An algorithm based on immunotherapy discontinuation and liver biopsy spares corticosteroids in two thirds of cases of severe checkpoint inhibitor-induced liver injury.

BACKGROUND: There are few data on corticosteroids (CS)-sparing strategies for checkpoint inhibitor (ICI)-induced liver injury (ChILI). AIM: We aimed to assess the performance of a 2-step algorithm for severe ChILI, based on ICI temporary discontinuation (step-1) and, if lack of biochemical improvement, CS based on the degree of necroinflammation at biopsy (step-2). METHODS: Prospective study that included all subjects with grade 3/4 ChILI. Peripheral extended immunophenotyping was performed. Indication for CS: severe necroinflammation; mild or moderate necroinflammation with later biochemical worsening. RESULTS: From 111 subjects with increased transaminases (January 2020 to August 2023), 44 were diagnosed with grade 3 (N = 35) or grade 4 (N = 9) ChILI. Main reason for exclusion was alternative diagnosis. Lung cancer (13) and melanoma (12) were the most common malignancies. ICI: 23(52.3%) anti-PD1, 8(18.2%) anti-PD-L1, 3(6.8%) anti-CTLA-4, 10(22.7%) combined ICI. Liver injury pattern: hepatocellular (23,52.3%) mixed (12,27.3%) and cholestatic (9,20.5%). 14(32%) presented bilirubin >1.2 mg/dL. Overall, 30(68.2%) patients did not require CS: 22(50.0%) due to ICI discontinuation (step-1) and 8/22 (36.4%) based on the degree of necroinflammation (step-2). Biopsy mainly impacted on grade 3 ChILI, sparing CS in 8 out of 15 (53.3%) non-improvement patients after ICI discontinuation. CD8+ HLA-DR expression (p = 0.028), central memory (p = 0.046) were lower in CS-free managed subjects, but effector-memory cells (p = 0.002) were higher. Time to transaminases normalisation was shorter in those CS-free managed (overall: p < 0.001, grade 3: p < 0.001). Considering our results, a strategy based on ICI discontinuation and biopsy for grade 3 ChILI is proposed. CONCLUSIONS: An algorithm based on temporary immunotherapy discontinuation and biopsy allows CS avoidance in two thirds of cases of severe ChILI.

Retreatment With Immune Checkpoint Inhibitors After a Severe Immune-Related Hepatitis: Results From a Prospective Multicenter Study.

BACKGROUND & AIMS: Liver injury related to immunotherapy is a relatively frequent immune-related adverse event that requires permanent discontinuation of immune checkpoint inhibitors (ICIs) in severe cases. We present the outcome of a cohort of patients who were retreated with immunotherapy after resolution of severe immune-related hepatitis. METHODS: We performed a prospective, multicenter, noninterventional study that included all consecutive patients with cancer and previous grade 3 or 4 immune-related hepatitis who were retreated with ICIs in 3 academic hospitals. RESULTS: Twenty-three patients who developed severe immune-related hepatitis were included: 20 of 23 (87.0%) received a single ICI and 3 of 23 (13.0%) received anti-programmed cell death protein-1 plus an anti-cytotoxic T-lymphocyte-associated antigen. The most frequent cancers were lung cell and urinary tract (7 and 6 cases, respectively). Immunotherapy was discontinued in all cases. Nineteen patients (82.6%) also received corticoids. Patients mainly were retreated with the same ICI (18 of 23; 78.3%) after a median time of 10 weeks (range, 1-54 wk) from the severe immune-related hepatitis. Fifteen patients (65.2%) did not have recurrence of the immune-related hepatitis after retreatment. Among the 8 (34.8%) subjects with recurrence, 5 of 8 were grade 3 and 3 of 8 were grade 4. Six (75%) had either an underlying autoimmune disease or antinuclear antibodies ≥1/80 (75% vs 26.7%; P = .037). None of the patients with previously grade 4 hepatitis had a recurrence, and those patients who had a recurrence tended to present with a better oncological prognosis. Overall, 19 (82.6%) subjects required permanent discontinuation of ICIs, with cancer progression the main reason for discontinuation (9 of 19; 47.8%). CONCLUSIONS: Retreatment with ICIs is a feasible option after a severe immune-related hepatitis, even with the same ICIs, without recurrence of the liver injury retreatment in up to 65% of patients.

