ASCO 2024 Meeting Report — Breast Cancer

The 2024 American Society of Clinical Oncology (ASCO) annual meeting, held May 30 to June 3 in Chicago, highlighted important advances in treatment across a broad spectrum of malignancies. Here, Editor-in-Chief Dr. William Gradishar reviews key trials in breast cancer.

The presentation of the industry-sponsored, phase 3 postMONARCH trial highlighted another treatment option for patients who develop progressive disease after being on a CDK4/6 inhibitor (CDK4/6i) in the metastatic setting (abstract LBA1001). For these patients, next-generation sequencing is usually performed at first recurrence to determine if there are any actionable mutations, such as PIK3CA or ESR1 mutations. Elacestrant is FDA-approved for patients with ESR1 mutations, and alpelisib and capivasertib are approved for PI3K/AKT pathway abnormalities. All these drugs are treatment options post-progression on a CDK4/6i. For tumors without a mutation, one might consider the combination of fulvestrant and an mTOR inhibitor, such as everolimus, or simply endocrine monotherapy.

Patients were eligible for postMONARCH if they had ER+/HER2− disease and disease progression on a prior CDK4/6i and aromatase inhibitor in the advanced disease setting, or disease recurrence on or after a CDK4/6i plus endocrine therapy in the adjuvant setting. Of 368 patients randomized to fulvestrant with either abemaciclib or placebo, almost all had received prior CDK4/6i in the metastatic disease setting (palbociclib in 59%, ribociclib in 33%, abemaciclib in 8%). At 6 months, progression-free survival (PFS), the primary outcome, was significantly improved by 27% with abemaciclib compared with placebo (50% vs. 37%); the benefit was seen across all subgroups. The objective response rate also improved with abemaciclib (23% vs. 8%).

Results from prior small trials of this approach were inconsistent. These findings support considering sequential CDK4/6i use, particularly in patients without other actionable mutations.

Although sequencing endocrine therapy over time is preferred, some patients may need to go straight to chemotherapy due to the tempo of the disease or presence of disease bulk that is immediately threatening. This scenario highlights the industry-sponsored, phase 3 DESTINY Breast-06 trial (abstract LBA1000). Patients with ER+/HER2-low or -ultralow expression (staining in >0 and ≤10% of tumor cells) metastatic disease who had not received chemotherapy for advanced disease were eligible if they had received at least two lines of endocrine-based therapy for metastatic disease or one line of endocrine therapy and progression on adjuvant endocrine therapy within 24 months or progression on a CDK4/6i within 6 months.

Nearly 900 patients were randomized to trastuzumab deruxtecan (T-DXd) or chemotherapy with capecitabine, paclitaxel, or nab-paclitaxel. Data presented from the primary analysis showed that T-DXd significantly improved PFS by 5 months compared with chemotherapy (median, 13.2 vs. 8.1 months); this effect was observed in the overall population as well as in the HER2-ultralow and HER2-low subsets. Overall survival was immature.

Another intriguing, though not yet actionable, observation came from circulating tumor DNA (ctDNA) analysis in the industry-sponsored monarchE trial, which randomized patients with high-risk early breast cancer to endocrine therapy alone or endocrine therapy plus adjuvant abemaciclib for 2 years (abstract LBA507). The researchers previously reported statistically improved invasive-disease–free survival (iDFS) with the addition of abemaciclib. ctDNA samples were obtained and evaluated from a subset of patients (n=910) at baseline and at 3, 6, or 24 months using the Signatera assay to develop a bespoke individual signature.

Among patients who were ctDNA− at baseline (92%), 10% became positive. Among patients who were baseline ctDNA+ (8%), 59% remained persistently positive on treatment. Patients who were ctDNA+ at baseline were more likely to have an iDFS event than those who were ctDNA− at baseline (80% vs. 23%). Patients who remained ctDNA+ or became positive on treatment were more likely to have an iDFS event than those who became negative or remained negative on treatment.

These findings suggest it may be possible to identify patients who are more likely to experience a worse outcome and be eligible for clinical trials evaluating novel interventions in the groups at highest risk for recurrence.

The debate about the benefit of platinum agents as a component of adjuvant therapy in triple-negative breast cancer (TNBC) was addressed in the industry-sponsored, Korean PEARLY study (abstract LBA502). A total of 878 patients with TNBC, negative or positive lymph nodes, and tumor size ≥2 cm were randomized to an anthracycline for 4 cycles (doxorubicin/cyclophosphamide) followed by a taxane for 4 cycles or the same with carboplatin (area under the curve = 5 every 3 weeks) added to the taxane. Either paclitaxel or docetaxel was allowed. Approximately 70% of patients received treatment as neoadjuvant therapy. Approximately 50% were node positive.

At a median follow-up of 57 months, event-free survival (EFS), the primary endpoint, was significantly higher in the carboplatin arm than the control arm (82% vs. 75%; hazard ratio, 0.67). The pathologic complete response (pCR) rate was higher, but not significantly so, in the carboplatin arm (46% vs. 39%, respectively). Patients attaining a pCR had markedly improved EFS compared with those who did not attain a pCR (HR, −0.16). More patients in the carboplatin arm than the control arm experienced grade ≥3 adverse events (75% vs. 57%) and dose reductions (33% vs. 14%).

Several other randomized trials have shown a similar increase in pCR rate with a platinum, and in contemporary clinical management of similar patients, most receive neoadjuvant treatment that includes both a platinum and immunotherapy per findings from the KEYNOTE 522 study. The data from PEARLY support the use of platinum in the neoadjuvant setting.

The industry-sponsored, European, phase 3 A-BRAVE trial recruited 477 patients with high-risk TNBC who either completed chemotherapy and surgery and had residual invasive cancer in the breast and/or axillary lymph nodes (stratum A) or underwent primary surgery and had stage II or III disease after surgery (stratum B; abstract LBA500). Patients were randomized to observation or to receive the PD-L1 and PD-L2 inhibitor avelumab every 2 weeks for a year. In the adjuvant stratum A (18% of patients) and the post-neoadjuvant stratum B (82% of patients), patient and disease characteristics were broadly similar between the observation and avelumab arms.

At a median follow-up of 52 months, disease-free survival, the primary endpoint, was not significantly different between the treatment arms; however, overall survival was improved with avelumab (3-year OS, 85% vs. 76%; HR, 0.66; P = 0.035). Approximately 70% of patients were able to complete 1 year of avelumab and approximately 30% experienced adverse events (17/20 were immune-related) leading to discontinuation.

These data suggest avelumab may improve outcome in patients with early-stage TNBC at high risk of recurrence after primary surgery or with invasive residual disease following neoadjuvant chemotherapy.