri KL, Neven P, Casalnuovo ML, et al; EMBER-3 Study Group. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. Published online December 11, 2024. doi:10.1056/NEJMoa2410858

2. ARX788 for treating patients with HER2-low locally advanced unresectable or metastatic breast cancer. ClinicalTrials.gov. Updated January 28, 2025. Accessed March 5, 2025. https://tinyurl.com/cy2dzfuz

3. Nadal-Serrano M, Morancho B, Escrivá-de-Romaní S, et al. The second generation antibody-drug conjugate SYD985 overcomes resistances to T-DM1. Cancers (Basel). 2020;12(3):670. doi:10.3390/cancers12030670

4. Saura Manich C, O’Shaughnessy J, Aftimos PG, et al. Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann Oncol. 2021;32(suppl 5):S1288-S1288. doi: 10.1016/j.annonc.2021.08.2088

5. Aftimos PG, Turner N, O’Shaughnessy J, et al. Trastuzumab duocarmazine versus physician’s choice therapy in pre-treated HER2-positive metastatic breast cancer: final results of the phase III TULIP trial. Ann Oncol. 2023;34(suppl 2):S340-S341. doi:10.1016/j.annonc.2023.09.563

6. U.S. Food and Drug Administration issues complete response letter for Byondis’ [vic-]trastuzumab duocarmazine. News release. Byondis B.V. May 15, 2023. Accessed March 5, 2025. https://tinyurl.com/bdfznvv4

7. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. FDA. January 17, 2025. Accessed March 5, 2025. https://tinyurl.com/2d274rkn

8. Bardia A, Jhaveri K, Kalinsky K, et al. TROPION-Breast01: datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Future Oncol. 2024;20(8):423-436. doi:10.2217/fon-2023-0188