Predictive value of fibroblast growth factor receptor (FGFR) mutations and gene fusions on anti-PD-(L)1 treatment outcomes in patients (pts) with advanced urothelial cancer (UC).

419 Background: FGFR alterations have been shown to be associated with immunologically “cold” UC tumors with low immune marker expression and T cell infiltrate, a poorly receptive environment for immune checkpoint inhibitors. Using a real world matched clinical and genomic dataset of pts with advanced UC, we explored their predictive value in pts receiving anti-PD-(L)1 therapy. Methods: The Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB) contained full clinical and treatment information and molecular data on a cohort of pts with confirmed advanced UC. The populations of interest are FGFR+ and FGFR- patients determined by the presence or absence of a prespecified panel of FGFR2/3 mutations and fusions. Overall survival (OS), measured from the start of anti-PD-(L)1 therapy, was analyzed using Kaplan-Meier estimation and Cox proportional hazards models adjusted for left truncation (delayed entry model). Results: 118 pts ( FGFR+ n = 26, FGFR- n = 92) treated with anti-PD-(L)1 therapy for advanced UC were assessed for OS. Median OS for FGFR+ pts who received any line of anti-PD-(L)1 therapy (n = 26) was 3.1 mo vs 6.1 mo for FGFR- pts (n = 92) (hazard ratio [HR] 1.33, 95% CI 0.78-2.26, p = 0.30). For first-line anti-PD-(L)1 therapy, median OS in FGFR+ pts (n = 12) was 4.7 mo vs 11.3 mo for FGFR- pts (n = 28) (HR 1.94, 95% CI: 0.78-4.82, p = 0.15); median OS in second-line were 3.1 mo (n = 12) vs 6.1 mo (n = 47), respectively (HR 1.17, 95% CI 0.53-2.59, p = 0.70). Per multivariate analysis, FGFR+ status appears to be associated with poorer OS in pts treated with any line of anti-PD-(L)1 therapy (HR 1.25, 95% CI 0.71-2.21, p = 0.43). Conclusions: These real-world data suggest that FGFR+ pts following anti-PD-(L)1 therapy for advanced UC may be associated with a trend in poorer overall survival outcome compared with FGFR- pts. These findings are in alignment with treatment history data from BLC2001 (Siefker-Radtke A, et al. ASCO-GU 2018), which showed low response rates to prior anti-PD-(L)1 therapies among FGFR+ pts.

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Multiple immune-related adverse events and anti-tumor efficacy: real-world data on various solid tumors

10.21203/rs.2.21095/v1 ◽

2020 ◽

Author(s):

Keitaro Shimozaki ◽

Yasutaka Sukawa ◽

Noriko Beppu ◽

Isao Kurihara ◽

Shigeaki Suzuki ◽

...

Keyword(s):

Retrospective Study ◽

Adverse Events ◽

Real World ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

University Hospital ◽

Real World Data

Abstract Background Immune checkpoint inhibitors have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in the real-world practice. Methods We conducted a retrospective study on patients with recurrent or metastatic non-small cell lung cancer, melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model. Results Among 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. OS in patients with multiple irAEs was significantly longer than that in patients with single irAE (42.3 months vs. 18.8 months; hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25–0.93; P = 0.03). Moreover, OS from the development of a second irAE in those with multiple irAEs was longer than that from the development of the first irAE in patients with single irAEs (median OS, 26.9 months vs. 17.7 months, respectively; HR, 0.59; 95% CI, 0.30–1.14; P = 0.11). Conclusions Our single-center retrospective study revealed a remarkable tendency associating the development of multiple irAEs with favorable prognoses.

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Real-world experience with sipuleucel-T (Sip-T) in Asian men with castrate-resistant prostate cancer (CRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17588 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17588-e17588

Author(s):

Jingsong Zhang ◽

Ming Liu ◽

Jiahua Pan ◽

Xiao X. Wei ◽

Matthew Harmon ◽

...

