Antibody-drug conjugates (ADCs) are becoming increasingly prominent in the oncology drug landscape due to their ability to combine powerful cytotoxic payloads with the unique targeting abilities of monoclonal antibodies. One of the first and most commercially successful ADCs, Kadcyla (T-DM1), is widely used in HER2+ breast cancer in the adjuvant and metastatic settings and constitutes a significant part of the treatment paradigm. This may be about to change.

At a planned interim analysis of the Phase III DESTINY-Breast03 trial, which is comparing Daiichi Sankyo and AstraZeneca’s Enhertu (trastuzumab deruxtecan) with Roche’s Kadcyla, in a head-to-head trial in the second-line metastatic setting, it was announced that Enhertu had demonstrated a ‘highly statistically significant and clinically meaningful benefit’, hitting its primary endpoint in improving progression-free survival compared with Kadcyla. This is practice-changing and is a potential blockbuster-enabling indication for Daiichi and AstraZeneca. In addition, two more ADCs (trastuzumab duocarmazine and disitamab vedotin) are currently in late-stage development for this indication. Based on these developments, GlobalData expects the HER2+ breast cancer ADC market to expand to $3.3bn by 2030.

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Key opinion leaders (KOLs) interviewed by GlobalData have highlighted possible underlying reasons for the benefit observed for Enhertu, compared to Kadcyla. The first is that Enhertu has a higher drug-to-antibody ratio (8:1) compared with Kadcyla (3.5:1). In addition, Enhertu is purported to have a ‘bystander effect’, allowing Enhertu to deliver its cytotoxic payload to neighbouring cancer cells that are HER2-negative. This is believed to allow Enhertu to destroy a HER2+ tumour mass that is heterogenous, and therefore harder to target with HER2-directed therapies that do not destroy HER2-negative cells, such as Kadcyla. Based on this, AstraZeneca and Daiichi are pursuing a further label in the adjuvant setting (DESTINY-Breast05), providing competition for Kadcyla in earlier settings, in addition to the metastatic setting.

Further competition derives from the development of antibody-drug conjugates such as trastuzumab duocarmazine and disitamab vedotin. KOLs highlight the impressive preliminary efficacy data from Byondis’ trastuzumab duocarmazine, which has a novel payload and may enter the market from next year, depending on demonstrable efficacy. Seattle Genetics, an established player in the HER2+ space, has also invested in the ADC market in a $2.6bn licensing agreement to market RemeGen’s disitamab vedotin outside Asia. The continual investment and innovation in the ADC market has led to improved patient outcomes and is ultimately expected to lead to the personalisation of ADC therapy by the molecular signature or specific sequencing of effective therapies. GlobalData expects the ADC market to grow over the next decade and HER2+ breast cancer to remain at the heart of innovation for this modality.