**6. Clinical outcomes of ADC in breast cancer treatment**

### **6.1 T-DM1**

T-DM1 was evaluated in the phase III, randomized clinical trial EMILIA, which enrolled 991 patients with metastatic, HER2+ breast cancer with disease progression after first line trastuzumab plus taxane based chemotherapy for metastatic disease or with disease recurrence during or within six months of completing adjuvant therapy [51]. Patients were randomized 1:1 to T-DM1 or lapatinib and capecitabine. The co-primary endpoints were progression free survival (PFS) and overall survival (OS). Most patients (88%) received prior chemotherapy for metastatic disease with a median of 3 prior lines of treatment. PFS was significantly improved with median PFS of 9.6 months in the T-DM1 arm versus 6.4 months in the control arm [hazard ratio (HR), 0.65; 95% CI, 0.55–0.77; p < 0.0001]. Overall survival was also significantly improved with median OS of 30.9 months in the T-DM1 arm vs. 25.1 months in the control arm (HR, 0.68; 95% CI, 0.55–0.85; P, 0.0006). Based on the results of this study, T-DM1 was FDA approved for the treatment of HER2+ metastatic breast cancer after progression on first line therapy, and T-DM1 became the standard second line treatment in this patient population until recent findings from DESTINY-Breast03 that demonstrated superiority of T-Dxd over T-DM1 as second line treatment for metastatic, HER2+ breast cancer [41].

Adjuvant T-DM1 for early stage, HER2+ breast cancer and residual disease post taxane and trastuzumab based neoadjuvant chemotherapy was evaluated in the KATHERINE trial, a randomized, phase III study [52]. The study enrolled 1486 patients who were randomized 1:1 to adjuvant T-DM1 or trastuzumab for 14 cycles. The primary outcome was invasive disease free survival (IDFS), which was defined as the time from randomization to first local or regional breast cancer recurrence, distant recurrence, or death from any cause. Key secondary outcomes were PFS and OS. Most patients (77%) received anthracycline based neoadjuvant chemotherapy, and 20% of patients received additional anti-HER2 therapy, 94% of which was pertuzumab. At a median follow up of 40 months, IDFS was significantly improved with T-DM1 versus adjuvant trastuzumab (HR, 0.50; 95% CI, 0.39–0.64; P < 0.001). The 3-year IDFS rate was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. The results of this study led to the FDA approval of T-DM1 as an adjuvant therapy for patients with early stage, HER2+ breast cancer with residual disease after neoadjuvant chemotherapy and surgery and has established adjuvant T-DM1 as a standard therapy in this patient population [2].

#### **6.2 T-Dxd**

T-Dxd was first FDA approved based on results from the single arm, multicenter, phase II DESTINY-Breast 01 trial that enrolled patients with HER2+ metastatic breast cancer who progressed on prior chemotherapy including T-DM1 [53]. The median number of prior lines of treatment was 6 (range, 2–27). T-Dxd was associated with an objective response rate of 60.9% (95% CI, 53.4–68.0) in a heavily pre-treated population. The benefit of T-Dxd for the treatment of HER2+ metastatic breast cancer after progression on T-DM1 was confirmed in the phase III, randomized clinical trial, DESTINY-Breast02 that demonstrated significant improvement in PFS and OS when compared to chemotherapy [54].

The clinical trial that changed practice when choosing a second line treatment for patients with HER2+, metastatic breast cancer whose disease progressed after first line anti-HER2 therapy plus taxane chemotherapy was the DESTINY-Breast03 trial, which was a randomized, phase III study that compared T-Dxd to T-DM1 in the second line setting [41, 55]. A total of 524 patients were randomized in 1:1 to T-Dxd or T-DM1. The primary endpoint of PFS was significantly improved with median PFS of 28.8 months with T-Dxd vs. 6.8 months with T-DM1 (HR, 0.33; P < 0.000001). Overall survival was significantly improved with T-Dxd with the median not reached in either treatment arm although the risk of death was reduced by 36% with T-Dxd (HR, 0.64; P, 0.0037) demonstrating superiority of T-Dxd and establishing its role as a preferred second line treatment in this patient population [2].

