Prolonged response to first-generation tyrosine kinase inhibitor in a metastatic non-small cell lung cancer harbouring complex G719X and S768I mutations: A case report from Vietnam and literature review

Lung cancer is among the most common and fatal cancers worldwide. Understanding molecular pathways has enabled targeted therapies, particularly for EGFR-mutated non-small cell lung cancer (NSCLC). Sensitizing EGFR mutations (exon 19 deletions and exon 21 L858R) are associated with substantial improvements in progression-free and overall survival with EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of first-generation TKIs for uncommon EGFR mutations remains uncertain. The authors report a patient with stage IV lung adenocarcinoma harboring rare compound EGFR mutations G719X (exon 18) and S768I (exon 20) who achieved a successful and prolonged response to first-generation TKI gefitinib for 44 months without serious adverse events.

Uncommon EGFR mutations comprise a heterogeneous group of alterations in exons 18–25 with generally reduced sensitivity to EGFR TKIs compared with common mutations. In clinical trials, 7%–23% of EGFR-mutant NSCLC cases harbor uncommon mutations. Complex (compound) mutations are frequent among the uncommon set; one study reported 53% of uncommon cases carried complex mutations. The specific combination G719X+S768I is extremely rare, representing less than 0.3% of all EGFR-positive NSCLC, with approximately 60 cases reported since its first description in 2012. - Third-generation TKI (osimertinib): Limited data exist for G719X+S768I. In the AURA program, one patient with this compound mutation treated with osimertinib 80 mg/day had a total treatment duration of 5.6 months. A multicenter phase II trial reported outcomes for uncommon mutations overall, with progression-free survival (PFS) under 13 months for patients with G719X and/or S768I, without separate reporting for the exact compound. Case reports show variability: Cai et al. described a response >31 months, whereas Zapata Laguado et al. reported progression after 4 months on first-line osimertinib. - Second-generation TKI (afatinib): More extensive clinical data are available. In pooled LUX-Lung analyses, patients with G719X and/or S768I had median PFS approximately 13–15 months. Case reports in patients with G719X+S768I showed responses lasting 12–17 months, though gastrointestinal toxicities were noted and dose reduction occurred in one case. - First-generation TKIs (gefitinib/erlotinib): Retrospective analyses and case reports show mixed outcomes. Chiu et al. reported median PFS 11.9 months in patients with G719X combined with S768I or L861Q. Svaton et al. reported PFS of 8 months with gefitinib. Lund-Iversen et al. documented a 14-month response to gefitinib. Yu et al. reported three patients with G719X+S768I treated with first-generation TKIs: disease control ranged from stable disease for just over 2 months to prolonged responses, with PFS and OS spanning 2–18 months and 2–44 months, respectively. Overall, literature indicates variable sensitivity of G719X+S768I to different TKIs, with some patients deriving durable benefit from first-, second-, or third-generation agents.

Case presentation: A 68-year-old male with a 2-year history of hypertension (on amlodipine) presented in June 2019 with dry cough, right-sided chest pain, and mild dyspnea. Imaging: Contrast-enhanced chest CT showed a large right lung mass measuring approximately 55 × 120 mm. PET/CT demonstrated a 5 × 12 cm hypermetabolic tumor in the right pulmonary lobe with multiple bilateral pulmonary nodules. Brain MRI and bone scan showed no metastases. Histopathology: CT-guided lung biopsy confirmed adenocarcinoma. Molecular testing: Real-time PCR detected compound EGFR mutations—G719X (exon 18) and S768I (exon 20). Treatment: After counseling on efficacy and costs of different TKI generations, the patient selected gefitinib (first-generation) 250 mg orally once daily due to financial constraints. Follow-up and outcomes: After 6 months, clinical symptoms (cough, chest pain) improved and imaging showed significant reduction in lung lesions (partial response). The patient continued gefitinib 250 mg daily with ongoing disease control; at the time of reporting, he had maintained a response and clinical stability for 44 months without adverse events of grade ≥2.

- Rare compound EGFR mutations G719X (exon 18) and S768I (exon 20) identified by PCR in a metastatic lung adenocarcinoma. - First-line gefitinib 250 mg daily led to symptomatic improvement and radiographic partial response at 6 months. - Durable disease control maintained for over 44 months on continuous gefitinib therapy. - No serious adverse events (no ≥ grade 2 toxicities) reported during treatment. - Case adds to literature showing that some NSCLC patients with G719X+S768I can experience prolonged benefit from first-generation TKIs, despite overall variable outcomes reported for uncommon EGFR mutations.

EGFR TKIs provide substantial benefit in NSCLC with common sensitizing mutations, but responses among uncommon mutations vary. The compound G719X+S768I mutation is rare and historically associated with inconsistent TKI sensitivity. Review of published data shows variable efficacy across TKI generations: afatinib demonstrates median PFS around 13–15 months in G719X and/or S768I cohorts; osimertinib has shown both durable and short-lived responses in individual reports; and first-generation TKIs have achieved outcomes ranging from brief stability to prolonged responses. In this context, the reported patient’s >44-month response to gefitinib is notable and suggests that first-generation TKIs can be effective for select patients with G719X+S768I. The case underscores the heterogeneity within uncommon EGFR alterations and highlights the need for individualized treatment decisions, considering clinical factors, access, cost, and potential toxicity profiles.

This case report documents a Vietnamese patient with metastatic NSCLC harboring rare compound EGFR mutations G719X and S768I who achieved a prolonged response exceeding 44 months on first-line gefitinib without significant toxicity. Although literature reports inconsistent outcomes with first-generation TKIs in this genotype, this case supports the potential effectiveness of gefitinib in select patients. Further studies and larger datasets are needed to define optimal TKI selection and to better characterize predictors of response for uncommon EGFR compound mutations.

This is a single-patient case report, limiting generalizability. Molecular profiling used real-time PCR rather than broader next-generation sequencing, which may not capture co-mutations that could influence response. There was no comparative control or standardized response assessment schedule beyond clinical practice. Existing literature on G719X+S768I is limited and heterogeneous, complicating definitive conclusions about optimal TKI choice.