Erlotinib response in a NSCLC patient with a novel compound G719D+L861R mutation in EGFR

CASE REPORT

A 62 year old never smoker Caucasian female was diagnosed with Stage IV lung adenocarcinoma. Staging revealed a left lower lobe primary, an associated pleural effusion and multiple bony and hepatic metastases (Figure 1). An IR-guided core biopsy of the primary lesion was performed, which demonstrated a well differentiated adenocarcinoma that was TTF-1 and CK7 positive and CK20 negative by immunohistochemistry. EGFR mutation analysis was performed via the EGFR RGQ PCR assay (Qiagen, Manchester, UK) showing a G719X mutation (exon 18). The patient was started on erlotinib at 150mg daily. Restaging PET/CT revealed decreased size and metabolic activity of the primary lesion and resolution of a hepatic metastasis (Figure 1). Approximately 9 months after starting erlotinib, restaging PET/CT revealed disease progression with new left pleural thickening and worsening effusion. A left sided VATS/biopsy and pleurodesis was performed for symptom management and further molecular diagnostics. Mutational analysis performed at the Colorado Molecular Correlates Laboratory (CMOCO) at the University of Colorado Hospital using the ABIPrism SNaPshot multiplex PCR platform (Applied Biosystems, Forest City, CA) followed by direct sequencing duplicated her previously known G719X mutation, which was further clarified to be a c.2156G>A (p.G719D) mutation in addition to a c.2582T>G (p.L861R) point mutation in exon 20 (Figure 2). Repeat molecular testing of the patient’s original diagnostic biopsy was performed at CMOCO, with both mutations (G719D and L861R) identified. The patient continued on erlotinib post-procedure in anticipation of enrollment in a clinical trial when she presented with progressive confusion, memory loss and disease progression in the CNS by MRI. The patient elected to forgo further therapy and enrolled in hospice, passing 11 months after initial diagnosis.

Figure 1.

Combined positron emission tomography/computed tomography images with Thoracic imaging (Panels A and B) demonstrating disease burden at initial staging (A) and intial response (B). Axial images of hepatic metastases (C and D) from intial staging (C) and initial response (D).

Figure 2.

Chromatograms demonstrating EGFR mutations - G719D exon 18 (A) and L861R in exon 21 (B) as detected in the October 2012 re-biopsy sample. Both mutations were identified in the pre-treatment sample upon repeat analysis.

COMMENT

Missense mutations at position 719 in exon 19 of EGFR gene (G719A/S/V/D) have been previously described, occurring in approximately 3% of all known EGFR mutations and cause constitutive activation of EGFR.^{1,2, 3} Mutations in position 861 (most commonly L861Q) have been described, occurring in approximately 2% of all EGFR mutant patients.¹ The specific mutations identified in this case are the least common of mutations at these two loci, and compound mutations with G719D and L861R have not been previously described. A recent retrospective analysis described objective response rates (ORR) of 53.3% on EGFR TKI’s with a median progression free survival (PFS) of 8.1 months, and a median overall survival (OS) of 16.4 months in a G719X patient cohort with additional L861Q EGFR mutated patient cohort with a ORR of 60%, PFS of and OS of 6.0 and 15.2 months, respectively, which were comparatively worse than the cohort harboring the more common deletion 19 and L858R mutations (ORR 74.1%, PFS 8.5 months, OS 19.6 months).⁴ Direct sequencing of exon 18–21 in 79 known EGFR mutation positive patients demonstrated a compound mutation rate of 14% with 3 response evaluable patients harboring a G719X compound mutation and modest response to erlotinib with no PR greater than 8 months and no OS greater than 12 months.⁵ These outcomes are consistent with our patient’s excellent but short lived response.