Epidermal Growth Factor Receptor Kinase Domain Duplication in Lung Adenocarcinoma with Response to Osimertinib: A Case Report and Literature Review

Abstract

Introduction

Liquid and tissue next-generation sequencing (NGS) are both important in oncological care. We report a case of metastatic non-small cell lung adenocarcinoma (NSCLC) with a rare epidermal growth factor receptor kinase domain duplication (EGFR-KDD) identified on liquid biomarker testing which led to sustained targeted treatment.

Case Presentation

A 54-year-old male was diagnosed with metastatic NSCLC and progressed on multiple lines of therapies: carboplatin-pemetrexed-pembrolizumab, cisplatin-docetaxel, and durvalumab-tremelimumab over a 6-month period. Liquid NGS identified a rare EGFR-KDD mutation that was treated with osimertinib leading to 5 months of progression-free survival and significant clinical improvement before ultimately opting for hospice due to intolerance with osimertinib.

Conclusion

Liquid and tissue NGS should be used in combination to guide treatment and monitor treatment response. Osimertinib may be particularly effective in metastatic NSCLC with EGFR-KDD mutations.

Introduction

Comprehensive genomic testing is fundamental for the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). The testing of circulating tumor for the identification of actionable genetic alterations has been approved by the FDA in 2020, and current NCCN Guidelines recommend its use in conjunction (not in lieu of) with tissue next-generation sequencing (NGS) testing, especially in instances where there are concerns regarding tissue sample adequacy for testing [1]. Studies have shown that utilizing circulating tumor DNA testing can accelerate time to treatment, aid in screening for local recurrence, and guide de-escalation of therapy [2–4].

We present a case of metastatic NSCLC found to have a rare epidermal growth factor receptor kinase domain duplication (EGFR-KDD) through liquid biomarker testing. After the patient failed multiple lines of treatment, liquid biopsy revealed an EGFR-KDD mutation and achieved a response to third generation EGFR tyrosine kinase inhibitor (TKI) treatment. The case emphasizes the importance of early companion liquid biomarker testing to guide oncological treatment. We also engage in a review of the literature regarding EGFR-KDD mutations and current therapies.

Case Report

A nonsmoking 54-year-old male presented to a hospital in Nevada originally in September 2022 for 2 months of worsening lower back pain. MRI and CT scans showed nodules with the right middle and lower lung lobes, mediastinal and supraclavicular lymph nodes, multiple lesions in the L1–L3 vertebral bodies, R iliac bone. He underwent bone biopsy, positive for NSCLC adenocarcinoma, CK7 and TTF-1-positive, PD-L1 8%. Unfortunately, due to decalcification of the bone biopsy, NGS was not sent. He underwent 30 Gy in 10 fractions of palliative radiation to the right hip in October 2022 with improvement in symptoms. He was initiated on triplet therapy with carboplatin, pemetrexed, and pembrolizumab in October 2022, upon completion of radiation. His first dose of pembrolizumab was complicated by severe nausea, vomiting, subacute rash, and acute lower extremity peripheral neuropathy requiring cessation of further pembrolizumab. He completed 4 cycles of carboplatin-pemetrexed in January 2023 and repeat PET-CT was obtained demonstrating mixed response, increased activity in pulmonary nodules, and improvement in metastatic bone disease, and he was transitioned to cisplatin-docetaxel. In March 2023, he completed 2 cycles of cisplatin-docetaxel. He was admitted in April 2023 for left popliteal vein DVT and a saddle pulmonary embolism. In April 2023, PET-CT showed increased spread of the cancer with extension to the right upper lobe, enlargement of the mediastinal nodes, new bony metastases to the right proximal humerus, right scapula, lower cervical/thoracic/lumbar spine.

In April 2023, he was transitioned to durvalumab-tremelimumab. One cycle after the dual checkpoint inhibition, his course was further complicated by CVA of the left middle cerebral artery requiring thrombectomy. MRI brain showed numerous brain metastases in the left hemicerebellum and cerebrum. He underwent 30 Gy in 10 fractions of whole brain radiation therapy, followed by 30 Gy in 10 fractions of palliative re-irradiation therapy to his spine. In October 2023, PET-CT showed significantly increased size of right hilar mass, multiple new osseous metastases, and new gastrohepatic lymph nodes.

