bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete evaluation of resistance mechanisms to first-line osimertinib requires tissue biopsy.
Authors: Piotrowska Zofia , Piper-Vallillo Andrew , Banwait Mandeep , Hung Yin P , Rao Revati , Muzikansky Alona , Meador Catherine Belle , Hata Aaron N. , Sequist Lecia V.
Published: June 2022

e21154

Background: Osimertinib (osi) is the preferred 1st line (1L) therapy for patients (pts) with EGFR-mutant NSCLC, but acquired resistance is universal. Identification of mechanisms of resistance (MoR) to 1L osi can inform subsequent treatment strategies. Here, we report MoRs identified at our institution from tissue and/or liquid biopsy (bx) upon 1L osi progression. Methods: We included pts seen at MGH with advanced EGFR+ NSCLC who had tissue and/or liquid bx (for ctDNA analysis) obtained at progression on 1L osi. Molecular testing was performed using local next-generation sequencing (NGS) and, when available, MET/ EGFR FISH. We retrospectively collected clinical characteristics, tissue histology and NGS results. Results: 54 pts (38 Female; median age 61 yrs) had tissue (n = 35) and/or liquid (n = 32) bx upon progression on 1L osi between November 2016-January 2022. 13/54 pts had both tissue and ctDNA testing. Primary EGFR mutations included del19 (32), L858R (16) and other (6). Median time from osi start to 1st resistance bx was 12.3 mos (range, 1-37). MoRs are summarized in the table. Among 35 pts with tissue bx, histologic transformations (trans) were the most common MoR, seen in 23% pts, including both small cell histology (tSCLC; 5/35), squamous histology (tSqCC; 2/35) and 1 pt with both SCLC + SqCC features in one bx. Among 5 pts with tSCLC and pre-trans NGS, only 2 had baseline TP53/RB1 loss. MET amp was seen in 20% tissue (including one with tSqCC) and secondary EGFR mutations in 9%; 43% of tissue bx had no identified MoR. Among 32 pts with ctDNA NGS, secondary EGFR mutations (16%) were the most prevalent MoR, with MET amp seen in 13%. 65% pts had no MoR by ctDNA. 6/13 pts with both tissue and ctDNA had concordant findings (MET amp-2, EGFR L718Q – 1; No MoR - 3). As expected, the 2 pts with tSCLC had no MoR in ctDNA. In 2 cases, MET amp was seen in tissue but not ctDNA; the converse was true in 1 pt. Conclusions: Histologic transformations were the most common MoR to first-line osimertinib accounting for 23% tissue biopsies and, in 3/5 pts, occurred in the absence of the known risk factor of baseline TP53/RB1 loss. In this small cohort, MET amp was more commonly seen in tissue than in ctDNA, and 63% of liquid biopsies showed no detectable MoR. Our findings suggest that tissue biopsy is critical for complete evaluation of MoRs in pts progressing on first line osimertinib, and that tissue and ctDNA may be complementary.[Table: see text]
Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: An open-label, single-arm, exploratory clinical trial.
Authors: Wang Na , Zheng Lie , Li Meichen , Hou Xue , Zhang Baishen , Chen Jing , Chen Likun
Published: June 2022

e21161

Background: Pembrolizumab with or without chemotherapy has become the standard therapy in advanced non-small cell lung cancer (NSCLC), with a fixed dose of 200mg every 3 weeks. We performed this study to explore the clinical efficacy and safety of pharmacokinetic (PK)-guided pembrolizumab administration in advanced NSCLC. Methods: In this prospective, open-label, single-arm exploratory study, we enrolled advanced NSCLC patients without sensitizing EGFR or ALK mutation in Sun Yat-Sen University Cancer Center. Eligible patients received pembrolizumab 200mg every 3 weeks with or without chemotherapy for four cycles, then for patients without progressive disease, pembrolizumab was administrated in new dose-intervals (T) until disease progression. We set the effective concentration (Ce) at 15μg/ml and new dose-intervals (T) was calculated according to steady state plasma-concentration (Css) of pembrolizumab using following equation: Css × 21D = Ce (15μg/ml) ×T. Primary endpoint was the progression-free survival (PFS), secondary endpoints were objective response rate (ORR), and safety. Besides, advanced NSCLC patients who regularly received pembrolizumab 200mg 3-weekly until disease progression and more than four cycles in our center were respectively enrolled as the history-controlled cohort. Patients with Css of pembrolizumab also underwent genetic polymorphism analysis of variable number of tandem repeats region (VNTR) in neonatal Fc receptor (FcRn). This study is registered at Clinicaltrials. gov, NCT05226728. Results: Between Nov 2019 and Dec 2020, total 58 patients were enrolled and received pembrolizumab 200mg every 3 weeks with or without chemotherapy, and 33 patients further received pembrolizumab in new adjusted dose-intervals according to Css after four cycles. The Css of pembrolizumab ranged from 11.01 to 61.21 μg/ml, 30 patients need prolonged intervals (22-80d) and 3 shortened intervals (15-20d). In PK-guided cohort, the median PFS was 15.1 months (95%CI 10.2-20.0 months) and ORR 57.6%, whereas the median PFS in history-controlled cohort was 7.7 months (95% CI 5.1-10.2 months) and ORR 48.2%. The immune-related adverse events occurred in 15.2% of patients in PK-guided cohort and 17.9% of patients in history-controlled cohort. The VNTR3/VNTR3 genotype of FcRn had significantly higher Css of pembrolizumab than VNTR2/VNTR3 ( p= 0.005). Conclusions: PK-guided pembrolizumab administration showed promising clinical efficacy and manageable toxicity, which provided an alternative rational therapeutic strategy of pembrolizumab in advanced NSCLC. Clinical trial information: NCT05226728.
Limited benefit from the addition of immunotherapy to chemotherapy in TKI-refractory EGFR-mutant lung adenocarcinoma.
Authors: Hong Lingzhi , Lewis Whitney E , Varghese Susan , Rivera Melvin , Du Robyn , Chen Pingjun , Kemp Haley , Rinsurongkawong Waree , Rehmani Sadiq , Spelman Amy R. , Elamin Yasir Y , Negrao Marcelo Vailati , Sepesi Boris , Gibbons Don Lynn , Lee J. Jack , Wu Jia , Vokes Natalie I , Heymach John , Zhang Jianjun , Le Xiuning
Published: June 2022

