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.

Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy.

Malignant pleural mesothelioma (MPM) is a locally aggressive disease related to asbestos exposure with a median survival for untreated patients of 4-8 months. The combination of chemotherapy based on platinum and antifolate is the standard treatment, and the addition of bevacizumab adds two months to median survival. Recently, in first-line treatment, immunotherapy combining nivolumab with ipilimumab has been shown to be superior to chemotherapy in the CheckMate-743 study in terms of overall survival (18.1 months), leading to its approval by the FDA and EMA. The positive results of this study represent a new standard of treatment for patients with MPM; however, not all patients will benefit from immunotherapy treatment. In an effort to improve the selection of patient candidates for immunotherapy for different tumors, biomarkers that have been associated with a greater possibility of response to treatment have been described. MPM is a type of tumor with low mutational load and neo-antigens, making it a relatively non-immunogenic tumor for T cells and possibly less susceptible to responding to immunotherapy. Different retrospective studies have shown that PD-L1 expression occurs in 20-40% of patients and is associated with a poor prognosis; however, the predictive value of PD-L1 in response to immunotherapy has not been confirmed. The purpose of this work is to review the state of the art of MPM treatment in the year 2023, focusing on the efficacy results of first-line or subsequent immunotherapy studies on patients with MPM and possible chemo-immunotherapy combination strategies. Additionally, potential biomarkers of response to immunotherapy will be reviewed, such as histology, PD-L1, lymphocyte populations, and TMB.

Brief report: High incidence of peridiagnosis thromboembolic events in patients with BRAF-mutant lung cancer.

INTRODUCTION: We aimed to determine if advanced BRAF-mutant NSCLC has a higher thromboembolic events (TEE) rate than the expected. METHODS: Between 2008 and 2021, 182 patients with BRAF-mutant advanced NSCLC (BRAF V600E, n = 70; BRAF non-V600E, n = 112) were retrospectively identified from 18 centers in Spain. Patients received chemotherapy (n = 147), immunotherapy (n = 69), targeted therapy (n = 42), and immunotherapy + chemotherapy (n = 26). RESULTS: Incidence rate of TEE was 26.4 % (95%CI: 19.9 %-32.9 %). A total of 72 TEE were documented among 48 patients, as 18 patients (37.5 %) developed more than one event. Median time to TEE onset was 2 months, 69 % of TEE occurred in the peridiagnostic period (+/- 90 days from cancer diagnosis), and in 16 pts. (33 %) TEE was the form of lung cancer presentation. Although most TEE were only venous (82 %; PE, n = 33; DVT, n = 16), arterial events were reported in 31 % and occurred earlier, or TEE presented in atypical locations (13.9 %). TEE were related to high hospitalization rate (59 %), recurrence (23 %), and mortality (10.4 %) despite appropriate anticoagulant/antiaggregant treatment. Median OS in patients without-TEE was 19.4 months (95%CI: 4.6-34.1), and significantly shorter in patients with arterial-TEE vs venous-TEE vs both of them: 9.9 months (95%CI: 0-23.5) vs 41.7 months (95%CI: 11.3-72.2 m) vs 2.7 months (95%CI: 2.1-3.3), p = 0.001. Neither clinical or molecular features (BRAF V600E/non-V600E), nor cancer treatment was associated to TEE occurrence. Khorana score underperformed to predict thrombosis at cancer diagnosis, as only 19.2 % of patients were classified as high-risk. CONCLUSIONS: Thrombotic events represent a new clinical feature of BRAF-mutant lung cancer. Patients with almost a 30 % incidence of TEE should be offered systematic anticoagulation.

[Risk factors for cancer-related cognitive impairment in breast and colorectal cancer patients who undergo chemotherapy].

BACKGROUND: Our study aims to evaluate the impact of different factors on cancer-related cognitive impairment in patients who undergo chemotherapy. METHODOLOGY: Prospective longitudinal single-centre study that included patients with breast and colon carcinoma who underwent chemotherapy as part of their treatment. Clinical and genetic characteristics of the patients (single nucleotide polymorphisms, SNPs) were collected. Patients' neurocognitive status was assessed using eleven validated tests at three time points: before chemotherapy (M0 - baseline), between one and four weeks after completing chemotherapy (M1), and between 24-30 weeks after completing chemotherapy (M2). RESULTS: Sixty-two patients were included in this study; 82% were female, median age was 56 years (range 30-74), and 64.5% had been diagnosed with breast cancer. Overall, better cognitive results at M0 were associated with age < 55 years, higher educational level, absence of comorbidities, and the CC variant rs471692 (TOP2A). Significant decline was found between M0 to M1 in the Rey Auditory Verbal Learning Test and the Letter and Number test, with evidence of recovery in M2 compared to M0 regarding the following test: Visual Memory, Functioning Assessment Short Test (FAST), Digit Symbol Substitution and Cube. In the multivariate analysis, being =55 years of age, adjuvant chemotherapy, presence of comorbidities, tobacco and alcohol use, and GT variant rs1800795 were associated with cognitive decline between M0 and M1. CONCLUSION: Being =55 years of age, female, presence of comorbidities and basic education level are related to a higher risk of cognitive impairment after chemotherapy.

Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients.

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.

Dynamic changes in circulating tumor DNA assessed by shallow whole-genome sequencing associate with clinical efficacy of checkpoint inhibitors in NSCLC.

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis are the main therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) without a druggable oncogenic alteration. Nevertheless, only a portion of patients benefit from this type of treatment. Here, we assessed the value of shallow whole-genome sequencing (sWGS) on plasma samples to monitor ICI benefit. We applied sWGS on cell-free DNA (cfDNA) extracted from plasma samples of 45 patients with metastatic NSCLC treated with ICIs. Over 150 samples were obtained before ICI treatment initiation and at several time points throughout treatment. From sWGS data, we computed the tumor fraction (TFx) and somatic copy number alteration (SCNA) burden and associated them with ICI benefit and clinical features. TFx at baseline correlated with metastatic lesions at the bone and the liver, and high TFx (≥ 10%) associated with ICI benefit. Moreover, its assessment in on-treatment samples was able to better predict clinical efficacy, regardless of the TFx levels at baseline. Finally, for a subset of patients for whom SCNA burden could be computed, increased burden correlated with diminished benefit following ICI treatment. Thus, our data indicate that the analysis of cfDNA by sWGS enables the monitoring of two potential biomarkers-TFx and SCNA burden-of ICI benefit in a cost-effective manner, facilitating multiple serial-sample analyses. Larger cohorts will be needed to establish its clinical potential.

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion.

INTRODUCTION: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. METHODS: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. RESULTS: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1-4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%-55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7-72.1] versus 16.3 mo [12.7-28.8], p < 0.0001). CONCLUSIONS: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer.

In recent years, immunotherapy-based regimens have been included into the treatment's algorithm of several cancer types. Programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) interact with their ligands found on the surface of antigen presenting cells (APC) or tumor cells (PD-L1/2 and CD80/86). Through these interactions, stimulatory or inhibitory signals are established. Immune checkpoint inhibitors (ICIs), block these interactions, and when administered not only as monotherapy but also as part of combination regimens, have shown to improve survival results in multiple advanced cancers leading to an increasing number of patients treated with ICI and, as a consequence, a rise in the number of patients developing immune-related adverse events (irAEs). Presence of irAEs has been associated with greater benefit from treatment, especially when blocking PD-L1. Recent data suggests that treatment benefit persists after discontinuation of ICIs due to a treatment related adverse event, regardless of the grade. Patients experiencing grade 3-4 irAEs are at risk of toxicity recurrence after reintroducing immunotherapy and therefore, the decision to resume the treatment is challenging. In these cases, a multidisciplinary approach is always needed and several factors should be considered. Management of severe toxicities may require systemic corticosteroids which can impact on T-cell function. Due to their immunosuppressive properties, it is necessary to deeper determine how corticosteroids influence responses. In terms of overall survival (OS), the use of steroids as therapy for irAEs seems not to reduce OS and several studies have reported durable responses in patients experiencing autoimmune toxicities treated with corticosteroids.

Hepatic Rupture as the Initial Presentation of an EGFR-Mutated Lung Adenocarcinoma: A Case Report.

Hepatic rupture is a rare complication of solid tumor malignancies, notably in lung adenocarcinomas, and carries an extremely poor overall prognosis. Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma predict benefit with tyrosine kinase inhibitors (TKIs). This case report describes a female patient who presented with a metastatic hepatic rupture and was subsequently diagnosed with EGFR-mutated lung adenocarcinoma. The tumor had an impressive response to TKI inhibitor treatment, reversing her extremely poor, short-term prognosis. We believe this unique case sheds light on the treatment management of hepatic ruptures and supports the high response rate seen with TKIs in EGFR-mutated lung cancers, regardless of the patient's performance status.

Efficacy of chemotherapy for malignant pleural mesothelioma according to histology in a real-world cohort.

CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line in MPM with some differences in the efficacy of chemotherapy according to histology. The objective of this study is to characterize the impact of chemotherapy according to histology in patients diagnosed with MPM at our institution. Clinical records of all MPM patients diagnosed at Vall d'Hebron University Hospital between November 2002 and April 2020 were reviewed. Associations between clinical variables and outcomes were assessed with Cox regression models. Survival data were calculated by the Kaplan-Meier method. 189 patients were included with 76% of tumors classified as epithelioid subtype. First line chemotherapy was offered to 85% of patients. Median survival in overall population was 21.3 months (95% CI 17.2-24.3). We found that patients with epithelioid tumors had better overall survival (OS) and progression free survival (PFS). Median OS of epithelioid patients treated with first line chemotherapy was 26.7 months versus 15.0 months in non-epithelioid patients (HR 2.25 CI 95% 1.4-3.4; p < 0.001). Median PFS for patients with epithelioid tumors treated with chemotherapy was 4.8 months versus 3.6 months in non-epithelioid (HR 1.5 CI 95% 1.0-2.3; p = 0.03). The improvement of outcomes in patients with epithelioid histology was detected in patients treated with cisplatin or carboplatin. Histology was not a predictive factor for the platinum agent sensitivity (p of interaction PFS = 0.09, p of interaction OS = 0.65). In our series, patients with non-epithelioid tumors presented worse prognosis. Although epithelioid tumors exposed to cisplatin had higher PFS, histology was not a clear predictor of chemotherapy efficacy.

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.

Interrelations between Patients' Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients.

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment. Unfortunately, only some patients benefit from these therapies. Thus, certain clinicopathological characteristics of the patients have been proposed as biomarkers of ICIs response. We assembled a retrospective cohort of 262 NSCLC patients treated with ICIs, compiled relevant clinicopathological characteristics, and studied their associations with treatment outcome using Cox proportional-hazards survival models. Additionally, we investigated the interrelations between clinicopathological features and devised a method to create a compendium associated with ICIs response by selecting those that provide non-redundant information. In multivariate analyses, ECOG performance status (hazard ratio (HR) 1.37 (95% CI 1.11 to 1.68), p < 0.005), LDH (HR 1.24 (95% CI 1.03 to 1.48), p = 0.02)) and PD-L1 negativity were associated with decreased PFS (HR 1.92 (95% CI 1.03 to 3.58), p < 0.04), whereas presentation of immune-related adverse events (irAEs) (HR 0.35 (95% CI 0.22 to 0.55, p < 0.005) or females (HR 0.52 (95% CI 0.33 to 0.80, p < 0.005) had longer progression-free survival. Additionally, numerous clinicopathological indicators were found to be interrelated. Thus, we searched for features that provide non-redundant information, and found the combination of LDH levels, irAEs, and gender to have a better association with ICIs treatment response (cross-validated c-index = 0.66). We concluded that several clinicopathological features showed prognostic value in our real-world cohort. However, some are interrelated, and compendiums of features should therefore consider these interactions. Joint assessment of LDH, irAEs, and gender may be a good prognostic compendium.

Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs.

Is aflibercept an optimal treatment for wt RAS mCRC patients after progression to first line containing anti-EGFR?

PURPOSE: To determine the efficacy and safety data of aflibercept + FOLFIRI in wt RAS mCRC patients after progression to standard chemotherapy + anti-EGFR treatment. METHODS: Retrospective, observational study in real life conducted in wt RAS mCRC patients treated with FOLFIRI-aflibercept after progression to standard first line chemotherapy + anti-EGFR treatment. RESULTS: A total of 120 patients from 12 Spanish hospitals were enrolled. Median age is 60 years (62.5%/37.5%male/female). Primary tumor site is 24.1%/75.9% right/left-side colon, and 40.8% of patients had a prior resection. All patients had wild-type RAS tumors including 5% of patients with BRAF mutations and received anti-EGFR treatment. At the time aflibercept was initiated, ECOG PS is 0/1 in 96% of patients. Median number of FOLFIRI-aflibercept cycles is 12. Efficacy results: Overall response rate is 33%; progression-free survival (PFS) is 6.9 months (95%CI: 6.1-7.8). Primary tumor resection was the only significant variable related to PFS in the multivariate analysis. Median overall survival (OS) is 14.5 months (95%CI: 9.7-19.3). ECOG and number of metastatic sites were related to OS in multivariate analysis. About 54.1% of patients received a third-line therapy including TAS-102 (23%), regorafenib (18.5%), and capecitabine (9.2%). TOXICITY: Grade 3-4 toxicities were observed in 37.5% of the patients (hematologic 16.6%, hypertension 7.5%, asthenia 5.9%, and perforation 2.5%). Aflibercept dose was reduced in 18.3% of patients. CONCLUSIONS: The results show that patients with wt RAS mCRC who received an anti-EGFR as part of the first-line treatment achieved similar RR, PFS, OS, and toxicities to those reported in VELOUR trial. These results suggest that FOLFIRI-aflibercept after first-line treatment with anti-EGFR is an appropriated option for RAS wt mCRC.

Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10-23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.