Icotinib Plus Osimertinib Overcome EGFR 19del/T790M/C797S/V834L Quadruplet Resistance Mutation in a Patient with Non-Small Cell Lung Cancer
Lung adenocarcinoma driven by epidermal growth factor receptor (EGFR) mutations represents a significant subset of non-small cell lung cancer (NSCLC) cases. Tyrosine kinase inhibitors (TKIs) targeting EGFR have revolutionized treatment, yet resistance remains a critical challenge. This case report details the clinical trajectory of a 66-year-old woman with advanced NSCLC harboring a rare EGFR quadruplet mutation (19del/T790M/C797S/V834L), illustrating the evolving complexity of resistance mechanisms and therapeutic strategies.
Clinical Presentation and Initial Treatment
In April 2014, the patient presented with severe cough and was diagnosed with stage IV lung adenocarcinoma. Positron emission tomography/computed tomography (PET/CT) revealed a 2.0 cm × 2.0 cm lesion in the left lower lung lobe, mediastinal lymphadenopathy, pleural effusion, and multiple brain metastases. Pathological confirmation of adenocarcinoma was obtained via pleural core needle biopsy. Direct sequencing of tumor tissue identified an EGFR exon 19 deletion (19del), prompting first-line therapy with icotinib, a first-generation EGFR TKI, administered orally at 125 mg three times daily. Concurrently, she received intensity-modulated radiation therapy (IMRT) targeting brain metastases (56 Gy/28 fractions). The patient achieved a partial response (PR) by RECIST 1.1 criteria, sustaining remission for 30 months.
Disease Progression and Second-Line Therapy
In October 2016, disease progression manifested as enlargement of the left lung lesion (Figure 1B). Re-biopsy and analysis via amplification refractory mutation system polymerase chain reaction (ARMS PCR) confirmed the persistence of EGFR 19del and revealed the acquisition of the T790M resistance mutation. The patient was switched to osimertinib, a third-generation EGFR TKI, achieving another PR within three months (Figure 1C). However, nine months later, slow progression was observed in the lung lesion (Figure 1D).
Emergence of Quadruplet Mutation and Third-Line Therapy
Next-generation sequencing (NGS) of re-biopsied tumor tissue in July 2017 uncovered a complex resistance profile: EGFR 19del, T790M, C797G, and V834L mutations. The mutant allele fractions (MAFs) were 85.5%, 61.5%, 36.6%, and 91.1%, respectively. Notably, T790M and C797G were located in cis on the same allele. Based on preclinical evidence suggesting sensitivity to combined first- and third-generation TKIs when C797 mutations occur in trans, the patient received dual therapy with icotinib (125 mg three times daily) and osimertinib (80 mg once daily). Follow-up CT imaging after two months demonstrated stable disease (Figure 1E).
Subsequent Progression and Fourth-Line Treatment
Despite initial stability, the patient developed severe back pain four months into combination therapy. Magnetic resonance imaging (MRI) revealed multiple vertebral metastases. Circulating tumor DNA (ctDNA) analysis via NGS confirmed the persistence of the quadruplet mutation (19del/T790M/C797G/V834L) at low MAFs (0.4%, 0.3%, 0.6%, and 0.8%, respectively). Fourth-line therapy with carboplatin, pemetrexed, bevacizumab, and palliative vertebroplasty followed by vertebral irradiation was initiated, achieving stable disease at the last follow-up in April 2018.
Mechanistic Insights into Resistance and Therapeutic Implications
The EGFR C797S/G mutation is a well-characterized resistance mechanism to third-generation TKIs like osimertinib, disrupting covalent binding to the kinase domain. Preclinical models indicate that T790M and C797S/G in cis confer resistance to combination TKIs, whereas in trans configurations may retain sensitivity. This case highlights the clinical relevance of these findings, as the patient’s in cis T790M/C797G likely contributed to the transient efficacy of dual TKI therapy.
The V834L mutation, rarely reported in literature, was initially hypothesized to correlate with prolonged progression-free survival (PFS). However, its role in modulating TKI sensitivity remains unclear. In this patient, the high MAF (91.1%) of V834L at progression suggests a potential contribution to resistance, warranting further investigation into its functional impact on EGFR signaling and drug binding.
Discussion of Therapeutic Strategies
The sequential use of EGFR TKIs in this case underscores the importance of repeated molecular profiling to guide treatment. Initial resistance to icotinib was driven by T790M, the “gatekeeper” mutation, which was effectively targeted by osimertinib. Subsequent acquisition of C797G and V834L reflects the remarkable plasticity of EGFR-driven tumors under TKI pressure.
While combination TKIs provided temporary disease control, the eventual progression emphasizes the limitations of current strategies. The low MAFs of mutations in ctDNA at vertebral progression suggest spatial heterogeneity or clonal evolution, necessitating broader targeting approaches. Chemotherapy and anti-angiogenic agents (e.g., bevacizumab) may remain essential in managing polyclonal resistance.
Conclusion
This case illustrates the dynamic landscape of EGFR mutation-driven resistance in NSCLC. The emergence of the quadruplet mutation (19del/T790M/C797G/V834L) following sequential TKI therapy highlights the need for longitudinal genomic monitoring and personalized therapeutic regimens. While combination TKIs may offer transient benefit in specific mutational contexts, durable responses require novel agents targeting complementary pathways or allelic configurations. Future studies should explore the biological significance of V834L and optimize combinatorial strategies to overcome in cis resistance mutations.
doi.org/10.1097/CM9.0000000000000196
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