e21169

Background: The benefit of adding immunotherapy to chemotherapy in EGFR-mutant lung adenocarcinoma (LUAD) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is not fully investigated. This study aimed to explore the outcomes of immunotherapy combinations in such population in a real-world setting. Methods: This retrospective analysis included patients with EGFR-mutant LUAD who progressed on EGFR TKIs and received subsequent therapy with chemotherapy (chemo; n = 84), chemotherapy with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n = 42), and IO monotherapy (IO-mono; n = 22). Clinical progression-free survival (cPFS) from the start of the therapy to discontinuation was assessed. Associations of clinical characteristics with cPFS were evaluated using univariable and adjusted Cox regression models. Results: A total of 178 patients (mean age = 62.6; 57.9% females) with a median cPFS (mcPFS) of 4.9 (95% CI: 4.4-5.4) months with 162 (91%) progression events. There was no difference in cPFS between chemoIO vs chemo groups (5.3 months vs 4.8, P = 0.8). Compared to the chemo group, patients who were treated withBev trended towards better PFS (6.1 months vs 4.8; P = 0.3; HR 0.79; 95% CI: 0.52-1.20;), while patients with IO-mono had inferior PFS (2.2 months; P = 0.001; HR 2.22; 95% CI: 1.37-3.59). Patients who were administered one-line of TKI prior to subsequent therapy acquired better PFS when compared to those with multiple prior TKIs (5.2 months vs 4.5; P = 0.011; HR 0.66; 95% CI: 0.48-0.91). The significance remained the same after adjusted by other clinicopathological variables including post-TKI treatment strategies and metastatic status (P = 0.005). Furthermore, among the chemoIO group, patients with PD-L1 expression had better PFS (n = 15, 7.7 months vs 4.5, P = 0.04; HR 0.36; 95% CI: 0.13-0.96) than those without PD-L1 expression (n = 6). However, PD-L1 was not associated with PFS among the patients treated with chemoIO plus bevacizumab. Brain or liver metastases were associated with worse PFS. Conclusions: Immunotherapy adds limited benefit when combined with chemotherapy in TKI-refractory EGFR-mutant LUAD. Chemotherapy +/- bevacizumab are reasonable treatment options for these patients.
Clinical characteristics and molecular features of non-small cell lung cancers (NSCLCs) following disease progression on immune checkpoint inhibitors (ICIs).
Authors: Gainor Justin F. , Ravi Arvind , Awad Mark M. , Holton Mark , Arniella Monica , Stewart Chip , Freeman Samuel , Leshchiner Ignaty , Chow Andrew , Henick Brian S. , Velcheti Vamsidhar , Griffin Aaron Timothy , Ricciuti Biagio , Riess Jonathan W. , Janne Pasi A. , Hacohen Nir , Wolchok Jedd D. , Hellmann Matthew David , Getz Gad
Published: June 2022

e21178

Background: ICIs are cornerstones of therapy for advanced NSCLC. Despite dramatic and sometimes durable responses to therapy, most patients (pts) either (i) do not respond to therapy (intrinsic resistance), or (ii) subsequently progress after initial clinical benefit (acquired resistance). Currently, insights into the molecular mechanisms of resistance to ICIs in NSCLC are lacking. Methods: To investigate clinical and molecular features of pts progressing on ICIs, we identified pts who underwent repeat tumor biopsies on and/or after disease progression on ICIs and were included in the Stand Up 2 Cancer (SU2C)/Mark Foundation multi-institutional cohort. Biopsy specimens underwent whole-exome sequencing (WES) and/or whole transcriptome sequencing (RNAseq). Results: We identified 37 pts who underwent a total of 47 repeat biopsies on or after ICIs. Six pts underwent multiple post-ICI biopsies (range 2-4). Twenty-five pts (68%) received PD-(L)1 inhibitor monotherapy, 6 (16%) received PD-(L)1 plus CTLA-4 inhibitors, and 6 (16%) received other PD-1 inhibitor-based combinations. Overall, the objective response rate was 46% among pts undergoing repeat biopsies (complete response 2 [5%], partial response 15 [41%], stable disease 14 [38%], progressive disease 5 [14%] and not evaluable 1 [3%]). Median progression-free survival (PFS) was 8.1 months. In total, pre-ICI biopsy specimens were available in 20 pts. WES and RNAseq were performed on 67 and 44 specimens, respectively. Median tumor mutation burden (TMB) in pre-ICI specimens was 5.0 mutations/Mb versus 4.9 mutations/Mb in post-ICI specimens ( p= 0.3, Mann-Whitney U test). Among 20 paired pre/post-ICI specimens, there was no significant difference in TMB (pre-treatment median 3.9 mutations/Mb; post-treatment median 4.3 mutations/Mb; p= 0.7, Wilcoxon signed-rank test). One pt with a complete response acquired a nonsense mutation in B2M, and one pt with a partial response acquired a nonsense mutation in JAK1. Among 10 paired pre/post-ICI specimens that underwent RNAseq, we observed significant decreases in granzyme B and perforin in post-ICI specimens ( p= 4×10-5 and p= 2×10-3, respectively, limma-voom analysis). Conclusions: Genomic alterations impairing antigen presentation (e.g., B2M) or immune activation (e.g., JAK1) may enable resistance to ICIs in a small subset of cases. However, the majority of repeat biopsies obtained from pts progressing on ICIs lacked clear genetic mediators of resistance, suggesting the presence of additional tumor-intrinsic and/or tumor-extrinsic factors underlying resistance to ICIs in NSCLC.
Melanoma of unknown primary: Favorable survival persists in the immunotherapy era.
Authors: Maharaj Satish , Jain Nikita , Albawaliz Anas , Miller Donald M. , Chesney Jason Alan
Published: June 2022

