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•Acute hepatitis resulting from treatment of metastatic cancer with immune checkpoint inhibitors is rare.•Immune-mediated hepatitis diagnosis requires exclusion of all causes of ...hepatitis.•Liver histology is paramount for the diagnosis and severity evaluation of liver damage.•Management should be based on biological and histological severity of liver injury.•Immune-mediated hepatitis does not require the systematic use of corticosteroids.
Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs).
Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens.
In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1–49) weeks and median number of immunotherapy injections was two (range, 1–36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5–1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction.
Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration.
Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.
Anti-PD-(L)1 can provide overall survival (OS) benefits over conventional treatments for patients with many different cancer types. However, the long-term outcome of cancer patients responding to ...these therapies remains unknown. This study is an exploratory study that aimed to describe the long-term survival of patients responding to anti-PD-(L)1 monotherapy across multiple cancer types.
Data from patients treated with an anti-PD-(L)1 monotherapy in a phase I trial at Gustave Roussy were retrospectively analyzed over a period of 5 years. All cancer types (
= 19) were included. Clinical and biological factors associated with response, long-term survival, and secondary refractory disease were studied.
Among 262 eligible patients, the overall objective response rate was 29%. The median progression-free survival of responder patients (RP) at 3 months was 30 months, and the median OS of RP was not reached after a median follow-up of 34 months. In RPs, 3- and 5-year OS percentages were 84% and 64%, respectively. No death occurred in the 21 complete responders (CR) during the overall follow-up. However, many partial responders (PR) showed subsequent tumor relapses to treatment. Long responders (response ≥2 years) represented 11.8% of the overall population. These findings should be validated in further prospective studies.
There are currently no differences in therapeutic strategies between CRs and PRs to anti-PD-(L)1. We found a striking difference in OS between these two types of responses. Our results are in favor of evaluating patient stratification strategies and intensification of treatments when tumor lesions of a partial responder to immunotherapy stop improving.
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Life expectancy evaluation is crucial when selecting patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on three objective variables (number of ...metastatic sites, lactate dehydrogenase (LDH) and serum albumin) was validated in patients treated with cytotoxics and targeted therapies. We aimed to determine if those factors were applicable to immune-checkpoint therapies (ICTs) in phase I trials and to evaluate new variables that may preclude a better prognosis in patients receiving ICT.
We conducted a retrospective analysis of survival risk factors in a discovery cohort of 155 patients enrolled into ICT phase I trials at our institution. We computed univariate analysis and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in phase I ICT trials was used to prospectively validate this score.
A total of 155 patients (M/F: 83/72; median age 59) receiving an experimental ICT between March 2012 and January 2016 were included in the discovery cohort. An MVA assessing the RMH score variables showed that low albumin (hazard ratio HR 1.73, 95% confidence interval CI 1.05–2.86) and LDH > upper limit normal (ULN) (HR 1.88, 95% CI 1.12–3.15) were independent negative prognostic factors for OS. Interestingly, neutrophil-to-lymphocyte ratio (NLR) > 6 (HR 1.75, 95% CI 1.04–2.95) was associated with a decrease in OS. The number of metastases was not associated with a poorer outcome for this ICT cohort (HR 0.83, 95% CI 0.51–1.35). A risk score based on the results of the MVA (NLR > 6 = 1; LDH > ULN = 1; albumin < 35 g/l = 1) showed that patients presenting a high score (>1) had a significantly shorter OS (20.4 weeks; 95% CI 5.7–35.2) compared to those with a low score (0 or 1) (68.9 weeks; 95% CI 50–83.7) (HR 2.9, 95% CI 1.87–4.64). In the validation cohort of 113 patients, again the patients presenting a high score showed an inferior OS (HR 6.3, 95% CI 2.7–14.8).
In ICT phase I trials, traditional prognostic variables included in the RMH score may be suboptimal to determine patient's prognosis. In this context, the NLR is a significant prognostic variable. The Gustave Roussy Immune Score, based on albumin, LDH and NLR, allows a better selection of patients for ICT phase I trials.
•A prognostic score for patients enrolled in immune phase I trials is purposed.•The GRIm-Score is based on three independent biomarkers: albumin, lactate dehydrogenase and neutrophil-to-lymphocyte ratio.•A prospective validation of the score had been realised.•This score is easily applicable in daily practice.
Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (eg, mutations or deletions of the subunits INI1 or SMARCA4) can lead to ...aberrant histone methylation, oncogenic transformation, and a proliferative dependency on EZH2 activity. In this first-in-human study, we aimed to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of tazemetostat, a first-in-class selective inhibitor of EZH2.
