The annual San Antonio Breast Cancer Symposium—the largest scientific conference devoted to breast cancer—provides the opportunity for basic and translational investigators to share the newest advancements from the field that can, in turn, inform breast cancer treatment. December’s meeting highlighted several studies and clinical trials that are potentially practice changing.
Read on to learn about potential treatments, including antibody-drug conjugates, next-generation SERDs, and more that were discussed at SABCS, and find all of BCRF’s SABCS highlights here.
Dr. Komal Jhaveri of Memorial Sloan Kettering Cancer Center reported the promising results of EMBER3 (NCT04975308), a trial that tested the efficacy of imlunestrant alone and in combination with the CDK4/6 inhibitor abemaciclib compared to standard hormone therapy. Imlunestrant is a next-generation oral selective estrogen receptor degrader (SERD) that showed promising results: It decreased the risk of disease progression and death in patients with estrogen receptor (ESR1) mutations, and with the addition of abemaciclib, it improved progression-free survival in all patients, regardless of ESR1 status. Other SERDs require patients to get in-office injections, so the fact that these results were seen with an oral medication was met with enthusiasm at SABCS.
The estrogen receptor (ER) has long been a target for treating ER-positive breast cancers with drugs called selective ER modulators (SERMs), which have been used in practice for over 30 years. These drugs, in combination with aromatase inhibitors (AIs), are effective in this type of breast cancer. However, 30 to 50 percent of these tumors develop resistance to the therapy after three to five years. SERDs were developed around the turn of this century to overcome endocrine resistance. They work by degrading ER so that it cannot promote tumor growth. Imlunestrant follows in the footsteps of fulvestrant (Faslodex©) and elacestrant (Orserdu©), the only SERDs that are currently FDA approved to treat ER-positive breast cancer. If approved, patients will have another, potentially more convenient SERD as a treatment option. Read more
Antibody-drug conjugates (ADCs) are among the most successful and most rapidly expanding therapeutic areas in breast cancer and across oncology. The success of ADCs has prompted much attention, and researchers continue to refine their use.
Research into a drug doesn’t stop when it’s approved for use by the FDA; there’s an ongoing process to maximize the utility of each drug, minimize toxicity, determine long-term effects including if tumors become resistant with continued use. For example, BCRF investigator Dr. Aditya Bardia reported updates from the DESTINY-Breast06 trial, which showed that administering trastuzumab deruxtecan (T-DXd/Enhertu©) following endocrine therapy plus a CDK4/6 inhibitor in tumors that develop resistance to endocrine therapy was more effective than chemotherapy.
Although ADCs such as T-DXd are revolutionizing how HER2-positive breast cancer is treated, new options are needed, as some patients experience disease progression with continued use of these drugs. Researchers are therefore leveraging technological advances in ADC design to improve their safety and efficacy and widen their therapeutic utility. This includes increasing the specificity of the therapy’s antibody portion, investigating newer and better drug payload components, and improving or refining the linker between the antibody and the drug payload. As reported at SABCS, several anti-HER2 ADCs with unique payloads are currently in development.
BCRF investigator Dr. Hope Rugo and her colleagues reported on ARX788, a next-generation anti-HER2 ADC. ARX788 is stably attached to the drug AS269, a potent inhibitor of tubulin, which is a vital structural component for cells. ARX788 has shown antitumor activity in patients with HER2-positive and HER2-low metastatic breast cancer, including those with prior T-DXd treatment. The phase 2 ACE-Breast-03 (NCT04829604) trial is underway to evaluate ARX788 in these patients.
Dr. Junjie Li of Fudan University Cancer Hospital presented results from the phase 2 FASCINATE-N trial (NCT05582499) testing the third-generation ADC: SHR-A1811. This ADC is comprised of an anti-HER2 antibody (trastuzumab) linked to a novel topoisomerase 1 inhibitor payload (rezetecan) that enters and kills cells more effectively than T-DXd. SHR-A1811 demonstrated promising anti-tumor activity with an acceptable safety profile in the neoadjuvant (before surgery) setting in patients with hormone receptor (HR)–positive/HER2-low breast cancer. Notably, SHR-A1811 showed promising intracranial response for patients with breast cancer brain metastases.
