Osimitinib has become the standard first-line treatment regimen for patients with advanced non-small cell lung cancer (NSCLC) with EGFR classical mutations. Ositinib is usually well tolerated and the adverse reactions are mildly controllable. However, a case of receiving osimertinib resulting in grade 4 explosive myositis was recently reported, raising new alarms.
Case profile
The patient, 52 years old, was diagnosed with stage IV adenocarcinoma with bone and intracranial metastases, and molecular tests showed EGFR L858R mutations with 10% PD-L1 TPS. Patients receive oscitinib 80 mg Qd with apixaban for asymptomatic pulmonary embolism.
Patients develop mild fatigue and muscle aches after taking osimertinib for 4 days. Weakness increases after 1 week. After 12 days, the short walk requires assistance and the muscle strength of the upper arm decreases.
Laboratory tests show elevated transaminases, aspartate aminotransferase (AST) 942 U/L, alanine transaminases (ALT) 433 U/L. Patients discontinued osimertinib, but AST continued to rise to >1000 U/L and creatine phosphokinase (CPK) to 29680 U/L. MRI of the spine and lower extremities suggests muscle oedema (figure 1).
Figure 1 MRI of the lower extremities shows muscle oedema (Source: Reference 1)
Patients did not have muscle biopsy and electromyography. Viral hepatitis, negative test for anti-mitochondrial antibodies, Epstein-Barr virus and cytomegalovirus. Rheumatic antibodies such as anti-Jo, anti-SS-A, anti-PL-7, anti-PL-12, anti-EJ, anti-SRP, and antinuclear antibodies are not abnormal. Mild elevation of anti-SS-A 52KD antibody is 50 (normal <20) and strong positive for HMGCR antibody 154 (normal<20). Nerve tumor tests such as anti-neuronal nucleus antibodies, anti-GAD antibodies, antiglia nucleus antibodies, Amphiphysin antibodies, etc. are negative.
Patients begin treatment with prednisone 40 mg orally Qd and CPK begins to decline. However, the feeling of weakness in the extremities is enhanced, and the deep tendon reflexes are retained. Dysphagia occurs afterwards, and laryngoscopic weakness of the oropharyngeal muscles is visible.
Empiric treatment with methylprednisolone 60 mg IV Qd and gamma 1 g/kg IV Qd. Patients develop progressive speech and breathing difficulties, and after 2 weeks of admission, negative suction (NIF) falls to a low point of -12 cm water column, hypoxemia develops, and is transferred to ICU respiratory monitoring.
Neurologic consultation diagnoses injury to presynaptic muscle fibers due to extensive muscle necrosis. Empirical use of pyridamine 2 mg IV q3 h is initiated to prolong acetylcholine action and compensate for synaptic insufficiency. Although the plasma acetylcholine receptor antibody is negative, the muscle strength increases after administration, and the NIF improves to -30 cm water column.
Gradually reduce the amount of hormones and pyridine, restore some of the distal strength, and reach level 4+/5 muscle strength in the limbs. The proximal muscles are still weak, but they can eat and drink normally and do not need oxygen. He was discharged after 2 months. He did not receive antitumor therapy within 2 months, the efficacy was stable, and he planned to receive chemotherapy and brain radiotherapy after recovery.
Oscitinib induces myositis
Concepts and occurrences
Myositis is a heterogeneous group of disorders, including chronic muscle weakness, decreased muscular endurance, or asymptomatic elevated CPK. May be positive with myositis-specific antibodies or myositis-related antibodies.
Osimitinib causes serious adverse reactions rarely. The incidence of grade 3 to 4 adverse events (AE) in the FLAURA study was 42%, with diarrhea being the most common. The incidence of musculoskeletal pain is 10%, and the incidence of elevated AST and ALT is 10% and 7%, respectively. Of the four key studies of osimerinib, only the AURA2 study reported elevated CPK in 2 (1%) patients, both grade 2 without rhabdomyolysis.
