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Khaled Tolba
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EP1.14 - Targeted Therapy (ID 204)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.14-24 - Lenvatinib for Recurrent Metastatic Adenoid Cystic Carcinomas (ACC) of the Lung (Now Available) (ID 2798)
08:00 - 18:00 | Author(s): Khaled Tolba
- Abstract
Background
Adenoid cystic carcinoma (ACC) is a rare malignant neoplasm that frequently originates from the salivary glands of the head and neck, but may also arise in the mainstem bronchus and major airways. The tumor is characterized by a tendency for both local and distant recurrences. Surgical resection remains the mainstay of treatment and radiotherapy is offered in select cases. Palliative systemic chemotherapy offers only modest benefit and is minimally effective. In preclinical studies, ACC has been shown to overexpress the oncogene MYB, which is involved in cell proliferation, apoptosis, differentiation and in upregulation of several growth and angiogenetic factors contributing to the autocrine activation of the FGFR and VEGFR-mediated angiogenesis. Two phase II studies have demonstrated that targeting salivary gland ACC with Lenvatinib, an oral multiple kinase inhibitor targeting VEGFR-1-3, FGFR-1-4, RET, c-KIT, and PDGFR, produced objective partial responses and tumor stabilization. Here we present a case of a patient treated with primary pulmonary ACC treated with Lenvatinib.
Method
A 62-year-old female underwent a right pneumonectomy for a localized endobronchial ACC of the right lung followed by post-operative radiotherapy for microscopic involvement of the resection margins. Two and a half years after primary therapy, she was noted on surveillance imaging to have multiple lung nodules in her left lung concerning for recurrent metastatic disease. Subsequently, she initiated palliative therapy with Lenvatinib 24mg daily.
Result
Tumor assessment by chest CT performed three months after start of Lenvatinib revealed partial response per RECIST V1.1 criteria with interval cavitation of several pulmonary nodules reflecting treatment response. She experienced the typical adverse events associated with Lenvatinib, including CTCAE V4.05 grade 3 hypertension that was managed with three anti-hypertensive medications and grade 3 diarrhea, which required dose reduction.
Conclusion
Consistent with other early phase clinical trials of Lenvatinib in salivary gland ACC, Lenvatinib may exert therapeutic activity in primary pulmonary ACC as has been demonstrated in this case.
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EP1.14-42 - De Novo Emergence of Isolated CNS T790M Mutation as a Mechanism of Resistance to First Generation EGFR-TKI Erlotinib (Now Available) (ID 2819)
08:00 - 18:00 | Author(s): Khaled Tolba
- Abstract
Background
A 57-year-old female never-smoker presented in 07/2009 with persistent cough and hemoptysis. Diagnostic imaging studies revealed 5.5-cm left upper lobe/hilar mass with mediastinal adenopathy, CT-guided biopsy revealed a TTF-1 positive pulmonary adenocarcinoma. Brain MRI identified a solitary 4mm metastatic lesion in the left superior precentral gyrus. Given her respiratory symptoms and hemoptysis, she proceeded with a platinum doublet and concurrent EBRT. Follow-up imaging revealed partial response. Tumor mutational analysis became available during radiation therapy and revealed an EGFR exon-19 deletion; she subsequently started treatment with erlotinib 150mg daily. Imaging performed six months after starting erlotinib revealed resolution of her residual lung disease and left precentral gyrus brain metastasis and she continued erlotinib for the next 7-years until 03/2017, when she presented with headaches and ataxia. Brain MRI identified a new 3.9cm left cerebellar mass, as well as reappearance of the left precentral gyrus lesion (Figure 1). Resection of the cerebellar mass identified metastatic lung adenocarcinoma with molecular analysis revealing the same exon-19 deletion plus T790M resistance mutation. Repeat PET/CT imaging failed to identify extracranial disease (Figure 2). She received post-operative stereotactic radiosurgery to the involved sites and started therapy with osimertinib 80mg daily. At the time of this writing, she remains in remission almost 10 years after initial diagnosis of metastatic NSCLC.