BCRF investigator Dr. Mafalda Oliveira discussed the newest ADCs currently in clinical trials. GQ-1005 is an innovative HER2 ADC comprised of trastuzumab linked to deruxtecan/DXd but with notable caveats compared to T-DXd: the linker is more stable, and the drug-to-antibody ratio is lower. GQ1005 demonstrated promising anti-tumor activity with a favorable safety profile in patients with heavily pretreated HER2-positive metastatic breast cancer. The superior safety profiles may be attributable to its higher linker stability and minimal payload shedding in circulation. Disitamab vedotin (RC48-ADC) is an anti-HER2 antibody uniquely linked to a drug (monomethyl auristatin E) that disrupts cells’ internal structure. It demonstrated significant efficacy in patients with HER2-positive advanced breast cancer liver metastases.
A number of ADCs are being developed and tested as researchers focus on expanding the armamentarium of targeted breast cancer therapies—including for early-stage breast cancers.
Dr. Oliveira also presented updates on an ongoing phase 2 clinical trial testing the first anti-HER3 ADC: HER3-DXd. The SOLTI VALENTINE trial (NCT05569811) demonstrated that in patients with high-risk, early-stage HR-positive/HER2-negative breast cancer, this novel ADC—alone or in combination with letrozole (an aromatase inhibitor)—achieves a pathological complete response (pCR) and overall response rate (ORR) similar to chemotherapy. Further, HER3-DXd treatment resulted in lower rates of adverse events with fewer dose reductions needed and fewer interruptions in treatment or treatment discontinuation compared to chemotherapy. Read more
Although eight novel ADCs have been developed in the last five years, sessions at SABCS highlighted how we have just scratched the surface of using ADCs to treat breast cancer. In fact, there are 200 ADCs currently in development: 110 contain topoisomerase 1 payloads; and 60 contain tubulin inhibitor payloads. ADCs are essentially modular with each component potentially interchangeable. And the future of the field involves defining novel constructs or novel biomarkers that are stable and effective.
The power and specificity of antibodies has been exploited to create ADCs, but this has also opened the door to other novel antibody-driven therapies as researchers leverage new technologies. Case in point, bi-specific antibodies recognize two distinct sites on a cell or protein and provide a strategy for increasing the patient population that can benefit—patients with both antibody targets as well as those with either target may benefit. Currently, two clinical trials with bi-specific antibodies have been initiated.
Still other techniques are being leveraged to create ADCs with dual payloads and radioimmuno-drug conjugates. And navigating around the large size of ADCs, investigators are developing small molecule conjugates such as bicycle toxin- and peptide-drug conjugates that can more efficiently permeate cells due to their smaller size, allowing payload delivery to more cells.
Other promising new approaches
The aforementioned SERDs traditionally promote ER degradation by passively destabilizing the receptor. In contrast, newer agents called PROTACs (PROteolysis TArgeting Chimeras) actively promote ER degradation. PROTACs are comprised of two small molecules: one that binds a target and the other that binds an enzyme that flags the target protein for cellular degradation. These agents are highly specific, with profound and durable degradation effects.
At SABCS, Dr. Stephen M. Hinshaw of the Stanford Cancer Institute described recent developments with PROTACs including vepdegestrant, which targets ER and has obtained FDA fast-track designation in breast cancer. He reported that in preclinical studies, vepdegestrant in combination with current CDK4/6 inhibitors promoted tumor regression in ER-positive/HER2-negative breast cancer. His lab is continuing to develop other PROTACs, including those that target CDK4/6 proteins for cellular degradation. Other notable constructs in development are called LYTACs (LYsosome Targeting Chimeras). These agents are also cellular degraders but bind to cell surface receptors and mark them for degradation unlike PROTACs that work inside the cell.
A deep understanding of breast cancer biology is key to developing future ADCs, antibody-driven treatments, and other breast cancer therapies. SABCS 2024 showed that advancements are being made at rapid speed and exciting progress will no doubt be reported at future meetings.
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