FGFR Fusions as an Acquired Resistance Mechanism Following Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) and a Suggested Novel Target in Advanced Non-Small Cell Lung Cancer (aNSCLC)
Abstract
:1. Introduction
2. Materials and Methods
2.1. Guardant Health (GH) Electronic Database (ED)
2.2. Tel-Aviv Sourasky Medical Center (TASMC) ED
2.3. Patients with FGFR1/2/3 Fusion as an Acquired Resistance Mechanism Following Treatment with EGFR TKIs
2.4. Ethical Aspects
3. Results
3.1. FGFR2/3 Fusion Frequency in GH Electronic Database
3.2. FGFR1/2/3 Fusion Frequency in TASMC Electronic Database
3.3. Case-Series of Patients with FGFR3-TACC3 Fusion as an Acquired Resistance Mechanism Following Treatment with EGFR TKIs
3.4. Clinical Case #1
3.5. Clinical Case #2
3.6. Clinical Case #3
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
- Wu, Y.L.; Tsuboi, M.; He, J.; John, T.; Grohe, C.; Majem, M.; Goldman, J.W.; Laktionov, K.; Kim, S.W.; Kato, T.; et al. Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2020, 383, 1711–1723. [Google Scholar] [CrossRef] [PubMed]
- Ramalingam, S.S.; Vansteenkiste, J.; Planchard, D.; Cho, B.C.; Gray, J.E.; Ohe, Y.; Zhou, C.; Reungwetwattana, T.; Cheng, Y.; Chewaskulyong, B.; et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N. Engl. J. Med. 2020, 382, 41–50. [Google Scholar] [CrossRef] [PubMed]
- Helena, A.Y.; Tian, S.K.; Drilon, A.E.; Borsu, L.; Riely, G.J.; Arcila, M.E.; Ladanyi, M. Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific EGFR Inhibitor Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain. JAMA Oncol. 2015, 1, 982–984. [Google Scholar]
- Thress, K.S.; Paweletz, C.P.; Felip, E.; Cho, B.C.; Stetson, D.; Dougherty, B.; Lai, Z.; Markovets, A.; Vivancos, A.; Kuang, Y.; et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nat. Med. 2015, 21, 560–562. [Google Scholar] [CrossRef] [Green Version]
- Le, X.; Puri, S.; Negrao, M.V.; Nilsson, M.B.; Robichaux, J.; Boyle, T.; Hicks, J.K.; Lovinger, K.L.; Roarty, E.; Rinsurongkawong, W.; et al. Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC. Clin. Cancer Res. 2018, 24, 6195–6203. [Google Scholar] [CrossRef] [Green Version]
- Lin, C.-C.; Shih, J.-Y.; Yu, C.-J.; Ho, C.-C.; Liao, W.-Y.; Lee, J.-H.; Tsai, T.-H.; Su, K.-Y.; Hsieh, M.-S.; Chang, Y.-L.; et al. Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: A genomic study. Lancet Respir. Med. 2018, 6, 107–116. [Google Scholar] [CrossRef]
- Oxnard, G.R.; Hu, Y.; Mileham, K.F.; Husain, H.; Costa, D.B.; Tracy, P.; Feeney, N.; Sholl, L.M.; Dahlberg, S.E.; Redig, A.J.; et al. Assessment of Resistance Mechanisms and Clinical Implications in Patients with EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib. JAMA Oncol. 2018, 4, 1527–1534. [Google Scholar] [CrossRef] [Green Version]
- Piotrowska, Z.; Thress, K.S.; Mooradian, M.; Heist, R.S.; Azzoli, C.G.; Temel, J.S.; Rizzo, C.; Nagy, R.J.; Lanman, R.B.; Gettinger, S.N.; et al. MET amplification (amp) as a resistance mechanism to osimertinib. J. Clin. Oncol. 2017, 35, 9020. [Google Scholar] [CrossRef]
- Yang, Z.; Yang, N.; Ou, Q.; Xiang, Y.; Jiang, T.; Wu, X.; Bao, H.; Tong, X.; Wang, X.; Shao, Y.W.; et al. Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients. Clin. Cancer Res. 2018, 24, 3097–3107. [Google Scholar] [CrossRef] [Green Version]
- Allen, J.M.; Schrock, A.B.; Erlich, R.L.; Miller, V.A.; Stephens, P.J.; Ross, J.S.; Ou, S.-H.I.; Ali, S.M.; Vafai, D. Genomic Profiling of Circulating Tumor DNA in Relapsed EGFR-Mutated Lung Adenocarcinoma Reveals an Acquired FGFR3- TACC3 Fusion. Clin. Lung Cancer 2017, 18, 219–222. [Google Scholar] [CrossRef] [Green Version]
