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Tofacitinib for Refractory Immune-Related Colitis

JAK inhibitor shows promise in a patient with refractory immune-related complication of pembrolizumab
17 Jun 2020
Cancer Immunology and Immunotherapy;  Palliative and supportive care

On 11 June 2020, the researchers of the McGill University in Montreal, Canada reported in a letter to editor published in The New England Journal of Medicine a case of woman with immune-related colitis from pembrolizumab treatment for cancer, a side-effect that was refractory to glucocorticoids, infliximab, and vedolizumab. Treatment with JAK inhibitor, tofacitinib, induced remission of this immune-related complication in 5 days.

Tofacitinib decreases cytokine production. Previously as a result of the OCTAVE studies, tofacitinib was established as a new strategy for management of patients with ulcerative colitis refractory to biologic agents. Canadian researchers reasoned that a similar clinical need exists in patients with immune-related colitis. In particular, immune-related colitis is a side-effect responsible for the highest absolute numbers of hospitalisations, discontinuations of therapy, and deaths among patients with cancer treated with immune checkpoint inhibitors.

Similar to ulcerative colitis, the guidelines for the treatment of immune-related colitis list use of first-line therapy with glucocorticoids, while biologic agents infliximab and vedolizumab are reserved for later lines of treatment. In a subgroup of patients, management of this side-effect is refractory to the biologic agents and in such case, there is no clear standard of care. Investigational, foecal material transplantation is not broadly available yet.

Canadian researchers evaluated tofacitinib in this patient with mismatch-repair–deficient gastric cancer who had a clinically significant antitumour response to pembrolizumab. However, her treatment was complicated with recurrent colitis. Treatment with glucocorticoids, infliximab, and vedolizumab did not control this side-effect and she had ongoing severe diarrhoea.

Tofacitinib administered at a dose of 10 mg orally twice per day, induced a clinical remission 5 days after the start of treatment. Tofacitinib was stopped after 30 days. After 4 months the patient had ongoing remission of the colitis, as well as tumour response.

The authors wrote that JAK-STAT pathway potentially plays an important role in autoimmunity and cancer immune surveillance, but the use of JAK inhibitors in the context of immune-related side-effects is not explored. The advantage is its oral administration and fast onset of action. According to the authors, it is interesting for further investigation in the context of well planned studies in patients with refractory immune-related colitis. However, they cautioned on a risk of thromboembolic events that have been observed among patients with rheumatoid arthritis treated with tofacitinib.

Reference

Esfahani K, Hudson M, Batist G. Tofacitinib for Refractory Immune-Related Colitis from PD-1 Therapy. N Engl J Med 2020; 382:2374-2375. DOI: 10.1056/NEJMc2002527.

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