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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Lapatinib is used in combination with capecitabine for patients with advanced or metastatic breast cancer whose tumors over-express HER2, and who have been previously treated with an anthracycline, a taxane and trastuzumab, or for postmenopausal women in combination with an aromatase inhibitor. It has also been approved by the FDA for use in combination with letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer over-expressing the HER2 receptor.
UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Tristan M. Sissung, Roberto Barbier, Lisa M. Cordes, William D. Figg
Breast, lung, pancreatic, and other solid tumors are also treated with TKIs. Lapatinib is used in combination for the treatment of metastatic HER2 + breast cancer [130, 131]. Lapatinib is not a strong inhibitor of UGT1A1; however, carriers of certain human leukocyte antigen (HLA) genotypes are at risk of liver injury, and UGT1A1*28/*28 status is helpful in determining the risk of lapatinib-induced liver injury in HLA [132]. Case reports also indicate that patients treated with erlotinib who carry UGT1A1*28/*28 are more susceptible to hyperbilirubinemia [133, 134].
Breast Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Amy Case, Gwenllian Edwards, Catherine Pembroke
Lapatinib is a small-molecule tyrosine kinase inhibitor directed against the HER2 and EGFR pathways. Its clinical effectiveness has been studied in combination with capecitabine in patients who have progressed on trastuzumab. Initial results of a phase III trial of 399 women who received either lapatinib and capecitabine in combination or capecitabine alone did reveal an improved time to progression and a trend towards improved OS; however there was no statistically significant difference in median OS (67.7 weeks for lapatinib plus capecitabine versus 66.6 weeks for capecitabine monotherapy [HR 0.78; 95% CI 0.55 to 1.12, p = 0.177]).180 In the UK, NICE guidance does not recommend the combination of lapatinib and capecitabine.
A systematic review of clinical trials of treatment regimens in HER2-amplified metastatic colorectal cancer
Published in Expert Review of Anticancer Therapy, 2023
Daniel Sur, Cristina Lungulescu, Elena Adriana Dumitrescu, Vlad Afrăsânie, Ștefan Spînu, Cristian Virgil Lungulescu, Hans- Joachim Schmoll
The most common treatment-related adverse events (AEs) of chemotherapy (capecitabine) in combination with lapatinib were fatigue (83%), hand-foot syndrome (69%), and diarrhea (59%). Lapatinib in combination with trastuzumab often caused diarrhea (78%), rash (48%), and fatigue (48%). In the FOCUS4-D trial skin rash occurred in 20% of the AZD8931 group versus none in the placebo group, and diarrhea occurred in 7% of the AZD8931 group versus 6% in the placebo group. The combination of trastuzumab and pertuzumab frequently caused fatigue (32%), diarrhea (34%), nausea (30%) in My-Pathway study, while the TRIUMPH trial found that infusion-related events, diarrhea, stomatitis, and malaise were the most common side effects. Trastuzumab-deruxtecan (T-DXd), an antibody–drug conjugate, was associated with a high incidence of nausea (60%), fatigue (33%), and diarrhea (28%), while ado-trastuzumab-emtansine (T-DM1) combined with pertuzumab-induced fatigue (18%), hyperbilirubinemia (9%), and thrombocytopenia (8%). Summaries of each of the seven papers included in this study are presented in Table 2.
Palliative chemotherapy in head and neck cancer: balancing between beneficial and adverse effects
Published in Expert Review of Anticancer Therapy, 2020
Akhil Rajendra, Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Nandini Menon, Kumar Prabhash
Small molecule non-monoclonal antibody EGFR inhibitors have been tested in R/M HNSCC. A Phase II study assessing the efficacy of lapatinib in this group of patients showed that none of the patients experienced partial or complete response (objective response rate – 0%). The best response was stable disease which was noted in 41% of the patients [55]. Single arm studies of gefitinib and erlotinib resulted in objective response rates of 1.8% and 10.6% respectively with a median PFS of 3 to 4 months; skin rash and diarrhea were the most common side effects [56–59]. In a Phase III trial conducted by Stewart et al., gefitinib at two doses (250 mg/day and 500 mg/day) was compared with intravenous methotrexate 40 mg/m2 weekly. Gefitinib at both the doses did not improve the survival in comparison to methotrexate (median OS: 5.6 [G250], 6 [G500] and 6.7 [M] months; HR 1.22; 95% CI, 0.95 to 1.57; P = .12; HR, 1.12; 95% CI, 0.87 to 1.43; P = .39) [60].
Current and future molecular diagnostics of gastric cancer
Published in Expert Review of Molecular Diagnostics, 2019
Rachel Sin-Yu Choi, Wing Yin Xenia Lai, Lok Ting Claire Lee, Wing Lam Christa Wong, Xiao Meng Pei, Hin Fung Tsang, Joel Johnson Leung, William Chi Shing Cho, Man Kee Maggie Chu, Elaine Yue Ling Wong, Sze Chuen Cesar Wong
In the field of cancer treatment, these biomarkers greatly contribute to the progression of cancer, selection of appropriate target therapy and efficient follow-up programs. Over-expression of EGFR and HER2 in various solid tumors including GC is associated with poor prognosis [75]. The level of HER2 gene amplification can be examined by quantitative real-time PCR (qPCR) or droplet digital PCR (ddPCR) [70]. Researchers have identified that EGFR-positive, but not HER2-positive patients, had lower overall and relapse-free survival rates compared to EGFR-negative and HER2-negative patients [76]. EGFR and HER2 are the most innovative targeting agents of GC treatment in recent years. For example, Trastuzumab, a HER2-targeted agent, binds to the HER2 domain IV – a region not involved in receptor dimerization [77]. Trastuzumab is the first molecular-targeted agent approved as standard treatment in GC [78]. Lapatinib is a small-molecule inhibitor of the intracellular domain of tyrosine kinase of EGFR and HER2 [79]. Cetuximab is a recombinant human-mouse chimeric anti-EGFR antibody [80]. Additionally, Panitumumab is a fully humanized anti-HER1 antibody [81].