Dacomitinib

Dacomitinib (Vizimpro) is a TKI that is not used too often (possibly because of its strong side effects) however recent studies show that it can be quite effective for exon 18 mutations. Results suggest that in the first line could be its efficacy probably as good as that of Afatinib. Dacomitinib has very good efficacy in the brain (likely better than Afatinib) so for patients with problematic brain metastasis, it can be a choice to try.
There was a study with Dacomitinib in common EGFR mutations (exon 19 and 21) and it for the subset of patients who started on full dose of 45 mg and were reduced to 15 mg daily later PFS was incredible 31 months (the longest PFS ever seen for a first line EGFR TKI treatment). So there might be some uncovered potential of this drug. Another study suggests that exon 18 mutations have even better sensitivity to Dacomitinib that common mutations.

Here is a recent study of Dacomitinib in uncommon mutations : https://www.frontiersin.org/articles/10.3389/fphar.2022.919652/full?fbclid=IwAR1Ec0P8oFuebh_EU41QdsLfkW_j2kzzSshmO0BcG6YGx0LPBQQZPRPDRIw

In the following case study there was a patient with G719X mutation who started on 1st line Afatinib and then was on various treatments. After 4 years Dacomitinib was tried and gave really good response: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046035/

Also in the next study from China there were two patients with G719X with response to Dacomitinib 1st line. https://ascopubs.org/.../10.1200/JCO.2021.39.15_suppl.e21043

Brain effect :

Dacomitinib has really good brain penetration.According to this study Dacomitinib can work really well in the brain- results for brain control here are impressive (in the 1st line) : https://www.sciencedirect.com/.../pii/S016950022030725X

In total, 14 of 59 EGFR-mutant advanced NSCLC patients who received first-line dacomitinib therapy had brain metastasis before treatment. Among these patients, 5 were given a dacomitinib starting dose of 45 mg once daily, while 9 received 30 mg daily until disease progression or unbearable toxicity. Eight patients harbored EGFR 19del, 5 had EGFR L858R, and one patient had EGFR G719A and I706 T co-mutations. The median duration of follow-up was 4.5 months. All patients received at least one review. The ORR was 92.9 % (13/14) and the disease control rate (DCR) was 100 %.

We have a member of exon 18 group, who has succesfully used Dacomitinib for her mum (G719S) with LMD (leptomeningeal disease) for maybe two years now. They alternate 160mg Tagrisso and 30 mg Dacomitinib weekly - a really remarkable treatment regimen.

Lowered dose of dacomitinib led to a incredible PFS of 31,2 months in a subgroup of patients in the following study in common mutations :                                                                                                                                                            Effects of dose modifications on the safety and efficacy of dacomitinib for EGFR mutation-positive non-small-cell lung cancer    https://www.futuremedicine.com/doi/10.2217/fon-2019-0299?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed&fbclid=IwAR26mjyqpzRYmCOrF74El87w7OasrelGBi8xdB_ie3nLekyKl_G7-_kwbdI

https://www.futuremedicine.com/doi/pdf/10.2217/fon-2019-0299

Median (95% CI) PFS by the lowest dose received was as follows: 9.1 (5.6-12.8) months for patients (n = 77) who remained on 45 mg QD and 12.9 (10.8-16.7) months for patients (n = 87) who received 30 mg QD as the lowest dose and 31.2 (16.5-35.1) months for patients (n = 63) who received 15 mg QD as the lowest dose (Figure 1B).