Table I.
Clinical trials assessing the effects of tyrosine kinase inhibitors in BC.
| First author (Refs.) | Year | Phase | Disease stage, regimen used | Outcome |
|---|---|---|---|---|
| A, Gefitinib (Gt) | ||||
| Baselga et al (15) | 2005 | II | -ABC, Gt monotherapy | -Reduced clinical antitumor activity |
| Green et al (16) | 2009 | II | -ABC, hormone-resistant/negative, Gt monotherapy | -Low CBR 11% vs. 7.7% |
| Smith et al (17) | 2007 | II | -EBC, Gt + anastrozole vs. anastrozole | -No additional clinical effect |
| Polychronis et al (18) | 2005 | II | Primary BC, ER+, HER2+, neoadjuvant, anastrozole + Gt vs. Gt | Significant mean reduction of proliferation-related Ki67 index (98% vs. 92.4%) |
| Cristofanilli et al (19) | 2010 | II | -MBC, ER+, Gt + anastrozole vs. anastrozole | -Increase of PFS by adding Gt |
| Carlson et al (20) | 2012 | II | -MBC, Gt + anastrozole/fulvestrant | Similar CBR, response rates similar with Gt or endocrine therapy alone |
| Bernsdorf et al (21) | 2011 | II | EBC, neoadjuvant, TNBC vs. non-TNBC | Higher pCR in TNBC, higher toxicity |
| Tryfonidis et al (22) | 2016 | II | -ABC, anastrozole + Gt vs. anastrozole + placebo | -No added benefit, higher toxicity; terminated prematurely |
| B, Erlotinib (Et) | ||||
| Dickler et al (23) | 2009 | II | -ABC, unselected BC population, progression under chemo | -Minimal efficacy in unselected population |
| Lau et al (24) | 2014 | I | -BBC, metformin + Et | -Increased apoptosis in a subset of BBC |
| Ueno et al (25) | 2011 | I | -TNBC, xenograft model | -Inhibition of metastasis, nonspecific effects |
| Guix et al (26) | 2008 | II | -HR+, stage I-IIIA | -Inhibition of proliferation in ER+, not in HER2+ or TNBC |
| C, Afatinib (At) | ||||
| Harbeck et al (27) | 2016 | III | -MBC, HER2+, progression on trastuzumab, At + vinorelbine | -Reduced efficacy of combination At + vinorelbine |
| Cortés et al (28) | 2015 | II | -Brain MBC progressive or recurrent, HER2+ | -No additional benefit, frequent adverse events |
| Hanusch et al (30) | 2015 | II | -ABC, At + trastuzumab, neoadjuvant | -Comparable pCR with other anti-HER2, but below expected |
| D, Lapatinib (Lt) | ||||
| Baselga et al (32) | 2012 | III | -EBC, HER2+, Lt, and Lt + trastuzumab | -pCR significantly higher after Lt + trastuzumab vs. trastuzumab alone |
| 2014 | III | |||
| 2014 | II | |||
| 2016 | III | |||
| 2006 | III | |||
| 2010 | III | |||
| 2010 | III | |||
| 2009 | III | |||
| 2010 | III | |||
| de Azambuja et al (33) | 2014 | III | -EBC, HER2+, Lt, Lt + trastuzumab | -Event-free survival and OS did not differ between groups |
| Bonnefoi et al (34) | 2015 | II | -ABC, HER2+, neoadjuvant setting, Lt, Lt + trastuzumab, trastuzumab alone | -Modest pCR increase with anti-HER2 blockade (60% vs. 52%) |
| Piccart-Gebhart et al (35) | 2016 | III | -EBC, HER2+, adjuvant setting, Lt, Trastuzumab or combination | -No improvement in DFS with Lt, but added toxicity |
| Geyer et al (36) | 2006 | III | -ABC, HER2+, Lt + capecitabine | -Lt + capecitabine was superior to capecitabine alone |
| Schwartzberg et al (37) | 2010 | III | -MBC, HER2+, HR+, Lt + letrozole | -Significantly higher PFS, ORR and CBR |
| Sherrill et al (38) | 2010 | III | -MBC, HR+, HER2+, Lt + letrozole | -Lt + letrozole increased PFS interval compared with letrozole alone |
| Johnston et al (39) | 2009 | III | -MBC, HR+, HER2+, 1st line therapy | -Combined treatment significantly enhanced PFS and CBR |
| Blackwell et al (40) | 2010 | III | -MBC, HeR2+, Lt vs. Lt + trastuzumab | -Combined treatment improved PFS and CBR |
| E, Neratinib (Nt) | ||||
| Chow et al (42) | 2013 | I/II | -MBC, HER2+, Nt + paclitaxel | -High rate of response, higher toxicity |
| Chan et al (43) | 2016 | III | -EBC/ABC, HER2+, adjuvant setting after chemo and trastuzumab | -Improvement of the DFS rate at the 2-year follow up |
| G, Canertinib (Ct) | ||||
| Rixe et al (44) | 2009 | II | -MBC, progressive or recurrent | -No clinically significant activity |
| F, Tucatinib (Tt) | ||||
| Murthy et al (45) | 2018 | Ib | -MBC, HER2+, progressive BC | -Favorable antitumor activity, acceptable toxicity |
| Muthy et al (46) | 2020 | II | -MBC, HER2+, progressive BC, Tt combined with trastuzumab and capecitabine | -Improved PFS and OS |
| H, Pyrotinib (Pt) | ||||
| Ma et al (47) | 2017 | I | -MBC, HER2+ | -Well tolerated, favorable antitumor activity |
| Ma et al (50) | 2019 | II | -MBC, HER2+, Pt combined with capecitabine vs. lapatinib with capecitabine | -Improved overall response rate and PFS rate |
| Jiang et al (51) | 2019 | III | -MBC, HER2+, Pt combined with capecitabine | -Improved PFS; Pt monotherapy-antitumor activity |
BC, breast cancer; PFS, progression-free survival; TNBC, triple negative breast cancer; EBC, early breast cancer; ABC, advanced breast cancer; MBC, metastatic breast cancer; CBR, clinical benefit rate; BBC, basal-like breast cancer; pCR, pathologic complete response rate; DFS, disease-free survival; OS, overall survival.