Introduction
With 34,000 participants, the 2024 congress of the European Society for Medical Oncology (ESMO) has again emphasized its global significance. In this context, exciting data in the field of breast cancer were presented. This article provides a short review of these results, focusing on clinically relevant abstracts.
Early-stage breast cancer
NATALEE: update
The prospective randomized phase 3 NATALEE trial evaluated the CDK4/6-inhibitor ribociclib as a component of adjuvant therapy in patients with early-stage HR-positive/HER2-negative breast cancer (BC) with an intermediate to high risk of recurrence. Of note, the trial allowed for the inclusion of patients with node-negative disease in the case of additional risk factors (G3 or G2 and Ki-67 ≥ 20% or high risk via genomic risk assessment). At the 2024 ESMO congress, results from an exploratory 4‑year invasive disease-free survival (iDFS) landmark analysis were presented [1]. At a median follow-up (mFU) of 44.2 months, all patients had discontinued ribociclib, with 62.8% having completed 3 years of therapy. The addition of ribociclib to endocrine therapy (ET) improved iDFS from 83.6% to 88.5% (hazard ratio [HR]: 0.715; 95% confidence interval [CI]: 0.609–0.840; p < 0.0001). This benefit was observed irrespective of clinical stage and nodal status, and no new safety signals were observed. These data therefore corroborate the results from the MonarchE trial, which reported a clinically relevant reduction of recurrence risk in patients with high-risk luminal early-stage BC [2], and the results from NATALEE allow for the extension of this concept to an intermediate-risk population.
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Young patients often present with clinically more aggressive disease and women under 40 years have worse outcomes compared with an older population [3]. In NATALEE, premenopausal participants received ovarian function suppression (OFS) combined with an aromatase inhibitor as endocrine backbone. Women under 40 years derived numerically more benefit from the addition of ribociclib to endocrine therapy (∆5.1% < 40 years and ∆2.8% ≥ 40 years at 33.1 and 33.3 months median follow-up [mFU], respectively) [4]. Notably, quality of life was similar between both age groups. These data emphasize the activity and safety of adjuvant ribociclib in a premenopausal population.
KEYNOTE-522: overall survival update
Neoadjuvant treatment is regarded as standard of care for the majority of patients with early-stage TNBC. In clinically stage II and III TNBC, the standard treatment approach is paclitaxel/carboplatin followed by an anthracycline plus cyclophosphamide, combined with the immune checkpoint inhibitor pembrolizumab, based on the results of the KEYNOTE-522 trial [5]. In this prospective randomized phase 3 study, the addition of pembrolizumab to standard chemotherapy yielded a significant improvement in pathologic complete remission (pCR) rates irrespective of PD-L1 expression, as well as a significantly prolonged event-free survival. On the downside, a relevant increase in terms of immune-related adverse events was observed. In an updated analysis at 75.1 months mFU, a significant improvement in overall survival (OS) was reported (OS: 86.6% vs. 81.7%; HR: 0.66; 95% CI: 0.50–0.87; p = 0.0015), which was most pronounced in the non-pCR population [6]. These results are clinically relevant as they once more indicate that despite its potential toxicity, the benefits of neoadjuvant immunotherapy clearly outweigh the risks.
HER2-positive early BC
The WSG-ADAPT trial family investigates different de-escalation strategies in early-stage BC. In the WSG-TP-II trial, 207 patients were randomized to 12 cycles of weekly paclitaxel (P) combined with trastuzumab and pertuzumab (TP) or endocrine therapy (ET), again combined with TP, as neoadjuvant treatment for HR-positive/HER2-positive early-stage BC. The pCR rate was defined as the primary study endpoint and has already been presented (pCR: 56.4% P + TP vs. 23.7% ET + TP; [7]). Omission of further adjuvant chemotherapy was recommended in all patients with pCR. At the ESMO 2024 congress, long-term results with mFU of 60 months were presented [8]. Of note, 60% of all participants in the chemotherapy arm had received no further chemotherapy. Event-free survival rates were 94.8% and 92.1% in the arms with or without chemotherapy and OS was 97.9% and 100%, respectively. While the results of this phase 2 trial do not suffice to define a new treatment standard, high pCR rates and excellent long-term outcomes suggest that de-escalated neoadjuvant P + TP could be considered an option on an individual basis.
