Interim safety and efficacy results of the Phase Ib/II Destiny-BREAST07 trial with Enhertu (trastuzumab deruxtecan), AstraZeneca and Daiichi Sankyo’s blockbuster antibody drug conjugate (ADC), have been presented at the ongoing American Society of Clinical Oncology (ASCO) Annual Meeting 2024.

The trial aims to assess the safety and tumour response with Enhertu alone or in combination with Genentech’s Perjeta (pertuzumab) in metastatic breast cancer (mBC) in the first-line setting. The current standard of care in the first line is a combination of Genentech’s Herceptin (trastuzumab) and Perjeta, two HER2-targeting monoclonal antibodies (mAbs). The “dual blockade” of Herceptin and Perjeta has been the standard of care in first-line mBC since the CLEOPATRA trial resulted in an FDA approval in 2012. Enhertu became the standard of care in the second line mBC setting after the Destiny-BREAST03 trial results were released and Enhertu took over Genentech’s Kadcyla, another HER2 targeting ADC, with its approval in 2022.

The presentation at ASCO delivered some significant safety implications with 50.7% of patients in the Enhertu arm and 54% of patients in the Enhertu and Perjeta combination arm reporting Grade ≥3 adverse events. However, no patients experienced Grade ≥3 interstitial lung disease. These safety results are in keeping with the known toxicities of Enhertu and Perjeta. Progression-free survival (PFS) at 12 months was 77.3% (80% confidence interval [CI]: 69.0, 83.7) with Enhertu alone and 89.4% (80% CI: 81.9, 93.9) for Enhertu and Perjeta. There is no control arm in this trial, but one can use the CLEOPATRA trial as a benchmark where the median PFS for Perjeta in combination with Herceptin and docetaxel was 18.5 months compared to just 12.4 months with Herceptin and docetaxel in the placebo arm (hazard ratio: 0.62; 95% CI: 0.51-0.75).

Multiple things remain to be assessed before clinicians can start using Enhertu in the first-line mBC setting, particularly the full data readout of the Destiny-BREAST09 trial, which will give PFS and OS results of Enhertu and Perjeta in comparison to Herceptin and Perjeta. However, even if those questions are answered, clinicians may still be uneasy about using such a toxic combination in the first line, particularly since Phesgo (hyalouronidase + trastuzumab + pertuzumab), a subcutaneous formulation of Herceptin and Perjeta is available. It is unlikely that Enhertu will be able to be reformulated into a subcutaneous injection as ADCs are unstable at the concentrations required to deliver them in that form.

There is also the debate of sequencing; Enhertu is effective in tumors with lower levels of HER2 expression, such as those that have already been treated with HER2-targeting agents, due to the “bystander effect” of its payload. If Enhertu moves into the first line, other HER2-targeting agents will not be able to have as much of an effect in later lines. Currently, around 6,000 patients a year receive first-line therapies for HER2+ mBC, of which about 70% receive a combo of Herceptin and Perjeta. Therefore Enhertu could treat about 4,200 patients a year with an approval in this setting.

Herceptin has been the standard of care in the first line mBC since its first approval in 1998 as a monotherapy and later as a combination with Perjeta in 2012. It will be historic when it is no longer the first prescribed agent in HER2+ mBC and Enhertu may just be the therapy that finally takes its place.

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