How do you treat a patient with widely metastatic, non T790M mutated, EGFR exon 20 insertion mutated lung cancer?

The EGFR exon 20 insertion mutations represent approximately 9% of all EGFR mutations, and affect a similar demographic/clinical group - never/light smokers, adenocarcinoma, tending towards a younger age (Oxnard et al., PMID 23328547). Unfortunately, the data (preclinical and clinical) to date do not support the use of 1st or 2nd generation TKIs in this patient population (Yasuda et al., PMID 24353160). The exception to this appears to be the A763_Y764insFQEA insertion mutation which more closely resembles the typical sensitizing mutations (Yasuda et al., PMID 24353160).

For these reasons, I typically treat patients (young or old) who bear this mutation with cytotoxic chemotherapy as their initial treatment (most commonly pemetrexed and carb...

Aside from poziotinib study, TAK-788 has shown signs of clinical activity in early clinical testing reported in ASCO 2018 (http://abstracts.asco.org/214/AbstView_214_209573.html).

Based on IMPOWER 150 results first reported in late 2017, updated results shown in ASCO 2018 (http://abstracts.asco.org/214/AbstView_214_215917.html) comparing carbo/pac/atezo versus carbo/pac/atezo/bev demonstrate that the quadruplet combination (chemo+anti-VEGF+IO) is superior to chemo+IO and chemo among patients with EGFR/ALK aberrations (NB. exon 20 insertion not specifically reported, hence extrapolating with the more common alterations). Hence, in the absence of an FDA-approved, available, effective oral TKI, first-line consideration would be chemo+bev+IO fo...

I agree with @Dr. First Last. Patients with EGFR exon 20 mutation tend to have disease that is refractory to 1st and 2nd generation TKIs. There are no standard targeted therapies for this subgroup of patients. I generally treat with standard platinum/pemetrexed chemotherapy or consider a clinical trial.

What a difference 3 years make! Aside from poziotinib and mobocertinib (aka TAK-788), we now also have early data regarding other small molecules in development (CLN-081) and even an EGFR-MET bispecific antibody (amivantamab) showing response rates up to 40% for amivantamab which received US FDA breakthrough therapy designation in 2020. Combination of amivantamab with lazertinib (3rd generation mutant-selective wildtype-sparing EGFR TKI) is also being investigated in this population. The results of ECOG/ACRIN 5162 phase II study of osimertinib 160 mg in this population were also reported in ASCO 2020, with ORR of 25%. Other small molecule inhibitors investigating EGFR exon 20/HER2 exon 20 mutations in development include pyrotinib, almonert...

We currently have data supporting the use of amivantamab in combination with chemotherapy in the first-line setting. The PAPILLON study (Zhou et al., PMID 37870976) showed superior PFS (HR by BICR 0.4, p<0.001) and ORR compared to chemotherapy alone in this patient population. Interim OS analysis reported at that time also showed a trend towards OS superiority (HR 0.67, p=0.11). Subsequent OS analyses using different statistical methods to adjust for the impact of cross-over (66% of patients in the control arm who had disease progression) indicated improved HR as well (HR ranging from 0.52-0.6).

Recently, at the ASCO 2026 annual meeting, the phase III WU-KONG28 study comparing sunvozertinib as monotherapy (300 mg once daily dose) versus chem...

Poziotinib trial, if not, chemo therapy.