Serotonin Transporters · January 3, 2022

Nevertheless, sufferers with these HER2-harmful/low tumors, thought as IHC 1+ or 2+, benefited from trastuzumab

Nevertheless, sufferers with these HER2-harmful/low tumors, thought as IHC 1+ or 2+, benefited from trastuzumab. a few months in 12 sufferers [29]. This trial didn’t satisfy its accrual objective; hence, the efficiency of this program is unclear. Stage I/II research also added gefitinib (Iressa; AstraZeneca, Wilmington, DE,, another EGFR-targeted TKI [27, 30], to trastuzumab in HER2-positive MBC. A study of trastuzumab and gefitinib resulted in 9% RR, and median TTP was 3 months in patients with no prior metastatic therapy and 5.3 months in those with prior therapy; median OS was 27 months [31]. A phase I/II study evaluating the addition of gefitinib to docetaxel and trastuzumab in MBC reported PFS of 12.7 months and RR of 64% [32]. Dual EGFR and HER2 Inhibitors BTZ043 (BTZ038, BTZ044) Racemate Lapatinib Dual TKIs that interact with several EGFR members have shown more promising results than EGFR inhibition alone. Lapatinib (Tykerb; GlaxoSmithKline, London, U.K., is an oral small-molecule reversible inhibitor of both EGFR and HER2 [33]. Lapatinib was first approved by the FDA in 2007 in combination with capecitabine for the treatment of HER2-positive MBC after prior trastuzumab/chemotherapy [34, 35] BTZ043 (BTZ038, BTZ044) Racemate (Table 2). Approval was based on a phase III study comparing lapatinib/capecitabine with capecitabine alone in patients with MBC progressing after chemotherapy/trastuzumab, as TTP improved from 4.4 to 8.4 months [36]. A phase III trial testing lapatinib BTZ043 (BTZ038, BTZ044) Racemate in combination with antiestrogen therapy also showed improvement, with a median PFS of 3.0 and 8.2 months with letrozole/placebo versus lapatinib/letrozole, respectively, in hormone receptor-positive HER2-positive MBC [37]. However, a phase III study of HER2-positive MBC patients demonstrated longer PFS with trastuzumab compared with lapatinib (11.4 vs. 8.8 months) when combined with first-line taxane-based therapy; no significant difference in OS was observed, and more grade 3 to 4 4 events of diarrhea and rash were observed with lapatinib [38]. Trastuzumab was also superior to lapatinib in the neoadjuvant setting in the phase III GeparQuinto trial, with pCR of 30.3% versus 22.7%, respectively (= .04) [39]. In the adjuvant setting, the TEACH phase III study evaluated lapatinib versus placebo, with improved DFS observed with lapatinib in patients with confirmed HER2-positive disease [40]. Thus, lapatinib may be an alternative in patients for whom adjuvant trastuzumab is contraindicated. Table 2. Completed and ongoing phase II and phase III clinical trials Thbd of approved and investigational multitargeted HER family tyrosine kinase inhibitors in HER2-positive breast cancera Open in a separate window Combination of Lapatinib and Trastuzumab In a phase III study, lapatinib plus trastuzumab significantly prolonged median PFS compared with lapatinib alone in HER2-positive MBC patients progressing on prior trastuzumab, although RRs were not significantly different [41]. An international phase III study is evaluating lapatinib/trastuzumab plus chemotherapy in the first-line setting for MBC [42], and another phase III study is examining whether addition of lapatinib improves PFS in MBC patients receiving trastuzumab maintenance (“type”:”clinical-trial”,”attrs”:”text”:”NCT00968968″,”term_id”:”NCT00968968″NCT00968968). The ALTERNATIVE phase III study will randomize hormone receptor-positive HER2-positive MBC patients to letrozole and trastuzumab with and without lapatinib (“type”:”clinical-trial”,”attrs”:”text”:”NCT01160211″,”term_id”:”NCT01160211″NCT01160211) [43]. The phase III ALTTO study (“type”:”clinical-trial”,”attrs”:”text”:”NCT00490139″,”term_id”:”NCT00490139″NCT00490139) is evaluating lapatinib, trastuzumab, trastuzumab followed by lapatinib, and both together in the adjuvant setting. The phase III NeoALTTO trial evaluated neoadjuvant/adjuvant lapatinib, trastuzumab, and the combination with chemotherapy in women with early-stage disease [44]. The combination of trastuzumab and lapatinib resulted in a higher pCR (51.3%) compared with trastuzumab (29.5%) or lapatinib (24.7%) alone [44]. NSABP B-41 involved 529 patients who received chemotherapy plus neoadjuvant trastuzumab (pCR, 52.5%), lapatinib (53.2%), or trastuzumab/lapatinib (62%; = .075), followed by a year of adjuvant trastuzumab [45]. Based on presented results of CALGB 40601, there was no significant difference in the pCR rate between weekly paclitaxel plus trastuzumab (40%) versus weekly paclitaxel plus trastuzumab/lapatinib (51%; = .11) [46]. A prior meta-analysis of neoadjuvant trastuzumab and lapatinib trials found that pCR was highest with trastuzumab plus lapatinib [47], suggesting that the optimal use of lapatinib may be in conjunction with trastuzumab through dual blockade of HER2 and EGFR, as lapatinib alone appears less effective than in combination with trastuzumab in the first-line setting. Neoadjuvant lapatinib and trastuzumab along with hormonal therapy were also administered to hormone receptor-positive/HER2-positive patients in a.