Triple-Negative Breast Cancer: Insights from ASCO 2024

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ONCOLOGY

Medical writer: Audrey TANG | Last updated: 10 July 2024 | In: Therapeutic Areas, Oncology

Article Keywords

pembrolizumab, talazoparib, antibody-drug conjugate, triple-negative breast cancer, trilaciclib

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterised by the absence of oestrogen receptors (ER), progesterone receptors, and human epidermal growth factor receptor 2 (HER2) amplification.^1,2 Representing about 10–15% of all breast cancer cases, TNBC is associated with poor prognosis and limited treatment options.² Recent research findings presented at the 2024 American Society of Clinical Oncology (ASCO) meeting provided updates on new advances in the treatment of TNBC.

Sacituzumab govitecan: Promising Treatment Combinations for Metastatic TNBC

Sacituzumab govitecan (SG) is an FDA-approved antibody-drug conjugate (ADC) that has shown favourable survival outcomes in metastatic TNBC (mTNBC) patients who were pretreated with at least two prior systemic therapies.³ A recent single-centre retrospective real-world study (RWS) explored the outcomes of 21 diverse women with mTNBC treated with SG over four years and compared the outcomes with the ASCENT trial of SG.³ The findings revealed a similar mean progression-free survival (PFS) of 5.00 months, resembling the PFS in ASCENT.³ The mean PFS for patients with brain metastasis (BM; n=8) in this cohort also resembled that of the ASCENT.³ However, the mean overall survival (OS) in this RWS study was lower than in ASCENT, measuring 8.33 months.³ The study’s results confirm SG as a valuable option for TNBC patients, including those with active BM.³

SG with talazoparib

Another phase 2 study investigated the addition of SG to a poly (ADP-ribose) polymerase inhibitor (PARPi) for mTNBC.⁴ SG invokes DNA damage and is thought to synergise with PARPi, but the combination led to high-grade myelosuppression in a phase 1b study.⁴ Therefore, this study enrolled 26 patients, who received SG and talazoparib sequentially to improve tolerability.⁴ Results showed a median PFS of 6.2 months and a median OS of 18.0 months. The objective response rate (ORR) was 30.1%, with a clinical benefit rate (CBR) at 6 months of 53.8%.⁴ Adverse events were common, with significant cases of anaemia (92.3%), neutropaenia (88.5%), and thrombocytopaenia (65.3%).⁴ These findings warrant further investigation of the SG-talazoparib combination in mTNBC.

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SG with trilaciclib

Myelosuppression is a common side effect of SG, and indeed in the phase 3 ASCENT trial SG was associated with neutropaenia (any grade, 63%; grade 3/4, 51%).⁵ Diarrhoea was another commonly observed side effect of SG (any grade, 59%; grade 3/4, 10%).⁵ The reversible cyclin-dependent kinase 4/6 inhibitor trilaciclib protects blood stem cells from chemotherapy damage, and enhances T-cell activity if administered prior to chemotherapy. Therefore, a phase 2 trial investigated the sequential combination of trilaciclib and SG in patients with mTNBC.⁵ Results showed that adding trilaciclib prior to SG reduced neutropaenia (any grade, 40%; grade 3/4, 7%) and diarrhoea (any grade, 36.7%; grade 3/4, 6.7%) compared to SG alone.⁵ Preliminary data indicate clinically meaningful OS outcomes, with the PFS measuring 4.1 months and a preliminary median OS of 17.9 months.⁵ The trial also found a confirmed ORR of 23.3% and a CBR of 46.7%.⁵ The median duration of response was. 9.1 months.⁵

