Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis

Zhang, Xi; Ran, Yu; Wang, Kun Jie; Zhu, Yuan; Li, Jing Hua

doi:10.2147/dddt.s115493

Cited by 31 publications

(22 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…37 In addition, the apparent potential of a JAK1 inhibitor to mitigate AST/ALT AEs associated with itacitinib might support combination studies of JAK1 and PD-1 inhibitors, which are known to produce immune-mediated hepatic toxicities, albeit of low severity. 38 For patients with DLBCL failing curative therapy, or for those not eligible for stem cell transplant, options remain very limited and without a standard of care. Six patients responded to the combination (for a 26% ORR in DLBCL), including 4 patients with non-GCB DLBCL (for a 31% ORR in non-GCB DLBCL).…”

Section: Discussionmentioning

confidence: 99%

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Phillips

Forero‐Torres

Sher

et al. 2018

Blood

View full text Add to dashboard Cite

Because both phosphatidylinositol 3-kinase δ (PI3Kδ) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kδ inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination pneumonia (n = 5), pneumonia (unrelated to; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Phillips

Forero‐Torres

Sher

et al. 2018

Blood

View full text Add to dashboard Cite

show abstract

“…Incidence of ALT and AST elevations were significant for both all-grade and high-grade events, but no RR analysis or stratification by underlying tumor type was performed. Another study analyzed 9 RCTs and did not find a significantly increased risk of high-grade toxicity [41]. Again, patients were not stratified by underlying tumor type for further analysis.…”

Section: Discussionmentioning

confidence: 99%

“…In the event of grade 3-4 toxicity without response to steroids, administration of mycophenolate mofetil is appropriate. There is no role for infliximab in cases of DILI as it confers its own risk of hepatotoxicity [41,49].…”

Section: Discussionmentioning

confidence: 99%

Risk of Liver Toxicity with Nivolumab Immunotherapy in Cancer Patients

Zarrabi

Wu²

2018

Oncology

View full text Add to dashboard Cite

Background: Nivolumab is approved for the treatment of many cancers. This meta-analysis was conducted to determine the risk of hepatotoxicity with nivolumab therapy. Methods: An analysis from all phase I–III clinical trials up to December 2016 examining nivolumab was conducted. Data on elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were extracted from the safety profiles of each trial. Incidence and relative risk (RR) were calculated using random- or fixed-effects models with 95% confidence intervals (CIs). Results: The incidences of all-grade and high-grade elevations in AST were 5.4% (95% CI 3.2–9.1) and 1.6% (95% CI 0.9–3.0), respectively. The incidences of all-grade and high-grade elevations in ALT were 4.9% (95% CI 2.9–8.2) and 1.7% (95% CI 0.9–3.1), respectively. Elevations of both laboratory markers were significantly increased when compared to control (p < 0.001). Nivolumab significantly increased the RR of AST/ALT elevations; RRs were 1.58 (95% CI 1.1–2.2) for all-grade AST elevation, and 1.62 (95% CI 1.2–2.3) for all-grade ALT elevation. Subgroup analysis of all-grade AST or ALT elevation revealed a significant variation among tumor types (p < 0.001) and with combination with ipilimumab (p < 0.001). Conclusions: Nivolumab is associated with significantly increased risk of liver toxicity.

show abstract

“…No signiicant diferences in the risk of all-grade and high-grade hepatic irAEs were found between PD-1 inhibitors monotherapy and ipilimumab monotherapy [27].…”

Section: Hepaticmentioning

confidence: 82%

Management and Supportive Care of Patients Undergoing Immunotherapy

Rapoport¹,

Eeden²

2017

Immunotherapy - Myths, Reality, Ideas, Future

View full text Add to dashboard Cite

In many tumor types, where the prognosis was shown to be extremely dismal before, immunotherapy is now a new beacon of hope to many patients. Immunotherapy has been approved for use in a many diferent cancers including metastatic melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, refractory Hodgkin's lymphoma, metastatic bladder cancer advanced head and neck cancer, and the list keeps growing each day. It seems to be generally beter tolerated in most patients and less toxic compared to what we have seen in diferent anticancer treatments from before. However, the toxicities here are termed immune-related adverse events. There is almost no prospective data on these toxicities, and guidelines or recommendations are mostly based on symptomatic management from the ongoing clinical trials. Treating oncologists need to be aware of the subtleties in presentation and the huge diference in the way we mange these side efects. Although most adverse events are low-grade and manageable, they have the potential to be life-threatening if not treated promptly. In this chapter, we address the diferent immune-related adverse events relating to the organ system they can involve, presentation and symptomatology, general recommendations of management, and individual toxicities. Keywords: immunotherapy, PD-1, CTLA-4.

show abstract

Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis

Cited by 31 publications

References 41 publications

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Risk of Liver Toxicity with Nivolumab Immunotherapy in Cancer Patients

Management and Supportive Care of Patients Undergoing Immunotherapy

Contact Info

Product

Resources

About