In previous studies, the research on osimertinib mostly focused on the mechanism, clinical trials, and literature analysis, etc., and few articles concentrated on the latest real-world research. Based on the largest samples of the real-world data, we collected and evaluated the pharmacovigilance of osimertinib in the post-market. The purpose is to analyze new and meaningful adverse reactions, to guide the update of instructions, and to provide a basis for clinical rational drug use.
The AEs of osimertinib occurred more commonly in famales (55.45%) than in males (29.94%). This may be related to the increase of female patients with lung cancer, which leads to the increase of drug use opportunities. Studies have shown that females are more likely than males to have non-smoking lung cancer (6). The causes of lung cancer in female may be related to the influence of estrogen (7), environment (8) and molecular factors (9). Also, the study described a higher AEs proportion in elderly patients (36.98% patients > 65 years), which was consistent with the FLAURA and AURA clinical trials that the number of AEs leading to the dose adjustment (suspension or reduction) of the study drug was higher in subjects aged over 65 years (10). With the increasing clinical application of osimertinib, it is important for clinicians to be alert to the AEs associated with osimertinib, especially in olderly patients. Early recognition of AEs is necessary because these effects can be life-threatening or lead to disease progression.
According to the disproportionality analysis, the most commonly reported and significant signals at SOC levels were general disorders and administration site conditions, and neoplasms benign, malignant and unspecified (incl cysts and polyps). These AEs included death, disease progression, malignant neoplasm progression, et al., which were not recorded in the drug insert of osimertinib and might be related to the patient's own disease progression rather than drug itselves. Evidence suggested that approximately 38% of all dead lung cancer patients had single site metastasis and 19% had two or more metastases (11). It might be irrational to judge whether tumor metastasis and tumor progression were caused by osimertinib only by ADR signals. Clinicians should distinguish whether tumor-related disease is caused by osimertinib. Besides, the significant signals respiratory, thoracic and mediastinal disorders were meaningful. Relevant studies have pointed out that different EGFR-TKIs can cause respiratory toxicity, and the incidence of ILD is 0 ~ 5.3%, while there is no significant difference between osimertinib and the first two generations. Blood and lymphatic system disorders which related to the laboratory abnormalities were commonly found in more than 20% of patients in clinical trial (10). However, AEs included hepatobiliary disorders, congenital, familial and genetic disorders are not mentioned in the instructions. We should pay attention to whether they have clinical significance to guide clinical medication.
Among all the AEs, the AEs involving respiratory system and cardiovascular system still deserve attention. The respiratory adverse reactions mentioned in the instructions of osimertinib include cough, pneumonia, and ILD. This study also excavated signs of AEs such as pneumothorax, pleural effusion, and hydrothorax. And the most common AEs leading to discontinuation of osimertinib was ILD/pneumonitis. Fan et al. (12) found that all EGFR-TKIs had drug-related toxicities included ILD, and the incidence of drug-related ILD in different EGFR-TKIs ranged from 0 to 5.3%. The mechanism of ILD may be different for third-generation EGFR-TKIs, because osimertinib induced ILD in patients who had no pulmonary toxicities during a prior treatment with first- or second-generation EGFR-TKI (13). The mechanism of osimertinib induced respiratory toxicity is not clear, but it may be related to the inhibition of the maintenance of epithelial cells. Osimertinib changed the expression of cytokines by impairing the growth and migration of epithelial cells, resulting in inflammatory cell recruitment and lung tissue injury (14). Although different EGFR-TKIs could cause respiratory toxicity, the AEs related to EGFR-TKI were usually tolerable and controllable. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, and chronic obstructive pulmonary disease,, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries (14). Noonan et al. (15) demonstrated NSCLC patients who had previously received chest radiotherapy or had a history of aspiration were more likely to have lung shadows or subpleural nodules after using osimertinib. Furthermore, a combination of drugs with or without radiotherapy can increase the risk of ILD (16). Therefore, we speculated that patients with chronic lung injury in the past were the high-risk population of respiratory toxicity. Nobuaki et al (17) reported a case of a 38-year-old woman patient with osimertinib-induced ILD after treatment with anti-PD1 antibody and speculated anti-PD1 therapies might be the risk factor of EGFR-TKI-induced ILD. Our study suggests that for patients with chronic respiratory diseases and combined PD-1/PD-L1 therapy, the pharmaceutical care of osimertinib should be strengthened.
