乌鸦传媒

Liver injury related to immunotherapy is a relatively common immune-related adverse event that requires discontinuation of immune checkpoint inhibitors (ICIs) in severe cases. To see how prevalent liver injury recurrence was in these patients, Mar Riveiro-Barciela, MD, PhD, of Hospital Universitari Vall d'Hebron in Barcelona, and colleagues took a closer look at a small cohort of patients who were retreated with immunotherapy after resolution of severe immune-related hepatitis.

Riveiro-Barciela discussed the study, recently published in in the following interview with the Reading Room.

What was the clinical context in which your group undertook this study?

Riveiro-Barciela: Since the approval of the first immune checkpoint inhibitor in 2010, immunotherapy has become the main pillar for treatment of many types of advanced cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma.

Though ICI therapy has remarkably improved survival for these patients, it has also been associated with immune-related adverse events in a high proportion of those treated with combined therapy with an anti-PD-1 and an anti-CTLA-4 agent, and often treatment has to be discontinued.

Yet many patients may benefit from maintenance of immunotherapy, since some studies have suggested that the higher severity of the immune-related adverse events, the better the prognosis for the underlying oncological disease. Small case series have suggested that retreatment with ICIs could be a feasible option after resolution of severe immune-related hepatitis. In addition, for some patients, immunotherapy is the only therapeutic option for their oncological disease.

Can you tell us about the study's design and patient composition?

Riveiro-Barciela: This was a prospective multicenter non-interventional study, begun in 2016, that included all consecutive patients with cancer and previous grade 3 or 4 immune-related hepatitis who were retreated with ICIs after recovery from their hepatitis. No patients were on immunosuppressive therapy at initiation of immunotherapy.

What were the principal findings?

Riveiro-Barciela: During the study period, 23 patients developed severe immune-related hepatitis and after recovery were retreated with ICIs. Of these, 20, or 87%, received a single ICI and 3, or 13%, received an anti-PD-1 plus an anti-CTLA-4. Immunotherapy was discontinued in all cases at the time of severe immune-related hepatitis. Nineteen patients also received steroids.

Patients were mainly retreated with the same ICI -- 18 of 23 after a a median time of 10 weeks from the occurrence of severe immune-related hepatitis. Fifteen patients, or 65.2%, had no recurrence of the immune-related hepatitis after retreatment.

Among the eight patients with recurrence, five were grade 3 and three were grade 4. In terms of immunological background, six had either an underlying autoimmune disease or antinuclear antibodies of at least 1/80.

No patients with previous grade 4 hepatitis recurred. Those who did recur tended to present with a better oncological prognosis.

Overall, 19 patients required permanent discontinuation of ICIs, with cancer progression being the main reason in almost half -- 47.8%.

What are the immediate implications for clinical practice?

Riveiro-Barciela: The results suggest that retreatment with ICIs is a feasible option after severe immune-related hepatitis, even with the same agents, since as many as 65% of retreated patients will have no recurrence of liver injury.

What's the next step that needs to be taken?

Riveiro-Barciela: Studies in larger cohorts will help determine the rate of hepatitis recurrence and confirm our findings, especially the association with the patient's immunological background and with a better oncologic prognosis.

You can read the abstract of the study here, and about the clinical implications of the study here.