SG with trastuzumab deruxtecan

The sequential use of two ADCs, SG and trastuzumab deruxtecan (T-DXd), was investigated in a multicentre retrospective cohort study.⁶ Of the total 84 patients, 28 (33.3%) had TNBC, defined as hormonal receptor (HR)-negative and HER2-low expression; 25 patients received SG first then T-DXd and the remaining 3 patients received T-DXd followed by SG.⁶ The results showed that median real-world PFS (rwPFS) was shorter for ADC2 than ADC1 in both HR+/HER2-low metastatic breast cancer (mBC) and TNBC, regardless of age or the presence of visceral disease.⁶ However, among patients with TNBC, those with central nervous system (CNS) disease had a shorter ADC1 rwPFS and real-world OS (rwOS) compared to those without CNS disease.⁶ Median rwPFS was 5.4 months for patients with CNS disease (n=6) vs 8.5 months for those without (n=22).⁶ Similarly, median rwOS was 11.6 months for patients with CNS disease vs 21.1 months for those without.⁶ The study also found no difference in ADC2 rwPFS whether an intervening therapy (IntTx) was used between ADCs or not.⁶ Overall, the findings suggest that patients with TNBC and CNS metastases may have a poorer prognosis when treated with sequential ADCs.⁶

Another RWS investigating sequential treatment with SG and T-DXd recruited 85 patients, of which 31 (36.5%) with mTNBC.⁷ The results showed that the median PFS was similar for both ADCs, regardless of whether SG or T-DXd was used first.⁷ Median PFS for SG as ADC1 was 5.1 months, while for T-DXd as ADC2 it was 3.5 months.⁷ On multivariate analysis, later treatment line at the time of ADC2 was significantly associated with shorter ADC2 PFS.⁷ The study suggests that the clinical activity of both SG and T-DXd may be modest in the ADC2 setting for patients with TNBC.⁷

Predictive Biomarkers for Pathological Complete Response

Identifying predictive biomarkers for TNBC is crucial for optimising neoadjuvant chemotherapy (NAC) strategies.⁸ A study involving 110 early-stage TNBC (eTNBC) patients investigated clinical and pathological biomarkers associated with pathological complete response (pCR) following anthracycline- and taxane-based NAC.⁸

The study found that the neutrophil-to-lymphocyte ratio (NLR) was significantly associated with pCR.⁸ The optimal NLR cutoff was 1.76 demonstrating 60.6% sensitivity and 71.8% specificity for pCR, with NLR cutoffs of 1.43 or below having specificities higher than 85%.⁸ Additionally, high stromal tumour-infiltrating lymphocytes values (≥50%) showed a specificity of 89.4% for pCR.⁸ These findings underscore the potential of NLR as an independent predictor of pCR in early-stage TNBC.⁸

Pembrolizumab for eTNBC: Expert Consensus Recommendations

Pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, has been approved for perioperative treatment of stage II and III eTNBC based on the KEYNOTE-522 study.⁹ The Hong Kong Breast Cancer Foundation convened a multi-disciplinary consensus panel to provide expert guidance on the daily clinical use of pembrolizumab in eTNBC.⁹

Key recommendations from the panel include treating the uncommon subtype ‘ER-low’ as TNBC, and potentially adding capecitabine to pembrolizumab for patients with residual disease after NAC.⁹ The panel also highlighted the need for individualised treatment decisions, particularly regarding the addition of immunotherapy for cT1c disease and the use of PARPi in patients with germline BRCA1/2 mutations.⁹

References

Li Y, et al. J Hematol Oncol. 2022;15(1):121.

Won KA & Spruck C. Int J Oncol. 2020;57(6):1245–61.

Singh V, et al. J Clin Oncol. 2024;42(16_suppl):e13137.

Abelman RO, et al. J Clin Oncol. 2024;42(16_suppl):1102.

Seneviratne LC, et al. J Clin Oncol. 2024;42(16_suppl):1091.

Huppert LA, et al. J Clin Oncol. 2024;42(16_suppl):1083.

Mai N, et al. J Clin Oncol. 2024;42(16_suppl):1085.

Polho GB, et al. J Clin Oncol .2024;42(16_suppl):598.

Yeo W, et al. J Clin Oncol. 2024;42(16_suppl):e12521.

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).