Cardiotoxicity is accompanied by a history of treatment with antitumor drugs. Whether traditional chemotherapy (18), new targeted therapy (19) or immunotherapy (20) can cause cardiac related AEs. Cardiac related AEs are a commom toxicity of TKIs existed in not only first and second generation but third generation (5, 21). Our study not only found out AEs signals of cardiac disorders like heart failure, QT interval prolongation, electrocardiogram QT prolonged, in the instruction of osimertinib, but also excavated AEs like ventricular dysfunction, cardiology, cardiac dysfunction and cardiotoxicity that do not exist in the instruction. In vitro, osimertinib not only inhibited EGFR but also HER2 at clinically relevant concentrations. The current mainstream view is that the inhibition of HER2 is the main reason for the cardiotoxicity of some antitumor drugs (22). HER2 is essential for maintaining cardiac function, and HER2 inhibition is the main cause of cardiotoxicity for some antitumor drugs. Trastuzumab is a monoclonal antibody targeting HER2. whose cardiotoxicity increased by 2.45 times after treatment (23). Perez et al. (24) also found that osimertinib might lead to dose independent reversible myocardial injury by inhibiting erythroblastic leukemia viral oncogene B (commonly referred to as HER). Kunimasa et al (25) found severe osimertinib-associated cardiotoxicities at a higher frequency (4.1%) than reported before, and suggested not only attach importance to QTc interval prolongation but also other cardiotoxicities in administrating osimertinib in clinical. Although osimertinib was highly specific for EGFR, study showed that osimertinib has a greater inhibitory effect on HER2 than other EGFR-TKIs (26). Furthermore, rates of QT prolongation, cardiac failure, and atrial fibrillation were found to be higher when osimertinib compared with other EGFR-TKIs in FAERS (5). Based on all the facts we speculated that HER2 was the main cause of osimertinib cardiotoxicity. The risk factors of cardiotoxicity caused by antitumor drugs include age, potential heart disease, renal insufficiency, and the combination of other cardiotoxic drugs, while the risk of cardiotoxicity caused by EGFR-TKI is more closely related to the patient's cardiovascular history (27). Thus, the early awareness of cardiotoxicities, monitoring for QT prolongation, managing symptoms of heart failure, and close follow-up, may enhance the benefits of therapy while taking osimertinib.
Excitingly, we found some unexpected and significant safety signals, which included BRAF V600E mutation positive, volvulus, hepatic function abnormal, and venous thromboembolism (VTE). BRAF is an important proto oncogene in human beings. About 15% of malignant tumors are related to BRAF mutation (28). At present, there are many mutations in this gene, of which BRAF V600E is the most common accounts for 75 ~ 82% of BRAF mutations in cutaneous melanoma (29). Different from EGFR and ALK gene mutations, BRAF V600 mutation is relatively rare in non-small cell lung cancer, about 2% ~ 3% of which are adenocarcinoma (30, 31). BRAF mutation will continuously activate the downstream MEK-ERK signal pathway and play a vital role in tumor growth, proliferation, invasion and metastasis. There is no specific treatment for NSCLC patients carrying a BRAF mutation, even if in melanoma, BRAF inhibitors were demonstrated to prolong progression-free survival and survival (32). Therefore, BRAF mutation represents strong tumor invasiveness. Therefore, we infer that BRAF gene mutation may be a signal reflected disease progression.