He transferred care to the Cleveland Veteran Affairs Hospital in October 2023. On initial interview, he endorsed pain requiring oxycodone ER 30 mg q8h, oxycodone IR 15 mg q4h as needed, cough requiring ipratropium/albuterol, guaifenesin, benzonatate as needed and had an oxygen saturation of 93% on 2 L of oxygen delivered by nasal cannula. FoundationOne Liquid CDx was sent on October 26, 2023, while arrangements were made for tissue biopsy. After a 10-day turnaround time, FoundationOne Liquid CDx returned on November 5, 2023, positive for EGFR-KDD with a variable allelic frequency of 8.4%. Due to advanced burden of disease, including brain metastases, he started 80 mg osimertinib on November 10, 2023, while also undergoing endobronchial biopsy of lymph node 11R. Tissue pathology resulted on November 14, 2023, consistent with adenocarcinoma, again positive for CK7, TTF-1. NGS of the lymph node biopsy was sent, but the commercial platform did not identify targetable mutations including EGFR-KDD. Within 2–4 weeks of osimertinib initiation, he endorsed a dramatic clinical response with improvement in cough and was no longer requiring oxygen to maintain adequate saturation. His pain requirements decreased dramatically – only requiring oxycodone ER 30 mg BID and oxycodone IR 15 mg once daily for breakthrough, corresponding to a 113 decrease in daily morphine milligram equivalents.

About 5 weeks into treatment, the patient developed progressive nausea and emesis. He was initially managed with olanzapine 5 mg at bedtime and ondansetron 8 mg TID as needed. Without dose interruption, he eventually progressed to grade III nausea and emesis, and osimertinib was temporarily withheld, and the patient was managed with olanzapine (5 mg QHS) and ondansetron (8 mg TID as needed). Two weeks after holding osimertinib, he was resumed with a dose reduction from 80 mg to 40 mg on December 19, 2023. Following dose interruption/reduction, he reported worsening pain and dyspnea requiring 2 L of oxygen by NC for adequate saturation. He was transitioned back to 80 mg on January 2, 2024. PET/CT 8 weeks after initiation showed stable R hilar mass, stable mediastinal lymph nodes, widespread osseous metastases, corresponding with stable disease. Repeat PET/CT in February 2024 showed stable disease; however, laboratory work showed new elevated transaminases and symptomatic anemia requiring blood transfusion. After discussion with patient and family, the decision was made to focus on maximizing quality of life and he was transitioned to hospice care before ultimately passing on March 25, 2024 (shown in Fig. 1). The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545543).

Fig. 1.

Timeline of significant events. The timeline details several significant events over our patient’s treatment time course: initial diagnosis, progression of 3 treatments, followed by 5 months of progression-free response, and eventual transition to hospice care.

Discussion

Paired liquid biomarker testing remains an essential component of oncological care providing guidance on therapy selection, detecting residual disease, and monitoring early therapy response [5]. In this case, liquid biopsy testing played a key role in detecting a rare genetic tumor mutation that helped guide sustained treatment.

EGFR-KDDs have been estimated to be found in approximately 0.12% of advanced NSCLC [6]. There is currently no standard of care treatment for these individuals with this rare, non-actionable EGFR mutation. The current paradigm for metastatic NSCLC is to test for PD-L1 expression and proceed with systemic chemotherapy, followed by immunotherapy as first-line treatment [7]. As seen in our patient, individuals with EGFR-KDD mutations may respond poorly to systemic chemotherapy and he unfortunately progressed on three treatment regimens. He was able to obtain 5 months of progression-free survival (PFS) from osimertinib which is shorter than other documented responses, possibly due to these prior lines of therapy. He had to dose reduce osimertinib for grade III emesis and was unable to tolerate the retrial at 80 mg dose due to emesis, fatigue, and anemia requiring blood transfusions. Ultimately, his unsatisfactory quality of life on osimertinib led to his decision to pursue best supportive care and enroll in hospice. Our case highlights the importance of early testing for targetable mutations which may lead to improved and sustained responses.

