Background
Our aim was to explore the prognostic value of anthropometric parameters in a large population of patients treated with immunotherapy.
Methods
We retrospectively included 623 patients with ...advanced non-small cell lung cancer (NSCLC) (n=318) or melanoma (n=305) treated by an immune-checkpoint-inhibitor having a pretreatment (thorax-)abdomen-pelvis CT scan. An external validation cohort of 55 patients with NSCLC was used. Anthropometric parameters were measured three-dimensionally (3D) by a deep learning software (Anthropometer3DNet) allowing an automatic multislice measurement of lean body mass, fat body mass (FBM), muscle body mass (MBM), visceral fat mass (VFM) and sub-cutaneous fat mass (SFM). Body mass index (BMI) and weight loss (WL) were also retrieved. Receiver operator characteristic (ROC) curve analysis was performed and overall survival was calculated using Kaplan-Meier (KM) curve and Cox regression analysis.
Results
In the overall cohort, 1-year mortality rate was 0.496 (95% CI: 0.457 to 0.537) for 309 events and 5-year mortality rate was 0.196 (95% CI: 0.165 to 0.233) for 477 events. In the univariate Kaplan-Meier analysis, prognosis was worse (p<0.001) for patients with low SFM (<3.95 kg/m
2
), low FBM (<3.26 kg/m
2
), low VFM (<0.91 kg/m
2
), low MBM (<5.85 kg/m
2
) and low BMI (<24.97 kg/m
2
). The same parameters were significant in the Cox univariate analysis (p<0.001) and, in the multivariate stepwise Cox analysis, the significant parameters were MBM (p<0.0001), SFM (0.013) and WL (0.0003). In subanalyses according to the type of cancer, all body composition parameters were statistically significant for NSCLC in ROC, KM and Cox univariate analysis while, for melanoma, none of them, except MBM, was statistically significant. In multivariate Cox analysis, the significant parameters for NSCLC were MBM (HR=0.81, p=0.0002), SFM (HR=0.94, p=0.02) and WL (HR=1.06, p=0.004). For NSCLC, a KM analysis combining SFM and MBM was able to separate the population in three categories with the worse prognostic for the patients with both low SFM (<5.22 kg/m
2
) and MBM (<6.86 kg/m
2
) (p<0001). On the external validation cohort, combination of low SFM and low MBM was pejorative with 63% of mortality at 1 year versus 25% (p=0.0029).
Conclusions
3D measured low SFM and MBM are significant prognosis factors of NSCLC treated by immune checkpoint inhibitors and can be combined to improve the prognostic value.
BackgroundIntratumoral (IT) administration of Ipilimumab (Ipi), could maximize its dose/efficacy ratio while preventing its on-target/off-tumor systemic adverse events. We report the results of a ...randomized multicenter Phase 1b study comparing IT vs IV Ipi with intravenous nivolumab (nivo) in patients with metastatic melanoma.MethodsPreviously untreated metastatic melanoma patients were randomly assigned 1:2, to receive IV Nivo (1mg/kg) in combination with either IV Ipi (3mg/kg) or 10x lower dose IT Ipi (0.3mg/kg) Q3W for 4 doses, followed by Nivo 3mg/kg Q2W for up to 2 years. The primary objective was to compare ≥grade 3 irAE rates at 6 months. Secondary objectives were to assess anti-tumor efficacy and related predictive immune biomarkers.Fresh tumor biopsies pre & on-treatment on both injected and non-injected tumors were analyzed by flow-cytometry, and soluble factors from their supernatant were titrated with Meso-Scale-Discovery® multiplex. Fresh sequential whole blood samples were collected for flow-cytometry phenotyping of immune cells, and for measuring systemic exposure to Ipi using ELISAResults40 patients were treated in the IT-arm and 21 in the IV-arm. The study met its primary endpoint with lower toxicity rate at 6 months in the IT-arm, with 30% 18.1;45.4 vs 57.1% 36.5;75.5 of patients presenting ≥grade 3 treatment related AEs, and no procedure-related ≥grade 3 AEs in the IT-arm out of 162 IT injections performed (including deep seated lesions).ORR per RECIST 1.1 were observed in 50% 32.9;67.1 in the IT-arm vs 65.0% 0.41;0.85 in the IV-arm. In the IT-arm, 65.7% of the injected tumors showed a CR or PR.Serum Ipi concentrations were much lower in the IT arm (:10). At C2, patients in both arms had significant decreased circulating naïve Tregs independently from tumor responses. Presence of intratumoral CD25hi CD39hi activated Tregs that decreased significantly upon IT (but not IV) injection only in responders, was predictive of the overall tumor response in the IT-arm. Moreover, granzyme B concentrations in tumor secretome at baseline were higher in responders than non-responders in both arms.Conclusions0.3mg/kg IT Ipi in combination with IV Nivo is not only safe but could reduce ≥grade 3 toxicity of the ICB combination. The high response rate in injected lesions was associated with the reduction of local Treg -not observed with systemic Ipi- and prompts a use in the oligometastatic and neoadjuvant setting. Direct assessment of cytolytic and regulatory pathways on fresh biopsies represents a novel, simple and rapid strategy to predict treatment efficacy.AcknowledgementsAuthors would like to thank the patients taking part to the Nivipit trial, and all the medical and paramedical staff that contributed to this trial.Trial RegistrationNCT02857569EudraCT 2015-005429-37Ethics ApprovalThis study was approved by the national ethics committee (CPP, ANSM). Written informed consent was obtained from all patients.ConsentN/A
The stereoselective synthesis of furanic-steroid derivatives involving ring-closing metathesis and catalytic hydrogenation as key steps is described. The synthetic strategy was first illustrated by ...the synthesis of the furanic-estrane derivative
1 in seven steps starting from estrone and 2-methylene-propane-1,3-diol. This compound initially targeted as a potential inhibitor of 17β-hydroxysteroid dehydrogenase type 1 by a docking experiment was found to inhibit the enzyme. The scope of this new strategy was also extended to furanic-androstane derivatives by synthesizing compound
20.