We did an open-label, multicentre, dose-escalation, phase 1 study using a 3 + 3 design with planned cohort expansion at the two highest doses below the maximally tolerated dose. The study was done at two centres in France: Institut Gustave Roussy (Villejuif, Val de Marne) and Institut Bergonié (Bordeaux, Gironde). Eligible patients had relapsed or refractory B-cell non-Hodgkin lymphoma or an advanced solid tumour and were older than 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Tazemetostat was administered orally from 100 mg twice daily to 1600 mg twice daily in 28-day cycles. The primary endpoint was to establish the maximum tolerated dose or recommended phase 2 dose of tazemetostat, as determined by dose-limiting toxicities, laboratory values, and other safety or pharmacokinetic measures in cycle one according to local investigator assessment. Safety was assessed in patients who received at least one dose of tazemetostat; antitumour activity was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01897571. The phase 1 part of the study is complete, and phase 2 is ongoing.
Between June 13, 2013, and Sept 21, 2016, 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours) received doses of tazemetostat. The most common treatment-related adverse events, regardless of attribution, were asthenia (21 33% of 64 treatment-related events), anaemia (nine 14%), anorexia (four 6%), muscle spasms (nine 14%), nausea (13 20%), and vomiting (six 9%), usually grade 1 or 2 in severity. A single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg twice daily. No treatment-related deaths occurred; seven (11%) patients had non-treatment-related deaths (one at 200 mg twice daily, four at 400 mg twice daily, and two at 1600 mg twice daily). The recommended phase 2 dose was determined to be 800 mg twice daily. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours.
Tazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours.
Epizyme and Eisai.
...this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.7 These two properties offer additional potential ...therapeutic activity and avoid off-target toxicities.1,7 Safety data are presented on all 323 patients treated.6 The safety profile appears particularly promising, as suggested by the absence of dose-limiting toxicity, and thus maximum tolerated dose level was not reached. ...the frequency of atrial fibrillation with pirtobrutinib (1%) is also favourably low (16·2% with ibrutinib,2 3·9% with acalabrutinib,3 and 2·0% with zanubrutinib4). ...the duration of follow-up (6 months) is insufficient to draw conclusions for long-term safety. Because side-effects of tyrosine kinase inhibitors, whether on target or off target, could eventually be cumulative, Mato and colleagues conclude longer follow-up is needed to better understand the pirtobrutinib safety profile associated with long-term administration.
Immune checkpoint inhibitors (ICIs) improve clinical outcomes in patients suffering from different types of cancer. Liver toxicity is one of the immune-related adverse events associated with ...immunotherapy; although not common, its management is challenging as it is extremely heterogeneous in terms of presentation and severity. Differences in the development and evolution of ICI-related toxicity in healthy or cirrhotic livers have not yet been elucidated. Assessing causality is key to diagnosing ICI-induced liver toxicity; liver biopsies can assist not only in the differential diagnosis but also in assessing the severity of histological liver damage. The current classification of severity overestimates the grade of liver injury and needs to be revised to reflect the views of hepatologists. Spontaneous improvements in ICI-related liver toxicity have been reported, so corticosteroid therapy should probably be individualised not systematic. The reintroduction of ICIs in a patient with previous immune-mediated hepatitis may be possible, but the risk/benefit ratio should be considered, as the risk factors for hepatitis recurrence are currently unclear. The management of these patients, requiring a balance between efficacy, toxicity and specific treatments, necessitates multidisciplinary collaboration. The incidence of immune-related liver toxicity will continue to rise based on the increasing use of ICIs for most cancers, mandating improved understanding and management of this complication.
Corticosteroids are among the most prescribed drugs in oncology. The indications range from cancer-related indications for refractory symptoms, anti-cancer effects mainly in hematology, supportive ...measures for cancer-specific treatments and more recently immune-related adverse events induced by modern immunotherapies. In oncological emergencies, corticosteroids are common first-line treatments because of their rapid effect and wide variety of actions. In the last 5 years, with the advance of immune checkpoint inhibitors, corticosteroids are becoming routinely used to manage immune-related adverse effects. Preclinical studies suggested that corticosteroid-induced immunosuppression might dampen the activity of immunotherapies. Prospective clinical studies show that corticosteroid use is a prognostic marker for the cancer outcome in metastatic setting but does not significantly alter the patient's response to immunotherapies per se. Here, we review the state of the art on corticosteroid use in oncology, with a focus on the drugs' potential impact on immunotherapy activity. The comprehensive pharmacological characteristics of corticosteroid drugs, clinical indications, modality of administration and associated precautions for use are discussed in this article.
•Corticosteroids have multiple indications that recently increase in immuno-oncology.•Corticosteroids have miscellaneous adverse events and should be used with caution.•Corticosteroids do not impact the efficacy of immunotherapy in metastatic patients.•Corticosteroids use may compromise the efficacy of immunotherapy in adjuvant setting.•Prolonged corticosteroid use should be accompanied by ad hoc anti-infectious prophylaxis.
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