ICI Treatment Necessitates Close Monitoring of Potential Myasthenia Gravis

Myasthenia gravis (MG) is a known immune-related adverse event (irAE) following first- or second-line treatment with immune checkpoint inhibition (ICI) treatment for any of several cancers (eg, colorectal cancer, melanoma, non–small cell lung cancer, head and neck squamous cell cancer, and gastric or gastroesophageal junction adenocarcinoma). However, the exact extent of a patient’s risk for developing the chronic autoimmune neuromuscular disorder following ICI treatment remains elusive.

Using data from the US FDA Adverse Event Reporting System (FAERS) for quarter 1 2004 through quarter 3 2022, a team of investigators examined data on AEs related to treatment with durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab for risk of a patient developing MG, myasthenic syndrome, and myasthenia crisis. The published their findings recently in Cancer Medicine. Results were considered statistically significant if data connected to a drug irAE showed 3 or more AE reports, a proportional reporting odds ratio (PRR) of 2 or more, and a chi-square (χ²) result of at least 4.

“Analyzing AE database information using signal detection methods can help identify potential risk signals of drugs and provide valuable insights for safe and rational clinical use of drugs,” they wrote. “This approach can also help overcome the limitations of clinical trials, which may not be able to evaluate all potential drug-related AEs due to limited sample size and duration of follow-up.”

The most irAEs reported were 380 for nivolumab, followed by 276 for pembrolizumab, 78 for atezolizumab, 53 for ipilimumab, 36 for durvalumab, and 5 for avelumab.

Results of PRR values were statistically significant for all 6 drugs for myasthenic syndrome and MG, indicating high correlation between risk of the condition and use of the immune checkpoint inhibitor:

• Myasthenic syndrome:
  • Durvalumab: 27.83 (χ² = 102.66)
  • Atezolizumab: 26.20 (χ² = 235.6)
  • Pembrolizumab: 44.17 (χ² = 1313.98)
  • Nivolumab: 32.09 (χ² = 1229.5)
  • Avelumab: 21.31 (χ² = 151.1)
  • Ipilimumab: 0
• MG:
  • Durvalumab: 24.21 (χ² = 682.04)
  • Atezolizumab: 18.34 (χ² = 900.2)
  • Pembrolizumab: 39.32 (χ² = 7945.1)
  • Nivolumab: 26.93 (χ² = 6636.4)
  • Avelumab: 14.73 (χ² = 566.47)
  • Ipilimumab: 15.69 (χ² = 54.7)

When myasthenia crisis was looked at, data were only found for pembrolizumab and nivolumab. For pembrolizumab, the PRR value was 16.54 (χ² = 225.23) and for nivolumab, 9.20 (χ² = 119.14).

Most patients in the analysis were aged 65 to 79 years (56.25%), female (34.38%) or unknown gender (15.63%), had a physician who reported their diagnosis and AEs to FAERS (53.13%), and from the United States (43.75%) or Japan (15.63%), and ultimately ended up hospitalized because of their condition (59.38%).

From initiation of ICI treatment to MG onset, atezolizumab has the widest time range of 1 to 955 days. Avelumab was next, with 19 to 827 days, followed by pembrolizumab with 1 to 571 days, nivolumab with 1 to 507 days, ipilumumab with 1 to 315 days, anddurvalumab with 1 to 63 days.

Pembrolizumab | Image Credit: luchschenF -stock.adobe.com

Overall, the study authors found that pembrolizumab and nivolumab carried the highest risk signals for developing myasthenia crisis; pembrolizumab for developing myasthenia syndrome; and all 6 medications for developing MG.

“These findings emphasize the importance of carefully monitoring patients who receive these drugs for any signs or symptoms of MG,” the authors concluded, “and considering alternative treatment options when appropriate.”

They also underscored that their findings do not mean immunosuppressive drugs should not be used, but that clinicians “should be vigilant and closely monitor patients for any AEs when using these drugs in combination.”

Reference

Kong Q, Wang H, Ren X, Zahuo Y, Peng J. Analysis on the risk of myasthenia gravis related to immune checkpoint inhibitors based on the US FDA Adverse Event Reporting System. Cancer Med. Published online September 19, 2023. doi:10.1002/cam4.6559