Keyword(s):

Overall Survival ◽

Real World ◽

Proportional Hazards ◽

Specific Antigen ◽

White Men ◽

Cox Proportional Hazards ◽

Real World Data ◽

Significant Difference ◽

The Difference ◽

Castrate Resistant

e17588 Background: Clinical trials of sip-T predominately included white men (over 90%). Previously we explored outcomes with sip-T in white and black patients (pts) (Kantoff PW, NEJM 2010; Sartor AO, ASCO 2019, #5035). In this retrospective analysis of data from electronic medical record and practice management systems, we explored the hypothesis that Asian and white pts who receive sip-T for CRPC exhibit similar overall survival. Methods: Data came from > 100 US community urology practices, predominantly large urology group practice associations. White and Asian pts were matched based on 5 criteria: sip-T treatment year; treatment pattern for oral and sip-T; metastatic site (Bone v. Nodal v. Visceral); prostate-specific antigen (PSA) within 10%; and age at treatment. Parameters retrieved include those listed in the table. Overall survival (OS) was analyzed using Kaplan Meier (KM) methodology with Cox Proportional Hazards Modelling used to generate the hazard ratio (HR) with Asians as the reference. Descriptive summary statistics were generated for other parameters. Results: The analysis identified 102 white and 77 Asian pts; treatment ranged from 2012 to 2019 with 60% receiving sip-T after 2016, impacting the ability to examine long-term outcomes. Characteristics of the 2 groups were broadly similar, although more Asians had Gleason scores ≥8 than whites (Table). In the KM analysis, most pts were censored. While the KM survival curves separate around month 25, favoring Asian pts, the difference is not significant (HR, 0.69 [95% CI: 0.4, 1.4]; P = 0.277). Conclusions: These real-world data do not show a significant difference in OS between Asian and white men. Both groups exhibited relatively low median PSAs near 5 ng/mL, an observation correlated with longer OS in previous studies. [Table: see text]

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Real-world data on overall survival associated with biweekly versus weekly cetuximab among metastatic colorectal cancer (mCRC) patients in the United States.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.33 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 33-33

Author(s):

Himani Agg ◽

Yimei Han ◽

Zhanglin Lin Cui

Keyword(s):

Overall Survival ◽

Real World ◽

Proportional Hazards ◽

Stage Iv ◽

The United States ◽

Cox Proportional Hazards ◽

Wild Type ◽

Real World Data ◽

Baseline Characteristics ◽

Ecog Ps

33 Background: Cetuximab 250mg/m2 weekly (Q1W) after an initial dose of 400mg/m2 is approved for treatment of K-Ras wild-type mCRC. In real world 29% of patients received cetuximab 500mg/m2 biweekly (Q2W). In this study overall survival (OS) associated with Q2W vs Q1W dosing of cetuximab for mCRC in real world was compared. Methods: This study utilized Flatiron Health electronic health record-derived database to identify adult patients with stage IV or recurrent K-Ras wild-type mCRC who received cetuximab+FOLFIRI/FOLFOX/irinotecan, or cetuximab monotherapy in first, second or third-line therapy from 01/01/2013 to 12/31/2019. Patients were assigned to Q1W or Q2W cohort if they had 70% or more cetuximab infusions with a gap of 4-10 days or 11-18 days from previous infusion. Patients who did not fall into either cohort were excluded from analysis. Propensity score (PS) matching was used to balance cohorts on their baseline demographic, clinical and treatment characteristics. Kaplan-Meier methods and Cox proportional hazards regressions were used to compare OS. Results: Baseline characteristics for Q2W (N = 422) vs Q1W (N = 653) cohorts before PS matching- median age 62 vs 65 years, male 58.5% vs 59.3%, white 68.3% vs 66.5%, stage IV 56.6% vs 58.5%, ECOG PS 0/1 61.6% vs 52.1%, ECOG PS 2+ 9.2% vs 9.5%. After PS matching, baseline characteristics were balanced. Hazard ratios (HRs) comparing OS in PS-matched Q2W vs Q1W cohorts were not significant for overall or line of therapy populations (Table). Conclusions: Weekly and biweekly cetuximab had comparable effectiveness in this real-world study. [Table: see text]

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Value of precision medicine in advanced NSCLC: Real-world outcomes associated with the use of companion diagnostics.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20015 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20015-e20015

Author(s):

