ESMO West 2023: Metastatic Breast Cancer Updates with Dr Elias
Presentation by Dr Anthony Elias, MD, University of Colorado Cancer Center
At the 2023 ESMO West review conference presented by Total Health in Colorado Springs, Colorado, Dr Anthony Elias, from the University of Colorado Cancer Center, presented updates in treatment for metastatic breast cancer (mBC), as reported at this year’s European Society for Medical Oncology (ESMO) Congress held in Madrid, Spain. His selected abstracts focused largely on updates from major trials examining the use of the antibody-drug conjugates in mBC (BOX 1). As a drug class, antibody-drug conjugates (ADCs) consist of 3 components, an antibody portion, which targets a specific molecule expressed on the cancer cell (the ‘target’), a linker, and the ‘payload’, typically a cytotoxic drug which, upon binding of the antibody, is released into the cell, causing cell death. Dr Elias also reviewed results from ESMO for a new agent in an emerging class of anti-estrogen drugs in mBC, the orally administered, selective estrogen receptor degraders (oral SERDs).
Box 1. ESMO 2023:Findings with Current and Investigational Antibody Drug Conjugates (ADCs) in mBC
| Agent | Target | Payload | Key Findings Reported at ESMO 2023 |
|---|---|---|---|
|
Trastuzumab deruxtecan (T-DXd) |
HER2 |
Deruxtecan (Topo-I inhibitor) |
|
|
Datopotamab deruxtecan (Dato-DXd) |
TROP2 |
Deruxtecan (Topo-I inhibitor) |
|
| Trastuzumab duocarmazine (T-Duo) | HER2 | Duocarmazine (Alkylating agent) |
|
| HS-20089 | B7-H4 | Topo-I Inhibitor |
|
Dato-DXd mBC (TROPION-Breast01): First Results
Dr Elias highlighted the first results from the TROPION-Breast01 trial (NCT05104866), which examined the use of a new ADC, datopotamab deruxtecan (Dato-DXd) as compared with investigator’s choice of chemotherapy (ICC), in patients with previously treated, inoperable or metastatic HR+, human epidermal growth factor 2 negative (HER2-) breast cancer. The dual primary endpoints in this trial were progression-free survival (PFS) and overall survival (OS). Results reported at ESMO 2023 showed a significant benefit in PFS (median 6.9 vs. 4.9 mo; P<0.0001) for patients on Dato-DXd versus those treated with ICC.
T-DXd in HER2 Low Patients (DESTINY-Breast04)
Dr Elias also detailed updated survival results reported at ESMO 2023 from the phase III DESTINY-Breast04 Study (NCT03734029), which examined the use of another ADC, trastuzumab deruxtecan (T-DXd), as compared with treatment of physician’s choice (TPC) in patients with “HER2-low” unresectable and/or metastatic breast cancer. HER2-low mBC patients have a low level of HER2 expression, as defined by specific molecular criteria, and T-DXd has previously shown efficacy in this subtype of mBC. The results showed a benefit of T-DXd over TPC in OS, both in the HR+ patients (23.9 mo vs. 17.6 mo; hazard ratio [HR]=0.69), as well as the overall population (22.9 mo vs. 16.8 mo; HR=0.69), corresponding to a 31% relative reduction in risk of death for both groups of patients. He noted the adverse events (AEs) of special interest with T-DXd in the trial (of any severity), which included interstitial lung disease (ILD)/pneumonitis (12.1% vs. 0.6%), decreased cardiac ejection fraction (4.9% vs. 0%), and cardiac failure (0.5% vs. 0%), which were more frequent in the T-DXd group.
Use of T-DXd for Brain Metastases: A Pooled Analysis
Results from a pooled analysis from three trials (DESTINY-Breast01, -02, and -03) evaluating the use of T-DXd for patients with mBC and brain metastases (BM) were also reported at ESMO 2023. A majority of patients in these three trials (70% - 96%) also had existing visceral metastases (e.g., lung or liver metastases), and most patients (49% - 68%) had recurrent (as compared to newly diagnosed) mBC across the three trials. Results showed an intracranial overall response rate (ORR) of 45% for patients treated with T-DXd, as compared with the comparator arm (12% - 27.6%), with ~16% of patients having a complete response (CR) in the T-DXd groups. Dr Elias noted there was a trend towards prolonged central nervous system (CNS) PFS with T-DXd versus the comparator, with a greater advantage for patients with untreated or active BMs, as compared to those with previously treated/stable BMs. Importantly, Dr Elias noted that these studies were initiated prior to the use of tucatinib, another agent which has been shown to be effective for patients with mBC and BM.
