Abstract PD3-01: Results from KATE2, a randomized phase 2 study of atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC)

Abstract

Background T-DM1 has improved PFS and OS in HER2+ advanced BC patients (pts) who previously progressed on trastuzumab and a taxane (Verma NEJM 2012). Preclinical data show that atezo (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1 to restore antitumor immunity. PD-L1 is often expressed on tumor-infiltrating immune cells (IC) in BC. KATE2 (NCT02924883) is the first study to assess atezo combined with T-DM1 in previously treated HER2+ advanced BC. Method Eligible pts had HER2+ advanced BC previously treated with trastuzumab and a taxane and progressed on treatment for metastatic disease or within 6 mo of adjuvant therapy. Pts were randomized 2:1 to atezo 1200 mg or pbo+T-DM1 3.6 mg/kg IV q3w (crossover not permitted). The primary endpoint was investigator-assessed PFS per RECIST v1.1. Additional endpoints included OS, ORR, DoR (secondary), PFS in the PD-L1+ subgroup (exploratory) and safety. Data cutoff: 11 Dec 2017. Result 133 pts were randomized to atezo+T-DM1 and 69 pts to pbo+T-DM1. 49% and 46% received prior pertuzumab for metastatic BC; median duration of pertuzumab treatment was 10 and 13 mo, respectively. Median follow-up was 8.5 and 8.4 mo, respectively. Efficacy in the ITT population and biomarker subgroups are shown. PFS HR was 0.82 (95% CI: 0.55, 1.23); p=0.3332. At data cutoff, 13 OS events (10%) in the atezo+T-DM1 arm and 8 (12%) in the pbo+T-DM1 arm had occurred. mDoR was not reached. 44% and 41% of safety-evaluable pts had an AE of Gr ≥3 with atezo+T-DM1 and pbo+T-DM1, respectively. The most common was thrombocytopenia (13% and 4%). The incidence of serious AEs (SAEs) was 33% with atezo+T-DM1 and 19% with pbo+T-DM1, with the most common being Gr 1-2 pyrexia with atezo+T-DM1 (5%) and abdominal pain (3%) and seizure (3%) with pbo+T-DM1. AE rates leading to atezo/pbo or T-DM1 discontinuation were 25% and 15%, respectively, with atezo+T-DM1 and 15% and 13% with pbo+T-DM1. 1 patient in the atezo+T-DM1 arm had a drug-related Gr 5 AE (hemophagocytic syndrome). ITT and Biomarker Subgroups: Efficacy Atezo+T-DM1 (n=133)Pbo+T-DM1 (n=69)mPFS, mo8.26.86-mo PFS, %585112-mo PFS, %3834ORR, %a4543CR67PR3936PD-L1 IHCb PD-L1+PD-L1-PD-L1+PD-L1-Patients, n57762742mPFS, mo8.56.84.18.2ORR, %a54403350Stromal TILsc TIL-high (≥5%)TIL-low (<5%)TIL-high (≥5%)TIL-low (<5%)Patients, n80454025mPFS, mo8.55.55.3NAORR, %a48383848HER2c IHC3+IHC0-2+IHC3+IHC0-2+Patients, n103305613mPFS, mo8.55.98.04.0ORR, %a52234631aORR-evaluable pts (measurable disease at baseline): n=132 in atezo+T-DM1 arm. bPD-L1+, IC1/2/3; PD-L1–, IC0; measured per the VENTANA SP142 IHC assay. cPost hoc exploratory analyses. Conclusion Atezo+T-DM1 did not demonstrate a clinically significant PFS benefit vs pbo+T-DM1; OS and DoR data are not yet mature. Numerically higher PFS and ORR were seen with atezo+T-DM1 in PD-L1+ pts. T-DM1 safety in both arms was consistent with its known profile. Although the combination of atezo+T-DM1 showed a numerically higher incidence of SAEs and discontinuation of atezo due to an AE, rates of Gr 3-5 AEs were similar between arms. Additional biomarker data, including gene expression and mutation data, will be presented. Citation Format: Emens LA, Esteva F, Beresford M, Saura C, De Laurentiis M, Kim S-B, Im S-A, Patre M, Wang Y, Mani A, Liu H, de Haas S, Loi S. Results from KATE2, a randomized phase 2 study of atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-01.

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

“…Accordingly, a few early clinical trials using the combination of ADCs and PD-1/PD-L1 inhibitors have already been conducted thus far. In the KATE2 trial, a randomized phase II study of atezolizumab and T-DM1 in heavily treated HER2-expressing breast cancer, a significant antitumor effect was not observed in the intention-to-treat population, although a potential survival benefit of such combinatorial therapy was suggested in PD-L1-positive patients (46). Furthermore, an early clinical trial evaluating the safety and efficacy of the combination of DS-8201a and nivolumab is now in progress (Clini-calTrials.gov NCT03523572).…”

Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index

“…2B). Early clinical data are available for two trials (66,67). For mirvetuximab in combination with pembrolizumab, data indicate that responses are similar to those with monotherapy; however, firm conclusions cannot be made at this time due to limited data (66).…”

“…For mirvetuximab in combination with pembrolizumab, data indicate that responses are similar to those with monotherapy; however, firm conclusions cannot be made at this time due to limited data (66). The combination of adotrastuzumab emtansine (T-DM1) and atezolizumab was investigated in HER2 þ metastatic breast cancer; although no clinically significant benefit was observed with the combination in the intent-to-treat population, there was a trend toward clinical benefit in biomarker-selected subsets of patients (67).…”

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…Moreover, most of the in vivo and in vitro studies on the use of immune checkpoint inhibition are done using antibody-based drugs that are associated with the high cost and long half-life [140]. The efficacy of small molecule PD-1/PD-L1 inhibitors in implementing a combination of immunotherapy and HER2-targeted therapy to enhance the potency of BC treatment should also be investigated [141][142][143][144]. Along with the suggested experimental analysis, mathematical model-based analysis is also desired in this area.…”