DESINY-Breast 04 (DB-04), a phase III randomized clinical trial, has transformed the way breast cancer is categorized and treated [42]. Through demonstrating superior efficacy of T-Dxd in breast cancer cells that has reduced HER2 expression (previously categorized as HER2 negative), DB-04 provided clinical evidence that the bystander effect is an important characteristic of ADCs. Up to 60% of HER2 negative breast cancer cells express low levels of HER2, and more than 50% of HR+ breast cancer is HER2 low making the findings from DB-04 clinically relevant [56, 57]. In DB-04, patients with metastatic, recurrent HER2-low breast cancer defined as IHC 1+ or IHC 2+/ISH- were randomized 2:1 to T-Dxd or chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). More than 70% of patients with HR+ disease received prior CDK4/6 inhibitors and more than 99% of patients progressed on 1 line of prior chemotherapy. T-Dxd was associated with significant improvement in PFS and OS in the HR+ cohort and all patients. The median PFS in the HR+ cohort was 10.1 vs. 5.4 months (HR, 0.51; 95% CI, 0.40–0.64 P < 0.001) and in HR-negative was 8.5 vs. 2.9 months (HR, 0.46; 95% CI, 0.24–0.89). Median OS in the HR+ cohort was 23.9 vs. 17.5 months (HR, 0.64; P, 0.003) and in HR-negative was 18.2 vs. 8.3 months (HR, 0.48; 95% CI, 0.24–0.95). Benefit was observed across all subgroups including HER2 IHC 1+ and IHC 2+/ISH negative [42]. For patients with HR+ metastatic breast cancer and visceral crisis or with endocrine resistant disease, the National Comprehensive Cancer Network (NCCN) guidelines list T-Dxd as a preferred, category 1 treatment in the second line setting [2]. The NCCN guidelines list SG as a preferred, category 1 option in the second line setting for this patient population if not candidate for T-Dxd. For TNBC with HER2-low, T-Dxd is listed as preferred, category 1 treatment option in the second line setting [2].

#### **6.3 SG**

SG is the first approved ADC targeting Trop-2 [58]. SG was evaluated in the ASCENT, a phase III, randomized clinical trial in patients with metastatic TNBC who

#### *Antibody Drug Conjugates DOI: http://dx.doi.org/10.5772/intechopen.110804*

progressed after at least two lines of chemotherapy, one of which had to be for metastatic disease [59]. Patients (N = 529) were randomized 1:1 to SG or chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine). The primary efficacy outcome was PFS in patients without brain metastases. Key secondary outcomes were PFS in all patients and OS. SG was associated with significant improvement in PFS and OS. In patients without brain metastases, median PFS in SG was 5.6 months vs. 1.7 months with chemotherapy (HR, 0.41; 95% CI, 0.32–0.52; P < 0.001). The median OS was 12.1 with SG vs. 6.7 months with chemotherapy (HR, 0.48; 95% CI, 0.38–0.59; P < 0.001). A total of 61 patients had stable, treated brain metastases at baseline, 32 of which were treated with SG. In a subgroup analysis, patients with stable baseline brain metastases treated with SG had median PFS of 2.8 months compared to1.6 months in patients treated with chemotherapy (HR, 0.65; 95% CI, 0.35–1.22). This analysis is exploratory and limited by small sample size [60]. The NCCN lists SG as a preferred, category 1 treatment option in the second line setting for patients with metastatic TNBC who progressed on at least 2 prior chemotherapy lines, at least one of which for metastatic disease [2].

SG was also evaluated in the TROPiCS-02, a phase III, randomized clinical trial evaluating SG in 543 patients with HR+, HER2 negative or low who have progressed on the following: a CDK 4/6 inhibitor, endocrine therapy, and a taxane and at least two prior chemotherapies in the metastatic setting [61]. The primary outcome of PFS was statistically significant with median PFS of 5.5 in the SG arm vs. 4 months in the chemotherapy arm (HR, 0.661; 95% CI, 0.529–0.826; P, 0.0003). The median OS was also significantly improved in these heavily pretreated patients with endocrine resistant disease with median OS of 14.4 in the SG arm vs. 11.2 months in the chemotherapy arm (HR, 0.789; 95% CI, 0.646–0.964; P, 0.020) [62].