e21513

Background: Patients with advanced melanoma have historically had better survival in those with unknown primary (MUP) than known primary (MKP). Trends in survival since the introduction of immunotherapy have not been established. Methods: We conducted a retrospective cohort study of patients with advanced/metastatic melanoma (Stage IIIC/IV disease) treated during the period 2014-2020 at the University of Louisville. The primary outcome was overall survival in MUP compared with MKP. Differences in clinical characteristics, BRAF status, tumor mutational burden and PD-L1 tumor proportion score (Dako 22C3 assay) were examined. Differences between numerical variables were calculated based on parametric or non-parametric comparisons accordingly and categorical data analyzed using chi-squared testing. Kaplan-Meier survival analyses were performed with log-rank testing to evaluate differences. Alpha was set at 0.05 for significance. Results: Of the 79 patients with advanced/metastatic melanoma included, 12 had MUP and 67 had MKP. Of those with MKP, the primary site was cutaneous melanoma in 65 and anal melanoma in 2. Clinical characteristics showed the majority were male, with median age of 61 years. There were no significant differences in demographics, distribution of stage, BRAF status, TMB, PDL-1 score or treatment modality between MUP and MKP groups (Table). The median follow-up time overall was 50 months. The MUP group demonstrated significantly better survival with 3-year OS of 92% vs. 62% in MKP, and 5-year OS of 83% vs 44% in MKP. Median survival was 54 months for MKP and not reached for MUP. For MKP, the 5-year OS of 44% compares similarly to other cohorts. The Keynote-001 trial of advanced/metastatic melanoma treated with pembrolizumab reported 5-year OS of 41%. This is approximately a 4-fold improvement compared to cohorts treated before the approval of immunotherapy, where the 5-year OS was in the range of 10% [Lee et al, 2009]. The 5-year OS for metastatic MUP was previously in the range of 18%, also suggesting improvement by about 4-fold with the use of immunotherapy. Conclusions: Melanomas of unknown primary continue to have better survival with durable response on immunotherapy even in the advanced/metastatic setting. The exact mechanisms for this survival advantage remain unknown but are likely immune-mediated.[Table: see text]
ANKRD36 mutation as a negative predictor for melanoma immunotherapy.
Authors: Chen Bing , Guo Shizhou , Xing Xiaodan , He Qianru , Zhang Qin , Duan Qianqian , Sun Tingting , Qi Chuang
Published: June 2022

e21517

Background: Melanoma is one of the most aggressive and immunogenic tumors. Current immunotherapies using immune checkpoint inhibitors such as CTLA4 and PD1 to stimulate T cell-mediated tumor killing significantly improved the overall survival of patients with metastatic melanoma. However, the clinical predictors of response to these therapies are still not fully characterized. Previous studies have shown that the high gene expression of Ankyrin repeat domain 36 (ANKRD36) can lead to the occurrence and poor prognosis of colon cancer and kidney cancer. In this study, we aimed to explore the role of ANKRD36 mutation in the prognosis of melanoma immune checkpoint inhibitors (ICIs). Methods: Public data of patients treated with ICIs(ipilimumab) from Van Allen (n = 110) cohort were obtained and analyzed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. The potential mechanism was subsequently explored through RNA expression data from The Cancer Genome Atlas (TCGA). Results: The frequency of ANKRD36 mutation in the Van Allen cohort and TCGA cohort was 7.2% (8 in 110) and 1.56% (7 in 448) respectively. We further analyzed the Kaplan Meier curve and multiple Cox regression model of the Allen cohort and found that the survival of the mutant type in immunotherapy was significantly shorter than that of the wild-type group (PFS: HR = 3.09 [95% CI: 1.47, 6.51], p = 0.002; OS: HR = 2.33 [95% CI: 1.12, 4.86], p = 0.02). Both mutant type and tumor metastasis would have negative effects on immunotherapy(PFS: HR = 3.66 [95% CI: 1.71, 7.85], p < 0.001***; OS: HR = 3.16 [95% CI: 1.47, 6.82], p = 0.003**). Analysis of the transcriptome data from the TCGA database found that resting CD4 memory T cells is highly expressed in ANKRD36 mutant patients (p = 0.032), which may indicate that the patient's immune system did not activate the anti-tumor immune mechanism. Conclusions: In our study, the frequency of ANKRD36 mutations was investigated in clinical and TCGA cohorts, which may provide useful information for guiding patient treatment. ANKRD36 mutation may be a negative predictor of ICIs in patients with melanoma and play a role in prognosis.
Efficacy of immunotherapy and sequencing of checkpoint inhibition for metastatic ocular melanoma.
Authors: Abhyankar Anuja , Maharaj Satish , Miller Donald M.
Published: June 2022