- Helsten, T.; Elkin, S.; Arthur, E.; Tomson, B.N.; Carter, J.; Kurzrock, R. The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing. Clin. Cancer Res. 2015, 22, 259–267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ou, S.-H.I.; Horn, L.; Cruz, M.; Vafai, D.; Lovly, C.M.; Spradlin, A.; Williamson, M.J.; Dagogo-Jack, I.; Johnson, A.; Miller, V.A.; et al. Emergence of FGFR3-TACC3 fusions as a potential by-pass resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR mutated NSCLC patients. Lung Cancer 2017, 111, 61–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Soria, J.-C.; Strickler, J.H.; Govindan, R.; Chai, S.; Chan, N.; Quiroga-Garcia, V.; Bahleda, R.; Hierro, C.; Zhong, B.; Gonzalez, M.; et al. Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA). J. Clin. Oncol. 2017, 35, 4074. [Google Scholar] [CrossRef]
- Loriot, Y.; Necchi, A.; Park, S.H.; Garcia-Donas, J.; Huddart, R.; Burgess, E.; Fleming, M.; Rezazadeh, A.; Mellado, B.; Varlamov, S.; et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N. Engl. J. Med. 2019, 381, 338–348. [Google Scholar] [CrossRef]
- Bahleda, R.; Italiano, A.; Hierro, C.; Mita, A.; Cervantes, A.; Chan, N.; Awad, M.; Calvo, E.; Moreno, V.; Govindan, R.; et al. Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors. Clin. Cancer Res. 2019, 25, 4888–4897. [Google Scholar] [CrossRef]
- Haura, E.B.; Hicks, J.K.; Boyle, T.A. Erdafitinib Overcomes FGFR3-TACC3–Mediated Resistance to Osimertinib. J. Thorac. Oncol. 2020, 15, e154–e156. [Google Scholar] [CrossRef]
- Odegaard, J.I.; Vincent, J.J.; Mortimer, S.; Vowles, J.V.; Ulrich, B.C.; Banks, K.C.; Fairclough, S.R.; Zill, O.A.; Sikora, M.; Mokhtari, R.; et al. Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies. Clin. Cancer Res. 2018, 24, 3539–3549. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lanman, R.B.; Mortimer, S.A.; Zill, O.A.; Sebisanovic, D.; Lopez, R.; Blau, S.; Collisson, E.A.; Divers, S.G.; Hoon, D.; Kopetz, S.; et al. Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. PLoS ONE 2015, 10, e0140712. [Google Scholar] [CrossRef]
- Qin, A.; Johnson, A.; Ross, J.S.; Miller, V.A.; Ali, S.M.; Schrock, A.B.; Gadgeel, S.M. Detection of Known and Novel FGFR Fusions in Non-Small Cell Lung Cancer by Comprehensive Genomic Profiling. J. Thorac. Oncol. 2019, 14, 54–62. [Google Scholar] [CrossRef] [Green Version]
- Wang, R.; Wang, L.; Li, Y.; Hu, H.; Shen, L.; Shen, X.; Pan, Y.; Ye, T.; Zhang, Y.; Luo, X.; et al. FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer. Clin. Cancer Res. 2014, 20, 4107–4114. [Google Scholar] [CrossRef] [Green Version]
- Capelletti, M.; Dodge, M.E.; Ercan, D.; Hammerman, P.S.; Park, S.I.; Kim, J.; Sasaki, H.; Jablons, D.M.; Lipson, D.; Young, L.; et al. Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma. Clin. Cancer Res. 2014, 20, 6551–6558. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Papadimitrakopoulou, V.A.; Wu, Y.L.; Han, J.Y.; Ahn, M.J.; Ramalingam, S.S.; John, T.; Okamoto, I.; Yang, J.H.; Bulusu, K.C.; Laus, G.J.A.O.O.; et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Ann. Oncol. 2018, 29, VIII741. [Google Scholar] [CrossRef]
- Rolfo, C.; Mack, P.C.; Scagliotti, G.V.; Baas, P.; Barlesi, F.; Bivona, T.G.; Herbst, R.S.; Mok, T.S.; Peled, N.; Pirker, R.; et al. Liquid Biopsy for Advanced Non-Small Cell Lung Cancer: A Consensus Statement from The International Association for the Study of Lung Cancer (IASLC). J. Thorac. Oncol. 2021, 16, 1647–1662. [Google Scholar] [CrossRef] [PubMed]
