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 remains a leading cause of cancer-related deaths globally. The discovery of molecular pathways involved in lung cancer development has revolutionized treatment, particularly with the advent of targeted therapies for specific gene mutations. EGFR mutations are prevalent in NSCLC, especially in Asian populations, with exon 19 deletions and the L858R mutation showing significant response to EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of TKIs, especially first-generation ones, for uncommon EGFR mutations remains unclear. This study presents a case of a patient with stage IV lung adenocarcinoma featuring a rare combination of G719X and S768I EGFR mutations who exhibited an unexpectedly prolonged and successful response to first-generation TKI gefitinib. This unusual response warrants investigation and further research into the effectiveness of first-generation TKIs in patients with these complex mutations.

The complex G719X and S768I EGFR mutations are exceedingly rare, comprising less than 0.3% of all EGFR-positive NSCLC cases. Published literature shows inconsistent responses to various TKIs in patients with these mutations. While third-generation TKIs like osimertinib are recommended for EGFR-sensitive advanced NSCLC, clinical data on their use for this specific compound mutation is limited. Studies have reported variable outcomes, ranging from prolonged responses (over 31 months) to disease progression within 4 months. Similarly, afatinib, a second-generation TKI, has shown responses lasting over a year in some cases, but also notable gastrointestinal toxicities. Several case reports have also shown promising results with first-generation TKIs (gefitinib and erlotinib), but further research is needed to clarify the efficacy and predictability of these treatments for patients with this rare mutation profile. The inconsistent outcomes reported highlight the need for more robust research to guide treatment decisions for this patient population.

This study is a case report detailing the clinical course of a 68-year-old male patient diagnosed with stage IV lung adenocarcinoma harboring the G719X and S768I EGFR mutations. Diagnosis was confirmed through CT scan, PET scan, MRI, bone scan, and CT-guided lung biopsy. Molecular analysis using real-time PCR identified the complex EGFR mutations. The patient, due to financial constraints, opted for first-generation TKI gefitinib (250mg daily). Clinical response was assessed through monitoring of symptoms (cough, chest pain, dyspnea), and imaging (chest CT scans). The study also involved a comprehensive literature review of existing reports on the treatment of NSCLC patients with the G719X and S768I compound mutation to compare the observed response to findings in the literature. The duration of response and presence of adverse events were meticulously documented. The images from the CT scans taken at the time of diagnosis, after 6 months of treatment and after 44 months were presented to illustrate the response to the treatment.

The patient demonstrated a remarkable response to gefitinib, maintaining stable disease for 44 months without experiencing any grade 2 or higher adverse events. Imaging studies showed a partial response in both the primary tumor and bilateral pulmonary nodules after 6 months of treatment, which was sustained throughout the 44-month follow-up. This contrasts with the inconsistent outcomes observed in the literature, which ranged from short-lived responses (less than a month) to prolonged responses (over 44 months) across different TKI regimens. The review of literature shows variable efficacy and toxicity profiles associated with the use of first, second and third generation TKIs to treat NSCLC with G719X and S768I mutations. The median PFS reported in the literature was under 13 months.

This case report highlights an exceptional response to first-generation TKI gefitinib in a patient with advanced NSCLC harboring the rare G719X and S768I EGFR mutations. The 44-month duration of response is noteworthy, particularly given the heterogeneity of responses reported in the literature. While this case demonstrates the potential efficacy of gefitinib, it underscores the unpredictable nature of treatment response for this uncommon mutation. This variability warrants further research to identify predictive biomarkers that might guide treatment selection and improve patient outcomes. The financial constraints of the patient played a role in the choice of the treatment, highlighting the inequalities in access to expensive newer generation TKIs. Further research is needed to better understand the response to different TKI regimens for this rare mutation combination.

This case report demonstrates a prolonged and successful response to first-generation TKI gefitinib in a patient with advanced NSCLC carrying the rare G719X and S768I EGFR mutations. This finding, along with the literature review, underscores the need for larger prospective studies to elucidate the optimal treatment strategies for this specific patient population. Future research should focus on identifying predictive biomarkers and clarifying the role of different generations of TKIs in managing NSCLC with complex EGFR mutations.

This study's primary limitation is its single-case nature, making it challenging to generalize the findings. Further research with larger sample sizes is needed to validate the observations. The absence of a control group also limits the ability to establish a causal relationship between gefitinib and the observed clinical response. The financial circumstances influencing the patient's treatment choice might not reflect the standard approach of cancer treatment.