Treating early-stage triple-negative breast cancer

Triple-negative breast cancer (TNBC) accounts for around 10 to 15% of all breast cancers and is associated with poor outcomes. However, emerging therapies such as PARP inhibitors, immune checkpoint inhibitors and antibody-drug conjugates mean that personalized medicine is increasingly taking a more prominent place in the TNBC treatment landscape.1

In this video, Rebecca Dent, MD, FRCP, of the National Cancer Centre Singapore, discusses key updates in the treatment of early-stage TNBC at the European Society for Medical Oncology (ESMO) Breast Cancer Congress 2021.

Dr Dent talks on the benefits of perioperative systemic therapy and gives an overview of key considerations for therapeutic decision-making, such as the impact of tumor size, and the role of tumor-infiltrating lymphocytes as a means of risk-stratification.

Dr Dent also debates the use of platinum versus non-platinum based chemotherapy, highlighting data from the Phase III BrighTNess trial (NCT02032277) which investigated the safety and efficacy of the addition of veliparib, a PARP inhibitor, plus carboplatin compared to the addition of carboplatin to standard neoadjuvant chemotherapy in patients with early-stage TNBC.

Dato-DXd: a new ADC on the block

At the virtual European Society for Medical Oncology (ESMO) Breast Cancer Congress 2021, Sara Tolaney, MD, of the Dana-Farber Cancer Institute in Boston, MA, discusses the preliminary findings of an ongoing Phase I study investigating the novel agent datopotamab deruxtecan (Dato-DXd) in patients with metastatic triple-negative breast cancer (mTNBC).

The TROPION-PanTumor01 trial (NCT03401385) is a first-in-human trial of Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) for patients with advanced solid tumors, including those with mTNBC.

In the preliminary results, among 21 patients evaluable for response, the overall response rate was 43% in heavily pre-treated patients with TNBC, with a disease control rate of 95%. 25% of patients had dose reductions as a result of adverse effects (AEs), however, no patients discontinued the treatment due to AEs.2

Dr Tolaney also discusses the role of sacituzumab govitecan, another anti-TROP2 ADC, which received accelerated FDA approval in April 2020 for the treatment of patients with metastatic TNBC who have received at least two prior lines of therapy in the metastatic setting.3 Approval was based on results of the ASCENT trial (NCT02574455).

BrainStorm: improving prediction, diagnosis and management of brain metastases

Advances in the treatment of patients with metastatic breast cancer have resulted in improved overall survival, and subsequently an increase in the number of patients presenting with brain metastases, which tend to occur in later-stage disease.4

The prognosis for patients with brain metastases is poor, and few treatments are able to penetrate the blood-brain barrier. The effective treatment of brain metastases in breast cancer presents an unmet medical need.5

In this video, Ahmad Awada, MD, PhD, of the Jules Bordet Institute in Brussels, Belgium, gives an overview of the BrainStorm program (NCT04109131) which aims to optimize the treatment and management of patients with breast cancer and central nervous system (CNS) metastases and in particular, brain metastases.

The BrainStorm program is a multidisciplinary clinical research platform, organized by the Oncodistinct network and the Jules Bordet Institute. It is focused on harnessing clinicopathological data from patients with newly diagnosed non-CNS metastatic solid tumors who are at a high risk of developing CNS metastases.

The data being collected in the BrainStorm program includes the results of analyses of circulating tumor DNA from cerebrospinal fluid, and MRI scans and aims to improve knowledge on the evolving epidemiology and biology of brain metastases to allow for the development of new treatment strategies, as well as the identification of promising therapeutic targets.

HER2CLIMB-04: tucatinib plus trastuzumab deruxtecan in HER2+ breast cancer

Over the last two years, the field of HER2-positive breast cancer has benefited from the approval of multiple novel therapies and combinations. Trastuzumab deruxtecan is an antibody-drug conjugate targeted against HER2 that was granted accelerated approval by the FDA in December 2019,6 for patients with unresectable or metastatic HER2-positive breast cancer who have been previously treated with two or more anti-HER2 drugs in the metastatic setting. Approval was based on results of the DESTINY-Breast01 (NCT03248492) trial where trastuzumab deruxtecan demonstrated durable antitumour activity.7

In April 2020, the FDA approved tucatinib8, a HER2 inhibitor, in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, who have previously been treated with one of more anti-HER2 regimens in the metastatic setting. This approval was based on results of the Phase II, placebo-controlled HER2CLIMB trial (NCT02614794).9

Neratinib in combination with capecitabine10 and margetuximab in combination with chemotherapy11 also received FDA approvals for HER2-positive breast cancer in 2020.

At the virtual European Society for Medical Oncology (ESMO) Breast Cancer Congress 2021, Erika Hamilton, MD, of the Sarah Cannon Research Institute at Tennessee Oncology in Nashville, TN, introduced the Phase II HER2CLIMB-04 trial (NCT04539938) which will investigate the safety and efficacy of tucatinib in combination with trastuzumab deruxtecan for patients with HER2-positive breast cancer.12

Dr Hamilton outlines the structure of the HER2CLIMB-04 trial, which will be similar to that of the HER2CLIMB trial, reporting that the trial expects to enrol ten patients initially, and up to 60 after the safety run-in phase. The primary endpoint of the trial is a confirmed objective response rate and secondary endpoints are progression-free survival, duration of response and disease control rate.