Ani John ◽

Roma Shah ◽

William Bruce Wong ◽

Charles Schneider ◽

Hamid H. Gari ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Real World ◽

Proportional Hazards ◽

Survival Rates ◽

Prognostic Index ◽

Cox Proportional Hazards ◽

Advanced Stage ◽

Clinical Value ◽

The Real

e20015 Background: Five-year survival rates as low as 2.8% have been reported in patients with non-small cell lung cancer (NSCLC), highlighting the need for individualized diagnosis and treatment. Companion diagnostic testing (CDx) identifies patients with molecular targets likely to respond better to particular therapies; however, not all cancer patients receive CDx in the real-world setting. This study evaluated the clinical value of CDx in the real world with respect to overall survival among patients with non-squamous advanced (Stage IIIB/IV) NSCLC (aNSCLC). Methods: Patients were from the Flatiron Health electronic health-derived database, treated with systemic therapy, and diagnosed with aNSCLC between January 1, 2011 and May 31, 2018; those who received CDx with their first line of treatment were compared with those who did not. Logistic regression using components of the modified Lung Cancer Prognostic Index (LCPI; age, sex, stage, actionable mutation(s), smoking, respiratory comorbidity; Alexander et al. Br J Cancer. 2017) and other factors were used to predict characteristics associated with receiving CDx. Overall survival was evaluated using Kaplan-Meier analysis. Unadjusted and adjusted Cox proportional hazards regression models were used to evaluate the association between CDx and overall survival. Results: A total of 17,143 patients with aNSCLC (CDx, n = 14,389; no CDx, n = 2754) and a mean (SD) age at diagnosis of 67.2 (10.0) years (CDx, 67.1 [10.1]; no CDx, 67.5 [9.2]) were included. There were more nonsmokers in the CDx group (17.4%) than the no CDx group (5.5%). Patients who were female, diagnosed after 2014, receiving multiple lines of therapy or had advanced stage at diagnosis were more likely to receive CDx. Patients receiving CDx had decreased mortality risk (unadjusted HR [95% CI] = 0.54 [0.52-0.57]) and lived longer than those not receiving CDx (median survival = 14 vs 7 months). The significant reduction in mortality associated with CDx remained after adjusting for factors included in the modified LCPI (adjusted HR [95% CI] = 0.78 [0.75-0.82]) as well as a model without actionable mutations (adjusted HR [95% CI] = 0.70 [0.66-0.73]). Conclusions: Among patients with non-squamous aNSCLC, use of CDx was associated with reduced risk of mortality compared with no CDx.

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Neutrophils lymphocyte ratio role in predicting response to checkpoint inhibitors in metastatic non-small lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20646 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20646-e20646

Author(s):

Hosam Hakim ◽

Ahmed Abdalla ◽

Tarik H. Hadid

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Statistical Significance ◽

Immune Therapy ◽

Cox Proportional Hazards ◽

P Value ◽

Lymphocyte Ratio ◽

Metastatic Nsclc

e20646 Background: There have been numerous advances in the management of metastatic lung cancer, including targeted therapy against certain mutations in cancer cells and later developing immune therapy with check point inhibitors.From the pre-immune therapy era, a simple blood test allowing the calculation of the neutrophil-to-lymphocyte ratio (NLR) was established as a strong prognostic marker associated with worse overall survival (OS) in several tumor types including non-small cell lung cancer (NSCLC). Methods: We have retrospectively reviewed electronic medical records for patients with Metastatic NSCLC whom received at least one dose of Checkpoint Inhibitors from January 2014 till January 2019 in Van Eslander Cancer Center.The analysis was done using SPSS v. 25.0 and a p-value of 0.05 or less was considered to indicate statistical significance. A univariant analysis was done using Student’s t-test, the Mann-Whitney U test and the chi-squared test. Survival analysis was conducted using Kaplan Meier methodology as well as Cox proportional hazards models. Results: There were 80 patients with metastatic NSCLC received at least one dose of a checkpoint inhibitor. Median age was 63.9 ± 9.3; Males were 45%; Whites were 62.5%. 67.5% of patient had adenocarcinoma and 24% had squamous cell carcinoma. Twenty patients had brain metastasis (25%) and nineteen patients had liver metastasis (24.6%). Eleven patients (13.8%) had PDL-1 greater than 50% and 11 patients (13.8%) had PDL-1 between 1%-50% and 22 patients (27.5%) had negative PD-L1 status. 18.8% received immunotherapy as a first-line treatment and 65% got immunotherapy on their second line and 16.3% had immunotherapy as the third line of treatment or more. Sixty-one patients (76.2%) received Nivolumab and nineteen patients (23.8%) received pembrolizumab. Mean duration of immunotherapy was 13.7 months ± 20.7. Mean NLR was 6.1 ± 5. Patient with NLR > 5:1 had statistically significant higher progression-free survival (PFS) 27.5 months compared to 12 months P = 0.02. Also, Patients with baseline NLR > 5:1 had a trend toward higher median overall survival (OS) but was not statistically significant 41 months compared to 12 months P = 0.08. Conclusions: Our data showed similar finding to Bagley et al and other retrospective analysis from multiple institutes showing that NLR could be a good predictor of response to checkpoint inhibitors And a cutoff of NLR higher than 5.1 was associated with statistically significant better PFS and a trend towards a better OS.

