Rare Incidence of ICI-Related Hepatotoxicity Frequently Ends in Treatment Discontinuation

Although immune checkpoint inhibition (ICI)—related hepatotoxicity is a rare occurrence, it leads to ICI treatment discontinuation in more than two-thirds of affected patients, according to the results of a retrospective study presented at the American Association for the Study of Liver Diseases’ 2018 Liver Meeting.¹In clinical trials, fewer than 10% of patients treated with single-agent immune checkpoint inhibitors reported elevated liver enzymes.^2,3

Investigators conducted the retrospective study to gain a greater understanding of the characteristics and outcomes of ICI-related liver injury. “Today, many patients with a variety of cancer types receive ICI therapy, and we know these therapies can cause liver injury in a small subset of patients,” study co-author Ethan D. Miller, MD, said in a statement before the presentation. “However, there is limited information about how best to diagnose and manage these individuals.”

“Our goals are to refine how we predict, characterize, and manage ICI hepatotoxicity so that patients can get the maximum benefit from ICI therapy, with minimal liver injury,” explained Miller, an associate professor in the Department of Gastroenterology, Hepatology, and Nutrition at The University of Texas MD Anderson Cancer Center.

The investigators identified 5762 patients treated with ICI at a tertiary cancer center between January 2010 and March 2018. Of these patients, only 100 (1.7%) exhibited moderate or severe hepatotoxicity from ICI treatment, which was defined as an alanine aminotransferase (ALT) level more than 5 times the upper limit of normal (ULN).

The median age among the identified patients with hepatotoxicity was 60 years. Sixty-one of the patients were male, and 85 were white. A quarter of the patients received anti—CTLA-4 therapy, 46 received anti–PD-1/PD-L1 therapy, and 29 received a combination of a PD-1/PD-L1 inhibitor and a CTLA-4 inhibitor.

The primary cancer types of the patients included 53 with melanoma, 14 with genitourinary cancer, 12 with head and neck or thoracic cancer, 9 with gastrointestinal cancer, and 12 with another form of a solid tumor. Across the 100 patients, hepatotoxicity developed after a median of 70 days (range, 4-377) and 3 infusions (range, 1-25). The median ALT level was 523 (range, 297-2991).

Overall, 69 of the patients permanently discontinued ICI treatment and 31 halted treatment temporarily. The hepatotoxicity was treated with steroids in 67 patients, and 3 of these patients received additional mycophenolate mofetil (MMF).

Among those with moderate hepatotoxicity (grade 3 ALT increase; n = 85), 56 patients (66%) discontinued ICI treatment; the hepatotoxicity was treated with steroids in 54 patients and with MMF in 1 patient. Improvement in hepatotoxicity, characterized as an ALT below 3 times the ULN, was seen after a mean of 26 days (standard derivation [SD], 21 days).

Severe hepatotoxicity (grade 4 ALT increase) was identified in 15 patients, and 13 (87%) of these patients discontinued treatment with ICIs. Thirteen patients were treated with steroids for the hepatotoxicity, and 2 were treated with MMF. Improvement was observed after a mean of 41 days (SD, 24 days). There was a statistically significant difference observed in the time to improvement of hepatotoxicity, based on the severity of the hepatotoxicity between those with moderate and severe liver injury (P = .02).

Among those with preexisting liver disease (n = 38), hepatotoxicity developed at a mean of 58 days (SD, 76 days) with a median ALT level of 563. Twenty-seven of these patients were treated with steroids and 2 with MMF. The hepatotoxicity improved after a mean of 25 days (SD, 19 days) in patients with liver disease.

Sixty-two patients did not have prior liver disease, and hepatotoxicity developed in these patients after a mean of 50 days (SD, 76 patients), with a median ALT level of 482. Treatment for the hepatotoxicity included steroids for 40 patients and MMF for 1 patient, which led to improvement after a mean of 29 days (SD, 22 days).

Twenty-seven of 67 patients (40%) who were treated with steroids had preexisting liver disease, as did 11 of 33 patients (33%) who did not receive steroids for hepatotoxicity. ICI therapy was permanently discontinued in 49 patients (73%) treated with steroids and in 20 patients (61%) who did not receive steroids. There was a mean of 29 days (SD, 21 days) to improvement of hepatotoxicity in those who received steroids compared with 24 days (SD, 23 days) in those who did not receive steroids (P = .25).

ICI treatment was resumed in 31 patients, including 5 on anti—CTLA-4 therapy, 25 on anti– PD-1/PD-L1 therapy, and 1 on the combination, but recurrent hepatotoxicity was observed in 1 patient receiving CTLA-4 inhibition and 7 receiving PD-1/PD-L1 inhibition.

In total, 36 patients died from any cause, including 2 from liver failure, yet no deaths or liver failure were attributed to ICI-related hepato-toxicity. Miller suggested that this was likely due to careful monitoring and quick response.

“Among those with significant ICI-associated hepatotoxicity, we found no instances of liver failure. We also saw that, in certain cases, ICI treatment was safely resumed,” he said. “These findings confirm that oncologists are doing a great job of identifying the potential for liver failure in their patients.”

Miller noted that further study is needed in a prospective study in an expanded cohort to review features of liver injury, risk factors, biomarkers, outcomes of liver injury and impact on cancer.

References:

1. Abu-Sbeih H, Styskel B, Blechacz B, Chalasani NP, Miller ED. Clinically significant hepatotoxicity due to immune checkpoint inhibitors is rare but leads to treatment discontinuation in a high proportion. Presented at: American Association for the Study of Liver Diseases 2018 Liver Meet- ing; November 9-13, 2018. San Francisco, CA. Abstract 39. aasldpubs. onlinelibrary.wiley.com/doi/10.1002/hep.30256.
2. Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):1270- 1271. doi: 10.1056/NEJMoa1504030.
3. Motzer RJ Rini BI, McDermott DF, et al. Nivolumab for metastatic re- nal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33(13):1430-1437. doi: 10.1200/JCO.2014.59.0703.