HER2-positive breast cancer, constitutes 15-20% of all breast cancer cases, and over the years, it has witnessed significant advancements in treatment options. However, patients encountering refractory disease after multiple therapies confront a critical challenge due to the limited efficacy of available HER2-targeted treatments. According to DelveInsight analysis, in the United States, there were approximately 44,600 cases of HER2+metastatic breast cancer in 2023, which was the highest among the seven major markets.

ENHERTU (fam-trastuzumab deruxtecan-nxki), leading the antibody-drug conjugate (ADC) franchise of Daiichi Sankyo and AstraZeneca, is approved for HER2+ advanced/metastatic breast cancer post-prior anti-HER2 treatment. DESTINY-Breast07, a Phase Ib/II study, assesses T-DXd alone or with other agents' safety and antitumor activity. This initial dataset demonstrates the promising clinical activity of T-DXd alone or with pertuzumab in first-line HER2+ mBC, irrespective of disease or HR status. The results presented at ASCO 2024 were as follows:

T-DXd monotherapy and T-DXd + pertuzumab (n=50) showed robust efficacy:

• Confirmed ORR was 76.0% and 84.0% for T-DXd monotherapy and T-DXd + pertuzumab, respectively

• Median DOR was not reached for T-DXd monotherapy or T-DXd + pertuzumab

• PFS rate at 12 months was 80.8% and 89.4% for T-DXd monotherapy and T-DXd + pertuzumab, respectively; the number of PFS events was small and most patients were censored

Safety profiles:

• The safety profile of T-DXd and pertuzumab were consistent 

• The incidence of ILD/pneumonitis events was 9.3% and 14.0% in the T-DXd monotherapy and T-DXd + pertuzumab modules, respectively; there were no ILD/pneumonitis-related deaths in either module

KOL insights

“DESTINY breast 07 shows remarkable response & durable efficacy for single agent T-Dxd alone and in combo with pertuzumab.” –Expert Opinion.

“Trastuzumab deruxtecan is considered as a game changer. According to some of the earliest clinical trials such as DESTINY, this potent medication showed promise quite early in its development. This medication, an antibody-drug conjugate, has a high activity level. The antibody-drug conjugate is a different way to deliver targeted chemotherapy payloads to the cells preferentially that overexpress or have a specific target while trying to spare the toxicity from normal tissues that do not express as much of the target as the pertuzumab and trastuzumab-based therapies, which are just monoclonal antibodies.”–Expert Opinion.

Conclusion- 

ENHERTU is designed by using Daiichi Sankyo’s proprietary DXd ADC technology, and has witnessed back-to-back label expansions since its first approval in 2019. Its recent tumor agnostic label for all HER2+ expressing solid tumors is a cherry on top, it comprises a HER2 monoclonal antibody attached to topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker. Initial data from ASCO reveals consistent safety profiles with Trastuzumab deruxtecan and pertuzumab, with no Grade ≥3 interstitial lung disease (ILD) events. Encouraging ORRs and PFS rates in both groups. These findings underscore the potential of T-DXd alone or with pertuzumab in first-line HER2+ mBC, regardless of disease or HR status.