The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Source
2.2. Descriptive Analysis
3. Results
4. Discussion
5. Conclusions
6. Strengths and Limitations
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Akhoon, N. Precision Medicine: A New Paradigm in Therapeutics. Int. J. Prev. Med. 2021, 12, 12. [Google Scholar] [PubMed]
- Tarantino, P.; Mazzarella, L.; Marra, A.; Trapani, D.; Curigliano, G. The Evolving Paradigm of Biomarker Actionability: Histology-Agnosticism as a Spectrum, Rather than a Binary Quality. Cancer Treat. Rev. 2021, 94, 102169. [Google Scholar] [CrossRef] [PubMed]
- Adashek, J.J.; Subbiah, V.; Kurzrock, R. From Tissue-Agnostic to N-of-One Therapies: (R) Evolution of the Precision Paradigm. Trends Cancer 2021, 7, 15–28. [Google Scholar] [CrossRef] [PubMed]
- Lavacchi, D.; Roviello, G.; D’Angelo, A. Tumor-Agnostic Treatment for Cancer: When How Is Better than Where. Clin. Drug Investig. 2020, 40, 519–527. [Google Scholar] [CrossRef] [PubMed]
- Flaherty, K.T.; Le, D.T.; Lemery, S. Tissue-Agnostic Drug Development. Am. Soc. Clin. Oncol. Educ. Book Am. Soc. Clin. Oncol. Annu. Meet. 2017, 37, 222–230. [Google Scholar] [CrossRef]
- Lemery, S.; Keegan, P.; Pazdur, R. First FDA Approval Agnostic of Cancer Site—When a Biomarker Defines the Indication. N. Engl. J. Med. 2017, 377, 1409–1412. [Google Scholar] [CrossRef]
- EMA Vitrakvi. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/vitrakvi (accessed on 5 July 2023).
- EMA Rozlytrek. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/rozlytrek (accessed on 5 July 2023).
- Liu, D.; Offin, M.; Harnicar, S.; Li, B.T.; Drilon, A. Entrectinib: An orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther. Clin. Risk Manag. 2018, 14, 1247–1252. [Google Scholar] [CrossRef]
- Drilon, A.; Tan, D.S.W.; Lassen, U.N.; Leyvraz, S.; Liu, Y.; Patel, J.D.; Rosen, L.; Solomon, B.; Norenberg, R.; Dima, L.; et al. Efficacy and Safety of Larotrectinib in Patients with Tropomyosin Receptor Kinase Fusion-Positive Lung Cancers. JCO Precis. Oncol. 2022, 6, e2100418. [Google Scholar] [CrossRef]
- Carlson, J.; Italiano, A.; Brose, M.; Federman, N.; Lassen, U.; Kummar, S.; Sullivan, S. Comparative Effectiveness of Larotrectinib and Entrectinib for TRK Fusion Cancer. Am. J. Manag. Care 2022, 28, S26–S32. [Google Scholar]
- Iannantuono, G.M.; Riondino, S.; Sganga, S.; Rosenfeld, R.; Guerriero, S.; Carlucci, M.; Capotondi, B.; Torino, F.; Roselli, M. NTRK Gene Fusions in Solid Tumors and TRK Inhibitors: A Systematic Review of Case Reports and Case Series. J. Pers. Med. 2022, 12, 1819. [Google Scholar] [CrossRef]
- A Study to Test the Safety of the Investigational Drug Larotrectinib in Adults That May Treat Cancer—Full Text View—ClinicalTrials.Gov. Available online: https://clinicaltrials.gov/ct2/show/NCT02122913 (accessed on 6 July 2023).
- A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors with NTRK-Fusion in Children—Full Text View—ClinicalTrials.Gov. Available online: https://clinicaltrials.gov/ct2/show/NCT02637687 (accessed on 6 July 2023).
- A Study to Test the Effect of the Drug Larotrectinib in Adults and Children with NTRK-Fusion Positive Solid Tumors—Full Text View—ClinicalTrials.Gov. Available online: https://classic.clinicaltrials.gov/ct2/show/NCT02576431 (accessed on 6 July 2023).