HERA, together with several other pivotal trials, firmly established 1 year of adjuvant trastuzumab after neoadjuvant or adjuvant chemotherapy in patients with early-stage HER2-positive BC [9]. Long-term follow-up indicated contrasting recurrence patterns between luminal and non-luminal HER2-positive tumors with late recurrences more commonly observed in the subset of patients with luminal B/HER2-positive disease [10]. A retrospective analysis now evaluated the role of OFS as a component of adjuvant ET in premenopausal women [11]. Overall, 965 patients were available for this analysis (51.9% tamoxifen; 48.1% ET with OFS). The addition of OFS to standard ET significantly improved disease-free survival (DFS; 70.9% vs. 59.6%; p < 0.001) and OS (84.7% vs. 74.0%; p < 0.001) over tamoxifen alone. This effect occurred irrespective of treatment arm and therefore persisted in the trastuzumab group, highlighting the relevance of optimal endocrine therapy even alongside HER2-directed treatments.
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OptiTrain trial
Observational studies suggest that physical activity is associated with a better prognosis in BC patients [12]. In the OptiTrain trial, 260 women with early BC were randomized to two different forms of high-intensity training during chemotherapy or usual care. The primary endpoint—a reduction in cancer-related fatigue during chemotherapy and after 1 year—has already been achieved and reported. At a mFU of 8.9 years, the investigators also observed a trend toward improved OS and BC-free survival. These findings were further supported by a pooled analysis of three randomized trials, reinforcing the role of exercise as part of treatment in early BC [13].
Advanced breast cancer
DESTINY-Breast12
Small brain-specific phase II trials, retrospective data, and a joined analysis of the pivotal studies suggest there is clinically relevant activity of T‑DXd in patients with HER2-positive BC and brain metastases (BM; [14‐17]). The DESTINY-Breast12 trial was initiated to validate these findings in a larger population [18]. The single-arm, two-cohort phase 3b/4 study investigated the activity and safety of T‑DXd in tucatinib-naive patients with HER2-positive BC and with (cohort 1) or without (cohort 2) BM. In the BM cohort, 263 patients were included, of whom 106 had active BM (i.e., newly diagnosed untreated or progressing after prior local therapy). The 12-month progression-free survival (PFS) rate in cohort 1 was 61.6% (95% CI: 54.9–67.6) and the median PFS was 17.3 months (95% CI: 13.7–22.1) in a post hoc analysis. The intracranial overall response rate (ORR) in the overall population with measurable disease was 71.7% (95% CI: 64.2–79.3), with the highest ORR observed in patients with newly diagnosed and previously untreated BM (ORR: 82.6%). Regarding toxicity, interstitial lung disease (ILD) of any grade was diagnosed in 16% of patients in the BM cohort. In four out of six patients with fatal ILD, opportunistic co-infections were observed; therefore, pneumocystis prophylaxis should strongly be considered in patients receiving continuous dexamethasone therapy for brain edema. In summary, data from the DESTINY-Breast12 trial support the use of T‑DXd when clinically indicated, irrespective of BM status.
ICARUS-Breast01
HER3 is a growth factor receptor in the EGFR family, and high HER3 expression is linked to resistance to both HER2- and HR-directed treatments [19, 20]. Patritumab deruxtecan (HER3-DXd) is a HER3-directed ADC using the same payload and linker technology as T‑DXd. In early-phase trials, HER3-DXd yielded significant clinical activity across all subtypes of BC, regardless of HER3 expression levels [21]. The single-arm phase II ICARUS-Breast01 trial investigated HER3-DXd in 99 patients with HR-positive/HER2-negative metastatic BC who had progressed on prior ET plus CDK4/6 inhibitors and one prior line of chemotherapy [22]. Patients with prior exposure to T‑DXd were excluded. The confirmed ORR, defined as the primary study endpoint, was 53.5% (95% CI: 43.2–63.6), and the median PFS was 9.4 months (95% CI: 8.1–13.4), suggesting improved activity over conventional chemotherapy in this setting. Regarding predictive biomarkers, a specific pattern of HER3 spatial distribution was linked to a higher probability of response; however, this concept awaits further confirmation.
DETECT V
Results from the MonarcHER trial and cohort C from the PATRICIA study already indicated clinically relevant activity of CDK4/6 inhibitors in HR-positive/HER2-positive metastatic BC [23, 24]. The phase III DETECT V trial was initially designed to investigate the role of induction chemotherapy in patients with HR-positive/HER2-positive metastatic BC [23‐25]. Overall, 271 patients were randomized to trastuzumab/pertuzumab plus ET with or without induction chemotherapy. In 75% of all patients, the study treatment was the first-line therapy in the metastatic setting. After 124 patients, the trial was amended to include the CDK4/6 inhibitor ribociclib in both treatment arms. At the second interim analysis, no differences in terms of PFS and OS were observed between the treatment arms with or without chemotherapy. However, when comparing outcomes in patients with or without ribociclib, a statistically significant and clinically relevant improvement in PFS (HR: 0.57; 95% CI: 0.39–0.85) and OS (HR: 0.47; 95% CI: 0.26–0.85) was noted in a post hoc analysis of sequentially treated populations. Outcomes of DETECT V therefore corroborate data from previous studies, as well as the more recently presented results of the PATINA trial, indicating clinically relevant activity of CDK4/6 inhibitors in luminal B/HER2-positive disease [26].