Dato-DXd Plus Durvalumab for Triple Negative mBC
Another abstract which Dr Elias highlighted examined the use of Dato-DXd in combination with an immunotherapy agent, durvalumab as a first line (1L) treatment for patients with unresectable or locally advanced/metastatic breast cancer that was triple negative (TNBC), defined as lacking expression of hormone receptors (estrogen and progesterone receptors), and HER2. The reported results were from one of several arms in a phase II study, BEGONIA (NCT03742102) which combined durvalumab immunotherapy with different targeted treatments for patients with metastatic TNBC. With a total of 62 metastatic TNBC patients treated, the observed ORR was 79%, which Dr Elias described as “quite remarkable”. The median PFS was 13.8 months, and the duration of response (DoR) was 15.5 months. He noted the AEs with the combination in the trial, generally low-grade gastrointestinal events and stomatitis (inflammation of mouth and lips mucous membranes), which was also the most common AE leading to Dato-DXd dose reduction. There was also a 5% incidence of treatment-related ILD/pneumonitis, a 13% incidence of any-grade diarrhea, and a 5% incidence of any grade neutropenia. The most commonly reported AEs of special interest were stomatitis (65%), rash (32%), dry eye (21%), hypothyroidism (14.5%), and keratitis (14.5%). Dr Elias also highlighted the ocular toxicities of dry eye and keratitis which are important to monitor if patients have complaints of blurry vision, and which may require ophthalmologic evaluation.
A Novel Anti-B7-H4 ADC
Dr Elias also briefly reviewed findings from a phase I study for a new ADC, HS-20089, in patients with advanced solid tumors, including 28 patients with TNBC. He noted the novel target of this ADC, the B7 homolog 4 protein (B7-H4) which shows high expression in various tumor types and low expression in normal tissues. The toxin (payload) is an anti-tubulin. HS-20089 has shown potent antitumor activity in preclinical studies, and results reported at ESMO showed an ORR of 27% – 33% for patients with advanced TNBC when used at potentially therapeutic doses. The safety profile was manageable, and a phase Ib expansion study is ongoing to assess efficacy and safety in several tumor types including TNBC.
Anti-HER2 Duocarmazine ADC: Results from the TULIP Study
Also reported at ESMO 2023 were final results from the TULIP Trial, a phase III study examining the efficacy of another ADC, trastuzumab duocarmazine (T-Duo), as compared with physician’s choice of therapy (PC) for patients with pre-treated, HER2-positive mBC. This ADC differs from T-DXd and Dato-DXd as it targets HER2, but has a novel payload, duocarmazine. Results for the primary endpoint of the trial, PFS, showed a significant benefit of T-Duo over the PC (median PFS 7.0 mo vs. 4.9 mo; HR=0.64; P=0.002) with a 36% relative reduction in risk of progression. The principal AEs associated with T-Duo were ocular toxicities (conjunctivitis and keratitis) and ILD pneumonitis (BOX 2).
Box 2. Ocular and ILD/Pneumonitis Adverse Events in the TULIP Trial
| Ocular Toxicity | ILD/Pneumonitis | |
|---|---|---|
|
Any Grade Grade 3 or higher Leading to Treatment Discontinuation Leading to Dose Modification |
T-Duo: 78.1% (vs. 29.9% with PC) T-Duo: 21.2% T-Duo: 21.5% T-Duo: 22.9% |
T-Duo: 7.6% T-Duo: 2.4% T-Duo: 5.2% T-Duo: 2.1% |
Commentary on ADCs in mBC
Commenting on the expanding use of ADCs in mBC, Dr Elias noted the expanding range of target molecules beyond HER2, such as TROP2, HER3, and B7-H4 (BOX 1), but a fairly limited range of payload components, most of which are either anti-tubulin or topoisomerase-1 (Topo-1) inhibitors (BOX 1), although a few other toxins with different mechanisms of action (e.g., T-Duo) are in development. He noted this could be problematic with sequential use of ADCs (one after another) as patients could theoretically develop resistance to the Topo-I inhibitor component of one ADC (e.g., T-DXd), which could restrict the subsequent use of another ADC with a different target (e.g., Dato-DXd) but which also has a Topo-I inhibitor as its payload. Another possible pathway to resistance is down regulation of a target molecule (e.g., HER2) that is shared by two ADCs with different payloads (e.g., T-DXd and T-Duo). As such, the optimal sequential use of ADCs will need to be investigated further across different subpopulations of mBC patients.
Initial Results for OP-1250 (Oral SERD) in mBC
Lastly, Dr Elias highlighted results from the phase I/II study of OP-1250 (palazestrant), an oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) in patients with advanced and/or metastatic ER-positive, HER2-negative breast cancer. In previous studies, OP-1250 was shown to be well-tolerated with no dose limiting toxicities. The results showed a clinical benefit rate (CBR), defined as complete response, partial response, or stable disease, in 40% of the overall population (median PFS, 4.6 mo), and in 52% (median PFS 5.6 mo) of those having a mutation in the estrogen receptor gene (ESR1 mutation), and the drug was overall well tolerated in this group of heavily pretreated patients. In the second or third line (2/3L) setting, the median PFS was 7.2 months, with a CBR of 48% for the overall population, and PFS was 7.3 months (CBR 59%) for those with an ESR1 mutation. A phase III study with palazestrant monotherapy versus standard of care is currently underway, and phase I/II studies are also underway in combination with other drug classes for ER+/HER2- mBC.
Speaker Disclosure Information: Dr Elias reported no relevant conflicts of interest, and the following disclosures for this presentation: Investigator: Astellas, Xenshine, I-SPY2, Ambrx, Cogent Pharm, C4 Therapeutics, Immune Oncology, Scorpion.
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