Patients with these mutations have experienced clinical benefit when treated with afatinib and osimertinib [8–15] (Table 1). While there are few case reports of EGFR-KDD, metastatic NSCLCs have responded well to osimertinib, the longest with PFS of 21 months [9]. There were 2 cases of metastatic NSCLC with lesions to the brain, treated with osimertinib with clinical response [10, 11]. Our patient experienced 5 months of clinical improvement while on this targeted TKI therapy, after previously progressing on multiple lines of prior therapy. Our study in combination with prior case reports re-demonstrates that osimertinib may be particularly effective for individuals with metastatic brain lesions. Given the rarity and difficulty in detection of EGFR-KDD mutations, there remain limited data regarding comparisons of different TKIs’ efficacy for these mutations. However, in the few case reports cited, osimertinib has been shown to produce longer lasting responses compared to both afatinib and erlotinib with a more favorable side effect profile [8–10, 13, 14]. This suggests that next generation TKIs may provide even more benefit for these individuals.

Table 1.

Review of EGFR-TKI treatments for EGFR-KDD mutations in NSCLC

Publication	Stage	EGFR-TKI	Sites of disease	Progression-free survival
Chen et al. [8] (2020)	IV	Afatinib	Lung, spine	10 months
Zhao et al. [13] (2021)	IIIB	Afatinib	Lung, bilateral supraclavicular LNs	12 months
He and Wang [14] (2022)	IIB	Afatinib	Lung, pleura	10 months
Li et al. [9] (2020)	IV	Osimertinib	Lung, liver	21 months
Kim et al. [11] (2021)	IV	Osimertinib	Lung, brain, bone, liver	11 months
Hirokawa et al. [10] (2021)	IV	Erlotinib, osimertinib	Lung, mediastinal nodes, brain, spine	4.4 months (erlotinib); 14.5 months (osimertinib)

The availability of molecular testing results prior to systemic therapy initiation is correlated with improved OS in NSCLC. While both liquid and tissue platforms are associated with false negatives and reliant on yield, paired liquid and tissue biopsy at diagnosis is associated with 2x higher likelihood of having NGS prior to systemic therapy [16]. Unfortunately, implementation of NCCN biomarker testing guidelines has been slow, as real-world database studies have shown <50% of NSCLC patient’s undergoing NGS testing [17]. In our case, tissue NGS testing was unable to be performed due to bone decalcification on initial biopsy and paired liquid biopsy was not performed at diagnosis. The patient unfortunately progressed on three lines of systemic therapy and presented with large disease burden prior to obtaining liquid biopsy. Given his clinical response to osimertinib, there is the possibility of increased PFS if the mutation was found earlier.

Interestingly, in our patient, the EGFR-KDD mutation was found only on FoundationOne Liquid CDx biomarker testing and not on tissue sampling using another commercial platform. Both NGS tests showed a TMB of 6 Muts/Mb, TP53 frameshift mutations, and PTEN mutations, indicative of a matched molecular profile. A large prospective study has demonstrated high concordance rates between liquid and tissue NGS up to 78% for EGFR mutations, with the main incongruence attributed to insufficient quality or quantity of tissue samples. When tissue sampling is inadequate or limited, liquid biomarker testing may find additional targetable mutations [18]. Diagnostic yield of bone biopsies can be as low as 65.2%, given that bony lesions are at risk of sclerosis and decalcification [19]. Furthermore, EGFR-KDD mutations are difficult to detect as the mutation itself is an in-frame kinase domain duplication of exons 18–25, leading to intronic breakpoints that make it difficult to detect using standard sequencing platforms. Fortuitously, FoundationOne is able to detect this because the intronic breakpoint lies close to the exonic probe of their NGS diagnostic assay [20]. The combination of paired liquid and tissue biopsy NGS reduces the possibility of false negatives and maximizes possibilities of additional targeted therapy.

Conclusion

Liquid biomarker testing remains an essential part of oncological care and identified a rare EGFR-KDD mutation that guided targeted therapy. Diagnostic yield of bone biopsies is often limited by sclerosis and decalcification. The combination of tissue biopsy and liquid biomarker testing can identify more potential mutations for additional therapies than either one alone. This case also demonstrates that osimertinib may be effective in metastatic NSCLC with EGFR-KDD mutations.

Statement of Ethics

Written informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

J.D.G.: conceptualization, methodology, investigation, data curation, visualization, writing – original draft, and writing – review and editing. A.M.: writing – review and editing and supervision. M.M.M.: conceptualization, methodology, data curation, writing – review and editing, and supervision.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

Data are available on request due to privacy/ethical restrictions. Further inquiries can be directed to the corresponding author.