- Doebele, R.C.; Drilon, A.; Paz-Ares, L.; Siena, S.; Shaw, A.T.; Farago, A.F.; Blakely, C.M.; Seto, T.; Cho, B.C.; Tosi, D.; et al. Entrectinib in Patients with Advanced or Metastatic NTRK Fusion-Positive Solid Tumours: Integrated Analysis of Three Phase 1–2 Trials. Lancet Oncol. 2020, 21, 271–282. [Google Scholar] [CrossRef] [PubMed]
- Dziadziuszko, R.; Krebs, M.G.; De Braud, F.; Siena, S.; Drilon, A.; Doebele, R.C.; Patel, M.R.; Cho, B.C.; Liu, S.V.; Ahn, M.-J.; et al. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2021, 39, 1253–1263. [Google Scholar] [CrossRef] [PubMed]
- Jiang, T.; Wang, G.; Liu, Y.; Feng, L.; Wang, M.; Liu, J.; Chen, Y.; Ouyang, L. Development of Small-Molecule Tropomyosin Receptor Kinase (TRK) Inhibitors for NTRK Fusion Cancers. Acta Pharm. Sin. B 2021, 11, 355–372. [Google Scholar] [CrossRef] [PubMed]
- Sakaeda, T.; Tamon, A.; Kadoyama, K.; Okuno, Y. Data Mining of the Public Version of the FDA Adverse Event Reporting System. Int. J. Med. Sci. 2013, 10, 796–803. [Google Scholar] [CrossRef] [PubMed]
- Singh, J. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. J. Pharmacol. Pharmacother. 2015, 6, 185–187. [Google Scholar] [CrossRef]
- Di Mauro, G.; Zinzi, A.; Vitiello, F.; Restaino, M.; Sportiello, L.; Rafaniello, C.; Sullo, M.G.; Capuano, A. Adverse drug reactions and gender differences: What changes in drug safety? J. Sex Gend. Specif. Med. 2019, 5, 114–122. [Google Scholar]
- Montastruc, J.-L.; Lapeyre-Mestre, M.; Bagheri, H.; Fooladi, A. Gender Differences in Adverse Drug Reactions: Analysis of Spontaneous Reports to a Regional Pharmacovigilance Centre in France. Fundam. Clin. Pharmacol. 2002, 16, 343–346. [Google Scholar] [CrossRef]
- di Mauro, G.; Zinzi, A.; Scavone, C.; Mascolo, A.; Gaio, M.; Sportiello, L.; Ferrajolo, C.; Rafaniello, C.; Rossi, F.; Capuano, A. PCSK9 Inhibitors and Neurocognitive Adverse Drug Reactions: Analysis of Individual Case Safety Reports from the Eudravigilance Database. Drug Saf. 2021, 44, 337–349. [Google Scholar] [CrossRef]
- Zucker, I.; Prendergast, B.J. Sex Differences in Pharmacokinetics Predict Adverse Drug Reactions in Women. Biol. Sex Differ. 2020, 11, 32. [Google Scholar] [CrossRef]
- Soldin, O.P.; Mattison, D.R. Sex Differences in Pharmacokinetics and Pharmacodynamics. Clin. Pharmacokinet. 2009, 48, 143–157. [Google Scholar] [CrossRef]
- Hendriksen, L.C.; van der Linden, P.D.; Lagro-Janssen, A.L.M.; van den Bemt, P.M.L.A.; Siiskonen, S.J.; Teichert, M.; Kuiper, J.G.; Herings, R.M.C.; Stricker, B.H.; Visser, L.E. Sex Differences Associated with Adverse Drug Reactions Resulting in Hospital Admissions. Biol. Sex Differ. 2021, 12, 34. [Google Scholar] [CrossRef] [PubMed]
- Domagala-Kulawik, J.; Trojnar, A. Lung Cancer in Women in 21th Century. J. Thorac. Dis. 2020, 12, 4398. [Google Scholar] [CrossRef] [PubMed]
- Doz, F.; van Tilburg, C.M.; Geoerger, B.; Højgaard, M.; Øra, I.; Boni, V.; Capra, M.; Chisholm, J.; Chung, H.C.; DuBois, S.G.; et al. Efficacy and Safety of Larotrectinib in TRK Fusion-Positive Primary Central Nervous System Tumors. Neuro-Oncology 2022, 24, 997–1007. [Google Scholar] [CrossRef]
- Help to Shape the MedDRA Terminology|MedDRA. Available online: https://www.meddra.org/ (accessed on 12 April 2023).
