To evaluate the efficacy and safety of cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), as a first-line monotherapy in patients with unresectable squamous ...cell carcinoma of the skin (SCCS).
Thirty-six patients received cetuximab (initial dose of 400 mg/m(2) followed by subsequent weekly doses of 250 mg/m(2)) for at least 6 weeks with a 48-week follow-up. The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors RECIST criteria). Secondary end points included best response rate, overall survival, progression-free survival (PFS), and toxicity assessment. Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated.
Median age of the study population was 79 years. DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. One HRAS mutation was identified. Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes.
As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR. A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition.
Considering the growing interest in matched cancer treatment, our aim was to evaluate the ability of a comprehensive genomic profiling (CGP) assay to propose at least one targeted therapy given an ...identified genomic alteration or signature (actionability), and to collect the treatment modifications based on the CGP test results in clinical practise for solid tumors. This retrospective, multicentre French study was conducted among 25 centres that participated in a free of charge program between 2017 and 2019 for a tissue CGP test. Data were collected on the patient, disease, tumor genomic profile, treatment suggested in the report (related to the genomic profile results) and subsequent therapeutic decisions according to the physician's declaration. Among the 416 patients, most had lung cancer (35.6%), followed by biliary tract cancer (11.5%) or rare cancers (11.1%); 75% had a metastatic disease. The actionability was 75.0% (95% CI 70.6%-78.9%) for all patients, 85.1% and 78.4%, respectively in lung cancer and metastatic patients. After exclusion of clinical trial suggestions, the actionability decreased to 62.3% (95% CI 57.5%-66.8%). Treatment modification based on the test results was observed in 17.3% of the patients and was more frequent in metastatic disease (OR = 2.73, 95% CI 1.31-5.71, p = 0.007). The main reasons for no treatment modification were poor general condition (33.2%) and stable disease or remission (30.2%). The genomic-directed treatment changes were performed mostly during the first six months after the CGP test, and interestingly a substantial part was observed from six to 24 months after the genomic profiling. This French study provides information on the real-life actionability of a CGP test based on tissue samples, and trends to confirm its utility in clinical practice across the course of the disease, in particularly for patients with lung cancer and/or advanced disease.
Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT).
IICF01012 presents a highly ...favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of
IICF01012 to administer for the treatment of patients with pigmented metastatic melanoma.
The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of
IICF01012 (185 MBq at D0) to select patients who might benefit from
IICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with
IICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m
, or 1600 MBq/m
, or 2700 MBq/m
or 4000 MBq/m
of
IICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of
IICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of
IICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part.
This study is a first-in-human trial evaluating the
IICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the
IICF01012 to select the patients who may benefit from a therapeutic dose of
IICF01012, with at least one tumor lesion with
IICF01012 uptake and an acceptable AD to healthy organ.
Clinicaltrials.gov : NCT03784625 . Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.
Purpose
Immunotherapy has dramatically improved the prognosis of patients with metastatic melanoma (MM). Yet, there is a lack of biomarkers to predict whether a patient will benefit from ...immunotherapy. Our aim was to create radiomics models on pretreatment computed tomography (CT) to predict overall survival (OS) and treatment response in patients with MM treated with anti-PD-1 immunotherapy.
Methods
We performed a monocentric retrospective analysis of 503 metastatic lesions in 71 patients with 46 radiomics features extracted following lesion segmentation. Predictive accuracies for OS < 1 year versus > 1 year and treatment response versus no response was compared for five feature selection methods (sequential forward selection, recursive, Boruta, relief, random forest) and four classifiers (support vector machine (SVM), random forest, K-nearest neighbor, logistic regression (LR)) used with or without SMOTE data augmentation. A fivefold cross-validation was performed at the patient level, with a tumour-based classification.
Results
The highest accuracy level for OS predictions was obtained with 3D lesions (0.91) without clinical data integration when combining Boruta feature selection and the LR classifier, The highest accuracy for treatment response prediction was obtained with 3D lesions (0.88) without clinical data integration when combining Boruta feature selection, the LR classifier and SMOTE data augmentation. The accuracy was significantly higher concerning OS prediction with 3D segmentation (0.91 vs 0.86) while clinical data integration led to improved accuracy notably in 2D lesions (0.76 vs 0.87) regarding treatment response prediction. Skewness was the only feature found to be an independent predictor of OS (HR (CI 95%) 1.34,
p
-value 0.001).