e21526

Background: Ocular melanoma (OM) is the most common intraocular tumor in adults. However, it is still rare as compared to other subtypes of melanoma. Treatment of primary OM is certainly successful, but most therapies assessed in treatment of metastatic OM have not shown promise. Immunotherapy (IO), which has otherwise held prospect for durable remissions in other metastatic melanoma has shown no evidence in metastatic OM. Our study aims at narrowing the gap in knowledge in the treatment of OM with IO. Methods: We conducted a retrospective cohort study of patients with metastatic OM treated during the period 2017-2021 at the University of Louisville. Patients aged 18 years or more with treatment-naïve metastatic (Stage IV) OM were included. Data was censored according to date of last recorded clinical follow up or death. The primary outcome of interest was overall survival (OS). Subgroup analysis was done to examine survival based on initial treatment with dual versus single checkpoint inhibition. After progression on initial therapy, patients previously on dual inhibition went on to receive single inhibition, and vice versa. Kaplan-Meier survival analyses were generated using all-cause mortality as the competing outcome event and log-rank testing to evaluate differences between groups with alpha set at 0.05 for significance. Results: A total of 21 patients with Stage IV OM were identified with 4 excluded due to lack of data. The majority were male (10/17) and median age was 66 years, ranging from 30 to 89 years. More than half (10/17) received dual checkpoint inhibition as initial IO, with ipilimumab and nivolumab. The remainder received pembrolizumab or Nivolumab monotherapy (7/17). IO was well tolerated with no treatment related mortality and incidence of immune-related adverse effects similar to cutaneous melanoma. The median follow-up time overall was 56 months using the reverse Kaplan-Meier method with a median OS of 15 months. Estimated 2-year OS was 41%. No significant difference was found between single and dual checkpoint inhibition as the initial treatment regimen. Conclusions: While IO has markedly improved survival in advanced melanomas, OM continues to have inferior survival. Consistent with the literature by Zimmer et al, survival in this cohort is better than that reported with ipilimumab monotherapy. The median survival of 15 months is consistent with that reported by Heppt et al in the German multicenter study. IO for Stage IV OM was well tolerated, resulting in median survival of 15 months and 2-year OS of 41%. There was no survival advantage to initial treatment with single versus dual checkpoint inhibition, allowing for crossover at progression. Further research with novel agents and enrollment in clinical trials are needed in ocular melanoma.
Comparison of PET-based criteria of evaluation of response to immunotherapy in patients with advanced melanoma.
Authors: Comito Francesca , Pagani Rachele , Aprile Marta , Dragonetti Valentino , Bonazzi Norma , Battisti Giacomo , Malizia Claudio , Nanni Cristina
Published: June 2022

e21536

Background: Immune checkpoint inhibitors (ICI), such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death-1 (PD-1), have evolved as a dominant strategy in the treatment of metastatic melanoma (MM) in the last decade. At least three PET-based criteria are available for the early assessment of response to immunotherapy: PET/CT Criteria for Early Prediction of Response to Immune Checkpoint Inhibitor Therapy (PECRIT), PET Response Evaluation Criteria for Immunotherapy (PERCIMT) and European Organization for Research and Treatment of Cancer (EORTC) criteria. The aim of this study was evaluation of the concordance of different PET-based criteria for the assessment of response to immunotherapy and to assess their capability of properly stratifying patients in terms of overall survival (OS) and progression free survival (PFS). Methods: We retrospectively enrolled patients with the following inclusion criteria: diagnosis of MM, treatment with ICI for MM and tumor assessment performed by at least two [18F]F-fluorodeoxyglucose (FDG) PET/CT scans (a baseline and ad interim scan). [18F]F-FDG PET/CT scans were analyzed according to PECRIT, PERCIMT and EORTC criteria. Agreement was assessed using Fleiss' kappa and Cohen’s kappa. Prognostic curves of PET/CT response according to different criteria were evaluated in terms of PFS and OS by Kaplan-Meier estimates and were compared by log-rank test. Results: From December 2021 to January 2022, 30 patients were enrolled. 18/30 patients received nivolumab, 8/30 pembrolizumab, 3/30 ipilimumab and 1/30 the combination of nivolumab and ipilimumab. According to PECRIT criteria, 6 patients achieved complete metabolic response (CMR), 7 partial metabolic response (PMR), 5 stable metabolic disease (SMD) and 12 (40%) progressive metabolic disease (PMD). By PERCIMT criteria, 6 patients had response classified as CMR, 9 PMR, 8 SMD and 7 (23.4%) PMD. Finally, by EORTC criteria there were 6 CMR, 10 PMR, 2 SMD and 12 (40%) PMD. In 9 cases out of 30, one criteria assessment differed from the other two and in one patient each criteria evaluation differed from the others (PMD by PECRIT, SMD by PERCIMT, PMR by EORTC). The percentage of patients concordantly evaluated by the three criteria was 68% (Fleiss’ kappa = 0.68). PECRIT and EORTC criteria showed the highest agreement (Cohen’s kappa 0.719), followed by PERCIMT and PERCRIT (Cohen’s kappa 0.69). PERCIMT and EORTC showed 64.4% of concordance. Furthermore, all three criteria were successful in stratifying patients in terms of OS and PFS (p-value < 0.05). Conclusions: We observed substantial agreement among different PET evaluation criteria, with PECRIT and EORTC criteria showing the highest concordance. Analysis of a larger population is needed to prove the utility of PET response evaluation in early prognostic stratification.
Toxicity and response to ipilimumab and nivolumab in elderly patients with metastatic melanoma: A multicenter retrospective analysis.
Authors: Pathmanathan Shivanshan , Babu Hari S , Dzienis Marcin Radoslaw , Azer Mary , Eastgate Melissa A.
Published: June 2022