MIMOSA: monalizumab and trastuzumab in HER2+ breast cancer

The MIMOSA trial (NCT04307329) is a Phase II trial exploring the efficacy of monalizumab and trastuzumab in combination, for the treatment of patients with metastatic HER2-positive breast cancer.

Monalizumab is a novel immune checkpoint inhibitor which targets NKG2A receptors expressed on tumor infiltrating cytotoxic CD8+ T-cells, preventing the inhibition of CD8+ T-cells and NK-cells by tumor cells which express HLA-E.13

In this video, Veerle Geurts, MD, of the Netherlands Cancer Institute in Amsterdam, gives an overview of the MIMOSA trial, which will enrol two cohorts of patients – one with high stromal tumor-infiltrating lymphocytes (TILs) and the other with low TILs – and discussess the rationale behind the trial.

By combining monalizumab and trastuzumab, the MIMOSA trial hopes to activate both NK-cells + CD8 T-cells to achieve a synergistic effect. The primary endpoint of the MIMOSA trial is the objective response rate according to RECIST1.1. Secondary endpoints include evaluation of clinical benefit and progression-free survival.14

Trastuzumab deruxtecan: a promising agent for treating HER2-low breast cancer?

Whilst the introduction of HER2-targeting agents over the last three decades has vastly improved the prognosis for patients with HER2-positive breast cancer, patients with low HER2 expression have only recently been identified as potential benefactors of anti-HER2 therapies.15

HER2-low breast cancer is a novel subgroup of breast cancer patients with an HER2 immunohistochemistry (IHC) assay score of 1+ or 2+ and negative in situ hybridization (ISH) assay results from testing of HER2 gene amplification.16

In this video, Paolo Tarantino, MD, of the Instituto Europeo di Oncologia in Italy, discusses promising results demonstrated with trastuzumab deruxtecan (T-DXd) therapy in patients with HER2-low breast cancer.

T-DXd is currently being investigated in two large Phase III trials, namely the DESTINY-Breast04 trial and the DESTINY-Breast06 trial. The DESTINY-Breast04 trial (NCT03734029) will compare T-DXd versus chemotherapy in patients with HER2-low breast cancer which has spread or cannot be surgically removed, whereas the DESTINY-Breast06 trial (NCT04494425) is investigating T-DXd versus chemotherapy in patients with HER2-low, hormone receptor-positive metastatic breast cancer.

Dr Tarantino also compares patterns of HER2 expression in metastatic, early-stage and relapsed breast cancer, commenting on the need to employ quantitative HER2 assays in clinical trials and improve our understanding of the role of HER2 in breast cancer.

References

  1. Agostinetto, E., Eiger, D., Punie, K., de Azambuja, E., Emerging Therapeutics for Patients with Triple-Negative Breast Cancer, Curr Oncol Rep., March 2021;24;23(5): 57
  2. Bardia, A., Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate (ADC), for triple-negative breast cancer (TNBC): Preliminary results from an ongoing phase 1 trial, ESMO Breast 2021, [Accessed 25/05/2021]
  3. US FDA, FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer, US Food & Drug Administration [Accessed: 27/05/21]
  4. Daylan, A. E. C., Leone, J. P., Targeted Therapies for Breast Cancer Brain Metastases, Clin Breast Cancer, December 2020;1: S1526-8209(20)30323-2
  5. Valiente, M., Ahluwalia, M. S., Boire, A., et al, The Evolving Landscape of Brain Metastasis, Trends Cancer, March 2018;4(3): 176-196
  6. US FDA, FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer, US Food & Drug Administration [Accessed: 27/05/21]
  7. Modi, S., Saura, C., Yamashita, T., et al, Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer, New England Journal of Medicine, February 2020; 382:610-621
  8. US FDA, FDA approves tucatinib for patients with HER2-positive metastatic breast cancer, US Food & Drug Administration [Accessed: 27/05/21]
  9. Murthy, R. K., Loi, S., Okines, A., et al, Tucatinib, Trastzumab, and Capecitabine for HER2-Positive metastatic Breast Cancer, New England Journal of Medicine, February 2020; 382:597-609
  10. US FDA, FDA approves neratinib for metastatic HER2-positive breast cancer, US Food & Drug Administration [Accessed: 27/05/21]
  11. US FDA, FDA approves margetuximab for metastatic HER2-positive breast cancer, US Food & Drug Administration [Accessed: 27/05/21]
  12. Hamilton, E., Ramos, J., Feng, W., Krop, I., HER2CLIMB-04: Phase 2 trial of tucatinib + trastuzumab deruxtecan in patients with HER2+ unresectable locally-advanced or metastatic breast cancer with and without brain metastases (Trial in Progress), ESMO Breast 2021, [Accessed 25/05/2021]
  13. Van Hall, T., André, P., Horowitz, A., et al, Monalizumab: inhibiting the novel immune checkpoint NKG2A, Journal for ImmunoTherapy of Cancer, 2019;7: 263
  14. Geurts, V., Voorwerk, L., Sikorska, K., Monalizumab and trastuzumab in metastatic HER2-positive breast cancer: MIMOSA-trial, ESMO Breast 2021, [Accessed 25/05/2021]
  15. Eiger, D., Agostinetto, E., Saúde-Conde, R., de Azambuja, E., The Exciting New Field of HER2-Low Breast Cancer Treatment, Cancers (Basel), March 2021;13(5)
  16. Tarantino, P., Hamilton, E., Tolaney, S., et al, HER2-Low Breast Cancer: Pathological and Clinical Landscape, Journal of Clinical Oncology, April 2020;38(17): 1951-1962

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