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Systemic immunotherapies such as immune checkpoint blockade targeted at PD(L)1 and CTLA4 have demonstrated their ability to provide durable tumor responses and long-term overall survival benefits for ...some patients in several solid tumor types. However, a majority of patients remain resistant to these treatments and a significant proportion of them develop severe autoimmune and inflammatory adverse events. Preclinical studies have demonstrated that intratumoral injections of immunostimulatory products (oncolytics, pattern recognition receptor agonists,…) that are able to trigger type I IFN release and enhance tumor antigen presentation on immune cells could generate a strong antitumor immunity and overcome the resistance to systemic immune checkpoint blockade therapies. The intratumoral immunotherapy strategies that are currently in clinical development offer a unique therapeutic and exploratory setting to better understand the immune contexture across tumor lesions of patients with metastatic cancer. Also these local therapeutic products could turn cold tumors into hot and improve the response rates to cancer immunotherapies while diminishing their systemic exposure and toxicities. Intratumoral immunotherapies could prime or boost the immunity against tumors and therefore radically change the combinatorial therapeutic strategies currently pursued for metastatic and local cancers to improve their long-term survival. We aimed to review and discuss the scientific rationale for intratumoral immunotherapy, the challenges raised by this strategy in terms of drug development within clinical trials and the current state-of-the-art regarding the clinical practice of this innovative approach.
Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a ...series of epoxide and furanic E2 derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of (14)C-E1 (100 nM) into (14)C-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17β-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 µM. All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T47-D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the (14)C-E1 (60 nM) into (14)C-E2 transformation at 1 and 10 µM, respectively.
Association of high body mass index (BMI) with longer survival has been reported in patients on immune checkpoint inhibitors (ICIs), but results are inconsistent. This ‘obesity paradox’ is ...potentially confounded by the effects of BMI change over time and of skeletal muscle depletion.
We conducted a secondary analysis of a prospective cohort, including consecutive patients receiving ICI treatment for melanoma (n = 411) and non-small cell lung cancer (NSCLC) (n = 389) in routine care.
In the univariable analysis of the entire population, overweight/obesity (BMI ≥ 25 kg/m2) was associated with longer survival (p < 0.01); however, this effect was limited to NSCLC (p < 0.01) and was absent in melanoma. Weight loss (WL) and reduced skeletal muscle mass were observed in patients within all BMI categories. WL was associated with shorter survival in multivariable analysis in both tumour sites (p < 0.01), and for NSCLC, BMI lost significance when WL was included (p = 0.13). In models further adjusted for CT-defined skeletal muscle mass, WL retained significance for both tumour types (p < 0.01), and reduced skeletal muscle only for NSCLC (p = 0.02) was associated with shorter survival. WL retained significance when biomarkers (lactate dehydrogenase enzyme, albumin and derived neutrophil to lymphocyte ratio) were added to the multivariable model.
The so-called ‘obesity paradox’, counterintuitive association between high BMI and longer survival, vanished when controlling for confounders, such as type of cancer, and manifestations of depletion (WL and reduced skeletal muscle mass).
•Association of high BMI with survival is eliminated when adjusted for confounders.•Association of high BMI with survival disappears when adjusted for weight loss.•Weight loss in NSCLC and melanoma is the predominant prognostic factor.•In patients with NSCLC, reduced skeletal muscle is an independent prognostic factor.
