Dr Isaacs on Establishing Consensus on DESTINY-Breast09 Data in HER2+ Metastatic Breast Cancer

"It's really important for us to try [to] figure out who we think we should be [receiving first-line T-DXd plus pertuzumab] because this treatment is certainly associated with greater potential toxicity. We need to balance the risks and benefits and try to sort out amongst ourselves where we think this really fits in today's paradigm of treatment."

Claudine Isaacs, MD, professor of medicine and oncology and co-director of the Breast Cancer Program at Georgetown Lombardi Comprehensive Cancer Center, emphasized the importance of establishing consensus on how to integrate data from the phase 3 DESTINY-Breast09 trial (NCT04784715) into clinical practice for patients with HER2-positive metastatic breast cancer.

DESTINY-Breast09 evaluated fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) vs a taxane, trastuzumab (Herceptin), and pertuzumab (THP) in the first-line setting for patients with advanced HER2-positive breast cancer. Data demonstrated a progression-free survival (PFS) benefit favoring the T-DXd–based regimen (HR, 0.56; 95% CI, 0.44-0.71; P <.00001). Patients treated with T-DXd plus pertuzumab (n = 383) experienced a median PFS of 40.7 months (95% CI, 36.5-not calculable [NC]) per blinded independent central review compared with 26.9 months (95% CI, 21.8-NC) among those who received THP (n = 387).

Although these results suggest that this antibody-drug conjugate–based treatment may improve frontline outcomes, Isaacs noted that the regimen’s toxicity profile, particularly the risk of interstitial lung disease (ILD), may complicate broad application. In DESTINY-Breast09, treatment-emergent adverse effects led to any dose interruptions and any dose reductions in 68.8% and 45.9% of patients, respectively, in the T-DXd/pertuzumab arm. These respective rates were 49.0% and 19.9% in the THP arm. However, the rates of TEAEs leading to any treatment discontinuation were 20.7% in the experimental arm vs 28.3% in the control arm.

According to Isaacs, despite the efficacy observed, the clinical community must carefully determine in which patients this approach offers a favorable risk-benefit ratio. T-DXd carries greater potential toxicity relative to existing standards, and its introduction earlier in the treatment paradigm requires further consensus on optimal patient selection. Patients with preexisting pulmonary risk or limited ability to undergo regular monitoring may not be ideal candidates for frontline T-DXd–based therapy.