After reading Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer journal article referenced on Yahoo, I'm placing one of my $2 bet on the horse "cetuximab".
Cetuximab and EGFR inhibitor combinations Based on in silico structural modeling, two EGFR exon 20 insertions, D770_P772del_insKG and D770>GY, were predicted to increase the electrostatic energy between EGFR monomers and therefore favor the formation of EGFR active dimers.79 This finding led the authors to hypothesize that patients harboring these insertions may be sensitive to a combination of EGFR kinase inhibitors and cetuximab, a monoclonal antibody that binds to the extracellular domain of EGFR and sterically hinders dimer formation.80 Case studies from two patients support the use of cetuximab in combination with EGFR inhibitors or chemotherapy, including one patient (D770>GY) treated with a combination of cetuximab and erlotinib in a phase I clinical trial with a reported PFS of 3.5 years.79,81 More recently, a clinical study found that three out of four EGFR exon 20 insertion-positive NSCLC patients had partial responses to a combination of afatinib and cetuximab, with a median PFS of 5.4 months.82 These results suggest that the cetuximab and EGFR inhibitor combination may have some efficacy in patients with exon 20 insertions; however, with limited clinical data, further work is necessary to determine the impact of the insertion size and location on the response to cetuximab combinations.
Haven't looked into it but I would think Erbtux is generic but not positive.
Here's what it says about pozi
Poziotinib Poziotinib (formerly HM781–36B) is a covalent, irreversible inhibitor of EGFR and HER270 that is currently the most advanced clinical candidate of compounds with the capacity to target EGFR exon 20 insertions. Initially, a phase II study of poziotinib in NSCLC patients with classical EGFR mutations who had acquired resistance to EGFR inhibitors via the T790M mutation or other mechanisms found that poziotinib had minimal clinical activity.71 Poziotinib was subsequently shown to have significant activity against EGFR exon 20 insertions in in vitro models, a result which was mirrored by encouraging clinical data from an ongoing phase II trial (NCT03066206).31 Robichaux et al. used 3D modeling to demonstrate how the rigid C-helix conformation induced by exon 20 insertions results in a relatively small drug binding pocket. This restricted conformation has been predicted to prevent the binding of drugs such as osimertinib, which has a large terminal group and a rigid pyrimidine core, by steric hindrance. By contrast, poziotinib is centered on a less rigid quinazoline core, akin to second-generation EGFR inhibitors. In addition, poziotinib has small terminal and substituent linking groups, making it more compact and flexible compared to current second-generation and third-generation inhibitors. Based on these features, 3D modeling predicts that poziotinib is able to tightly bind the restricted exon 20 insertion binding pocket of EGFR and may also be effective against structurally analogous exon 20 insertions in HER2.
Following these structural modeling studies, the authors demonstrated potent inhibition of exon 20 insertion EGFR and HER2 mutants in a series of engineered Ba/F3 cell line models. In these cell lines, poziotinib was shown to be uniquely selective for exon 20 insertions over T790M mutants, providing a possible explanation for the initial disappointing results in patients with acquired resistance to EGFR inhibitors in the phase II trial.71 However, it is important to note that poziotinib also demonstrated activity against wild-type EGFR in vitro, highlighting a possible narrow therapeutic window that may give rise to dose limitations in EGFR exon 20 insertion patients. Using genetically engineered mouse models harboring EGFR D770insNPG or HER2 A775insYVMA lung tumors, a durable response to poziotinib was shown over 12 weeks of treatment in vivo. Additionally, poziotinib was compared to afatinib in a mouse xenograft model of a patient-derived cell line, YUL-0019, which harbors EGFR N771delinsFH. Although YUL-0019 tumors did not grow in the presence of afatinib, tumor volume remained stable over the course of 10 days. By contrast, poziotinib treatment resulted in a 50% reduction of tumor volume within the same time frame.
The authors also reported preliminary data from an ongoing phase II clinical trial for poziotinib in EGFR exon 20 insertion-positive lung cancer patients (NCT03066206). Although the patient cohort was small, a striking 64% confirmed response rate was achieved in 11 patients harboring EGFR exon 20 insertion mutations. This promising result is in stark contrast to the 8.7% response rate that has previously been observed for afatinib in exon 20 insertion patients.59 It is important to note, however, that the clinical data from this trial are not mature and the median PFS and OS have not yet been reported. Therefore, a question remains: how durable will the response to poziotinib be in patients with exon 20 EGFR insertions? Anticipating the emergence of acquired resistance, Robichaux et al. indirectly showed a possible mechanism that parallels osimertinib resistance by demonstrating that Ba/F3 cells expressing EGFR L858R/T790M/C797S or EGFR exon 19 deletion/T790M/C797S triple mutants are resistant to poziotinib treatment in vitro. The C797S EGFR mutation has been found to be a major clinical mechanism of acquired resistance to osimertinib treatment in patients with classical EGFR mutants who are concurrently T790M positive.72 However, whether the C797S mutation arises in patients with exon 20 insertion mutations has yet to be determined. Similarly, whether poziotinib is clinically effective across a broad spectrum of different EGFR exon 20 insertions with sufficient selectivity over wild-type EGFR to achieve target inhibition with minimal toxicity remains unknown. Based on preliminary results from a phase II clinical trial including data from a small cohort of 30 patients, poziotinib was recently declined Breakthrough Designation Therapy status by the FDA,73 although the trial remains ongoing to assess poziotinib in a larger cohort of NSCLC patients harboring EGFR or HER2 exon 20 insertions (NCT03318939).
Another immediate take home form the article was the disproportionate presence of egfr exon 20 insertions in a type of Head and Neck cancer
Until recently, EGFR exon 20 insertion mutations have been exclusively reported in NSCLC. Interestingly, however, recent analysis of a rare form of head and neck cancer known as sinonasal squamous cell carcinoma (SNSCC) demonstrated a remarkably high frequency of EGFR mutations (77% of SNSCC tumors), the majority of which were exon 20 insertions (88% of all EGFR mutations).27 This result is striking given that EGFR mutations in head and neck cancer are rare overall, and moreover, the frequency of EGFR mutations is inverse to that of NSCLC; in SNSCC tumors, exon 20 insertion mutations predominate, while exon 19 deletions are detected at low frequency.27,28 Thus, EGFR exon 20 insertions are not entirely restricted to lung cancer as previously believed but can also act as oncogenic drivers in SNSCC, which represents approximately 3% of all head and neck cancers.29,30
I got to say he almost seemed surprised of finding out this mutation in other than NSCLC. Of course, we already know from the MDACC at WL that it exists in over 20 tumor types besides head and neck cancer and if you include both EGFR and HER2 exon20 insertion mutations, just in the US, patients with non-lung exon 20 solid tumors are around 8,400. Lots of other good stuff in the article. Will have to reread in the near future with some more time on hand.Thanks Paolo https://www.nature.com/articles/s41392-019-0038-9
