Table 5

HER2 double blockade and second-generation anti-HER2 therapies

StudyTrial nameSettingPrimary outcomeMedian follow-upDFS control (%)DFS gain (%)DFS HR*OS control (%)OS gain (%)OS HR*pCRQoLToxicityESMO-MCBS V.1.1Reference
Neratinib vs placeboExteNETStage 2–3 HER2+ after 12 months trastuzumab, stratified for HR statusiDFS all5.2 years87.72.50.73 (0.57–0.92)After first month similar for both arms40% grade 3 diarrhoeaA44
Neratinib vs placeboExteNETStage 2–3 HER2+ after 12 months trastuzumab, stratified for HR statusiDFSHR+5.2 years86.84.40.60 (0.43–0.83)After first month similar for both arms40% grade 3 diarrhoeaA44
Neratinib vs placeboExteNETStage 2–3 HER2+ after 12 months trastuzumab, stratified for HR statusiDFS HR−ve5.2 years88.80.10.95 (0.66–1.35)After first month similar for both arms40% grade 3 diarrhoeaNEB44
AC-PH vs AC-PHPzAPHINITYHER2+, stratified for nodal statusiDFS all45.4 months93.20.90.81 (0.66–1.00)B41
AC-PH vs AC-PHPzAPHINITYHER2+, stratified for nodal statusiDFS Node+44.5 months90.21.80.77 (0.62–0.96)Not scorable†41
TDM1 vs HKATHERINEHER2+ residual disease after neoadjuvant therapyiDFS3 years77.011.30.50 (0.39–0.64)A45
TH±PzNeoSphereHER2+ (phase 2)pCR29.0% vs 45.8%C8
H vs LHNeoALTTONeoadjuvantpCR3.77 years76.08.00.78 (0.47–1.28)85.06.00.62 (0.3–1.25)24.7% vs 29.5% vs 51.3%NEB42 43
H vs LHALTTOAdjuvantDFS4.5 years86.02.00.84 (0.70–1.02)94.01.00.80 (0.62–1.03)NEB85
H 6 vs 12 monthsPERSEPHONEHER2+DFS (non- inferiority)4 years89.889.41.07 (0.93–1.24)B40
  • Chart blanks—relevant variables not available in manuscript.

  • *HR values in parentheses refer to 95% CI.

  • †More than three prespecified subgroups violates scoring rules.

  • A, doxorubicin; C, cyclophosphamide; chemo, chemotherapy; DFS, disease-free survival; ESMO-MCBS, The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; H, trastuzumab; HER2+, HER2 overexpressed; HR+, hormone-positive; HR-neg, hormone-negative; iDFS, invasive disease-free survival; L, lapatinib; NEB, no evaluable benefit; OS, overall survival; P, paclitaxel; pCR, pathological complete response; Pz, pertuzumab; RFS, relapse-free survival; T, docetaxel.