Breast Cancer Breakthroughs: 2024 ESMO Highlights

Neil M. Iyengar, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medicine, New York, NY

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.

KEYNOTE-522

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.

NATALEE

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

DESTINY-Breast12

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.

ICARUS-BREAST01

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.

Quality of Life

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.

References

1. Schmid P, Cortes J, Dent R, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: overall survival results from the phase III KEYNOTE-522 study. Presented at: 2024 European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA4.
2. Fasching PA, Stroyakovskiy D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor in patients with HR+/HER2– early breast cancer: 4-year outcomes from the NATALEE trial. Presented at: 2024 European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA13.
3. FDA approves Novartis Kisqali to reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis Pharmaceuticals Corporation. September 17, 2024. Accessed September 26, 2024. https://shorturl.at/p0jbc
4. Lin N, Ciruelos EM, Jerusalem G, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINYBreast-12 primary results. Presented at: 2024 European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA18.
5. Pistilli B, Pierotti L, Lacroix-Triki M, et al. Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase II study of patritumab deruxtecan (HER3-DXd) in patients (pts) with HR+/HER2- advanced breast cancer (ABC). Presented at: 2024 European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain. Abstract 340O.
6. Vanlemmens L, Lefeuvre-Plesse C, Thery J, et al. eMouvoir: randomised phase III trial evaluating the impact of a personalized and remote physical activity (PA) for breast cancer survivors (BCS): results on the quality of life (QoL). Presented at: 2024 European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA12.
7. Franzoi MA. Invited discussant for abstracts 1814O and 1815O. Presented at: 2024 European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain.
8. Ligibel J, Ballman K, Mccall L, et al. Effect of a weight loss intervention (WLI) on exercise behaviors in women with breast cancer: results from the breast cancer weight loss (BWEL) trial. Presented at: 2024 European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain. Abstract 1817MO.
9. Rundqvist H, Rietz M, Mijwel S, Lindström LS, Wengström Y. Effects of a high-intensity exercise intervention on recurrence and survival: the OptiTrain breast cancer trial. Presented at: 2024 European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain. Abstract 232O.