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Outcomes following resumption of immune checkpoint inhibitor therapy after high-grade immune-mediated hepatitis.
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Resuming ICI in Melanoma Patients Usually Safe After ICI Hepatitis
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
Among 31 people who stopped then resumed immune checkpoint inhibitors (ICI) after grade 3-4 ICI hepatitis, 15 had another immune-related adverse event but only 6 (19%) had to stop ICIs again [1]. Researchers from Boston's Brigham and Women's Hospital believe their findings "suggest that high-grade hepatitis need not be considered an absolute contraindication to resumption of checkpoint inhibitor therapy."
By preventing tumor cells from side-stepping T-cell-driven immune defenses, ICIs have revamped cancer therapy. But these novel agents come with potential drawbacks, including immune-related adverse events such as grade 3-4 hepatitis [2] and occasionally steroid-refractory ICI hepatitis [3].
Current cancer guidelines recommend permanently stopping ICI therapy after grade 3-4 hepatitis-advice based on expert opinion. Because little research supports this guidance (3 case series include a total of 37 patients), the Brigham team conducted this retrospective cohort study to assess clinical outcomes after ICI rechallenge in people with resolved high-grade ICI hepatitis.
The analysis involved people in the Mass General Brigham database who had grade 3 or higher ICI hepatitis during melanoma treatment with ICIs in 2010-2019. Among 1913 people who ever got an ICI for melanoma, 257 (13.4%) had a subsequent alanine aminotransferase (ALT) at or above 200 U/L and 102 (5.3% of 1913) had grade 3 or worse ICI hepatitis.
After ICI hepatitis resolved in these 102 people, 31 (30%) resumed ICI therapy. Compared with people not rechallenged with ICI, those rechallenged were younger (average 52.2 vs 58.8 years, P = 0.050), were more likely to have received the ICI combination ipilimumab/nivolumab (71% vs 45%, P = 0.016), and had less severe ICI hepatitis: lower median maximum steroid dose (1.0 vs 2.0 mg/kg/day, P = 0.023), less frequent steroid-refractory hepatitis (15% vs 43%, P = 0.016), and less frequent gastroenterology/hepatology consultation (45% vs 82%, P < 0.001).
Forty-five of 102 people with grade 3 or worse ICI hepatitis died. Median time to death did not differ significantly between ICI-rechallenged people and those not rechallenged (324 vs 230 days, P = 0.212). Cox regression analysis adjusted for age, the ipilimumab/nivolumab combination, and stage 4 melanoma determined that ICI rechallenge did not affect risk of death (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.44 to 1.79, P = 0.729). Treatment with an ICI combination cut chances of death about 50% (HR 0.46, 95% CI 0.24 to 0.90, P = 0.023).
Figuring overall treatment response by oncology documentation, the researchers found no significant difference between rechallenge and no rechallenge for overall response or disease control rate. They found a trend toward greater likelihood of complete or partial response in rechallenged people (65% vs 45%, RR 1.5, 95% CI 1.0 to 2.1, P = 0.078).
Among 31 ICI-rechallenged people, 28 (90%) got rechallenged with anti-PD-1 monotherapy (nivolumab or pembrolizumab). The remaining 3 people received ipilimumab (an anti-CTLA-4 agent) or atezolizumab (an antiPD-L1 agent). Among 23 people initially treated with ipilimumab/nivolumab, all were rechallenged with anti-PD-1 monotherapy. Rechallenge therapy lasted for a median 223 days.
An immune-related adverse event developed in 15 of 31 ICI-rechallenged people (48%). Six people (19% of 31) had an immune-related adverse event upon rechallenge that required ICI treatment to stop after a median of 91 days (recurrent hepatitis in 4, pneumonitis in 1, and hypophysitis-inflammation of the pituitary gland or pituitary stalk-in 1). In 9 other people (29% of 31), ICI rechallenge provoked an immune-related adverse event that did not require ICIs or steroids to stop.
Three factors predicted not stopping ICI rechallenge because of an immune-related toxicity: (1) less likely to be rechallenged with ipilimumab versus anti-PD-1 or anti-PD-L1 monotherapy (0% vs 33%, RR 0.1, 95% CI 0.1 to 0.3, P = 0.032), (2) less likely to be rechallenged with the same ICI that initially caused hepatitis (8% vs 50%, RR 0.2, 95% CI 0.1 to 0.7, P = 0.038), and (3) more likely to receive an ICI with a lower immune-related adverse event risk (88% vs 50%, P = 0.069, a nonsignificant trend).
The investigators concluded that "melanoma patients who undergo ICI rechallenge following resolution of high-grade [ICI] hepatitis have a relatively modest risk of hepatitis recurrence." They noted that only about 1 in 5 people had to stop rechallenge because of immune-related toxicities. The Brigham team proposed that high-grade ICI hepatitis should not be considered a contraindication to ICI rechallenge. But they cautioned that whether ICI rechallenge improves clinical outcomes remains unclear.
References
1. Li M, Sack J, Zucker SD, Grover S. Outcomes following resumption of immune checkpoint inhibitor therapy after high-grade immune-mediated hepatitis. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 116.
2. Suzman DL, Pelosof L, Rosenberg A, Avigan MI. Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int. 2018;38:976-987. doi: 10.1111/liv.13746. https://onlinelibrary.wiley.com/doi/full/10.1111/liv.13746
3. Li M, Sack J, Rahma OE, Grover S, Zucker SD. Predictors and outcomes of steroid-refractory immune checkpoint inhibitor hepatitis. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 115. (Reviewed separately by NATAP at the AASLD Liver Meeting.)
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