- Mascolo, A.; Scavone, C.; Sessa, M.; di Mauro, G.; Cimmaruta, D.; Orlando, V.; Rossi, F.; Sportiello, L.; Capuano, A. Can Causality Assessment Fulfill the New European Definition of Adverse Drug Reaction? A Review of Methods Used in Spontaneous Reporting. Pharmacol. Res. 2017, 123, 122–129. [Google Scholar] [CrossRef] [PubMed]
- Geraci, J.M.; Tsang, W.; Valdres, R.V.; Escalante, C.P. Progressive Disease in Patients with Cancer Presenting to an Emergency Room with Acute Symptoms Predicts Short-Term Mortality. Support. Care Cancer 2006, 14, 1038–1045. [Google Scholar] [CrossRef] [PubMed]
- Oxnard, G.R.; Morris, M.J.; Hodi, F.S.; Baker, L.H.; Kris, M.G.; Venook, A.P.; Schwartz, L.H. When Progressive Disease Does Not Mean Treatment Failure: Reconsidering the Criteria for Progression. JNCI J. Natl. Cancer Inst. 2012, 104, 1534–1541. [Google Scholar] [CrossRef] [PubMed]
- Aepala, M.R.; Peiris, M.N.; Jiang, Z.; Yang, W.; Meyer, A.N.; Donoghue, D.J. Nefarious NTRK Oncogenic Fusions in Pediatric Sarcomas: Too Many to Trk. Cytokine Growth Factor Rev. 2022, 68, 93–106. [Google Scholar] [CrossRef]
- Laetsch, T.W.; DuBois, S.G.; Mascarenhas, L.; Turpin, B.; Federman, N.; Albert, C.M.; Nagasubramanian, R.; Davis, J.L.; Rudzinski, E.; Feraco, A.M.; et al. Larotrectinib for Paediatric Solid Tumours Harbouring NTRK Gene Fusions: Phase 1 Results from a Multicentre, Open-Label, Phase 1/2 Study. Lancet Oncol. 2018, 19, 705–714. [Google Scholar] [CrossRef]
- Loeb, D.M.; Thornton, K.; Shokek, O. Pediatric Soft Tissue Sarcomas. Surg. Clin. N. Am. 2008, 88, 615–627. [Google Scholar] [CrossRef]
- Damásio, I.; Simões-Pereira, J.; Donato, S.; Horta, M.; Cavaco, B.M.; Rito, M.; Gomes, P.; Leite, V. Entrectinib in the Neoadjuvant Setting of Anaplastic Thyroid Cancer: A Case Report. Eur. Thyroid J. 2023, 12, e220179. [Google Scholar] [CrossRef]
- Lanman, T.; Hayden Gephart, M.; Bui, N.; Toland, A.; Nagpal, S. Isolated Leptomeningeal Progression in a Patient with NTRK Fusion+ Uterine Sarcoma: A Case Report. Case Rep. Oncol. 2021, 14, 1841–1846. [Google Scholar] [CrossRef] [PubMed]
- Bihan, K.; Lebrun-Vignes, B.; Funck-Brentano, C.; Salem, J.-E. Uses of Pharmacovigilance Databases: An Overview. Therapie 2020, 75, 591–598. [Google Scholar] [CrossRef] [PubMed]
- Mascolo, A.; Scavone, C.; Ferrajolo, C.; Rafaniello, C.; Danesi, R.; Del Re, M.; Russo, A.; Coscioni, E.; Rossi, F.; Alfano, R.; et al. Immune Checkpoint Inhibitors and Cardiotoxicity: An Analysis of Spontaneous Reports in Eudravigilance. Drug Saf. 2021, 44, 957–971. [Google Scholar] [CrossRef] [PubMed]
Agnostic Drug | Date of FDA Approval | Target | Indication(s) | Available as |
---|---|---|---|---|
Larotrectinib | 26 November 2018 | NTRK | Adult and pediatric patients with solid tumors that display a NTRK gene fusion: - who have a disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity, and - who have no satisfactory treatment options | Hard capsules (100 mg or 25 mg) Oral solution (20 mg/mL) |
Entrectinib | 15 August 2019 | NTRK/ROS1 | Adult and pediatric patients (≥12 years of age) with solid tumors that display a NTRK gene fusion: - who have a disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity, and - who have not received a prior NTRK inhibitor - who have no satisfactory treatment options Adult patients with ROS1 -positive, advanced NSCLC not previously treated with ROS1 inhibitors | Hard capsules (200 mg or 100 mg) |
Larotrectinib | Entrectinib | Total | |||||