e21540

Background: Dual immunotherapy (nivolumab and ipilimumab) is an effective therapy in the treatment of metastatic melanoma, however, its benefit in older patients is unclear. This study aims to investigate the impact of age on the efficacy and toxicity of dual immunotherapy. Methods: A multicentre retrospective study involving centres in Australia [Royal Brisbane and Women’s Hospital, Gold Coast University Hospital and Sunshine Coast University Hospital] was performed to compare the efficacy and toxicity of dual immunotherapy in metastatic melanoma in patients ≥65 years versus patients < 65 years old treated between 2017 and 2021. Data collected included: baseline demographics, PFS, OS, Grade 3 or higher (Gr3+) adverse events as per CTCAEv5, discontinuation rate, duration and complications of steroids used to treat toxicity. Groups were compared using the Fisher exact test for categorical variables and Mann-Whitney test for continuous variables. Survival outcomes were compared using Kaplan Meier, Log rank test and multivariate Cox regression analysis. Results: A total of 139 patients were included with 52 patients ≥65 years and 87 patients < 65 years. There were more males in patients ≥65years [78.9 v 59.8% p = 0.025], and a trend towards fewer BRAF mutations as expected [32.7 v 50.6% p = 0.053]. Other baseline characteristics were similar. Fewer patients received prior BRAF/MEK inhibitor therapy in patients ≥65 years [19.2 v 41.4% p = 0.009]. Median dose of ipilimumab received was 3 cycles in both groups. Median OS was similar in patients ≥65 years v < 65 years [14.9 v 17.3mths p = 0.58]. Median progression free survival was also similar in patients ≥65 years v < 65 years [7.1 v 6.9mths p = 0.79]. Age was not associated with a difference in overall survival on multivariate analysis. There was similar rates of Gr3+ adverse events in patients ≥65 years v < 65 years [50 v 49% p = 1.0] and discontinuation rates secondary to toxicity [55.8 v 56% p = 1.0]. Arthritis lead to more discontinuation in the older patients [9.6% v 0% p = 0.006]. There was one death secondary to pancreatitis in a patient ≥65 years. Median duration of steroids used to treat adverse events was similar in patients ≥65 years v < 65 years [12.2 v 11.7mths p = 0.46]. Complications of steroids requiring inpatient admission was numerically higher in the elderly population [41.3 v 20.4% p = 0.07]. The most common complication related to immunosuppression was infection. There were 2 deaths in patients ≥65 years secondary to infection while on higher dose steroids. Conclusions: Patients ≥65years received similar benefit from dual immunotherapy in comparison to their younger counterparts with similar toxicity. There was a trend towards greater number of complications secondary to steroids. Optimisation of steroid dose and duration in the older patients may reduce the above risk, while maintaining clinical benefit.
New diagnostic index for prediction of severe irAEs in patients with metastatic melanoma taking checkpoint inhibitors.
Authors: Zhukova Natalia V. , Orlova Rashida , Malkova Anna , Kaledina Ekaterina , Demchenkova Alexandra , Naymushina Polina , Nazarov V , Mazing A , Lapin S , Beliak Natalia P. , Shoenfeld Y
Published: June 2022

e21565

Background: Immune-related adverse events (irAEs) occur in up to 50% of patients treated with immune checkpoint inhibitors (ICI). Severe forms of toxicity are observed in 3% of patients and require systemic steroid therapy and constant monitoring. One of the considered predictor biomarkers of irAEs development is HLA-genotypes. This research aims to evaluate the diagnostic significance of HLA-DRB1 genotypes and other clinical, laboratory parameters to predict the development of irAEs. Methods: The study involved 28 patients (pts) with metastatic melanoma taking ICI (nivo 53.6%, ipi+nivo 32.1%, other 14.3%). The PD-L1 expression, HLA-DRB1 genotype were evaluated. After 2-3 months the development of irAES was assessed. The complications of 3-4 grade or multi-organ damage were termed as a severe irAEs. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using Fisher, Mann-Whitney, ROC statistical analysis. The project is supported by a grant (14. W03.31.0009). Results: Different IrAEs developed in 57.1% (16/28) of patients, while severe irAEs in 35.7% (10/28). Among all patients HLA-DRB1 genotypes associated with the risk of autoimmune diseases were found in 78.5% (22/28). The PD-L1 expression was detected in 60.7% (17/28) of individuals.Combination treatment increases the risk of toxicity, p = 0.003, with a diagnostic sensitivity (S) of 56% and a diagnostic specificity (Sp) of 100% (RR = 2.71, OR = 31.67). The analysis of specific complications revealed associations between HLA-DRB1*04 with diabetes mellitus, p = 0.026 (OR = 33.57, S = 100%, Sp = 88.5%), HLA-DRB1*04/15 with autoimmune hepatitis or increased transaminases, p = 0.037 (OR = 17.27, S = 100%, Sp = 72%). An index based on the parameters studied (HLA-DRB1, the absence of PD-L1 expression, type of treatment) was created. With index value ≥2 a sensitivity for predicting severe toxicity is 40.00% and a specificity is 83.33%, p = 0.0126. Conclusions: According to the results obtained it can be assumed that the development of severe forms of irAES has a multifactorial origin, in particular, combination therapy, the absence of PD-L1 expression, which can lead to the loss of ICI drug specificity, and the presence of HLA-DRB1 genotypes associated with the risk of developing autoimmune diseases. The new diagnostic index to predict severe complications based on these parameters was created and showed a sensitivity of 40.00% and a specificity of 83.33%. The authors consider the limitations of the study, such as the small sample, the short observational period.
Usage of immunotherapy in Merkel cell carcinoma from 2004 to 2016: A National Cancer Database (NCDB) analysis.
Authors: Luka Michael , Burright Isaac , Townley Liam , Silberstein Peter T. , Eaton Vincent
Published: June 2022