The Low Incidence of Viral Hepatitis Reactivation Among Subjects on Immunotherapy Reduces the Impact of Suboptimal Screening Rate.

Background and Aims: Immunotherapy with immune checkpoint inhibitors (ICIs) is a pillar of many advanced tumors. However, there is scarce data concerning the rate of viral hepatitis screening in this population or the risk of viral reactivation. Methods: Retrospective-prospective study that includes all patients who began ICIs between January/2019 and December/2020 in a University Hospital. Data on viral hepatitis screening prior to the beginning of ICIs were collected. In subjects lacking information, serological tests were requested prospectively. Among HBsAg, anti-HBc, or anti-HCV positive subjects, reactivation was prospectively assessed. Results: During the 2-year period of study, 595 subjects received ICIs (61.2% male, mean age 63 years). The most prevalent cancers found were 35.5% lung cancer, 12.1% melanoma, and 8.2% head and neck; ICIs schemes were mainly anti-PD1 (65.7%), followed by anti-PD-L1 (19.2%), and combined therapy (13.6%). Prior to immunotherapy, anti-HCV screening was performed in 462 (77.6%) subjects, HBsAg in 462 (77.6%), anti-HBc in 335 (56.3%), and the complete screening in 328 (55.1%). The anti-HBc screening was more frequently ordered among patients treated with concomitant systemic therapy (p = 0.003), especially in the case of chemotherapy (p = 0.015), though HCV screening was more commonly performed in concomitant therapies different from chemotherapy (p = 0.001). Serological tests were completed prospectively in those alive, leading to an overall prevalence for anti-HCV of 3.5%, HBsAg at 1.3%, and anti-HBc of 15.2%. HCV-RNA was detected in 2/19 (both patients with hepatocellular carcinoma), HBV-DNA in 4/7 HBsAg positive, and in 1/75 anti-HBc positive subject. Five out of the 7 HBsAg carriers and 1/75 anti-HBc+ subjects (due to concomitant antiretroviral therapy) received antiviral prophylaxis. Neither cases of HBV reactivation nor changes in HCV viral load were observed. Discussion: HBV and HCV screening prior to immunotherapy is suboptimal. Though the rate of viral hepatitis reactivation seems extremely low, efforts should be made to optimize viral hepatitis screening prior to immunotherapy for the selection of candidates for either antiviral prophylaxis or periodical follow-up.

Genetic evolution to tyrosine kinase inhibitory therapy in patients with EGFR-mutated non-small-cell lung cancer.

BACKGROUND: Tumour heterogeneity impacts the efficacy of metastatic cancer treatment even if actionable mutations are identified. Clinicians need to understand if assessing one lesion provides reliable information to drive a therapeutic decision in non-small-cell lung cancer (NSCLC) patients. METHODS: We analysed inter-tumour heterogeneity from five autopsied individuals with NSCLC-harbouring mutations in the epidermal growth factor receptor (EGFR), treated with EGFR tyrosine kinase inhibitors (TKIs). Through a comprehensive next-generation sequencing (NGS) oncopanel, and an EGFR panel for digital droplet PCR (ddPCR), we compared metastases within individuals, longitudinal biopsies from the same lesions and, whenever possible, the primary naive tumour. RESULTS: Analysis of 22 necropsies from five patients revealed homogeneity in pathogenic mutations and TKI-resistance mechanisms within each patient in four of them. In-depth analysis by whole-exome sequencing from patient 1 confirmed homogeneity in clonal mutations, but heterogeneity in passenger subclonal alterations. Different resistance mechanisms were detected depending on the patient and line of treatment. Three patients treated with a c-MET inhibitor in combination with TKI lost MET amplification upon progression. CONCLUSION: At a given point and under selective TKI pressure, a single metastasis biopsy in disseminated tumours from EGFR-mutated NSCLC patients could provide a reasonable assessment of actionable alterations useful for therapeutic decisions.