Drug-induced liver injury is an important adverse effect of TKIs. In vitro, osimertinib was mainly eliminated by the liver and metabolized by CYP3A4 and CYP3A5. The main metabolic pathways are oxidation and dealkylation. In the AURA2 study, 1 patient developed drug induced liver injury (DILI) which was manifested by elevated serum aminotransferase levels (< 1%) (33). Elevated liver transaminases (all grades) associated with EGFR-TKI use are seen in 25–55%, 27–38%, 10%, and 9% of patients treated with gefitinib, erlotinib, afatinib, and osimertinib, respectively. Severely (grade 3 or 4) elevated liver transaminases is found in 1% of patients treated with osimertinib (34). The mechanism of liver injury caused by EGFR-TKI has not been fully elucidated. Some researchers believe that the liver toxicity of TKI drugs is related to the metabolism of their active metabolites, which can interfere with cellular molecules and thus affect cell function and death (35). Autoimmune activation is also a mechanism by which TKIs cause hepatotoxicity (36). Ivan Gonzalez et al, (37) reported that pericentral confluent necrosis and parenchymal collapse in liver biopsy after the patient treated with osimertinib and developed transaminitis of unclear etiology, which has been reported in other TKIs. Hirabayashi et al, (38) reported a case that osimertinib induced hepatotoxicity after 15 days of treatment. Although there are not many case reports about liver injury, it is undeniable that it has become a class of AEs that needs to be paid enough attention to liver disorders are often improved with dose reduction or transient discontinuation of EGFR-TKIs, and concomitant use of hepatoprotective agents (11).
Nowadays, there has been no association with volvulus and EGFR inhibition. The occurrence of volvulus is caused by a variety of reasons, and physiological or pathological factors are the predisposing factors. The risk factors of cecal volvulus included chronic constipation, distal colon obstruction, high-fiber diets, ileus, prior colonoscopy, and late pregnancy (39). Constipation, a known risk factor for volvulus, was only found in 7 cases in clinical trial. Patil et al, (40). reported 3 case associating cecal volvulus with the 160 mg dose of osimertinib, and highlighted a potentially vital surgical complication associated with the 160 mg dose of osimertinib.
Tumor patients have a higher incidence of VTE than normal people. The mortality of tumor patients with VTE is a 2-fold increased mortality rate compared to cancer patients without VTE (41). Accurate assessment of patients' risk of VTE can effectively prevent the occurrence of VTE events and reduce mortality. According to our study, osimertinib can also lead to deep vein thrombosis, venous thrombosis limb, pulmonary embolism. A meta-analysis of venous thromboembolic events associated with VEGFR-TKIs found that the use of VEGFR-TKIs does not significantly increase the risk of VTEs, the risk of VTEs in cancer patients is mainly affected by tumor types, host factors and concomitant usage of anticancer drugs (42). Hotta et al, (43) aimed to identify anticancer drugs and anticoagulants that can be used safely in combination, as accompanying study to an observational research on VTE incidence rates in lung cancer patients. And the study indicated that the PK of anticoagulants was not affected by co-administration of EGFR-TKIs (gefitinib, erlotinib, and afatinib). While, early diagnosis, appropriate treatment, and prevention are considered to improve prognoses.
Results of our study showed that the median onset time was 58 days, and most cases occurred within the first month (n = 1460, 38.01%), after osimertinib initiation. In FLAURA and AURA, 49% of patients reported diarrhea with a median duration of 19 and 22 days and a median duration of 19 and 6 days, respectively. We also found that except for the first month, the probability of AEs within one year was similar. The median time of ILD or ILD like adverse reactions in the global population is 85 days. These results suggested that we should pay special attention to the AEs of patients in the first month and early recognition of AEs caused by osimertinib therapy could reduce the agony of patients which can be life-threatening.
Based on FAERS database, our study excavates and analyzes the adverse reaction signals of osimertinib, discusses the respiratory toxicity and cardiotoxicity related to osimertinib, and some other meaningful AEs, in order to provide some reference for improving the safety of clinical medication. FAERS database is a spontaneous reporting system. Due to its own limitations, there are phenomena such as underreporting, re-reporting, incomplete case information and so on. And lack of underlying disease and concomitant medication may affect the results. Therefore, despite the facts that FAERS database has some limitations in pharmacovigilance studies, a comprehensive characterization of the AE signals from osimertinib and the discovery of some unexpected AE signals might provide foundation for further clinical studies of osimertinib. And the efficacy and safety of osimertinib still need to be continuously monitored.