EGFR G724S

Conclusions : To our knowledge, this is the largest liquid biopsy analysis comparing common/uncommon ex19dels in NSCLC and shows similar genomic findings across groups. Further work should be done to explore additional genomic and non-genomic factors to aid in patient selection for EGFR TKIs for uncommon findings.

EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.

P1, N=170, Recruiting, ArriVent BioPharma, Inc.

P1, N=170, Recruiting, ArriVent BioPharma, Inc. | Phase classification: P1b --> P1

She was treated with intrathoracic infusion chemotherapy (pemetrexed 200mg+nedaplatin 20mg) on October 11, 2018...Based on the above findings, the patient was administered with gefitinib 250 mg daily as first-line therapy on November 15, 2018, and achieved partial response (PR)...On January 25, 2022, the patient was hospitalized for shortness of breath, and received intrathoracic Infusion chemotherapy (cisplatin 80mg)... The combination therapy of afatinib and osimertinib could be a new therapeutic option for patients with lung adenocarcinoma harboring EGFRG724S/T790M/19Del mutation.

Recently, we read a paper "Dacomitinib overcomes afatinib-refractory carcinomatous meningitis in a lung cancer patient harbouring EGFR Ex.19 deletion and G724S mutation" published in Investigational New Drugs. To share our experience, we present a case of 58-year-old man with a long-term response to afatinib in a patient with previously unreported compound EGFR mutation. In patients with rare compound EGFR mutations, afatinib might be one of the treatment option.

A patient diagnosed with advanced EGFR-mutated (exon 19 deletion) NSCLC after several lines of treatment - gefitinib, osimertinib, heat shock protein inhibitors and chemotherapy-developed EGFR G724S mutation retaining the exon 19 deletion. She was then treated successfully with afatinib leading to a progression free survival of 9 months (and counting). This is the first report of the emergence of G724S mutation, together with ex19del, after three subsequent lines of therapy following progressive disease to Osimertinib, and we report for the first time the activity of afatinib against EGFR exon 18 G724S mutation in this setting.

Dacomitinib may be effective choice in afatinib-refractory carcinomatous meningitis harboring G724S mutation. This is the first case report showing that a change to dacomitinib responded to afatinib refractory cancerous meningitis.

Acquired resistance in EGFR mutant NSCLC remains very heterogeneous; the frequency of individual mutations is low, one of the reasons might be lack of testing at resistance. While T790M and C797S mutations are well described, this report also documents a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the need to increase NGS evaluation of patients with EGFR mutant lung cancers who have developed clinical resistance.

This study indicated a worse response and prognosis of patients with NSCLC harboring complex EGFR mutations than those harboring common EGFR mutations when treated with dacomitinib. Further studies and data are needed to confirm this conclusion.

Afatinib should be considered as a first-line treatment option for NSCLC patients with major uncommon, compound, 'other' (including E709X and L747X) and some specific exon 20 insertion mutations. Moderate activity was seen against osimertinib resistance EGFR mutations.

Pts with an identified mechanism of resistance did not have improved post-progression survival (12 mo HR 1.6, p = 0.09), but receiving next line of therapy based on post-progression tumor biopsy results (including platinum-etoposide for transformation) did improve post-progression survival (12 mo HR 0.4, p = 0.01). Pts with atypical EGFR drivers or concurrent TP53+/-RB1 alterations have significantly shorter rwPFS on first line osimertinib, highlighting need for additional interventions for these patients. Given the high frequency of transformation and improvement in post-progression survival by tailoring next line of therapy to the identified mechanism, pts with EGFR-mutant lung cancer on first line osimertinib may benefit from tissue biopsies at progression. For pts without an identified resistance mechanism by NGS, additional methods of interrogating tumors at progression are needed.

In the subset who had progressed on osimertinib, afatinib also yielded a superior progression-free survival (6.2 mo) than non-afatinib therapies (1.0 mo, HR = 0.04, p = 0.005) and alternative EGFR TKIs (1.8 mo, HR = 0.06, p = 0.033). EGFR G724S emerges as a resistant mutation against EGFR TKI preferentially in the context of a rare variant of 19del, whereas it might mediate differential mechanisms in the context of exon 20 mutation. We also found that afatinib could be a potential therapeutic option for patients with NSCLC with G724S.

We analysed the interaction of three drugs(Afatinib, Gefitinib, Osimertinib) with EGFR from three aspects: the spatial structure of the binding region, the scoring function value and the interaction force between drug molecules and active center of EGFR. Treated with Afatinib, he received a progression-free survival(PFS) of more than 1 year. With the guidance of this case report, we provide the clinical evidence of using Afatinib for G724S-mutant patients and obtain long-term clinical survival.

15 pts with known acquired EGFR resistance mutations to osimertinib (osi; G724S, L718X, C797S) were given afa post osi: ORR: 36%. Afa showed activity against major uncommon, compound, other (including E709X and L747X) and some specific ex20ins mutations. Afa showed activity against major uncommon, compound, other (including E709X and L747X) and some specific ex20ins mutations. The data support the use of afa in these settings. Moderate activity was seen post-osi.

In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit.

Third-generation inhibitors of the epidermal growth factor receptor (EGFR), best exemplified by osimertinib, have been developed to selectively target variants of EGFR bearing activating mutations and the mutation of gatekeeper T790 in patients with EGFR-mutated forms of Non-Small Cell Lung Cancer (NSCLC)...The challenge of overcoming newly developed and recurrent resistances mediated by EGFR-mutations is thus driving the search of alternative strategies in the design of new therapeutic agents able to block EGFR-driven tumor growth. In this manuscript we review the recently emerged EGFR-dependent mechanisms of resistance to third-generation inhibitors, and the achievements lately obtained in the development of next-generation EGFR inhibitors.

Funding: Foundation Medicine Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance... Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition . EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.

Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes.

Based on these findings, the patient was administered with afatinib (a dose of 30 mg/d) combined with bevacizumab. Conclusion This is the first report of co-mutation of EGFR R776H/G724S in a patient with lung adenocarcinoma. Afatinib may be a beneficial therapeutic option for a subset of NSCLC with rare EGFR co-mutation.

Results EGFR G724S was identified from 2 patients prior to the administration of any treatment, (baseline) from 1 patient after gefitinib failure and from 5 patients after osimertinib failure. Conclusion Our study provides clinical evidence that afatinib monotherapy could be a potential therapeutic option for NSCLC patients with EGFR G724S. Further studies for evaluating the efficacy of afatinib in advanced NSCLC patients harboring EGFR G724S and the underlying resistance mechanism are warranted.

The study revealed heterogeneous mechanisms of resistance to osimertinib in advanced NSCLC patients and their association with clinical outcomes. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism had longer clinical outcome benefits.

Our study provides clinical evidence of the efficacy of combinatorial regimen with either first- or third-generation EGFR-TKI and crizotinib after the emergence of MET amplification-mediated EGFR-TKI resistance in patients with EGFR-mutant NSCLC.