Beyond Steroids: Immunosuppressants in Steroid-Refractory or Resistant Immune-Related Adverse Events.

The optimal management for immune-related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants on the basis of case reports and expert opinion. We evaluated patients with lung cancers at Memorial Sloan Kettering Cancer Center treated with immune checkpoint blockade from 2011 to 2020. Pharmacy records were queried to identify patients who received systemic steroids and an additional immunosuppressant (e.g., tumor necrosis factor-α inhibitor, mycophenolate mofetil). Patient records were manually reviewed to evaluate baseline characteristics, management, and outcomes. Among 2750 patients with lung cancers treated with immune checkpoint blockade, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (tumor necrosis factor-α inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after the start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (five of six) and colitis (18 of 27) but less common in neuromuscular (one of five) and pneumonitis (3 of 10). Of the patients who died, 8 of 13 were attributable directly to the irAE and 4 of 13 were related to toxicity from immunosuppression (three infection-related deaths, one drug-induced liver injury leading to acute liver failure). Steroid-refractory or resistant irAEs events are rare. Although existing treatments help patients with hepatitis and colitis, many patients with other irAEs remain refractory or experience toxicities from immunosuppression. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically-informed treatments for severe irAEs.

Luo J ，Beattie JA ，Fuentes P ，Rizvi H ，Egger JV ，Kern JA ，Leung DYM ，Lacouture ME ，Kris MG ，Gambarin M ，Santomasso BD ，Faleck DM ，Hellmann MD ... -  《-》

Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade.

Pneumonitis related to immune checkpoint blockade is uncommon but can be severe, fatal or chronic. Steroids are first-line treatment, however, some patients are refractory or become resistant to steroids. Like many immune-related adverse events, little is known regarding the outcomes and optimal management of patients in whom steroids are ineffective. We performed a single-center retrospective cohort study at a high-volume tertiary cancer center to evaluate the clinical course, management strategies and outcomes of patients treated for immune checkpoint pneumonitis with immune modulatory medications in addition to systemic steroids. Pharmacy records were queried for patients treated with both immune checkpoint blockade and receipt of additional immune modulators. Records were then manually reviewed to identify patients who received the additional immune modulators for immune checkpoint pneumonitis. From 2013 to 2020, we identified 26 patients treated for immune checkpoint pneumonitis with additional immune modulators in addition to steroids. Twelve patients (46%) were steroid-refractory and 14 (54%) were steroid-resistant. Pneumonitis severity included grade 2 (42%) or grade 3-4 (58%). Additional immune modulation consisted of tumor necrosis factor-alpha inhibitor (77%) and/or mycophenolate (23%). Durable improvement in pneumonitis following initiation of additional immune modulators occurred in 10 patients (38%), including three patients (12%) in whom pneumonitis resolved and all immunosuppressants ceased. The rate of 90-day all-cause mortality/hospice referral was 50%. At last follow-up, mortality attributable to pneumonitis was 23%. In addition to mortality from pneumonitis and cancer, 3 patients (12%) died due to infections possibly associated with immunosuppression. Steroid-refractory or -resistant immune checkpoint pneumonitis is uncommon but associated with significant morbidity and mortality. Additional immunomodulators can yield durable improvement, attained in over one third of patients. An improved understanding of the underlying biology of immune-related pneumonitis will be crucial to guide more precise and effective treatment strategies in the future.

Beattie J ，Rizvi H ，Fuentes P ，Luo J ，Schoenfeld A ，Lin IH ，Postow M ，Callahan M ，Voss MH ，Shah NJ ，Betof Warner A ，Chawla M ，Hellmann MD ... -  《Journal for ImmunoTherapy of Cancer》

Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.

Ruf T ，Kramer R ，Forschner A ，Leiter U ，Meier F ，Reinhardt L ，Dücker P ，Ertl C ，Tomsitz D ，Tietze JK ，Gutzmer R ，Dabrowski E ，Zimmer L ，Gesierich A ，Zierold S ，French LE ，Eigentler T ，Amaral T ，Heinzerling L ... -  《-》

Second-line immunosuppressant administration for steroid-refractory immune-related adverse events in patients with lung cancer.

Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases. This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects. Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0 months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection. Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs.

Ogusu S ，Harutani Y ，Tozuka T ，Saito R ，Koyama J ，Sakamoto H ，Sonoda T ，Tsuchiya-Kawano Y ，Oba T ，Kudo K ，Gyotoku H ，Nakatomi K ，Ariyasu R ... -  《-》

The Safety of Immunosuppressants Used in the Treatment of Immune-Related Adverse Events due to Immune Checkpoint Inhibitors: a Systematic Review.

Machado AP ，Ratliff H ，Abdelwahab A ，Vohra MH ，Kuang A ，Shatila M ，Khan MA ，Shafi MA ，Thomas AS ，Philpott J ，Alhalabi O ，Wang Y ... -  《Journal of Cancer》