Neil M. Iyengar, MD, highlighted the most important data in breast cancer to come from 2024 ESMO.
The incredible pace of advancements in breast cancer therapeutics was again demonstrated at the 2024 European Society for Medical Oncology (ESMO) Congress. At the forefront of these advances were new data for several antibody-drug conjugates (ADCs) and molecular therapeutics. Here are some of the impactful presentations and data sets that are immediately practice-changing or provide important updates in the development of novel treatments.
The final overall survival data from the phase 3 KEYNOTE-522 trial (NCT03036488) were perhaps the most impactful data presented at ESMO, confirming the benefit of adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy for early-stage triple-negative breast cancer.1 At a median follow-up of 75.1 months, 14.7% (115/784) of patients in the pembrolizumab arm had died vs 21.8% (85/390) of patients in the control arm (HR, 0.66; 95% CI, 0.50-0.87; P = .0015). The 5-year overall survival (OS) rates were 86.6% vs 81.7%, and the 5-year event-free survival rate was 81.2% in the pembrolizumab arm vs 72.2% in the placebo arm (HR, 0.65; 95% CI, 0.51-0.83). However, it is important to note that careful patient selection is critical due to the risks of immune-related toxicities and further studies are needed to identify clinically useful biomarkers.
The 4-year update from the NATALEE trial (NCT03701334) of adjuvant ribociclib (Kisqali) for high-risk primary breast cancer was arguably the headliner of breast cancer data presented at ESMO.2 In the phase 3 NATALEE trial, the addition of ribociclib to adjuvant aromatase inhibition for stage II and III hormone receptor–positive early breast cancer led to an improvement in invasive disease–free survival (iDFS). Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III breast cancer. Patients were randomly assigned to receive ribociclib at 400 mg daily, 3 weeks on and 1 week off for 3 years plus a nonsteroidal aromatase inhibitor, or aromatase inhibitor alone. At the data cutoff of April 29, 2024, 63% of patients completed 3 years of ribociclib, while 20% stopped early due to adverse effects. With a median follow-up time of 44.2 months, the addition of ribociclib demonstrated a significant iDFS benefit (HR, 0.715; 95% CI, 0.609-0.840; P < .001). Ribociclib added a 4-year absolute iDFS improvement of 4.9%, an increase from the previously presented improvement of 2.7% at 3 years. Notably, the 4-year absolute iDFS benefit was 5.1% in the N0 population and 5.0% in the N+ population. No new safety signals were identified. On the basis of data from the NATALEE trial, ribociclib plus endocrine therapy received FDA approval for use in the adjuvant setting on September 17, 2024.3
The DESTINY-Breast12 trial (NCT04739761) was a phase 3b/4 multicenter trial in which patients with HER2-positive metastatic breast cancer who received up to 2 lines of therapy in the metastatic setting and had stable or active brain metastases were treated with the HER2-directed ADC, trastuzumab deruxtecan (T-DXd; Enhertu).4 In patients with brain metastases, the 12-month progression-free survival (PFS) rate was 61.6% (95% CI, 54.9%-67.6%) and the 12-month central nervous system PFS was 58.9% (95% CI, 51.9%-65.3%). The rates were similar in patients with stable (57.8%; 95% CI, 48.2%-66.1%) and active (60.1%; 95% CI, 49.2%-69.4%) brain metastases. The rates of interstitial lung disease (ILD) were similar to previously reported rates (16% all-grade ILD in the brain metastasis cohort, including 6 [2.3%] grade 5 events). These results demonstrated significant intracranial activity of T-DXd.
Phase 2 results from the ICARUS-BREAST01 trial (NCT04965766) testing the novel HER3-directed ADC patritumab deruxtecan (HER3-DXd) were also presented.5 Patients with hormone receptor–positive, HER2-negative metastatic breast cancer who had progression on CDK4/6 inhibitor and 1 line of chemotherapy were enrolled. At the data cutoff, 99 patients were included and 19 patients were still on treatment. At a median follow-up of 15.3 months, the confirmed objective response rate was 53.5% (95% CI, 43.2%-63.6%) and the median PFS was 9.4 months (95% CI, 8.1-13.4). The most frequent treatment-related adverse effects were nausea (all grade, 75%; grade 3, 5%) and diarrhea (all grade, 53%; grade 3, 1%), and 6 patients had ILD (grade 1, n = 5; grade 2, n = 1). These results support the continued development of this novel ADC.
Finally, multiple trials were presented demonstrating the beneficial effects of exercise on symptom management/quality of life, weight loss, and even improvements in invasive breast cancer–free survival and OS with 16 weeks of high-intensity interval training plus resistance training during chemotherapy for early breast cancer.6-9 These studies provide welcome adjunctive data emphasizing the importance of lifestyle interventions to support standard cancer therapies.
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