---|---|---|---|---|---|---|---|
N | % | N | % | N | % | ||
ICSR a | 405 | (50.2) | 402 | (49.8) | 807 | (100.0) | |
Sex | Female | 179 | (44.2) | 214 | (53.2) | 393 | (48.7) |
Male | 159 | (39.3) | 143 | (35.6) | 302 | (37.4) | |
NA | 67 | (16.5) | 45 | (11.2) | 112 | (13.9) | |
Age group | <18 | 31 | (7.7) | 3 | (0.7%) | 34 | (4.2) |
18–64 | 92 | (22.7) | 107 | (26.6) | 199 | (24.7) | |
≥65 | 69 | (17.0) | 98 | (24.4) | 167 | (20.7) | |
NA | 213 | (52.6) | 194 | (48.3) | 407 | (50.4) | |
Median age (IQR b) | 58.5 (32.2–68.0) | 63.0 (52.0–72.0) | 61.0 (48.7–70.0) | ||||
Reporter country | United States | 277 | (68.4) | 278 | (69.2) | 555 | (68.8) |
Japan | 9 | (2.2) | 70 | (17.4) | 79 | (9.8) | |
France | 27 | (6.7) | - | - | 27 | (3.3) | |
Germany | 13 | (3.2) | 7 | (1.7) | 20 | (2.5) | |
Canada | 16 | (4.0) | 2 | (0.5) | 18 | (2.2) | |
Switzerland | 14 | (3.5) | - | - | 14 | (1.7) | |
Israel | - | - | 11 | (2.7) | 11 | (1.4) | |
Great Britain | 8 | (2.0) | 2 | (0.5) | 10 | (1.2) | |
Brazil | 10 | (2.5) | - | - | 10 | (1.2) | |
Type of reporter | Consumer | 104 | (25.7) | 185 | (46.0) | 289 | (35.8) |
Physician | 138 | (34.1) | 130 | (32.3) | 268 | (33.2) | |
Health professional | 110 | (27.2) | 35 | (8.7) | 145 | (18.0) | |
Pharmacist | 17 | (4.2) | 35 | (8.7) | 52 | (6.4) | |
Other health professional | 35 | (8.6) | 1 | (0.2) | 36 | (4.5) | |
NA | 1 | (0.2) | 16 | (4.0) | 17 | (2.1) | |
Reporting year | 2019 | 78 | (19.3) | 4 | (1.0) | 82 | (10.2) |
2020 | 114 | (28.1) | 62 | (15.4 | 176 | (21.8) | |
2021 | 110 | (27.2) | 136 | (33.8 | 246 | (30.5) | |
2022 | 103 | (25.4) | 200 | (49.8) | 303 | (37.5) |
Therapeutic Indication | Larotrectinib N (%) | Entrectinib N (%) | Total N (%) |
---|---|---|---|
Respiratory tract and pleural neoplasms malignant cell type unspecified NEC a | 24 (5.9) | 130 (32.3) | 154 (19.1) |
Non-small cell neoplasms malignant of the respiratory tract cell type specified | 11 (2.7) | 113 (28.1) | 124 (15.4) |
Not specified | 112 (27.7) | 2 (0.5) | 114 (14.1) |
Therapeutic procedures NEC | 3 (0.7) | 71 (17.7) | 74 (9.2) |
Neoplasms malignant site unspecified NEC | 23 (5.7) | 19 (4.7) | 42 (5.2) |
Thyroid neoplasms malignant | 32 (7.9) | 5 (1.2) | 37 (4.6) |
Breast and nipple neoplasms malignant | 20 (4.9) | 7 (1.7) | 27 (3.3) |
Soft tissue sarcomas histology unspecified | 21 (5.2) | 3 (0.7) | 24 (3.0) |
Colorectal neoplasms malignant | 14 (3.5) | 7 (1.7) | 21 (2.6) |
Neoplasms unspecified malignancy and site unspecified NEC | 16 (4.0) | 4 (1.0) | 20 (2.5) |
Pancreatic neoplasms malignant (excluding islet cell and carcinoid) | 14 (3.5) | 2 (0.5) | 16 (2.0) |
Glial tumors malignant | 11 (2.7) | 1 (0.2) | 12 (1.5) |
Salivary gland neoplasms malignant | 12 (3.0) | - | 12 (1.5) |
Preferred Terms | Frequency (N) | Frequency (%) |
---|---|---|
Myalgia | 3 | 8.1% |
Fatigue | 2 | 5.4% |
Blood thyroid stimulating hormone increased | 1 | 2.7% |
Constipation | 1 | 2.7% |
Dizziness | 1 | 2.7% |
Feeling cold | 1 | 2.7% |
Feeling hot | 1 | 2.7% |
Flushing | 1 | 2.7% |
Hemianesthesia | 1 | 2.7% |
Hepatic enzyme increased | 1 | 2.7% |
Nausea | 1 | 2.7% |
Paresthesia | 1 | 2.7% |
Loss of therapeutic response | 1 | 2.7% |
Cellulitis | 1 | 2.7% |
Hypotension | 1 | 2.7% |
Leukopenia | 1 | 2.7% |
Sepsis | 1 | 2.7% |
Cerebrovascular accident | 1 | 2.7% |
General physical health deterioration | 1 | 2.7% |
Loss of consciousness | 1 | 2.7% |
Nasal aspiration | 1 | 2.7% |
Pulmonary thrombosis | 1 | 2.7% |