PARP inhibitors in advanced prostate cancer: when to use them?

Poly (ADP-ribose) polymerase (PARP) inhibitors have antitumor activity in advanced prostate cancer associated with loss of homologous recombination repair (HRR) function. About 20% of all patients with advanced prostate cancer present germline or tumor mutations in HRR-related genes, the most common being BRCA2, mutated in approximately 10% of all advanced prostate cancers. Challenges related to sample availability, tumor heterogeneity and access to NGS technology need to be addressed for a successful implementation of genomic stratification in routine clinical practice. The recent regulatory approvals of PARP inhibitors olaparib and rucaparib represent the first molecular biomarker-guided drugs for men with prostate cancer. While these findings represent a significant advance in the field of precision medicine and prostate cancer, there are still many unsolved questions on the optimal use of PARP inhibitors in this disease. Several clinical trials have shown that different mutations in various genes are associated with distinct magnitudes of sensitivity to PARP inhibitors, with BRCA2 mutations associating with more frequent and durable responses, questioning the benefit for subset of patients with mutations in other HRR-associated genes. In this review, we scrutinize the clinical development of different PARP inhibitors for the treatment of advanced prostate cancer, and we discuss how the study of additional biomarkers and the design of rational drug combinations can maximize patient benefit from this drug class.

Metastatic nonclear renal cell carcinoma current review in evolving treatment strategies.

PURPOSE OF REVIEW: Renal cell carcinoma (RCC) is the 6th most often diagnosed cancer in men and the 10th in women. Nearly 75% of the renal cancer cases are clear cell histologic subtype, whereas nonclear cell histologies represent the remaining 25%. Treatment options for clear renal type are well established. However, as nonclear RCC represents a heterogenous and less frequent group. Current treatment options for these tumors are limited and mostly based on evidence derived from small phase II clinical trials. The present review aims to provide an update of the available treatment options for nonclear RCC. RECENT FINDINGS: In the past decade, the vascular endothelial growth factor tyrosine kinase inhibitor, sunitinib, and mammalian target of rapamycin inhibitors, everolimus, and temsirolimus, have demonstrated limited efficacy in nonclear RCC. Recent studies with MET inhibitors and immunotherapy-based combinations have proven promising activity, especially in certain subgroups of patients, such as patients with MET-driven disease or patients with sarcomatoid features RCC. SUMMARY: Here, we report currently available data about biology and treatment of nonclear cell RCC.

Do the SGLT-2 Inhibitors Offer More than Hypoglycemic Activity?

Type 2 diabetes mellitus (T2DM) is one of the most common chronic health conditions in the USA; it affects approximately 10% of adults with up to one-quarter being undiagnosed. T2DM is associated with substantial cardiovascular (CV) morbidity and mortality. T2DM is a pathological condition characterized by elevated levels of glucose and associated with high CV risk. Traditional hypoglycemic drugs have demonstrated their capability for effective and maintained management of high glucose levels, but they have not significantly impacted on the incidence of CV events. Recently, a new class of hypoglycemic agents, SGLT-2 receptor inhibitors, has been developed. The EMPA-OUTCOME trial involving empagliflozin (a SGLT-2 receptor inhibitor) has shown significant reductions in major adverse cardiac events (MACEs), cardiovascular mortality, and hospitalization for heart failure (HF) when administered on top of standard-of-care therapy for T2DM patients at high CV risk. The dramatic change driving the superiority of the primary composite outcome (major adverse CV events) was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35 and 32% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively. These effects are even more important given the difficulties for treating concomitant HF in T2DM patients. These surprising results have been also corroborated by another agent of this class, canagliflozin, and the CANVAS trial. The magnitude of these somehow surprising cardiac benefits attained in the absence of major differences in glycemic, lipid, or blood pressure (BP) control has led to several groups to suggest that these benefits may be independent of its hypoglycemic activity and whether this new class could be considered a "cardiac" drug. The objective of this review has been to review the different hypotheses proposed to explain the cardiac benefits of this new class of antidiabetic drugs.