Case Report: Afatinib Treatment in a Patient With NSCLC Harboring a Rare EGFR Exon 20 Mutation

Unlike most other primary epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), exon 20 insertions, comprising approximately 4% to 10% of all EGFR mutations, are generally considered to be resistant to EGFR tyrosine kinase inhibitors (TKIs). However, EGFR exon 20 insertions are structurally and pharmacologically heterogeneous, with variability in their position and size having implications for response to different EGFR TKIs. The second-generation ErbB family blocker, afatinib, is approved for the first-line treatment of EGFR mutation-positive NSCLC and has been shown to have a broad inhibitory profile against common and uncommon EGFR mutations. Here, we describe a patient with bilateral multifocal lung adenocarcinoma harboring a very rare EGFR exon 20 insertion (c.2317_2319dup3; p.H773dup), who has been receiving treatment with afatinib for 4.5 years. To our knowledge, this is the first report describing long-term benefit for a patient treated with afatinib with this rare exon 20 insertion. We are aware of two further cases with this rare EGFR mutation. One patient, also reported here, has early-stage lung adenocarcinoma and has not yet received systemic therapy for NSCLC. The other patient received afatinib in the context of a global compassionate use program and had progressive disease. Our findings may be of clinical relevance for patients carrying tumors with this rare mutation as epidemiological evidence suggests that p.H773dup may function as a driver mutation in NSCLC. Together with previous preclinical and clinical evidence for the activity of afatinib against certain EGFR exon 20 insertions, these findings warrant further investigation.

Afatinib as a novel potential treatment option for NRG1 fusion-positive tumors.

110 Background: Neuregulin 1 (NRG1) is a growth factor that binds HER3/4 and activates ErbB signalling pathways. NRG1 gene fusions function as oncogenic drivers and represent a potential therapeutic target across tumour types. Afatinib, an ErbB-family blocker, is a potential treatment option for some patients with NRG1 fusion-positive ( NRG1+) tumours, as supported by preclinical evidence and clinical case reports. Of 13 patients with NRG1+ lung adenocarcinoma (ADC; n = 9), pancreatic ADC (n = 2), cholangiocarcinoma (n = 1), and ovarian cancer (n = 1) treated with afatinib, eight patients achieved a best response of partial response (PR; median duration 7.3 months, range 3–12), three patients had stable disease (SD) and two patients had progressive disease. Methods: Here, we report the clinico-pathological and molecular characteristics and current status of four additional cases of afatinib-treated NRG1+ tumours. Results: Patient 1, 66 year-old female, never-smoker with metastatic non-mucinous lung ADC. CD74-NRG1 fusion was identified, and 5th-line afatinib initiated. PR is ongoing after 16 months. Patient 2, 43 year-old female, non-smoker with advanced invasive mucinous lung ADC. CD74-NRG1 fusion was identified and 3rd-line afatinib initiated (PR, 18 months); treatment is ongoing following local progression. Patient 3, 69 year-old male, with KRAS-mutated metastatic colorectal cancer. Following a right hemicolectomy and liver/lung metastasectomies, a novel POMK-NRG1 fusion was detected and afatinib initiated (SD, 4 months). Eight months after initiation, afatinib treatment is ongoing, in combination with radiotherapy, with SD. Patient 4, 54 year-old male, with KRAS-wild-type metastatic pancreatic cancer. Following progression on chemotherapy, APP-NRG1 fusion was detected as part of the Personalized Oncogenomics study (NCT02155621), and afatinib initiated; PR is ongoing after 7 months. Conclusions: These findings add to a growing body of evidence that afatinib is a potential treatment option for patients with NRG1+ tumours. Prospective study is ongoing/planned in the Drug Rediscovery Protocol trial (DRUP; NCT02925234) and Targeted Agent and Profiling Utilization Registry study (TAPUR; NCT02693535).