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Risk factors for myocarditis associated with immune checkpoint inhibitors using real-world clinical data.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15100 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15100-e15100 ◽

Cited By ~ 1

Author(s):

Prantesh Jain ◽

Jahir Gutierrez Bugarin ◽

Avirup Guha ◽

Chhavi Jain ◽

Tingke Shen ◽

...

Keyword(s):

Risk Factors ◽

Liver Disease ◽

Cancer Patients ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Cancer Type ◽

Real World Data

e15100 Background: Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related myocarditis has the highest fatality rate (~50%). Cardiovascular monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterizing rare but fatal cardiac toxicities requires integration of real-world data. Methods: U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011-2018. Patients ≥18 years of age treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. Myocarditis, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics and Cox proportional hazards regression. Results: 16,541 ICI treated cancer patients were included (median age 60; 58% male). Myocarditis was identified in 252 (1.5%) patients, majority (90%) ≥50 years old (median 63) with 12,040 person-years of follow up. 62% received anti-PD1 monotherapy, 12% anti-CTLA4, and 15% received combination treatment with other ICIs and/or chemotherapy. Most common cancer types were lung (48%), melanoma (25%), and renal cancer (14%). Cumulative incidence of myocarditis at 1 year was 2.06%; 95% CI (1.78-2.37), median onset of 80.5 days, 42% occurring within 60 days of treatment. By univariate analyses, age, cancer type, diabetes (DM), hypertension (HTN), kidney, liver disease, atrial fibrillation (AF) were related to myocarditis. Risk was lower in patients who received anti-CTLA4 monotherapy (HR: 0.490; 95% CI: 0.26-0.92; p = 0.0251). On multivariable regression analyses only age, cancer type (renal, lung cancer), comorbidities DM and liver disease were significantly associated with myocarditis (Table). Conclusions: This is the largest real-world longitudinal study for ICI associated myocarditis showing higher than reported incidence and identifiable risk factors. [Table: see text]

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Phenotypic expression of Bax is a predictive marker of 5-fluorouracil treatment in colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3605 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3605-3605

Author(s):

U. Manne ◽

C. Suarez-Cuervo ◽

N. C. Jhala ◽

J. Posey ◽

C. B. Herring ◽

...

Keyword(s):