e21576

Background: Merkel Cell Carcinoma (MCC) is a rare and aggressive skin malignancy with increasing incidence, likely due to an aging population. MCC has been shown to have an increased prevalence in immunosuppressed patients, and current clinical trials are investigating the potential for immunotherapy treatments. As the understanding of the underlying pathogenesis of MCC progresses, the ability to implement specific immunotherapy targets is being investigated and showing promise. Methods: Using the NCDB, we identified 6,918 patients diagnosed with Merkel Cell Carcinoma between 2004-2016 using ICD-O-3 histology code 8247. The cohort was analyzed to identify differences in survival outcomes among patients who received immunotherapy, chemotherapy, a combination of chemotherapy and immunotherapy, and neither chemotherapy nor immunotherapy. We performed univariate analysis to assess median length of survival for each of these specific treatment modality cohorts, in addition to descriptive statistics. Data were analyzed using SPSS and statistical significance was set at α = 0.05. Results: Between 2004 and 2016, 118 patients in the NCDB received immunotherapy. From 2004-14, 21 patients received immunotherapy (1.9 patients per year). The usage of immunotherapy increased drastically in 2015 and 2016 with 18 patients and 79 patients being treated with immunotherapy, respectively. Most immunotherapy patients (59%) received treatment at an academic research center while the remaining patients received immunotherapy at a comprehensive community cancer program (24.8%), an integrated cancer network (12%), or a community cancer program (4.3%). 41.7% of MCC immunotherapy patients were between 33 and 69 years of age, whereas 59.3% ranged from 70-90 years of age. Of the 118 MCC patients who received some form of immunotherapy, 39% had stage IV MCC, 38.1% had stage III MCC, 5.9% had stage II MCC, and 9.3% had stage I MCC. Conclusions: As the use of immunotherapy in MCC continues to rise, especially at academic research centers, future studies should investigate the trends of its usage, its effects on patient survival, and the stage of MCC in which immunotherapy is most often used. We found that patients that received both chemotherapy and immunotherapy had a significantly lower median survival than all other treatment combinations. We hypothesize that the poorer survival rates in the patients that received some form of immunotherapy is due to a later stage of treatment, but this will become clearer as the sample size of MCC patients receiving immunotherapy continues to grow.[Table: see text]
Immunotherapy versus targeted therapy in the adjuvant setting for resected stage III melanoma: A single institution study.
Authors: Dima Danai , Lopetegui-Lia Nerea , Ogbue Olisaemeka , Osantowski Bennett , Ahmed Ramsha , Basali Diana , Chamseddine Fatimah , Eicher Donald Matthew , Song Jung Min , Gastman Brian , Kennedy Lucy Boyce , Funchain Pauline
Published: June 2022

e21578

Background: Both immunotherapy (IO) and targeted therapy (TT) are approved as adjuvant (Adj) treatment for stage III melanoma, as they have proven to significantly decrease disease recurrence. While there is evidence to suggest overall survival (OS) benefit with TT, data demonstrating OS advantage with Adj IO is lacking. There are no prospective head-to-head trials to date comparing these two treatment modalities. Our aim is to determine whether Adj IO equally improves outcomes compared to Adj TT. Methods: We retrospectively analyzed 104 patients (pts) with resected stage III melanoma who received Adj IO or TT from 1/2016 - 12/2021. Relapse free survival (RFS), distant metastasis free survival (DMFS) and OS rates were assessed between the 2 groups. Results: Of 104 pts, 78 received IO (91% nivolumab, 7% pembrolizumab, 2% other) and 26 pts TT (100% dabrafenib/trametinib). Median follow up was 21 months. At data cutoff, among the 26 pts who received TT, 50% completed 1 year of planned therapy, whereas 50% discontinued TT prematurely (42% due to adverse events [AEs], 8% due to disease relapse). Among the 78 pts who received IO, 70% completed 1 year of planned treatment or continued to receive IO at the end of the study, whereas 30% discontinued IO prematurely (18% due to disease relapse, 12% due to AEs). Relapsed disease was noted in 6/26 (23%) and 27/78 (34.6%) pts of the TT and IO groups, respectively. With regards to location of recurrence, in the TT group 2/6 pts relapsed locally and 4/6 distally, whereas in the IO group 14/27 pts relapsed locally and 13/27 distally. The estimated median RFS of the TT vs IO groups was not reached (NA) (95% Cl: 17 months, NA) vs. 30 months (95% CI: 17 months, NA) respectively, which was not statistically significant (p = 0.49). Comparison of DMFS rate was found not to be statistically significant between the 2 groups (p = 0.86). Finally, median OS was NA in either group. At the end of the study 91% and 90.5% of the pts in the TT and IO arms, respectively, were still alive. The most common AEs in the TT group were fatigue (23%), fever (23%), nausea/vomiting (19%), whereas in the IO group were fatigue (22%), hypothyroidism (14%), diarrhea/colitis (10%), pruritic rash (9%). Conclusions: Both TT and IO appear to equally decrease disease recurrence, locally or distally, when given as Adj therapy for stage III melanoma. Prospective, randomized control trials with longer follow up and larger sample size are warranted to determine any difference in potential OS benefit.[Table: see text]
Multicenter prospective clinical trial of molecular genetic markers for non-invasive differential diagnosis of benign and malignant melanocytic skin lesions.
Authors: Samoylenko Igor , Zaretsky Andrew R , Chudakova Lidia V , Drozd Oleg V , Garanina Oksana E , Shlivko Irena L , Zinovev Grigory , Baryshnikov Kirill A , Orlova Kristina V. , Maximova Tatiana , Sinelnikov Igor , Kim Anna , Mikhaylova Irina N. , Demidov Lev V.
Published: June 2022