CAPItello-290
The CAPItello-291 trial established the AKT inhibitor capivasertib combined with ET for patients with pretreated HR-positive/HER2-negative metastatic BC and PI3K/AKT/mTOR pathway alterations [27]. Since such pathway alterations are also common in TNBC, the phase 3 CAPItello-290 trial randomized 812 treatment-naïve patients to paclitaxel with either capivasertib or placebo [28]. The dual primary endpoint—OS in the overall and the pathway-altered populations—was not met. However, PFS showed a numerical improvement from 5.6 to 7.5 months (HR: 0.70; 95% CI: 0.52–0.95) in the capivasertib arm. Side effects, such as diarrhea, rash, and hyperglycemia, occurred more frequently in the experimental arm. In addition, criticism emerged regarding the control arm of single-agent paclitaxel despite the inclusion of patients with PD-L1-positive tumors. Thus, the inhibition of the PI3K/AKT/mTOR pathway appears to remain ineffective in treating metastatic TNBC.
Bispecific antibodies
Recent years have witnessed vast improvements in antibody technology, and synergistic effects have been suggested for combinations of immune checkpoint inhibitors and anti-angiogenic agents, such as anti-vascular endothelial growth factor (VEGF) α antibodies. At the 2024 ESMO conference, promising results were presented from two single-arm phase 2 trials investigating PD‑1 [29] or PD-L1 [30]/VEGFα-targeting bispecific antibodies in combination with (nab-) paclitaxel. When used as a first-line treatment in patients with metastatic TNBC, the combination of immune checkpoint inhibition and anti-angiogenesis demonstrated high response rates, irrespective of PD-L1 expression and across all TNBC subtypes.
Take-home message
Updates from the NATELEE trial highlight the clinical significance of adding CDK4/6 inhibitors to endocrine therapy in early-stage luminal BC. In contrast to the MonarchE trial, which focused on a high-risk population, NATALEE also included an intermediate-risk group, with this population deriving a comparable benefit. Additionally, patients under 40 years of age experienced a numerically greater benefit from the addition of ribociclib compared to those aged 40 years or older. An update of the KEYNOTE-522 study reported improved OS with the addition of pembrolizumab to neoadjuvant chemotherapy in early-stage TNBC. In HER2-positive early-stage BC, de-escalation strategies remain a scientific focus. A retrospective analysis from the HERA trial highlighted the relevance of OFS in premenopausal patients with HR-positive/HER2-positive disease. In metastatic HER2-positive BC, DESTINY-Breast12 supports the use of T‑DXd, when clinically indicated, even in the presence of active BM. The phase 2 ICARUS-Breast01 trial suggests promising activity of the HER3-directed ADC patritumab deruxtecan in a pretreated population with luminal metastatic disease. The potential role of CDK4/6 inhibitors in metastatic HR-positive/HER2-positive BC is again demonstrated in the DETECT V trial, where the addition of ribociclib after a protocol amendment yielded a significant improvement in PFS and OS in a post hoc analysis. In metastatic TNBC, strategies including the addition of growth factor pathway inhibitors to conventional chemotherapy have largely been unsuccessful. By contrast, bispecific antibodies inhibiting immune checkpoints and VEGF have shown promising early results.
Conflict of interest
S. Udovica has received honoraria from Johnson & Johnson, Amgen, Oncopeptides, Novartis, Servier, Eli-Lilly, and MedMedia and travel support from AbbVie, AOP-Orphan, Beigene, GlaxoSmithKline, Janssen, Eli-Lilly, Pfizer, Roche, Servier, and Stemline. M. Ferner has received honoraria from MSD and travel support from Roche, Pfizer, Daiichi Sankyo, and Novartis. M. Marhold has received honoraria from Roche, Eli Lilly, Novartis, Astra Zeneca, Daiichi Sankyo, Pfizer, MSD, Gilead, and Medmedia and travel support from Amgen, Gilead, Roche, Novartis, Pierre Fabre, Daiichi Sankyo, and Eisai. K. Strasser-Weippl has received honoraria from Roche, Pfizer, Novartis, Lilly, Daiichi Sankyo, Myriad, Seagen, MSD, and Astra Zeneca and travel support from Roche, Pfizer, and MSD. R. Bartsch has received honoraria from Amgen, Astra-Zeneca, BMS, Daichi, Eisai, Eli-Lilly, Gilead, Gruenenthal, MSD, MedMedia, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen, and Stemline, research support from Daiichi, and travel support from Astra-Zeneca, Daiichi, Ely-Lilly, MSD, and Novartis.
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