Thrombosis | 1 | 2.7% |
Vomiting | 1 | 2.7% |
Drug ineffective | 1 | 2.7% |
Asthenia | 1 | 2.7% |
Eye hemorrhage | 1 | 2.7% |
Neuralgia | 1 | 2.7% |
Eyelid irritation | 1 | 2.7% |
Muscle spasms | 1 | 2.7% |
Muscle tightness | 1 | 2.7% |
Musculoskeletal stiffness | 1 | 2.7% |
Cardiac disorder | 1 | 2.7% |
Intracranial mass | 1 | 2.7% |
Case n. | Suspect Drug | Sex | Age | Indication | ADR (PT) | TTO a (Days) | Outcome |
---|---|---|---|---|---|---|---|
1 | Larotrectinib | NA | 10 | NA | Vomiting | NA | NA |
2 | Larotrectinib | NA | 11 | Urinary bladder sarcoma | Renal impairment | NA | Other serious (IME b) |
3 | Larotrectinib | Female | 16 | Desmoplastic small round cell tumor | Desmoplastic small round cell tumor, Off label use, Product use in unapproved indication, Therapy non-responder | 4 | Other serious (IME) |
4 | Larotrectinib | Female | 12 | NA | Rash | NA | NA |
5 | Larotrectinib | Male | 14 | Congenital fibrosarcoma | Blood alkaline phosphatase increased | NA | NA |
6 | Larotrectinib | NA | 1.5 | Fibrosarcoma metastatic | Fibrosarcoma metastatic, Metastases to the central nervous system | NA | NA |
7 | Larotrectinib | Male | 1 | NA | Varicella | NA | Other serious (IME) |
8 | Larotrectinib | Female | 14 | Soft tissue sarcoma | Vomiting, Intestinal obstruction, Abdominal pain | 0 | Other serious (IME) |
9 | Larotrectinib | Male | 1 | Malignant neoplasm of spinal cord | Nephrocalcinosis | NA | Other serious (IME) |
10 | Larotrectinib | Female | 16 | Sarcoma | Blood disorder, Acute myeloid leukemia, Pancytopenia, Ascites | 5 | Death |
11 | Larotrectinib | Male | 0.5 | NA | Lethargy, Somnolence | NA | NA |
12 | Larotrectinib | Female | 16 | Ovarian melanoma | Multiple organ dysfunction syndrome | NA | Death |
13 | Larotrectinib | NA | 0.5 | Congenital fibrosarcoma | Body height increased, Weight increased, Growth accelerated | NA | NA |
14 | Larotrectinib | Female | 15 | Glioneuronal tumor | Gastroenteritis norovirus, COVID-19, Acute kidney injury | NA | Hospitalization |
15 | Larotrectinib | NA | 0.5 | Congenital fibrosarcoma | Anemia, C-reactive protein increased, Neutrophilia, Leukocytosis | NA | Other serious (IME) |
16 | Larotrectinib | Female | 0.5 | Soft tissue sarcoma | Cough, Nausea, Pyrexia | NA | NA |
17 | Larotrectinib | NA | 1 | Neoplasm malignant | Head circumference abnormal | NA | NA |
18 | Entrectinib | Female | 16 | Neuroendocrine tumor | Disease progression | NA | Other serious (IME) |
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Liguori, V.; Gaio, M.; Zinzi, A.; Cagnotta, C.; Riccardi, C.; Docimo, G.; Capuano, A. The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database. Biomedicines 2023, 11, 2538. https://doi.org/10.3390/biomedicines11092538
Liguori V, Gaio M, Zinzi A, Cagnotta C, Riccardi C, Docimo G, Capuano A. The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database. Biomedicines. 2023; 11(9):2538. https://doi.org/10.3390/biomedicines11092538
Chicago/Turabian StyleLiguori, Valerio, Mario Gaio, Alessia Zinzi, Cecilia Cagnotta, Consiglia Riccardi, Giovanni Docimo, and Annalisa Capuano. 2023. "The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database" Biomedicines 11, no. 9: 2538. https://doi.org/10.3390/biomedicines11092538
APA StyleLiguori, V., Gaio, M., Zinzi, A., Cagnotta, C., Riccardi, C., Docimo, G., & Capuano, A. (2023). The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database. Biomedicines, 11(9), 2538. https://doi.org/10.3390/biomedicines11092538