Cancer Updates GI and Breast Memphis: Dr Lammers Discusses New and Novel Agents in Breast Cancer
Presenter:
Phil Lammers, MD, MSCI, Baptist Cancer Center
Conference:
2025 Cancer Updates GI and Breast, Memphis
Overview
At the 2025 Cancer Updates GI and Breast Dinner Conference in Memphis, TN, Dr Phil Lammers from Baptist Cancer Center focused his presentation on new treatment paradigms in hormone receptor–positive (HR+) breast cancer, highlighting the use of antibody-drug conjugates (ADCs), phosphatidyl inositol-3 kinase (PI3K) pathway inhibitors, and the emergence of oral selective estrogen receptor degraders (SERDs). With an emphasis on clinical trial evidence, real-world relevance, and emerging strategies, his talk underscored the rapid evolution of these new and novel treatment options in metastatic breast cancer.
Antibody-Drug Conjugates (ADCs): Redefining HR+ Breast Cancer Therapy
Datopotamab Deruxtecan (Dato-DXd)
Dr Lammers began with an overview of Dato-DXd, a TROP2-targeting ADC. He noted that, while the exact role of TROP2 in tumorigenesis remains unclear, its prevalence on breast cancer cells makes it an ideal target for ADCs. In the TROPION-Breast01 trial, Dato-DXd showed improvement in progression-free survival (PFS) as compared to the investigator’s choice chemotherapy (6.9 versus 4.9 months), with a higher overall response rate also observed (36% vs 23%). Despite the significance of the findings, Dr Lammers cited the pronounced underrepresentation of Black patients in the trial, (only 1%), and called for a more equitable access to important trials such as this, particularly in community oncology settings like Memphis. While data from TROPION-Breast01 are promising, he cautioned about the unique side effects of Dato-DXd such as ocular toxicity and stomatitis, which require proactive management (e.g., dexamethasone drops and mouthwashes). Dr Lammers also noted that, importantly, Dato-DXd was studied in patients who had not previously received other ADCs such as trastuzumab deruxtecan (T-DXd) or sacituzumab govitecan (SG) which, accordingly, raises questions about sequencing and efficacy in the face of a prior ADC treatment.
Trastuzumab Deruxtecan (T-DXd)
Describing it as “one of the top three breast cancer drugs ever developed”, Dr Lammers noted that T-DXd has reshaped treatment across the landscape of Human epidermal growth factor receptor 2 (HER2)-positive, as well as the newly defined “HER2-low” breast cancer subtypes. The DESTINY-Breast02 and DESTINY-Breast06 trials demonstrated substantial benefit of this ADC in both HER2-low and “ultra-low” tumors (the latter defined as an immunohistochemical (IHC) staining of 0, but with faint HER2 membrane staining), and Dr Lammers noted: "It really just takes a hint of HER2 to see activity with this drug." In DESTINY-Breast06, for example, T-DXd extended PFS by about 5 months over standard chemotherapy (13.2 versus 8.1 months), although Dr Lammers noted that interstitial lung disease (ILD) remains a serious complication with the drug, as it has been associated with some deaths. Overall, Dr Lammers recommends that T-DXd should be considered a first- or second-line cytotoxic chemotherapy option for patients with advanced or metastatic disease after failure of endocrine therapy.
Targeting the PI3K Pathway: Inavolisib
Dr Lammers also discussed findings from the INAVO120 trial which evaluated the efficacy of inavolisib, a selective PI3Kα inhibitor, in patients with PIK3CA-mutant HR+ breast cancer and early endocrine resistance (defined as progression on, or shortly after adjuvant endocrine therapy). As compared to the use of the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib with a SERD (fulvestrant) alone, the addition of inavolisib significantly improved PFS (15.0 versus 7.3 months) and response rate (58% vs 25%). Dr Lammers noted, however, that adverse events of hyperglycemia and gastrointestinal side effects are common with this agent. As such, strict glycemic eligibility criteria were used in the trial (i.e., fasting glucose <126 mg/dL, A1C <6%) which, he suggested, limits the real-world applicability of the findings: "I think there may be like seven of those patients in Memphis, maybe…" Dr Lammers also highlighted some lingering uncertainties around sequencing of this therapy—especially in patients who have already received CDK4/6i—and the tolerability challenges that may limit its broader use.
Oral SERDs and CDK4/6i Retreatment: A New Frontier
EMBER-3 Trial (Imlunestrant ± Abemaciclib)
Dr Lammers noted that oral SERDs like imlunestrant are gaining traction, particularly in patients with estrogen receptor gene (ESR1) mutations, which can arise in approximately 40% of patients treated with endocrine therapy. In the EMBER-3 trial, imlunestrant outperformed standard endocrine therapy, primarily in ESR1-mutated populations. More promising, Dr Lammers noted, was the combination with the CDK4/6i abemaciclib, which showed a meaningful PFS benefit even in patients with prior CDKi exposure: "This looks like a potential option in combination… a retreatment strategy…" he commented. He further noted that the combination was well tolerated and without significant additive toxicity.
SERENA-6: ESR1 Mutation Surveillance and Early Intervention
Dr Lammers also described the SERENA-6 trial which explored a new surveillance strategy in metastatic HR+ patients on an aromatase inhibitor (AI) in combination with a CDKi, where treatment was switched to camizestrant plus a CDKi upon detection of ESR1 mutations—even in the absence of radiographic progression. He commented on the interesting study design, which, he thought might necessitate checking patients’ mutational status through blood work every three months. Dr Lammers also noted a recent press release which suggests positive results from the trial, although full data are still pending. He suggested that, if validated, this approach could introduce a new paradigm of preemptive molecular switching of treatment, based on real-time resistance monitoring.
New and Novel Agents in Breast Cancer - Summary of Key Updates
Dato-DXd: A new ADC option in HR+/HER2-negative mBC, especially after prior chemotherapy and endocrine therapy.
T-DXd: Use is expanding in HER2-low and ultra-low disease, with caution needed for the adverse event of ILD.
Inavolisib: Shows promising efficacy in PIK3CA-mutated early recurrent HR+ disease, although toxicity and patient eligibility remain challenges.
Oral SERDs: Imlunestrant ± abemaciclib shows strong potential, especially in patients with ESR1mutant tumors.
ESR1 mutation surveillance (SERENA-6): May usher in a new approach to early intervention for emergent molecular resistance.
Speaker Disclosure Information: Dr Lammers reported the following disclosures for this presentation: Consulting / Advisory Role and Speaker Program: Astra-Zeneca, Amgen; Consulting / Advisory Role: Daiichi-Sankyo, BMS/Sanofi, Merck