Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Abstract

BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n ¼ 100), objective response rate was 19.0% (95% confidence interval (CI): 11.8 -28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9 -34.7). One out of 22 HER2-negative tumour was documented as complete response (n ¼ 22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P ¼ 0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

Emerging evidence on the pathobiology of mucositis

“…Further, unlike conventional mucositis, oral lesions secondary to targeted agents are often accompanied by a skin rash. These observations suggest that the pathogenic mechanisms of targeted therapy-induced toxicity are not necessarily the same as for other cancer treatments, and there remains a vast gap in our knowledge regarding the biological mechanisms responsible [81][82][83]. The term "stomatitis" has been used in several recent publications for oral lesions secondary to targeted agents to distinguish them from mucositis secondary to conventional chemotherapy and radiation therapy.…”

Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

“…The PIK3CA activating mutations (E545K and H1047R) cause resistance to lapatinib 58 . Patients with tumors harboring an H1047R PIK3CA mutation or low expression of PTEN, derived clinical benefit from lapatinib in one phase II study 92 .…”

“…Knockdown of PTEN did not alter response to lapatinib in vitro and PTEN loss was not associated with reduced response to lapatinib in a phase II monotherapy trial in IBC, as approximately 70% of responders showed PTEN deficiency 9,87,96 . Patients with tumors harboring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib in one phase II study 92 . On the other hand, a combined in vitro and in vivo study using a genome wide loss-of-function short hairpin RNA (shRNA) screen identified loss of PTEN expression as one of causes of lapatinib resistance 58 .…”

Evaluation of PTEN loss and PIK3CA mutations and their correlation with efficacy of trastuzumab treatment in HER2-positive metastatic breast cancer: A retrospective study (KBC-SG 1001)

“…This PTEN protein loss was observed in 20.5-76.3% of the HER2-positive breast cancer cases (6)(7)(8)(9)(10), demonstrating an existing correlation between the treatment effect of T and the level of PTEN protein expression (6,7). PIK3CA mutation is observed in 10.3-37.5% of the HER2-positive breast cancer cases (9)(10)(11)(12). Exons 9 (E542K, E545K) and 20 (H1047R) are the hot spots for mutation (13,14), demonstrating that the effect of T treatment was affected by these mutations (10).…”

“…Exons 9 (E542K, E545K) and 20 (H1047R) are the hot spots for mutation (13,14), demonstrating that the effect of T treatment was affected by these mutations (10). However, the effect of lapatinib treatment has been proven not to be correlated with the p95HER2 expression levels or PTEN proteins, or the status of PIK3CA gene mutation (8,11,12,15). These biological features are worth examining in terms of their treatment response to T or lapatinib.…”