FGFR Fusion Type | Large-Cell Carcinoma | ADC | Adeno-Squamous Carcinoma | SCC | NSCLC NOS Carcinoma | Total |
---|---|---|---|---|---|---|
FGFR2-BICC1 | 4 | 4 | ||||
FGFR2-CCDC6 | 1 | 1 | ||||
FGFR2-KIAA1598 | 3 | 1 | 4 | |||
FGFR2-SLC45A3 | 1 | 1 | ||||
FGFR2-TACC2 | 2 | 1 | 3 | |||
FGFR3-TACC3 | 4 | 71 | 1 | 61 | 13 | 150 |
FGFR3-WHSC1 | 1 | 1 | ||||
Total | 4 | 81 | 1 | 62 | 16 | 164 |
FGFR Fusion Type | EGFR Sensitizing Mutation Type | EGFR Resistance Mutation Type | ||||||
---|---|---|---|---|---|---|---|---|
Exon 19 Deletion, n (%) | L858R, n (%) | L861Q, n (%) | Total, n (%) | T790M, n (%) | C797X, n (%) | T790M and C797X, n (%) | None, n (%) | |
FGFR2-CCDC6 | 1 (2.6) | 0 (0) | 0 (0) | 1 (2.6) | 1 (2.6) | 0 (0) | 0 (0) | 0 (0) |
FGFR2-KIAA1598 | 1 (2.6) | 1 (2.6) | 0 (0) | 2 (5.1) | 1 (2.6) | 0 (0) | 0 (0) | 1 (2.6) |
FGFR2-TACC2 | 0 (0) | 1 (2.6) | 0 (0) | 1 (2.6) | 1 (2.6) | 0 (0) | 0 (0) | 0 (0) |
FGFR3-TACC3 | 23 (58.9) | 11 (28.2) | 1 (2.6) | 35 (89.7) | 5 (12.8) | 1 (2.6) | 7 (17.9) | 22 (56.4) |
Total | 25 (64.1) | 13 (33.3) | 1 (2.6) | 39 (100) | 8 (20.5) | 1 (2.6) | 7 (17.9) | 23 (59.0) |
Case Number | Sex | Age, Years | Tumor Histology | Smoking History | EGFR Mutation Subtype | Treatment History before FGFR3-TACC3 Fusion Diagnosis: Agent (PFS, mo) | FGFR3-TACC3 Fusion MAF, % | Concurrent Alterations, MAF, % |
---|---|---|---|---|---|---|---|---|
#1 | F | 59 | ADC | Never- smoker | L858R | Gefitinib (7 mo), osimertinib (13 mo), carboplatin/pemetrexed (6 mo) | 0.3 | EGFR L858R, 33.4, PIK3CA E545K, 47.5, CCND1 amplification, CDK4 amplification, KRAS amplification, MYC amplification |
#2 | M | 84 | ADC | Never- smoker | E746_A750del | Osimertinib (11 mo) | 0.04 | EGFR E746_A750del, 1.3, TP53 Y163C, 0.4 |
#3 | F | 63 | ADC | Never- smoker | L747_A750delinsP | Gefitinib (52 mo), osimertinib (14 mo) | 0.07 | Gardant360: EGFR L747_A750delinsP, 0.5, PIK3CA V344G, 1.3 Tempus xT: EGFR L747_A750delinsP, 14.4, EGFR p. C797S, 3.6, PIK3CA V344G, 15.9 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Raphael, A.; Dudnik, E.; Hershkovitz, D.; Jain, S.; Olsen, S.; Soussan-Gutman, L.; Ben-Shitrit, T.; Dvir, A.; Nechushtan, H.; Peled, N.; et al. FGFR Fusions as an Acquired Resistance Mechanism Following Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) and a Suggested Novel Target in Advanced Non-Small Cell Lung Cancer (aNSCLC). J. Clin. Med. 2022, 11, 2475. https://doi.org/10.3390/jcm11092475
Raphael A, Dudnik E, Hershkovitz D, Jain S, Olsen S, Soussan-Gutman L, Ben-Shitrit T, Dvir A, Nechushtan H, Peled N, et al. FGFR Fusions as an Acquired Resistance Mechanism Following Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) and a Suggested Novel Target in Advanced Non-Small Cell Lung Cancer (aNSCLC). Journal of Clinical Medicine. 2022; 11(9):2475. https://doi.org/10.3390/jcm11092475
Chicago/Turabian StyleRaphael, Ari, Elizabeth Dudnik, Dov Hershkovitz, Suyog Jain, Steve Olsen, Lior Soussan-Gutman, Taly Ben-Shitrit, Addie Dvir, Hovav Nechushtan, Nir Peled, and et al. 2022. "FGFR Fusions as an Acquired Resistance Mechanism Following Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) and a Suggested Novel Target in Advanced Non-Small Cell Lung Cancer (aNSCLC)" Journal of Clinical Medicine 11, no. 9: 2475. https://doi.org/10.3390/jcm11092475