Conclusion
This is the first study to investigate CT texture parameter selection and classification methods for predicting MM prognosis with treatment by immunotherapy. Combining pretreatment CT radiomics features from a single tumor with data selection and classifiers may accurately predict OS and treatment response in MM treated with anti-PD-1.
The conventional diagnostic and prognostic biomarkers (i.e. Clark Level (CL), Breslow Index (BI) or immunohistochemical markers 2) seem insufficient to distinguish precisely primary epidermis-limited ...neoplasms from aggressive or advanced/metastatic melanomas, and to assess the outcome for individual patients. ...additional relevant biomarkers are needed to predict the individual risk of metastasis and monitor disease progression. ...we identified several Tspan8 transcriptional regulators whose deregulation leads to Tspan8 expression 3, 5, 6, which could help to design new therapeutic strategies targeting Tspan8. Tspan8 protein expression in human primary melanomas was correlated with a higher propensity to give rise to distant metastases and an increased risk of death To evaluate the impact of Tspan8 expression at the protein level, we performed Tspan8 immunohistochemical staining analysis in a cohort of 100 primary melanoma samples: 73% of primary melanomas were positive for Tspan8 protein expression (sup. Tspan8 protein seemed more frequently expressed in the thinnest melanomas from patients dead during the 5-year period after diagnosis (92.3% of samples). ...the thinnest primary melanomas seemed to express the highest levels of Tspan8 protein (immunointensity score 4 exclusively in < 1 mm samples), especially in patients’ dead 5-years after diagnosis (60% of immunointensity scores 3–4; Fig. 2c).
Background Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A ( CDKN2A ) mutations have been identified in families with 3 or more patients with cutaneous ...melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. Objective We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family). Methods We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. Results The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. Limitations The study was not population based. Conclusions This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.
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.
To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs).
Patients, predominantly men, with their CSSCs' ...immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort's objective response rate at week 15 (ORR
). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy-General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORR
difference between PD-L1+ and PD-L1- patients, was assessed for ORR, disease control rate, and safety, but not survival.
Median age of all patients was 79 years. The primary cohort's ORR
was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORR
for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1- patients (17%;
= .02). Responders' W15 total FACT-G score had improved (
= .025) compared with nonresponders.
First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.
So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and ...nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
Immune checkpoint inhibitors (ICI) significantly improve overall survival (OS) in patients with advanced melanoma, but immune-related colitis may occur and warrant anti-tumor necrosis factor α (TNFα) ...treatment in severe forms. A nationwide, multicenter retrospective survey was conducted to assess both, the real-life incidence of grade 3/4 ICI-induced colitis treated with anti-TNFα, in patients with advanced melanoma, and the consequence of this therapeutic strategy on disease outcome. All patients with advanced melanoma treated with anti-TNFα agents for severe ICI-related colitis in the participating centers were included. Relative incidence was calculated according to the total number of patients treated with ICI in network centers during the period of inclusion. The possible impact of anti-TNFα treatment on disease outcome was evaluated through comparison of objective response rate, progression-free survival, and OS with pivotal literature data. Twenty-seven patients from 13 tertiary referral centers were included. Overall, severe ICI-related colitis treated with anti-TNFα occurred in 1% of patients with advanced melanoma, mostly with ipilimumab. Infliximab was successfully used in all patients but 1, mostly after 1 infusion. OS and progression-free survival of 12 and 3 months, respectively, were observed in these patients, along with an objective response rate of 41% at 12 months. This survey shows a low real-life incidence of severe colitis requiring anti-TNFα. Response rates to immunotherapy and survival data do not appear to significantly differ from those observed in pivotal studies. Severe ICI-induced colitis requiring anti-TNFα treatment appears to be a rare event in advanced melanoma, and infliximab does not seem to adversely affect disease outcome.
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