Proffered paper session: Metastatic Breast Cancer

In this video, Dr Françoise Derouane, a medical oncologist at the University Hospitals Leuven, discusses a selection of abstracts presented during the proffered paper session on metastatic breast cancer during ESMO 2024.

The DESTINY Breast-12 study focuses on patients with metastatic HER2-positive breast cancer, including those with and without brain metastases, aiming to evaluate the efficacy of trastuzumab deruxtecan. This drug is already known for its potential intracranial activity based on smaller studies, making it relevant for a population in which 50% of patients may develop brain metastases, often associated with a poor prognosis. The study had two cohorts—253 patients with brain metastases and a separate cohort without. In the brain metastasis cohort, 60% of patients achieved PFS at 12 months, with no significant difference between those with stable or active brain metastases. The objective response rate for CNS metastases was notably high, at 70%. Interestingly, patients with untreated active brain metastases responded better to trastuzumab deruxtecan than those with previously treated active metastases. Currently, tucatinib combined with capecitabine and Herceptin is often used for active brain metastases, but these findings suggest that trastuzumab deruxtecan could become a second-line treatment option for this group. In the cohort without brain metastases, the ORR was consistent with previous trastuzumab deruxtecan trials, reaffirming its effectiveness. Safety data were in line with earlier studies, with interstitial lung disease and pneumonitis being key adverse effects that require careful monitoring.

The ICARUS-BREAST01 trial presented during this session investigates patritumab deruxtecan (HER3-DXd), a novel ADC targeting HER3 in metastatic hormone-sensitive breast cancer. HER3 positivity in breast cancer is associated with poor prognosis and resistance to other therapies, such as those targeting HER2, PI3K, or endocrine therapies. This ADC, consisting of a monoclonal antibody targeting HER3 linked to a topoisomerase inhibitor, holds promise for addressing these challenges. Key to this trial is the inclusion of patients who had previously received CDK4/6 inhibitors or first-line chemotherapy, positioning it as a therapy for patients already exposed to multiple lines of treatment. A particularly interesting aspect of this study is its translational component, which involves collecting blood and tumour samples at baseline, during treatment, and during progression. These samples are used for biomarker exploration, aiming to correlate response to treatment with molecular and genomic characteristics. With a median follow-up of 15.3 months, the trial reported an ORR of approximately 50%, a median PFS of 9.4 months, and a median duration of response of 8.7 months. In terms of safety, the profile was consistent with other ADCs, with around 50% of patients experiencing grade 3 to 4 adverse events, leading to discontinuation in 11% of cases. Interstitial lung disease and pneumonitis were also observed, as is common with many ADCs.

The translational analysis revealed several insights. Immunohistochemistry showed no significant difference in HER3 expression between responders and non-responders, indicating the drug’s efficacy across a range of HER3 positivity. Spatial analysis of HER3 distribution identified specific clusters potentially associated with response, and gene profiling suggested up-regulation of immune-related pathways, such as interferon-gamma and -alpha, in responders, which opens avenues for future research into immune modulation. The study’s combination of efficacy evaluation with exploratory biomarker research sets a strong precedent for future trials, emphasising the need for continued efforts to identify biomarkers of response. This approach could ultimately help refine patient selection and treatment optimisation in this challenging cancer subtype.

The CAPItello-290 trial, presented during this session, evaluated the combination of capivasertib, an AKT inhibitor, with paclitaxel compared to paclitaxel with placebo in the first-line setting for patients with metastatic triple-negative breast cancer (TNBC). The rationale for this study stems from previous evidence that capivasertib is effective in hormone-sensitive breast cancer, along with the fact that two-thirds of TNBC patients harbour mutations in the PIK3CA/PTEN/AKT pathway. Previous trials, like LOTUS and PACT, had also demonstrated a potential benefit of AKT inhibitors in TNBC, making this study particularly relevant. The trial included 812 patients divided into two arms: one receiving capivasertib with paclitaxel and the other receiving paclitaxel with placebo. Of these patients, 40% presented with de novo metastatic disease, and 30% had mutations in the PIK3CA/AKT/PTEN pathway. 

The primary endpoint was OS, but unfortunately, no significant benefit was observed in either the overall population or the subgroup of patients with PIK3CA-mutated cancers. Despite this, some secondary endpoints, such as PFS and ORR, showed a more favourable trend toward the capivasertib-paclitaxel combination, suggesting some clinical activity. The safety profile of capivasertib was in line with expectations, although one notable finding was the increased incidence of hyperglycemia in this trial, with 22% of patients experiencing this side effect compared to 16% in previous studies. In conclusion, while capivasertib did not improve overall survival in this trial, the observed benefits in PFS and ORR, as well as its manageable safety profile, suggest that it could have potential in TNBC. Further studies may be needed to better understand its role, possibly in combination with other therapies or in more molecularly defined subgroups.

The final trial discussed during the session was the TRIPLE-B study, which evaluated two different chemotherapy regimens, either with or without the addition of atezolizumab, in the first-line treatment of metastatic TNBC.  This study aimed to address two important questions. First, it sought to determine whether carboplatin or paclitaxel was more effective in patients with homologous recombination deficiency (HRD) mutations, as it is known that while BRCA1/2-mutated patients tend to respond well to carboplatin, those with HRD mutations generally do not. The second objective was to identify the best chemotherapy partner for atezolizumab, as previous trials, such as KEYNOTE-355, allowed physicians to choose between taxane- or carboplatin-based chemotherapy when pairing it with checkpoint inhibitors. The TRIPLE-B study recruited 305 patients with metastatic TNBC, irrespective of PD-L1 status. It included four treatment arms: carboplatin plus cyclophosphamide, carboplatin plus cyclophosphamide with atezolizumab, paclitaxel monotherapy, and paclitaxel with atezolizumab. Approximately 9% of the patients in the trial were BRCA-mutated, and around 50% were HRD-positive. The study’s primary endpoint was PFS, but no significant differences in PFS were observed between the different treatment arms. However, secondary endpoints revealed some more interesting findings. In terms of PFS for patients receiving checkpoint inhibitors, paclitaxel combined with atezolizumab was shown to be more effective than carboplatin and cyclophosphamide with atezolizumab, suggesting that paclitaxel may be a better chemotherapy partner for atezolizumab. Further analysis was conducted in the subgroup of patients who were PD-L1 positive, with a CPS of 10 or higher. In this group, paclitaxel plus atezolizumab also demonstrated greater benefits than carboplatin and cyclophosphamide with atezolizumab. Another key aspect of the study was the re-challenge of taxane therapy. Despite many patients having already received taxane-based treatments in the neoadjuvant or adjuvant setting, the study showed that the combination of paclitaxel and atezolizumab remained beneficial even in these patients. The study also included a crossover design, allowing patients who initially received chemotherapy alone to receive atezolizumab after their disease progressed. When analysing OS, it was found that second-line atezolizumab was as effective as first-line atezolizumab, suggesting that checkpoint inhibitors could still offer benefit when used as a second-line treatment for metastatic TNBC.