Human intratumoral immunotherapy (HIT-IT) is under rapid development, with promising preliminary results and high expectations for current phase III trials. While outcomes remain paramount for ...patients and the referring oncologists, the technical aspects of drug injection are critical to the interventional radiologist to ensure optimal and reproducible outcomes. The technical considerations for HIT-IT affect the safety, efficacy, and further development of this treatment option. Image-guided access to the tumor allows the therapeutic index of a treatment to be enhanced by increasing the intratumoral drug concentration while minimizing its systemic exposure and associated on-target off-tumor adverse events. Direct access to the tumor also enables the acquisition of cancer tissue for sequential sampling to better understand the pharmacodynamics of the injected immunotherapy and its efficacy through correlation of immune responses, pathologic responses, and imaging tumor response. The aim of this article is to share the technical insights of HIT-IT, with particular consideration for patient selection, lesion assessment, image guidance, and technical injection options. In addition, the organization of a standard patient workflow is discussed, so as to optimize HIT-IT outcome and the patient experience.
The objective of the study is to propose the immunotherapy progression decision (iPD) score, a practical tool based on patient features that are available at the first evaluation of immunotherapy ...treatment, to help oncologists decide whether to continue the treatment or switch rapidly to another therapeutic line when facing a progressive disease patient at the first evaluation.
This retrospective study included 107 patients with progressive disease at first evaluation according to RECIST 1.1. Clinical, radiological, and biological data at baseline and first evaluation were analyzed. An external validation set consisting of 31 patients with similar baseline characteristics was used for the validation of the score.
Variables were analyzed in a univariate study. The iPD score was constructed using only independent variables, each considered as a worsening factor for the survival of patients. The patients were stratified in three groups: good prognosis (GP), poor prognosis (PP), and critical prognosis (CP). Each group showed significantly different survivals (GP: 11.4, PP: 4.4, CP: 2.3 months median overall survival, P < 0.001, log-rank test). Moreover, the iPD score was able to detect the pseudoprogressors better than other scores. On the validation set, CP patients had significantly worse survival than PP and GP patients (P < 0.05, log-rank test).
The iPD score provides oncologists with a new evaluation, computable at first progression, to decide whether treatment should be continued (for the GP group), or immediately changed for the PP and CP groups. Further validation on larger cohorts is needed to prove its efficacy in clinical practice.
Many intratumoural (IT) immunotherapies are currently developed in the clinic with the aim of overcoming primary and secondary resistance and/or to limit on-target/off-tumour toxicities of immune ...checkpoint targeted therapies. This study aimed to describe the feasibility, safety and efficacy of IT immunotherapy treatments.
This retrospective single-centre study included the first 100 consecutive patients enrolled in Gustave Roussy's Human IntraTumoral-ImmunoTherapy (HIT-IT) program. Patient characteristics, target description, image guidance, safety and response according to iRECIST (Response Evaluation Criteria in Solid Tumours for immunotherapy trials) were recorded. Predictive factors of complications and responses were analysed. Survival was also reported.
From 09/2015 to 05/2020, 100 patients had 115 tumours injected during 423 treatment cycles. Most frequent primary tumour arose from the skin (n = 49), digestive track (n = 4) or head and neck (n = 8). Injected tumours’ mean diameter was 37 ± 23 mm, and a median number of 4 IT injections per patient (interquartile range:3–5) were performed. Targeted tumours for IT injections were superficial lymph nodes (36.5%), subcutaneous lesions (25.2%), liver tumours (20.9%) and others (17.4% including tumour sites such as deep lymph nodes or lung). Most patients (72%) received systemic immunotherapy in combination with HIT-IT. Procedure- and drug-related adverse events (AEs) occurred in 11.3% and 33.3% of the treatment cycles, respectively. Only 3 procedure-related AEs were grade-3 (0.7%); and no grade-4 or 5 occurred. Among all cycles, 7 grade-3 and 1 grade-5 drug-related AEs were reported. Complete and partial responses were achieved for 5% and 18% of patients, respectively, while stable disease was the best response for 11%. Patients receiving HIT-IT as a 1st-line treatment (24%), or not previously pre-treated with immunotherapy (53%) responded better, p = 0.001 and p = 0.004, respectively. From 1st cycle of IT, 12-month overall progression-free survival and overall survival were 21% (14–31%) and 57% (47–68%), respectively.
This retrospective study, conducted on patients with cancer and treated within clinical trials at Gustave Roussy, demonstrates the feasibility and safety of the IT immunotherapy strategy.
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•Image-guided intratumoural immunotherapy is feasible for both superficial and deep lesions.•No procedure-related grade 4 or 5 adverse events were observed.•A high response rate of injected tumours has been observed.
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