The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of ...immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care.
The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString
PanCancer IO360™ CodeSet using nCounter
technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these.
TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI 1.4; 6.0, p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI 1.2; 11.6, p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI 0.18, 0.76, p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI 0.14, 0.90, p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2).
These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.
Summary
Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We ...explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m
2
) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney’s tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m
2
and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m
2
. For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m
2
;
p
= 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%;
p
= 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.
Primary cutaneous mucinous carcinoma (PCMC) is a rare malignant skin adnexal tumor. Recurrences are most often localized, and long-term follow-up after complete surgery consists essentially of ...self-examination of skin. We report one case of metastatic PCMC with elevated levels of serum CEA and CA15.3. Because of the difficulty to differentiate PCMC and metastasis of mucinous breast cancer, the hypothesis of a metastasized breast cancer was ruled out. These tumor markers contributed to the monitoring of the metastatic disease. Since metastatic disease was diagnosed after several years of seeming complete remission, CEA and CA15.3 would likely have allowed the clinicians to detect the relapse earlier. Although the use of tumor biomarkers in PCMC is not rooted in clinical practice and not mentioned in guidelines, we suggest that CEA and CA15.3 could be of particular interest to monitor and detect early metastatic PCMC.
Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, ...hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (
< 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively,
< 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC
/AUC
≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56);
= 0.023 and 10.61 (2.34-48.15),
= 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50);
= 0.032 and HR = 1.23 (1.35-10.39),
= 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUC
/AUC
deserves more investigation in a larger cohort of MM patients.
There is concern about the burden of liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs).
In a retrospective cohort study, we evaluated the likelihood of grade 3/4 ...liver injury, of grade 3/4 cholestatic liver injury, and of liver failure, as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5, following treatment with ICIs. We compared these occurrences with a group of cancer patients who were propensity-matched and treated with conventional chemotherapy. For all ICI patients experiencing grade 3/4 liver injury, we conducted a causality assessment using the RUCAM method and examined patient outcomes.
Among 952 patients (median IQR age 66 57-73 years, 64% males) who were treated with ICI between January 1, 2015, and December 31, 2019, a total of 86 (9%) progressed to grade 3/4 liver injury, and liver failure was not observed. Anti-PD-(L)1/anti-CTLA-4 antibodies combinations (adjusted hazard ratio 3.36 95% CI: 1.67-6.79;
0.001), and chronic hepatitis B (adjusted hazard ratio 5.48 95% CI: 1.62-18.5;
= 0.006, were independent risk factors. Liver injury was attributed to ICI treatment in 19 (2.0%) patients. Patients with ICI toxicity typically presented with granulomatous hepatitis or cholangiocyte inflammation. ICI withdrawal was associated with cancer progression and mortality. Re-introduction of ICI was not associated with recurrent grade 3/4 liver injury. Compared with matched patients treated with conventional, non-ICI-based chemotherapy, anti-PD-(L)1/anti-CTLA-4 combinations (
0.001) and anti-PD-(L)1 monotherapies (
= 0.053) increased the risk of grade 3/4 liver injury and of grade 3/4 cholestatic liver injury, respectively.
An increased risk of grade 3/4 liver injury under anti-PD-(L)1/anti-CTLA-4 antibodies was observed, whereas no substantial increase in the likelihood of liver failure occurred even after treatment reintroduction.
There is concern about liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs). We investigated the burden of grade 3/4 liver injury after treatment with ICIs in a multicentric cohort of patients with cancer. Overall, a 9% incidence of grade 3/4 liver injury was detected after ICIs, and direct ICI hepatotoxicity was demonstrated in 2% of patients. Anti-PD-(L)1/Anti-CTLA-4 antibody combinations, and chronic HBV infection were independent risk factors. ICI withdrawal for grade 3/4 liver injury was associated with cancer progression. Re-introduction of ICI treatment was not associated with recurrent grade 3/4 liver injury.
Objective
Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune‐related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been ...excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer.
Methods
A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response.
Results
The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty‐four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression‐free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression‐free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation.
Conclusion
Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.
Les neuropathies immuno-induites associées aux inhibiteurs de checkpoint immunitaires (ICIs) sont généralement sensibles à la corticothérapie et aux IgIV. Néanmoins, la prise en charge des formes ...réfractaires et des rechallenges reste mal codifiée.
