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Rare EGFR mutations as oncogenic drivers

Presented by
Dr Alfredo Addeo (University Hospital of Geneva, Switzerland) and Dr Giulia Pasello (Veneto Institute of Oncology, Italy)
ELCC 2022
In an educational session, Dr Alfredo Addeo (University Hospital of Geneva, Switzerland) and Dr Giulia Pasello (Veneto Institute of Oncology, Italy) overviewed rare EGFR mutations as oncogenic drivers of lung cancer and (emerging) strategies to target these mutations.

Dr Addeo focused on EGFR exon 20 insertions, a heterogeneous group of mutations predominantly found between amino acids 766 and 775 of exon 20. The prevalence of EGFR exon 20 insertions in non-small cell lung cancer (NSCLC) is about 1.5% (4–10% of all EGFR mutations in lung cancer) and treatment outcomes for patients with EGFR exon 20 insertions are less favourable than those of patients with other EGFR mutations [1,2]. This is because the EGFR exon 20 insertions induce clinical resistance for the majority of standard tyrosine kinase inhibitor treatment options like erlotinib or gefitinib. This resistance is due to a conformational change in the alphaC-helix of the EGFR molecule caused by the exon 20 insertion, promoting the activation of the receptor.

Several drugs are developed that specifically target tumours with EGFR exon 20 insertions. Two of them, amivantamab and mobocertinib, respectively, are already FDA-approved for second-line treatment based on results from phase 1/2 trials [3,4]. Both amivantamab and mobocertinib are being evaluated as first-line treatment in two phase 3 trials (NCT04538664 and NCT04129502, respectively). In addition, other drugs are currently evaluated for their efficacy as second-line treatment in EGFR exon 20 insertion NSCLC in phase 1 or phase 1/2 trials, like osimertinib, poziotinib, tarloxotinib, CLN-081, and DZD9008. Objective response rates observed in these trials range from 15% to 40%.

However, there are still a lot of open questions, Dr Addeo said. “There is currently no data about intracranial efficacy of these drugs, about potential combinations of drugs, etc. Also, different EGFR exon 20 insertions might have different prognostic and/or predictive value.”

Next, Dr Pasello focussed on additional atypical or uncommon EGFR mutations, like G719X, S768I, and L861Q, with prevalences that are even lower than that of EGFR exon 20 insertions [5]. These mutations also render lung cancer cells less sensitive to current EGFR tyrosine kinase inhibitors, resulting in a shorter time to treatment failure, and shorter overall survival [6]. However, most data on tyrosine kinase inhibitor sensitivity of uncommon EGFR mutations are retrospective and based on low numbers of patients, Dr Pasello said. For example, a post-hoc analysis of 3 clinical trials (NCT00525148NCT00949650, and NCT01121393) showed that afatinib was active in NSCLC patients that harboured G719X, L861Q, or S768I mutations, but was less active in other mutations types, like exon 20 insertion mutations [7]. In addition, differences are observed between uncommon mutations in study outcomes. For example, response rate to osimertinib was higher for patients with an L861Q mutation compared with S768I mutation carriers, but response rate to afatinib showed the opposite relation [8].

Like in tumours with EGFR exon 20 insertions, also in tumours with other uncommon EGFR mutations the optimal sequence of treatment options is not yet known. When defining an optimal sequence, the presence of other mutations, safety profiles, and intracranial activity should be taken into consideration. Few data is available on the efficacy of (second-line) immune checkpoint inhibition in patients with uncommon EGFR mutations [9].

“Currently, data is lacking on other uncommon EGFR mutations, on the efficacy of EGFR tyrosine kinase inhibitors as adjuvant treatment in NSCLC with uncommon EGFR mutations, and on the efficacy of combination treatments with antiangiogenics and/or chemotherapy in NSCLC with uncommon EGFR mutations,” concluded Dr Pasello.

  1. Friedlaender A, et al. Nat Rev Clin Oncol 2022;19:51–69.

  2. John T, et al. Cancer Epidemiology 2022;76:102080.

  3. Park K, et al. J Clin Oncol 2021;39:3391–3402.

  4. Zhou C, et al. JAMA Oncol. 2021;7(12):e214761.

  5. Janning M, et al. Ann Oncol 2022;S0923-7534(22)00361–1.

  6. Robichaux JP, et al. Nature 2021;597:732–737.

  7. Yang J C-H, et al. Lancet Oncol. 2015;16: 830–838.

  8. Cho JH, et al. J Clin Oncol. 2020;38: 488–495.

  9. Yamada T, et al. Cancer Med. 2019;8:1521–1529.


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