Table 2.
Key phase 3 clinical trials investigating HER-2-targeted tyrosine kinase inhibitors in breast cancer.
| Trial information | Study design | Sample size | Population | Findings |
|---|---|---|---|---|
| Lapatinib | ||||
| Early stage | ||||
| NeoALTTO (Baselga27) | Neoadjuvant (+ taxane) and post-neoadjuvant lapatinib (L) vs trastuzumab vs lapatinib (TL) + trastuzumab (T) | 455 | Women, HER2+, >2 cm localized BC | pCR 51.3% of TL vs 29.5% with T (p = 0.0001) |
| GeparQuinto GBG 44 (Untch30) | Neoadjuvant EC followed by docetaxel with trastuzumab (T) vs lapatinib (L) | 620 | Women, HER2+, lymph node+, BC | pCR 30.3% in T and 22.7% in L (0.04) |
| NSABP B-41 (Robidoux29) | Neoadjuvant AC followed by WT + lapatinib (L) vs trastuzumab vs lapatinib (TL) + trastuzumab (T) | 519 | HER2+, >2 cm localized BC, LVEF > 50% | pCR 52.5% of T, 53.3% of L, 62% of TL (p = 0.95) |
| CALBG 40601 (Carey28) | Neoadjuvant paclitaxel + lapatinib + trastuzumab (THL) vs paclitaxel + lapatinib (TL) vs paclitaxel + trstuzumab | 305 | HER2+, >1 cm localized BC, LVEF > 50% | pCR 56% TPL, 46% in TP (p = 0.13). After 7 years of follow up there was an improvement in recurrence free survival and OS with the triplet31 |
| TEACH (Goss35) | Adjuvant chemotherapy followed by lapatinib vs placebo | 3147 | Stage I-IIIc BC, not previously treated with trastuzumab | DFS 13% lapatinib vs 17% placebo (p = 0.53; no difference in OS or TTR) |
| ALTTO (Piccart-Gebhart36)a | Adjuvant trastuzumab + lapatinib (TL) vs sequential trastuzumab followed lapatinib (T → L) vs trastuzumab alone (T) | 8381 | HER2+, >1 cm localized BC | No difference in disease free survival (p = 0.61) with the addition of lapatinib when compared with T alone |
| Metastatic | ||||
| Lapatinib plus capecitabine (Geyer46) | Lapatinib + capecitabine (LC) vs capecitabine (C) | 324 | HER2+, metastatic BC, who progressed with chemotherapy and trastuzumab | TTP was 8.4 months in LC and 4.4 in C |
| Lapatinib plus letrozole (Johnston47) | Lapatinib + letrozole (LL) vs letrozole + placebo (LP) | 219 | HR+, HER2+ or −metastatic BC | HER2+: PFS was 8.2 in LL vs 3 months LP |
| COMPLETE (MA.31) (Gelmon48) | Lapatinib + paclitaxel vs trastuzumab + capecitabine | 537 | HER2+, metastatic BC | PFS was 9 months in the lapatinib arm and 13.6 with trastuzumab (HR 1.48, p = .001) |
| CEREBEL (Pivot65)a | Lapatinib + capecitabine (LC) vs trastuzumab + capecitabine (TC) | 540 | HER2+, metastatic BC, no known history of brain metastases | No difference of brain metastases as first site of relapse (p = 0.360). OS and PFS longer in the TC arm |
| Neratinib | ||||
| Early stage | ||||
| ExteNET (Chan39) | Extended adjuvant therapy with neratinib (N) for a year vs placebo (P) | 2840 | HER2+, stage I–III BC that completed therapy including 1 year of trastuzumab therapy | DFS was lower in the N group (p = 0.0091). At 8 years follow up there was a an absolute benefit of 7.4% in iDFS and 9.1% in OS for patients who initiated treatment <1 year post-trastuzumab40 |
| Metastatic | ||||
| NEfERT-T (Awada50) | Neratinib + paclitaxel (NP) vs trastuzumab + paclitaxel (TP) | 480b | Previously untreated HER2+ metastatic BC | Median PFS was 12.9 months with NP and 12.9 months with TP. The incidence of CNS metastases was lower in the NP arm (relative risk 0.48, p = 0.004) |
| NALA (Saura20) | Lapatinib + capecitabine (LC) vs neratinib + capecitabine (NC) | 621 | HER2 + , metastatic BC, received two lines of HER2-directed therapy | PFS was improved with NC (p = 0.0059). No difference in OS. DOR was 8.5 months in NC and 5.6 in LC (p = 0.0004). Fewer interventions to CNS disease in NC vs LC (p = 0.043) |
| Tucatinib | ||||
| Metastatic | ||||
| HER2CLIMB (Murthy19) | Tucatinib + trastuzumab + capecitabine (TTC) vs placebo + trastuzumab + capecitabine (PTC) | 612 | HER2 + , metastatic BC, received two lines of HER2-directed therapyc | PFS at 1 year was 33.1% in TTC vs 12.3% in PTC (p = 0.001). PFS was better in TTC 7.8 vs 5.6 months. OS in TTC was 44.9 vs 26.6% in PTC (p = 0.005) |
pCR pathologic complete response, EC epirubicin, cyclophosphamide, AC doxorubicin, cyclophosphamide, WT weekly taxane, LVEF left ventricular ejection fraction, DFS disease-free survival, OS overall survival, TTR time to first recurrence, PFS progression-free survival, TTP time to progression, HR hormone receptor, CNS central nervous system, DOR duration of response.
aTerminated early.
bInitially designed as a phase 3 study but accrual was reduced from 1200 to 480, therefore it was no longer powered as a phase 3 study and results were considered preliminary according to the conclusions of the authors.
cPFS, OS, and intracranial ORR was better in patients that received TTC vs PTC.