Breast cancer leads the way in ADC therapy

The use of ADCs has significantly changed the treatment of breast cancer in recent times. Trastuzumab emtansine has long been part of treatment for HER2-positive breast cancers and has proved to be of paramount importance in both the metastatic and early disease settings. The arrival of the second generation of ADCs saw the incorporation of technical improvements that resulted in enhanced activity, even when acting at the same molecular target as earlier agents. In this respect, we have seen trastuzumab deruxtecan transform the way we treat HER2-positive metastatic breast cancer and replace trastuzumab emtansine as the standard second-line treatment, according to an unmatched reduction of 72% in the risk of progression and a clinically and statistically meaningful improvement in overall survival (N Engl J Med. 2022;386:1143–1154; The Lancet. 2023;401:105–117). The TROP2-directed ADC sacituzumab govitecan not only set a new standard for the treatment of metastatic triple-negative breast cancer, demonstrating an unprecedented halving of the risk of death, with a hazard ratio of 0.48 (N Engl J Med. 2021;384:1529–1541), but also showed benefit in patients with hormone receptor (HR)-positive/HER2-negative breast cancer (J Clin Oncol. 2022;40:3365–3376). There have also been signs of a benefit in some quality-of-life parameters with ADCs and the ESMO-Magnitude of Clinical Benefit Scale generally scores these agents highly. However, what is particularly exciting about these second-generation ADCs is that they are active also in tumours with intermediate or low target expression, as shown for trastuzumab deruxtecan in the DESTINY-Breast04 (N Engl J Med. 2022;387:9–20) and TROPiCS-02 studies (J Clin Oncol. 2022;40:3365–3376). The results of the latter trial in HER2-low tumours (HER2 1+ and 2+, not amplified breast cancers, with or without HR expression) are ground-breaking, because they reshape the way we consider a therapeutic target, challenging the long-held concept that HER2-targeted therapies were active only in tumours addicted to HER2 signalling (HER2-positive tumours). These findings demonstrate that the target of the ADC can instead be seen as an opportunity to deliver a drug and its payload in a ‘trojan horse’ fashion. The same concept applies to Trop-2, which is a valid therapeutic target despite not being a critical biological molecular driver.

The success of ADCs in breast cancer has resulted in the clinical investigation of a number of new agents, the most promising of which appears to be the TROP2-directed datopotamab deruxtecan, which has shown encouraging early-phase activity in advanced relapsed/refractory HER2-negative breast cancer (Cancer Res. 2022;82(4 Suppl):GS1-05). The phase III TROPION-Breast01 trial in previously treated HR-positive, HER2-negative, inoperable or metastatic breast cancer (NCT05104866) – which is part of an extensive development plan for this agent – has completed enrolment and we look forward to seeing the results. Encouraging data are also being seen with patritumab deruxtecan, targeting HER3, in all breast cancer subtypes.

One of the biggest unmet needs in the development of ADCs in breast cancer is determining if they are effective in the metastatic setting when used sequentially and, if so, what the most effective sequence is. It is exciting, therefore, to see the recent publication of the DESTINY-Breast02 trial, reporting the efficacy of trastuzumab deruxtecan in patients previously treated with trastuzumab emtansine (Lancet. 2023:April 19. Online ahead of print). This is the first demonstration in solid tumours that a subsequent-line ADC directed towards the same target as the previously used ADC, but employing a different linker and payload, can provide meaningful progression-free and overall survival benefit. On the basis of this evidence, it seems likely that different ADCs could be successfully implemented at different steps, although this is probably dependent on the type of ADC, and it needs to be demonstrated formally in clinical trials or at least using large-scale real-world data. Crucial to defining the optimum treatment algorithm is an in-depth understanding of the mode of action and the mechanisms of resistance of these compounds. The fact that the activity of these agents is not restricted by target expression – such that trastuzumab deruxtecan has demonstrated clinical activity even in formally HER2-0 breast cancers and that sacituzumab govitecan is effective regardless of the level of TROP2 expression (SABCS 2022, Abstract GS1-11) – highlights our current limited understanding of just how they exert their effects.

The demonstration that second-generation ADCs have extensive activity across the broad spectrum of breast cancer subtypes clearly provides the rationale for testing these compounds in different solid tumours. Indeed, both trastuzumab deruxtecan and sacituzumab govitecan have broad strategies in place for a number of solid tumour types. In addition, the finding that ADCs appear to have activity in multiple malignancies sharing the expression of a specific antigen suggests that these agents may be mirroring the experience of histology-agnostic targeted treatments. This opens up the possibility of utilising ADCs across different cancer types in a non-biomarker-driven fashion, as illustrated by high-level results from the phase II DESTINY-PanTumor02 trial.