Overall Survival ◽

Predictive Value ◽

Proportional Hazards ◽

Phenotypic Expression ◽

Tumor Stage ◽

Cox Proportional Hazards ◽

Nuclear Accumulation ◽

Adjuvant Therapies ◽

Post Surgery ◽

Significant Difference

3605 Background: The anti-tumor activity of 5-fluorouracil (5-FU) has been related to its ability to induce apoptosis. Therefore, we assessed the predictive value of phenotypic expression of key apoptotic molecules in colorectal adenocarcinomas (CRC) of patients treated with 5-FU-based adjuvant therapies. Methods: Archival tissues of CRCs from 56 patients who received a complete regimen of 5-FU-based chemotherapy after surgery, and 56 age, gender, ethnicity, tumor stage, tumor location, and tumor differentiation matched patients who had undergone only surgery (without any pre- or post-surgery chemo- or radiation therapy), were evaluated for immunophenotypic expression of Bax, Bcl-2 and nuclear accumulation of p53 (p53nac). Immunophenotypic expression of these markers was categorized into low and high expressors and cut-point values were determined based on their expression in benign epithelium. These tumors Ability of these markers in predicting the efficacy of 5-FU-based treatment was assessed by estimating overall survival utilizing the Kaplan-Meier and Cox proportional hazards methods. Results: There was no significant difference in overall survival rates between the two patient categories (logrank P=0.487). However, a better survival was observed for patients who received chemotherapy when their CRCs lacked Bax expression; in contrast, patients with high Bax expression CRCs had worse survival when they received chemotherapy (logrank P=0.016). Surgically treated patients with CRCs lacked Bax expression had 5.33 times higher mortality than those with high Bax expression (HR, 5.33; CI: 1.78–15.94), when controlled for tumor stage and other confounding variables. Bcl-2 or p53nac had no predictive value in either patient group. Conclusions: These preliminary findings are the first to provide good evidence to suggest that patients with CRCs lacking Bax phenotypic expression benefit from 5-FU-based adjuvant therapies but not those with high Bax expression (Supported by NIH/NCI R01-CA98932–01). No significant financial relationships to disclose.

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Real-world adherence in patients with metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil (FTD/TPI) or regorafenib (REG).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.30_suppl.11 ◽

2018 ◽

Vol 36 (30_suppl) ◽

pp. 11-11

Author(s):

Anuj K. Patel ◽

Victoria Barghout ◽

Mihran Ara Yenikomshian ◽

Guillaume Germain ◽

Philippe Jacques ◽

...

Keyword(s):

Real World ◽

Lower Risk ◽

Proportional Hazards ◽

Medication Possession Ratio ◽

Baseline Period ◽

Cox Proportional Hazards ◽

Data Availability ◽

Real World Data ◽

World Data ◽

Nationally Representative

11 Background: Adherence to oral chemotherapies is a critical but difficult to measure factor in the care of patients with advanced cancer. FTD/TPI and REG have both demonstrated prolonged survival in patients with refractory mCRC, but with notably different side effect profiles. This study utilizes real-world data to assess adherence and discontinuation of patients treated with FTD/TPI or REG and explore the effect of sequencing on adherence. Methods: Adults diagnosed with mCRC were identified using the nationally representative IQVIA Real-World Data Adjudicated Claims – US database (10/2014–07/2017). The first dispensing date of FTD/TPI or REG (if after FTD/TPI approval [10/2015]) was defined as the index date and the 3 months before as the baseline period. The observation period spanned from the index to the earliest date of a switch to another mCRC agent, end of continuous enrollment, or end of data availability. Medication possession ratio (MPR), proportion of days covered (PDC) at 3 months, and discontinuation (i.e., allowable gap≥45 days) were compared. Logistic (odds ratio [OR]) and Cox proportional hazards (hazard ratio [HR]) regressions, adjusting for baseline characteristics, were used to compare adherence and discontinuation, respectively. A subgroup analysis was conducted among switchers (FTD/TPI to REG vs REG to FTD/TPI). Results: A total of 469 FTD/TPI and 311 REG users were identified. FTD/TPI users had higher compliance with an MPR ≥ 80% (OR = 2.47; p < 0.001) and PDC ≥ 80% (OR = 2.77; p < 0.001). FTD/TPI users had lower risk of discontinuation (HR = 0.76; p = 0.006). Among switchers (96 FTD/TPI to REG; 83 REG to FTD/TPI), those switching from FTD/TPI to REG were more likely to have an MPR ≥ 80% (OR = 2.91; p < 0.001) and PDC ≥ 80% (OR = 4.60; p < 0.001) compared to REG to FTD/TPI switchers. Additionally, FTD/TPI to REG switchers had a lower risk of first treatment discontinuation (HR = 0.66; p = 0.009). Conclusions: In this study, FTD/TPI users had significantly higher compliance, lower discontinuation rate, and switchers treated first with FTD/TPI had better compliance, demonstrating that claims data can provide insight into oral chemotherapy adherence patterns in mCRC.

