China
Africa
Explore chapters and articles related to this topic
Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Penelope Bradbury, John Hilton, Janet E. Dancey
HER-2 has been a target in NSCLC for over 15 years. Initial focus was on patients with HER-2 protein overexpression; however, trials combining trastuzumab with chemotherapy failed to demonstrate benefit from this approach, although subsets of patients with HER-2 FISH positive tumors seemed to have a greater response rate. (Gatzemeier, 2004). HER-2 mutations occur in 1–3% of patients with NSCLC and are most commonly an insertion in exon 20, although point mutations have been described. HER-2 mutations are more commonly found in females, never smokers with adenocarcinoma, although this is not always the case, therefore recommendations that HER-2 testing should be undertaken in all patients with adenocarcinoma has been made. In a retrospective series of 101 patients with HER-2 mutations, the overall survival from the start of first-line systemic therapy for advanced disease was 23.4 months. In this cohort, patients had been treated with a range of HER-2 targeted agents. Response to trastuzumab or ado-trastuzumab-emtansine combined with chemotherapy was 50% with a progression-free survival of 5.1 months. TKIs including neratinib, lapatinib, and afatinib had a lower response rate of <8% with a progression-free survival of 3.4 months (Mazières, 2016). A similar response rate was reported with dacomitinib, with responses in 3 of 26 patients HER2 exon 20 mutations positive NSCLC with duration of 3+, 11, and 14 months, but no responses from 4 patients enrolled with HER2 amplification (Kris, 2015). Data from a cohort enrolled as part of a prospective basket trial to evaluate ado-trastuzumab-emtansine reported a response rate of 44% and a progression-free survival of 5 months from 18 patients enrolled which included 6 patients that had received prior HER-2 targeted agents (Li, 2018). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase had a response rate of 53% from 15 patients with HER-2 mutation positive NSCLC, with a median progression-free survival of 6.4 months (Wang, 2019), and similar results reported from a cohort of 12 evaluable patients treated with poziotinib with a response rate of 50% (Heymach, 2018).
Assessments of CYP‑inhibition‑based drug–drug interaction between vonoprazan and poziotinib in vitro and in vivo
Published in Pharmaceutical Biology, 2023
Shan Zhou, Fang-Ling Zhao, Shuang-Hu Wang, Yi-Ran Wang, Yun Hong, Quan Zhou, Pei-Wu Geng, Qing-Feng Luo, Jian-Ping Cai, Da-Peng Dai
Poziotinib is a novel tyrosine kinase small molecule inhibitor that targets the rare exon 20 insertion mutations in epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (Kim et al. 2013). Previous studies revealed that poziotinib was beneficial for the treatment of acquired mutations (EGFR) caused by clinically localized non-small cell lung (Rosell and Cardona Zorrilla 2021), breast (Kim et al. 2020), and gastric cancer (Kim et al. 2019). In the clinic, many cancer patients need to take antineoplastic drugs for a long time, and some of them have to take acid suppressive drugs at the same time to cure the gastrointestinal side effects of antitumor drugs. Patients with digestive system tumors, such as gastric cancer, are required to take drugs for both antineoplastic therapy and acid suppression. A previous study reported that poziotinib was mainly metabolized to M1 by CYP3A4 and partly metabolized to M2 by CYP2D6 (Ji et al. 2021). Considering that poziotinib and vonoprazan are both newly developed drugs mainly metabolized by CYP3A4 and have a high possibility of coadministration, it is very important to investigate the potential interactions between them to provide a theoretical basis for their coadministration and dose adjustment in the clinic.
Targeted therapy of oncogenic-driven advanced non-small cell lung cancer: recent advances and new perspectives
Published in Expert Review of Respiratory Medicine, 2020
Carlo Genova, Giovanni Rossi, Marco Tagliamento, Erika Rijavec, Federica Biello, Luigi Cerbone, Lodovica Zullo, Francesco Grossi
Poziotinib is an irreversible inhibitor active on EGFR or HER2 exon 20-mutant pre-treated NSCLC patients, both TKI-naive and not. Approximately 60% of patients had AE of grade ≥3 (particularly skin rush and diarrhea), in almost half of patients dose reduction was required [27]. TAS6417 demonstrated encouraging results in vitro, by the direct action on the ATP binding site of the exon 20 insertion EGFR kinase [23]. TAK-788 is an oral EGFR/HER2 inhibitor, whose antitumor activity has been assessed in a phase I/II trial among advanced NSCLC patients with exon 20 insertion. Twenty-eight patients received the dose of 180 mg/day in the dose escalation or dose expansion cohort: at data cutoff, there were seven confirmed responses, other six awaiting confirmation and one unconfirmed PR. Treatment discontinuation rate due to AE was 10.7% in pts treated at 160 mg/day [28].
Amivantamab for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer
Published in Expert Review of Anticancer Therapy, 2022
Mobocertinib (formerly known as TAK-788/AP32788) is an irreversible, covalent kinase inhibitor of EGFR and HER2 with activity against EGFR exon 20 insertion mutations [54]. A phase I/2 trial (EXCLAIM; NCT02716116) which evaluated 160 mg mobocertinib once daily in 114 EGFR exon 20 insertion patients with prior platinum-based therapy reported a RR of 28% and median PFS of 7.3 months which is superior to poziotinib [44,55]. Based on these results, the Food and Drug Administration (FDA) granted an accelerated approval for mobocertinib as a second-line therapy to treat NSCLC with EGFR exon 20 insertion mutations with progression on platinum-based chemotherapy in September 2021 [44]. Mobocertinib has a more tolerable toxicity profile compared to poziotinib, with grade 3 or 4 TRAEs occurring in 40% of patients in the dose escalation cohort of 136 patients, the most common TRAEs being diarrhea (83%), nausea (43%) and rash (33%) [56]. The phase III EXCLAIM-2 cohort (NCT04129502) will directly compare first-line platinum-based chemotherapy versus mobocertinib in treatment-naïve EGFR exon 20 insertion NSCLC patients, with median PFS as a primary endpoint [57]. This study will be the first to compare a novel therapy with activity against EGFR exon 20 insertions as a first-line treatment against standard-of-care chemotherapy. Importantly, EXCLAIM-2 will include patient stratification for the presence of brain metastases. Mobocertinib was previously reported to have a lower RR in patients with baseline brain metastases compared to patients without (25% vs 56%) [56], however, the results from the EXCLAIM-2 trial will provide more robust evidence to help clearly establish the CNS activity of mobocertinib.