L’objectif de l’étude est de décrire la réponse clinique du tocilizumab (anti-récepteur pour l’interleukine 6R IL-6R) dans les neuropathies immuno-induites corticorésistantes et/ou de réintroduction des ICIs.
Nous avons recueilli de façon rétrospective les cas de neuropathies immuno-induites corticorésistantes adressés à notre service ou discutés dans le cadre du réseau OncoNeuroTox de janvier 2021 à août 2023. Les critères d’inclusion étaient (i) une neuropathie d’installation subaiguë à moins de trois mois après la dernière perfusion d’ICIs (ii) après exclusion des diagnostics alternatifs, et (iii) résistante après corticothérapie à 1mg/kg ou 3 bolus de méthylprednisolone 1g+une cure d’IgIV.
Quatre cas de polyradiculoneuropathies sous ICIs pour un mélanome ont été identifiés (anti-PD1 2/4 ; anti-PD1+anti-CTLA4 2/4). La médiane du délai d’apparition était de 47 jours. Le phénotype électrophysiologique était variable (démyélinisant 3/4, axono-myopathique 1/4) et le LCR inflammatoire avec une protéinorachie médiane à 0,68g/L. Le tocilizumab (8mg/kg/mois) a permis une régression de la symptomatologie neurologique, ceci même en cas de réintroduction des ICIs.
Peu de cas sont rapportés concernant la gestion de l’immunotoxicité réfractaire aux corticoïdes et aucun en cas de réintroduction des ICIs pour progression tumorale malgré la persistance de la toxicité neurologique. Nous rapportons ici quatre cas de polyradiculoneuropathie associée aux ICIs résistante aux corticoïdes et aux IgIV mais répondant au tocilizumab avec une efficacité neurologique maintenue après réintroduction des ICIs.
Face à une neuropathie ICI-induite corticorésistante ou lorsqu’une reprise de l’immunothérapie est indispensable pour la prise en charge oncologique, le tocilizumab semble être un traitement efficace et sûr à proposer.
BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) significantly improved metastatic melanoma prognosis. Ocular adverse effects (OAEs) represent an uncommon but disabling toxicity of these drugs. We ...aimed to characterize the ocular safety profile of BRAFi or MEKi and to detect possible safety signals.
We performed a retrospective, observational, pharmacovigilance study using VigiBase, the World Health Organization global safety database. Ocular adverse effects were classified according to the eye segments and the inflammatory pattern based on the Standardization of Uveitis Nomenclature. Associations among BRAFi monotherapy, MEKi monotherapy, and BRAFi+MEKi combination therapy and OAE reporting were assessed using disproportionality analysis. Results were expressed with the reporting odds ratio (ROR) and its 95% confidence interval (CI).
From January 2010 to October 2019, 1568 OAE cases were reported with BRAFi or MEKi. Among them, 1006 cases with sufficient data were included, corresponding to 310 (30.8%), 124 (12.3%), and 572 (56.9%) cases reported with BRAFi, MEKi, or BRAFi+MEKi combination therapy, respectively. BRAF inhibitor monotherapy was significantly associated with the reporting of iris and ciliary body abnormalities (ROR, 8.7; 95% CI, 6.0-12.5), diffuse abnormalities (ROR, 7.1; 95% CI, 5.4-9.4), anterior uveitis (ROR, 8.6; 95% CI, 6.0-12.1), and panuveitis (ROR, 7.1; 95% CI, 5.4-9.4). MEK inhibitor monotherapy was associated with the reporting of retinal and choroid abnormalities (ROR, 9.5; 95% CI, 7.4-12.2), diffuse abnormalities (ROR, 2.5; 95% CI, 1.1-6.1), and panuveitis (ROR, 2.5; 95% CI, 1.1-6.1). Combinations of BRAFi and MEKi therapies were associated with OAEs from both drugs, with a possible synergistic or additive effect for diffuse abnormalities and panuveitis.
Our study characterizes the ocular safety profile of BRAFi and MEKi. We identify possible safety signals for several OAEs not previously reported with BRAFi and MEKi. Our data provide the rationale for a personalized management of OAE in patients with BRAFi+MEKi combination therapy according to the type of ocular reaction.
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