Little Evidence Found to Link LEMS to Immune Checkpoint Inhibitors

Review study fails to show causal relationship with cancer treatment

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

Share this article:

Share article via email
This announcement illustration shows the word

Little evidence was found for a causal relationship between the use of an immune checkpoint inhibitor (ICI) for the treatment of cancer and the onset of Lambert-Eaton myasthenic syndrome (LEMS) or myasthenia gravis (MG), according to a new review study.

Still, because most included data came from case series, rather than controlled, mechanistic studies, it’s possible that a stronger relationship might have been missed, the study’s researchers noted.

Research in mice and some case studies have reported a link between the use of an immune checkpoint inhibitor and incidents of LEMS and MG, the team noted.

“We propose that there is a need for mechanistic and large-scale prospective studies investigating the etiological role of ICIs in MG/LEMS, an important prerequisite in better understanding the risk of these diseases with increasing use of ICIs in clinical medicine,” the researchers wrote.

The study, “Exploring the role of immune checkpoint inhibitors in the etiology of myasthenia gravis and Lambert-Eaton myasthenic syndrome: A systematic review,” was published in the journal Frontiers in Neurology

Recommended Reading
An illustration shows gauges of risk.

Cancer Immunotherapy Tecentriq Tied to Higher LEMS Risk in Study

Examining whether immune checkpoint inhibitor use poses a risk

Immune checkpoint molecules, which are activated by cancer cells, regulate the activation of T-cells, a class of immune cells that can initiate anti-tumor responses. ICIs are a class of antibody-based medications that inhibit or block these molecules, helping to restore T-cell-mediated anti-tumor responses.

ICIs — including those targeting the programmed death protein-1 (PD-1), programmed death ligand-1 (PD-L1), or cytotoxic T-lymphocyte antigen-4 (CTLA-4) — are thus a promising treatment approach for various types of cancer.

However, because of their immune-enhancing effects, ICIs have been linked to a number of immune-related side effects, including the emergence of autoimmune diseases like LEMS or MG.

Both LEMS and MG are marked by the body’s self-reactive attacks on the neuromuscular junction — the site where nerve cells and muscles meet to communicate and coordinate voluntary movement.

In particular, patients with thymic cancer and small cell lung cancer (SCLC) are known to be at an increased risk of developing MG or LEMS. Thus, “particular caution may be warranted” for these patients when using ICIs, the researchers noted.

While some studies have investigated the potential relationship between ICIs and MG/LEMS, a thorough analysis hasn’t yet been performed. Now, to learn more, researchers conducted a systematic review of published studies related to the topic.

The analysis included 94 such studies — 93 in humans and one mouse study — cumulatively involving 220 patients.

Sufficient clinical information about cancer type and prior therapies was available for 92 people. Cancer types included melanoma, affecting 29 people, and non-small cell lung cancer, in 16 people. Others were SCLC (three people), renal/urothelial/hepatocellular carcinoma (16 people),  squamous cell carcinoma (six people), and thymoma (four people). A total of 18 people had other or unspecified cancers.

The link between ICIs and MG/LEMs was investigated for each class of ICIs. For each, an integrated metric of evidence (IME) was generated. This metric takes into account the study design, the quality of the paper, the likelihood of a causal link between the immune checkpoint inhibitor and MG/LEMS, the confidence of the MG/LEMS diagnosis, and the number of patients involved.

An IME score of up to 2.76 was considered negligible evidence of an association, while a score between 2.76–3.96 was low evidence, and 3.96–4.96 was intermediate. A score of 4.96–7 was considered high evidence.

Overall, low evidence was seen for a causal link between ICI courses and the onset of MG or LEMS.

The use of at least one anti-PD1 medication, including Opdivo (nivolumab), Keytruda (pembrolizumab), Libtayo (cemiplimab), and Tuoyi (toripalimab), was associated with a median IME of 2.86, falling into the “low evidence” category.

Likewise, anti-PD-L1 medications, including Imfinzi (durvalumab), Tecentriq (atezolizumab), and Bavencio (avelumab), had an overall median IME of 3.41.

Consistent with the other two classes of ICIs, anti-CTLA-4 medications, including Yervoy (ipilimumab) and Imjudo (tremelimumab), showed low evidence of an association with LEMS or MG, with an overall median IME of 2.93.

Among the 94 manuscripts, 20 mentioned the used of combination therapies. Still, these studies in general provided low to intermediate evidence for a causal link between combination therapies and MG/LEMS onset.

Researchers noted, however, that this “lack of cogent evidence stems from the design of the papers themselves.” Given that most of the reports were case studies, in-depth or mechanistic evidence was lacking, they noted.

Notably, the single mouse study, which used a mouse model of MG, found that treatment with an anti-CTLA-4 antibody worsened MG. The link was strong, with an IME of 6.61, reflecting high evidence of a causal link.

“This observation suggests that if more mechanistic studies had been conducted and thus included in our analysis, the median IME value of the dataset would demonstrate higher levels of evidence,” the researchers wrote.