e21581

Background: Improving the accuracy of non-invasive diagnosis of skin tumors is becoming an urgent problem, given the clear increase in the incidence of melanoma in many countries. Dermoscopy and examination by an experienced dermatologist can reduce the NNE to 5–10 per melanoma (M) detected, however, achieving even this, clearly suboptimal, rate requires a long specialist training. Methods: We report results of prospective nonrandomized trial evaluating sensitivity and specificity of RNA profiling of cytological samples from adhesive transparent patches (ATP) applied to skin lesions. Routine pathology reports were obtained for all surgery samples. RNA extracted from ATP specimens (N = 126) was tested for mRNA expression of PRAME and LINC00518 genes. GAPDH was used as a reference gene. Sample was considered marker-positive if either PRAME or LINC00518 expression was detected. Results: Between June 2021 and November 2021, 126 pts undegoing excisional biopsy of skin lesions were included in the study at 5 centers. On pathology, invasive M was detected in 49 (38.9%) patients (mean Breslow thickness was 2.41 mm [95%CI 1,44 to 3.37]), M in situ in 6 (4.8%), non-melanoma skin cancer in 4 (3.2%) and dysplastic nevus in 56 (44.4%). In the day of preplanned excision ATP was applied to the target lesion for 5–6 min and sent to the central lab. Amplifiable mRNA was found in all 126 ATP samples. 82 samples of 126 (65,1%) tested marker-positive. Sensitivity of RNA profiling for detection of skin cancers reached 88.14% (95% CI 77.07% – 95.09%), while specificity was only 53.85% (41.03% – 66.30%), with PPV of 63.41% (56.74% – 69.61%), NPV of 83.33% (70.65% – 91.22%) and accuracy of 70.16% (61.29% – 78.04%). Among the seven false negative results there were 3 M in situ and 4 invasive M. Conclusions: RNA profiling of skin ATP specimens is feasible and has high sensitivity but rather low specificity. Randomized studies are needed to evaluate if this technique can add anything to dermoscopy or other noninvasive diagnostic modalities. Clinical trial information: NCT04353050. [Table: see text]
Oncolytic and protective effects of strain 100 of a new group of non-classified rotavirus of reoviridae family on B16/F10 melanoma growth in experiment.
Authors: Kolpakova Elena P. , Zlatnik Elena Yu , Shulgina Oksana G. , Zolotareva Ekaterina I. , Vashchenko Larisa N. , Ausheva Tatiana V. , Bakulina Svetlana M. , Dashkova Irina R.
Published: June 2022

e21587

Background: The purpose of this study was to assess the effect of a strain 100 of a new group of rotavirus of Reoviridae family on the growth of transplantable B16/F10 melanoma in mice and the survival of the animals. Methods: We studied the strain 100 of a new group of rotavirus of Reoviridae family (RVK) ( http://jbks.ru/archive/issue-10/article-6 ). RVK 100 is a live attenuated non-pathogenic virus growing on pig embryo kidney cell culture with concentration 5·109 per 1 ml. The dynamics of melanoma growth and the survival of tumor-bearing animals receiving RVK were studied in 25 male mice divided into 5 equal groups, each n = 5. RVK was administered intramuscularly and orally once a week 0.3 mL and 25 µL, respectively: to groups 1-2 21 days prior to the tumor inoculation, a total of 4 injections (“vaccination” regimen); to groups 3-4 – 7 days after tumor inoculation with the onset of tumor nodes, a total of 3 injections (“treatment” regimen); group 5 included controls receiving 0.85% NaCl solution. Groups 1 and 3 received live RVK, groups 2 and 4 - RVK inactivated by UV radiation. Results: Survival of mice in groups 1-2 receiving both live and inactivated RVK in the “vaccination” regimen was increased statistically significantly: in group 1, Me = 25 days after melanoma transplantation (LQ 24; UQ 30), in group 2 Me = 26 days (LQ 25; UQ 30), in controls Me = 14 days (LQ 10; UQ 22); p = 0.032 and p = 0.0079, respectively. RVK administration in the “treatment” regimen did not cause such changes. While mice of group 3 receiving the live strain 100 showed a tendency to higher survival, compared to controls (Me = 23 days, LQ 22; UQ 24, p = 0.056), the administration of inactivated RVK (group 4) did not significantly improve the survival of animals, compared to controls (Me = 22 days (LQ 21; UQ 33, p = 0.151). Conclusions: Improved survival of animals with B16/F10 melanoma after the RVK administration indicates the virus ability to slow down tumor growth and confirms our previously published data on the RVK strain 228, although, in contrast to it, the strain 100 is able to increase the survival rate of tumor-bearing mice only when used in the “vaccination” regimen, which refers mainly to the inactivated virus. Since the inactivation of the RVK strain 100 eliminates its effect when used in the “treatment”, but not “vaccination” regimen, it seems to be associated with an immunostimulatory effect but not with an oncolytic one.
Uveal melanoma: Real-world analysis of immune checkpoint inhibitors efficacy and lymphocyte-to-monocyte ratio as a biomarker of response.
Authors: Desilets Antoine , Beland Chloe , Hladky Valerie , Pang Steph A. , Elkrief Arielle , Stepanov Andreea , Routy Bertrand , Belanger Karl , Miller Wilson H. , Larochelle Olivier , Jamal Rahima
Published: June 2022

e21590

Background: Uveal melanoma (UM) is a rare subtype of melanoma. Real-world data is needed to guide management since patients with advanced UM were excluded from immune checkpoint inhibition (ICI) phase III clinical trials. Lymphopenia and elevated monocyte count, which represents a surrogate marker of systemic inflammation and a source of pro-angiogenic tumor-associated macrophages (TAM), have been associated with poor treatment outcomes in various solid tumors. We sought to characterize ICI efficacy in patients with UM vs cutaneous melanoma (CM) and to investigate pre-treatment lymphocyte-to-monocyte ratio (LMR) as a biomarker of response. Methods: We conducted a multicentric cohort study across 3 academic centers in Canada. Best overall responses as per the investigators were recorded. Overall survival (OS) and progression-free survival (PFS) were compared using the log rank (Mantel-Cox) test, with univariate analyses performed using Cox proportional hazard regression model. Results: A total of 122 patients with metastatic melanoma were included, either UM (n = 60) or CM (n = 62). UM patients were treated either with anti-PD-1 monotherapy (69%) or combination with anti-CTLA-4 (31%). Median OS was 35.4 months for CM versus 8.0 months for UM (HR 0.38, 95%CI 0.24-0.60, p = 0.0001). Median PFS was 10.7 months for CM versus 3.5 months for UM (HR 0.38, 95%CI 0.22-0.65, p = 0.0001). Best overall response in the UM group was progressive disease (74%), stable disease (10%) or partial response (16%). In UM patients, higher baseline LMR (HR 0.48, 95%CI 0.24-0.97, p = 0.04) and presence of immune-related adverse events (HR 0.42, 95%CI 0.20-0.89, p = 0.02) were associated with improved OS in univariate analysis. In CM, such association with high LMR was not significant (HR 0.58, 95% 0.28-1.21, p = 0.10) unless excluding patients with corticosteroid-induced lymphopenia due to recently treated brain metastases (HR 0.42, 95%CI 0.19-0.92, p = 0.03). Conclusions: Advanced UM treated with ICI have inferior survival outcomes compared with cutaneous primaries. Higher pre-treatment LMR is associated with improved OS to ICI in UM patients and could represent a surrogate marker of immune activation. Our findings reinforce the need for new treatment strategies in UM.
Efficacy and safety of outpatient based therapy in childhood acute lymphoblastic leukemia.
Authors: Zulfikar Osman Bulent , Koc Basak
Published: June 2022

