Clinical development of antibody-drug conjugates in triple negative breast cancer: can we jump higher?

ABSTRACT

Introduction

Triple negative breast cancer (TNBC) is an aggressive BC subtype, associated with higher rates of relapse and shorter overall survival upon metastatic relapse. The advent of antibody-drug conjugates (ADC), able to deliver selectively potent chemotherapeutic agents, has demonstrated promising clinical activity, with the first approval of an ADC, i.e. Sacituzumab Govitecan, in the metastatic setting. This paperprovides the most recent data indicating the promise of this novel class of drugs, as potential tools to improve clinical outcomes of patients diagnosed with TNBC.

Areas Covered

Upon review of the main characteristics of TNBC, and those of ADCs, an overview of the data from clinical trials assessing ADCs in TNBC is provided, including those that led to the first approval of such a drug for patients with metastatic disease; furthermore, several other ADCs targeting different proteins (over)expressed by TNBC undergo clinical development. Combinations of ADCs with other targeted agents are discussed; the most pertinent considerations for improving the chances of successful clinical development of ADCs in TNBC are provided.

Expert Opinion

ADCs could further improve clinical outcomes of patients with TNBC, and successful development depends upon: i) successful triaging of patients with the right ADC, ii) technical optimization of ADCs to maximize the efficacy, while reducing toxicity, and iii) assess rationally chosen combinations with synergistic antitumor activity and acceptable safety profile.

KEYWORDS:

• Antibody-drug conjugate (ADC)
• ASCENT study
• breast cancer (BC)
• HER2
• metastatic disease
• Sacituzumab govitecan
• Trastuzumab deruxtecan
• triple-negative breast cancer (TNBC)
• TROP2

Article highlights

• TNBC constitutes an aggressive subtype of breast cancer with higher rates of relapse and short overall survival in the primary and metastatic disease setting, respectively.

• For patients with primary TNBC, no targeted agents are currently available and conventional cytotoxic chemotherapy is the only treatment option; in the metastatic setting, PARP inhibitors and PD-(L)1 inhibitors are the only targeted treatment options.

• ADCs constitute a class of targeted anticancer agents, combining the selectivity of monoclonal antibodies with the cytotoxicity of potent chemotherapeutic agents, actively developed in the TNBC setting.

• The first approval of an ADC in the TNBC setting occurred recently, with Sacituzumab govitecan, an anti-TROP2 ADC, demonstrating significant survival improvement for patients with pre-treated metastatic TNBC in the ASCENT trial, compared to conventional chemotherapy: HR for PFS 0.41; 95% CI 0.32 – 0.52; p<0.001 and HR for OS 0.48; 95% CI 0.38 – 0.59; 0<0.001.

• Several other ADCs targeting different proteins (over)expressed by TNBC cells, loaded with different cytotoxic compounds undergo clinical development, with promising clinical data having been reported; indicative examples included trastuzumab deruxtecan for patients with low HER2 expressing BC (ORR = 37% for patients with HER2-negative BC and 14% for patients with TNBC), or Datopotamab Deruxtecan, an anti-TROP2 ADC, achieving ORR of 43% in patients with TNBC (confirmed ORR 24%).

• Continued success of ADCs’ clinical development in TNBC will depend upon successful matching of such agents with patients, further technical optimization of ADCs, as well as rationally chosen combinations with other molecularly targeted agents, to achieve synergistic activity, with acceptable safety profile.

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Disclaimer

Any opinions expressed herein are solely of the authors and do not express the views or opinions of his employer

Declaration of interest

The author has declared employment and stock ownership by BMS and Pfizer during the last 12 months. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has received honoraria from Daiichi Sankyo and I is a PI in trials sponsored by Daiichi Sankyo, Gilead, and SeaGen. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

Funding This paper was not funded.