However, four cases of myositis due to osimertinib were reported in one case series, with an incidence of up to 10.5%. Of these, 2 had mild symptoms, 2 were detected by CPK monitoring alone, occurred 2 to 11 weeks after administration, both were grade 1 to 2, and 1 case later developed CPK to grade 4 (2511 U/L) but remained asymptomatic.
mechanism
This patient had different presentations from previously reported cases, progressed after discontinuation of the drug, and presented as an explosive process of severe myositis. Patients have elevated anti-SS-A 52KD antibodies, a myositis-associated antibody common in systemic autoimmune diseases such as Sjogren syndrome or systemic lupus erythematosus, but there are no autoimmune disease manifestations in this case.
In addition, patients present with elevated HMGCR antibodies. HMGCR antibodies and statins are associated with immune-mediated necrotizing myopathy. Statin-induced myopathy can present with elevated CPK and proximal muscle weakness, usually with the process continuing after statin cessation. Statins alter the HMGCR protein conformation, activating autoimmunity by exposing hidden epitopes. However, the patient in this case did not take a statin, and it is unclear whether EGFR inhibitors can affect HMGCR antibodies.
In addition, the case authors believe that osimertinib is metabolized primarily by CYP3A4/5 and is a weak inducer of CYP3A4. Apixaban, which patients are taking at the same time, is also metabolized by CYP3A4, which may affect each other and lead to poor metabolism. However, according to pharmaceutical studies, the combination of the two does not require dose adjustment.
There are currently limited reports of myositis caused by osiminib, while more research has been done on myositis caused by immune checkpoint inhibitors (ICI). Although the mechanism of occurrence of the two may be different, there are also lessons to be learned.
One study reported that some patients with ICI causing myasthenia gravis (MG) had myositis/myocarditis. These patients have a 66% positive rate of anti-acetylcholine receptor anti-AChR, not all patients have typical symptoms of ptosis, elevated CPK, and rapid disease progression with a mortality rate of up to 23%.
Therefore, the patient in this case has an explosive manifestation, myositis after discontinuation of oshitinib continues to progress, and gradually becomes effective after treatment with hormones and pyridinesterine, and the possibility of overlapping complications should be considered.
diagnosis
In the case, the patient did not undergo electromyography, muscle biopsy and other tests, so the diagnosis was actually unclear. When a patient is suspected of having myositis, both diagnosis and differential diagnosis should be thought of.
treat
Corticosteroids: Corticosteroids remain the drug of choice for myositis mediated by highly suspected immune mechanisms. Referred to ICI-induced myositis use, for example, grade 1 to 2 myositis can be treated with prednisone 0.5 to 1 mg/kg/day, and grade 3 to 4 with methylprednisolone 1 g/day impact for 5 days.
Gamma globulin and plasma exchange: in severe cases where hormone therapy does not respond, the addition of gamma globulin or plasma exchange should be considered.
Cholinesterase inhibitors: for patients with suspected MG, concomitant use of pyridinetimine may be considered.
Forecasting and monitoring
Studies of ICI-associated myositis have shown that if antibodies are positive before treatment, ICI treatment can lead to an explosive onset, so some scholars recommend testing for related antibodies at baseline. Osimitinib causes myositis rarely, so routine testing at baseline is less cost-effective. However, physicians should be aware of this and do a good job of patient education.
Once this occurs, disease monitoring can be carried out using indicators such as CPK, ESR, CRP, etc., which can reflect the effectiveness of treatment.
bibliography
1. Crowley F, Fitzgerald B, Bhardwaj A, Siraj I, Smith CB, Life-Threatening Myositis in a Patient with EGFR-mutated NSCLC on Osimertinib: case report, JTO Clinical and Research Reports (2022)
2. Parafianowicz P, et al. Myositis - A common but underreported adverse effect of osimertinib: Case series and review of the literature. Cancer Treat Res Commun . 2020;25:100254.
3. Solimando AG, et al. Immune Checkpoint Inhibitor-Related Myositis: From Biology to Bedside. Int J Mol Sci. 2020;21(9):3054.zhil
4. Safa H, et al. Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature. J Immunother Cancer. 2019;7:319.
This article is for the reference of medical and health professionals only
Curator: GoEun, Mei Zhe
This article was first published on Lilac Garden's professional platform: Tumor Time