e22001

Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. With the improvements in effective antileukemic drugs and the risk stratification treatment approach, the cure rate for pediatric ALL has increased to >90%. The effect of outpatient treatment and developing supportive care have a very important role in this success. We evaluated the disease outcomes and severe complications (complication causes hospitalization in ICU, encephalitis) of children who had been treated with the Children’s Oncology Group (COG) protocols, and follow-up protocol during a 20-year study period. Methods: From 1999 to 2020, 134 patients who had been diagnosed with ALL in the Department of Pediatric Hematology-Oncology at the Istanbul University Oncology Institute were included in the present study. Nine patients excluded from all analysis that 5 of them admitted with relapse, 2 had been diagnosed with mature aggressive B-cell acute leukemia, and 2 had been diagnosed with mixed phenotype and 7 who had been lost to follow-up were also excluded from survival analyses. Results: Mean age was 7.7±4.89 years old in 125 patients (Table). The 5- and 10-year and 20-year Event Free Survival (EFS) rates were 90.2% (standard error [SE], 4.2%) in standart risk B-ALL (n=54) and Overall Survival (OS) rates were 100%, 96% and 96% ([SE], 3.9%), respectively. In high risk group B-ALL (n=53) 5-year EFS was 80.7% (standard error [SE], 5.8%) and 78.2% ([SE], 6.1%) for both 10 and 20 year period and OS rates were 76.9% ([SE], 5.9%) for all periods. Although the number of patients is low in T-ALL (n=11), 5- and 10-year and 20-year EFS and OS rates were 63.6% (standard error [SE], 14.5%) for all periods. Fifteen severe complication recorded in 12 patients (10 B-ALL, 2 T-ALL). One patient hospitalized in ICU due to gram negative sepsis for 3-times and epidural hemorrhage. Conclusions: The survival rate for pediatric ALL has increased in recent years according to improvements of treatment.In our cohort, 20-year OS rate is 96% for standart risk B-ALL and 76.9% for high risk B-ALL. Additionally, regularly and closely monitored patients, complications can be effectively prevented, treated, and eliminated. In our study, the short hospitalization period, rapid analysis of laboratory tests, continuous supportive care, efficient education given to the parents of children increased the success of the therapy and ensured low complication rates. [Table: see text]
Epidemiology, clinical features and outcomes of ganglioneuroblastoma: An analysis of the National Cancer Database.
Authors: Nelson Bridgett , Silberstein Peter T. , Cichon Gregory
Published: June 2022

e22013

Background: Ganglioneuroblastoma (GNB) is a rare tumor of the sympathetic nervous system composed of both immature neuroblasts and mature ganglion cells. It has an intermediate malignant potential that lies between a low grade ganglioneuroma and a high-grade neuroblastoma and has the capability to transform into a neuroblastoma. While more information is known regarding pediatric neuroblastoma, little is known regarding the epidemiology and clinical features of GNB. To our knowledge, this is the first analysis of ganglioneuroblastoma using the National Cancer Database (NCDB) and potentially the largest and most comprehensive studies of this subtype of tumor to date. Methods: Using the National Cancer Database (NCDB), 273 patients diagnosed with ganglioneuroblastoma (ICD-0 9490/3) from 2004-2018 were identified. Kaplan-Meir analysis was used to estimate survival and log-rank tests were used to compare survival between stage groups. Results: The median age of diagnosis for patients with ganglioneuroblastoma was found to be 4 years. Girls were affected more commonly than boys, with a male to female ratio of 1.6/1. A majority of patients were white (77.7%) and African American (13.6%), followed by minor representations from multiple other races. The most common primary site of ganglioneuroblastoma was the thorax (40.5%), followed by the abdomen (35.7%). A minority of patients (14%) had distant metastases at diagnosis. At the time of disease presentation, 56% of patients were classified as stage I, 9.2% as stage II, 18.4% as stage III and 16.3% as stage IV. Stages I, II, and III conferred an excellent prognosis with a 99.2% survival rate as compared to patients with stage IV disease who had a survival rate of 65.2% (p < 0.001). Nearly all patients underwent surgery of the primary site, with the most common approach being local excision. Around one quarter of patients received chemotherapy while very few patients required radiation or immunotherapy. Conclusions: A number of unique findings help to distinguish ganglioneuroblastoma from the more common variant neuroblastoma. GNB seems to affect slightly older children (median age of 4 years) compared to a median age of 22 months in neuroblastoma. Interestingly, GNB was found to occur significantly more frequently in girls. On the contrary, neuroblastoma has been reported to be slightly more common in males than females. Additionally, the majority of ganglioneuroblastomas arise in the thorax. This is in comparison to neuroblastomas, of which the large majority arise in the abdomen, specifically in the adrenal glands. Stage IV GNB carries a significantly worse prognosis than stages I-III, with a survival rate of 62.5% which is similar to stage IV neuroblastoma.