Outcomes after resumption of immune checkpoint inhibitor therapy after high‐grade immune‐mediated hepatitis

Abstract

Background In the current study, the authors assessed the risks and outcomes of immune checkpoint inhibitor (ICI) rechallenge in patients with resolved grade 3 to 4 ICI hepatitis because current guidelines recommend permanent ICI discontinuation in these patients. Methods The authors performed a retrospective cohort study from 2010 through 2019 of patients with melanoma who were treated with ≥1 ICIs and who recovered from grade 3 to 4 ICI hepatitis. The primary outcome was hepatitis recurrence and the secondary outcome was the development of any immune‐related adverse event (irAE) requiring the discontinuation of ICI rechallenge. Best overall response and time to all‐cause death were compared between the patients who did and those who did not undergo ICI rechallenge. Grading was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Results Of the 102 patients with melanoma who developed high‐grade ICI hepatitis, 31 underwent ICI rechallenge. Although 15 of 31 patients (48%) developed an irAE of any grade, only 6 patients (19%) required ICI discontinuation due to irAE severity (4 of 29 patients [14%] rechallenged with anti–PD‐1 or anti‐PD‐L1 and 2 of 2 patients [100%] rechallenged with ipilimumab). Recurrent hepatitis accounted for 4 of these 6 cases. Rechallenged patients who did not require ICI discontinuation were found to be significantly less likely to receive ipilimumab rather than anti–PD‐1 or anti‐PD‐L1 monotherapy (0% vs 33%; relative risk (RR), 0.1 [95% CI, 0.1‐0.3; P = .032]) and significantly less likely to be rechallenged with their original ICI (8% vs 50%; RR, 0.2 [95% CI, 0.1‐0.7; P = .038]). There was no difference noted with regard to best overall response or time to death between rechallenged and non‐rechallenged patients. Conclusions ICI therapy can be resumed in patients with melanoma who have recovered from grade 3 to 4 ICI hepatitis with a modest risk of serious irAEs. It remains unclear whether ICI retreatment improves clinical outcomes.

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…The time to recurrence was 41 days. Liver metastases were present in three of six (vs six of 25 without recurrence), but the overall presence of any metastatic disease was not different between the groups [117]. A similar success rate of rechallenge was also reported by Patrinely Jr et al with 39 of 66 cases (62.12%) having no hepatitis, a recurrence rate of hepatitis in 25.76% (seen in a median time of 32 days), and the appearance of another form of immune-mediated adverse reaction (irAE) in 13.64% [100].…”

“…While many societal and FDA guidelines call for the permanent discontinuation of ICI therapy for high-grade hepatotoxicity, many oncologists reported their willingness to resume treatment in select patients with grade 3 ILICI and in some cases, even grade 4 in the past year. Li et al described the outcomes of 31 patients who were rechallenged out of a total of 102 patients with melanoma who had their treatment discontinued because of grade 3-4 ILICI [117]. Of these 31 patients, 25 (80.6%) were able to successfully tolerate resumption of their ICIs and only six individuals had to have their rechallenge treatment discontinued.…”

“…In a large literature review of all articles published in English from 2000 to 2018, Houron et al evaluated 29 FDA-approved Cho et al [116] Korean study excluding HCC and elevated AST at baseline Liver metastases? Li et al [117] Overall, metastatic disease not a risk factor Rechallenge with combination therapy of anti-CTLA-4 and anti-PD1…”

Extending the conversation over the immune-related hepatotoxicity: author response to Dr. Gauci et al

“… 23 According to the most recent retrospective analysis of 31 patients with melanoma with IRH who underwent ICPI rechallenge, 6 required ICPI discontinuation due to severe ir-AE of any type and 4 of these 6 cases developed recurrent IRH. 29 The rapid rate of resolution of transaminase elevations may also give some more points in a resumption decision. 10 In all cases of ICPI rechallenge, it is important to note that close monitoring is critically important as liver injury may recur rapidly and may be difficult to control.…”

Bridging the Gap: Connecting the Mechanisms of Immune-Related Adverse Events and Autoimmunity Through PD-1

“…A practical question is how to approach patients with preexisting autoimmune diseases prior to initiation of ICIs. Initial clinical trials excluded patients with preexisting autoimmune disease ( Li et al, 2020 ), and for this reason, there are limited data available on responsiveness and development of irAEs in these patients ( Weber et al, 2016 ; Reck et al, 2021 ). Most currently, available data do suggest that autoimmune disease does not greatly interfere with the safety of ICIs ( Cappelli et al, 2017 ; Abdel-Wahab et al, 2018 ; Arbour et al, 2018 ; Schadendorf et al, 2019 ; Dolladille et al, 2020 ; Efuni et al, 2021 ; Reck et al, 2021 ), although a higher incidence of irAEs related to the initial autoimmune disease or worsening of the underlying autoimmune disease has been observed ( Cappelli et al, 2017 ; Abdel-Wahab et al, 2018 ; Arbour et al, 2018 ; Dolladille et al, 2020 ; Li et al, 2020 ; Reck et al, 2021 ).…”