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Methotrexate Reduces the Probability of Discontinuation of TNF Inhibitors in Seropositive Patients With Rheumatoid Arthritis. A Real-World Data Analysis

Frontiers in Medicine ◽

10.3389/fmed.2021.692557 ◽

2021 ◽

Vol 8 ◽

Author(s):

Borja Hernández-Breijo ◽

Claudia M. Brenis ◽

Chamaida Plasencia-Rodríguez ◽

Ana Martínez-Feito ◽

Marta Novella-Navarro ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Real World ◽

Proportional Hazards ◽

Serum Levels ◽

Cox Proportional Hazards ◽

Real World Data ◽

World Data ◽

Kaplan Meier ◽

Cox Proportional Hazards Models ◽

Necrosis Factor

Tumor necrosis factor inhibitors (TNFi) are widely used for the treatment of patients with rheumatoid arthritis (RA), however a considerable percentage of patients discontinued the therapy. The aim of this study is to explore real-world TNFi survival, stratified for seropositivity, and to determine the factors that may influence it. This is a retrospective, observational and longitudinal study, using real-world data of patients, who started their first TNFi therapy between 1999 and 2018 from the RA-PAZ cohort. Patients were considered seropositive if they showed positive serum levels of either RF, ACPA, or both. Treatment survival was analyzed using Kaplan-Meier curves, and Cox proportional hazards models were used to compare the risks of TNFi discontinuation for seronegative and seropositive patients. Of the included 250 patients, 213 (85%) were seropositive. Results showed that TNFi survival did not depend on seropositivity status. However, median survival time was significant longer for seropositive patients who received concomitant MTX compared to patients who did not receive it (median [95% CI]: 3.3 yr. [2.3–4.2] vs. 2.6 yr. [1.7–3.6], respectively; p = 0.008). Furthermore, seropositive patients who received concomitant MTX were 49% less likely to discontinue TNFi therapy than patients who did not receive it (HR: 0.51; 95% CI: 0.35–0.74). In addition, we found that in seropositive patients, the use of prednisone throughout the TNFi treatment was associated with a higher likelihood of therapy discontinuation (OR: 2.30; 95% CI: 1.01–5.23). In conclusion, these data provide evidence to support the use of concomitant MTX in seropositive patients to prolong the effectiveness and the survival of the TNFi therapy. Moreover, the co-administration of prednisone in seropositive patients receiving TNFi was highly associated with TNFi discontinuation.

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Integrative transcriptome analysis of malignant pleural mesothelioma reveals a clinically relevant immune-based classification

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001601 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001601

Author(s):

Ania Alay ◽

David Cordero ◽

Sara Hijazo-Pechero ◽

Elisabet Aliagas ◽

Adriana Lopez-Doriga ◽

...

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Malignant Pleural Mesothelioma ◽

Drug Response ◽

Proportional Hazards ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Transcriptional Level ◽

Pleural Mesothelioma

BackgroundMalignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lung mesothelium. Immune checkpoint inhibitors (ICI) in MPM have not been extremely successful, likely due to poor identification of suitable candidate patients for the therapy. We aimed to identify cellular immune fractions associated with clinical outcome and classify patients with MPM based on their immune contexture. For each defined group, we sought for molecular specificities that could help further define our MPM classification at the genomic and transcriptomic level, as well as identify differential therapeutic strategies based on transcriptional signatures predictive of drug response.MethodsThe abundance of 20 immune cell fractions in 516 MPM samples from 7 gene expression datasets was inferred using gene set variation analysis. Identification of clinically relevant fractions was performed with Cox proportional-hazards models adjusted for age, stage, sex, and tumor histology. Immune-based groups were defined based on the identified fractions.ResultsT-helper 2 (TH2) and cytotoxic T (TC) cells were found to be consistently associated with overall survival. Three immune clusters (IG) were subsequently defined based on TH2 and TC immune infiltration levels: IG1 (54.5%) was characterized by high TH2 and low TC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high TC levels. IG1 and IG3 groups were associated with worse and better overall survival, respectively. While no differential genomic alterations were identified among immune groups, at the transcriptional level, IG1 samples showed upregulation of proliferation signatures, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, the integration of gene expression with functional signatures of drug response showed that IG3 patients might be more likely to respond to ICI.ConclusionsThis study identifies a novel immune-based signature with potential clinical relevance based on TH2 and TC levels, unveiling a fraction of patients with MPM with better prognosis and who might benefit from immune-based therapies. Molecular specificities of the different groups might be used to tailor specific potential therapies in the future.

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