This report presents an unusual clinical scenario, where visceral disease achieved durable remission on erlotinib while an isolated T790M acquired resistance mutation emerged de novo in the CNS. T790M often emerges as a resistance mechanism under selective pressure from early-generation EGFR-TKI. However, due to low BBB penetrance of 1st/2nd generation EGFR-TKI at standard dose, erlotinib concentration that frequently drives the de novo development of T790M mutation in visceral organs is rarely achieved in CNS metastases. In rare occasions where T790M is detected in the CNS, it is often metastatic from a distant visceral organ. In our patient, low concentration of erlotinib in the CNS might have created a permissive environment for the development of drug-tolerant “persister” cells that remained dormant for several years before eventually acquiring de novo T790M-mutation. The latter enabled accelerated growth of CNS metastatic disease in the presence of continuous treatment with erlotinib.
Method
Section not applicable
Result
Section not applicable
Conclusion
Our case report illustrates a real-life example of how spatiotemporal differences in the tumor micro-environment could give rise to intra-tumor heterogeneity and shape response to therapy.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-25 - Targeting NRG1-Fusions in Lung Adenocarcinoma: Afatinib as a Novel Potential Treatment Strategy (ID 1805)
09:45 - 18:00 | Author(s): Khaled Tolba
- Abstract
Background
Neuregulin 1 (NRG1) gene fusions result in activation of ErbB2-/ErbB3-mediated signaling pathways, and may function as oncogenic drivers. NRG1 fusions have emerged as a potential therapeutic target across multiple tumor types, including non-small-cell lung cancer (NSCLC). Afatinib, a pan-ErbB-family blocker, may be a treatment option for patients with NRG1+ NSCLC, as supported by preclinical evidence and seven published case reports (Table).
Method
Here, we report clinico-pathological and molecular characteristics of four new cases of NRG1 fusion-positive lung adenocarcinoma treated with afatinib. Afatinib activity is reported.
Result
Case 1 is a 70-year-old, female, never-smoker, diagnosed with pan-wildtype, non-mucinous, adenocarcinoma. She received afatinib in the fifteenth-line setting and experienced a partial response (PR) for 24 months. Following further progression on chemotherapy, NRG1-fusion was identified using NanoString analysis (re-biopsy was performed to find an explanation for afatinib efficacy). The patient was re-challenged with afatinib (best response: PR [3 months]), before switching to atezolizumab (best response: progressive disease).
Case 2 is a 66-year-old female, never-smoker, diagnosed with metastatic, non-mucinous adenocarcinoma. A CD74-NRG1 fusion was identified by Oncomine™ Comprehensive Assay, and fifth-line afatinib treatment was initiated. She experienced a PR, ongoing after 14 months of treatment.
Case 3 is a 68-year-old male diagnosed with lung adenocarcinoma. A SDC4-NRG1 fusion was subsequently identified using Next Generation Sequencing and the patient initiated second-line afatinib treatment. He achieved stable disease as best response, lasting for four months.
Case 4 is a 43-year-old, female, non-smoker, diagnosed with advanced invasive mucinous adenocarcinoma. A CD74-NRG1 fusion was subsequently identified by RNA sequencing and the patient initiated third-line afatinib treatment; PR is ongoing.
Conclusion
These findings add to a growing body of evidence suggesting afatinib activity in NRG1-fusion positive NSCLC. Prospective study of a larger cohort of patients with NRG1-fusion positive NSCLC treated with afatinib is warranted to better evaluate this potential activity.
Patient
Tumor type
NRG1 fusion partner
Best response
Duration of response (months)
Reference
i
Non-mucinous lung adenocarcinoma
SLC3A2
PR
12
Gay, et al. J Thoracic Oncol 2017
ii
IMA
CD74
PR
10
Gay, et al. J Thoracic Oncol 2017
iii
Non-mucinous lung adenocarcinoma
SDC4
PR
12
Jones, et al. Ann Oncol 2017
iv
IMA
CD74
PR
6.5
Cheema, et al. J Thoracic Oncol 2017
v
IMA
CD74
SD
3
Drilon, et al. Cancer Discov 2018
vi
IMA
SDC4
PD
-
Drilon, et al. Cancer Discov 2018
vii
IMA
CD74
PD
-
Drilon, et al. Cancer Discov 2018
IMA, invasive mucinous lung adenocarcinoma; PD, progressive disease; SD, stable disease