Table 5:
FDA Benefit-Risk Assessment of T-DXd (12)
| Dimension | Evidence and Uncertainties | Conclusion and Reasons |
|---|---|---|
| Analysis of Condition | • Breast cancer is the most common cancer in women, with more than 260,000 new cases and 40,000 deaths annually. Approximately 20% of patients with breast cancer have HER2-positive tumors. • Breast cancer in male patients is rare and presents at a higher stage • Advanced or metastatic breast cancer is incurable. |
Advanced or metastatic HER2-positive breast cancer is a serious and life-threatening condition with ongoing unmet medical need in both female and male patients. |
| Current Treatment Options | • Metastatic HER2-positive breast cancer is not curable with treatment goals palliative in nature to delay disease progression, prolong survival, and reduced cancer-related symptoms. • The combination of trastuzumab, pertuzumab, and taxane is an FDA approved treatment for patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. • T-DM1 is FDA approved for the treatment of patients with HER2- positive, metastatic breast cancer who previously received trastuzumab and a taxane. • Other options beyond 2 lines of HER2-based therapies can include lapatinib and capecitabine, or trastuzumab combined with either lapatinib, capecitabine, neratinib plus capecitabine*, tucatinib in combination with trastuzumab and capecitabine**, or another chemotherapeutic agent. |
Additional treatment options are needed forfemale and male patients with HER2-positive advanced or metastatic breast cancer whose disease has progressed on available HER2-directed therapies. |
| Benefit | • The efficacy of T-DXd was evaluated in study DS8201-A-U201, a multicenter, single-arm, trial that enrolled 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies. • ORR was 60.3% (95% CI: 52.9, 67.4), with a 4.3% complete response rate and a 56% partial response rate. Median response duration was 14.8 months (95% CI: 13.8, 16.9). |
Study DS8201-A-U201 resulted in substantial and durable ORR that represents an improvement compared to that of available therapies and is reasonably likely to predict clinical benefit. |
| Risk and Risk Management | • The most common adverse reactions were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia. • Serious adverse reactions occurred in 20% of patients receiving T-DXd. • Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%). • Interstitial lung disease (ILD) is an important safety signal identified during the clinical development program for T-DXd. Fatal outcomes due to ILD occurred in 2.6% of patients. • Labeling includes a Boxed Warning to advise health professionals of the risk of interstitial lung disease (ILD), and embryo-fetal toxicity. |
The safe use of T-DXd can be managed through appropriate labeling, including boxed warnings for interstitial lung disease, and embryo-fetal toxicity. No REMS is indicated. |
*
Neratinib in combination with capecitabine was granted regular approval by the FDA in February 2020 after the accelerated approval of T-DXd.
**
Tucatinib in combination with trastuzumab and capecitabine was granted regular approval by the FDA in April 2020 after the accelerated approval of T-DXd.