bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beyond steroids: Immunosuppressants in steroid-refractory/resistant immune related adverse events.
Authors: Luo Jia , Beattie Jason , Fuentes Paige , Rizvi Hira , Egger Jacklynn V. , Kern Jeffrey , Leung Donald Y. M. , Lacouture Mario E. , Kris Mark G. , Gambarin Maya , Santomasso Bianca , Faleck David M. , Hellmann Matthew D. 
Published: June 2021

9092 Background: The optimal management for immune related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants based on case reports and expert opinion. Methods: We examined patients with advanced lung cancers at MSK treated with immune checkpoint blockade (ICB) from 2011-2020. Pharmacy records were queried to identify patients who received systemic steroids as well as an additional immunosuppressant (eg TNFα inhibitor, mycophenolate mofetil). Patient records were manually reviewed to examine baseline characteristics, management, and outcomes. Results: Among 2,750 patients with lung cancers treated with ICB, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (TNFα inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (5/6) and colitis (18/27) but less common in neuromuscular (1/5) and pneumonitis (3/10). All patients with hepatitis received mycophenolate mofetil 500-1000mg BID for a median of 3 months, range 2-5 months. Of the 18 patients with colitis who improved with a TNFα inhibitor, 10 needed just one dose. Of 13 patients who died, 4 were related to toxicity from immunosuppression (3, infection-related deaths; 1, drug-induced liver injury leading to acute liver failure). Those who died from immunosuppressive therapy received higher amounts of systemic steroids than those who did not (max median 525 vs 132 mg prednisone equivalent, Mann Whitney U p = 0.004, total median 5.9k vs 2.3k mg prednisone equivalent, p = 0.004). Of 31 patients who received at least 3 weeks of prednisone ≥ 20mg, most (90%, 28/31) had at least one side effect that was brought to clinical attention (most commonly altered mood/ sleep, 52%, increase in BMI > 1kg/m2, 45%, and infection, 32%). Conclusions: Steroid-refractory/resistant immune related adverse events are rare. While existing treatments help patients with hepatitis and colitis, most patients with other irAEs remain refractory and/or experience toxicities from immunosuppression. Systemic steroid use likely contributed to side effects and mortality. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically informed treatment regimens for severe irAEs to realize the true benefit of ICB therapy.
Impact of immune checkpoint inhibitor (CPI) and EGFR tyrosine kinase inhibitor (TKI) sequence on time to treatment failure (TTF) among EGFR plus NSCLC treated in a community-based cancer research network.
Authors: Jones Carissa , Lachs Rebecca , Sturgill Emma , Misch Amanda , Lietman Caressa , Jones Suzanne Fields , Johnson Melissa Lynne , Spigel David R. , McKenzie Andrew Jacob 
Published: June 2021

9099 Background: The development of CPIs and driver-targeted TKIs has transformed the treatment of NSCLC and increased survival rates. However, the role of CPIs in patients with oncogenic-driven NSCLC remains an area of investigation. We sought to examine the impact of CPI sequence on treatment response among patients with oncogenic-driver mutation-positive NSCLC. Methods: Patients with NSCLC being treated within the Sarah Cannon Research Institute network were identified through Genospace, Sarah Cannon’s clinico-genomic analytics platform. Advanced stage oncogenic-driven tumors (driver+) were defined as those with a record of receiving an FDA-approved TKI targeting EGFR, ALK, RET, ROS1, NTRK, MET, or BRAF. Kaplan-Meier estimates were used to examine TTF (defined as time from therapy start to start of next therapy, death, or loss to follow-up) and overall survival (OS). Results: We identified 12,352 patients with lung cancer and available therapy data (2005-2020), including 2,270 (18%) driver+ patients. Eleven percent (N=245) of driver+ patients received a CPI, including 120 (49%) with CPI prior to TKI, 122 (50%) with CPI post TKI, and 3 (1%) who received CPI both pre and post TKI. The CPI TTF was significantly longer for those who received CPI post TKI compared to those who received it prior (Table). EGFR+ tumors accounted for 82% (N=1,867) of driver+ patients, 10% of whom (N=188) received a CPI. Of the EGFR+/CPI+ patients, 78 patients (41%) received CPI prior to TKI, 107 (57%) received CPI post TKI, and 3 (2%) received CPI both pre and post TKI. EGFR+ tumors exposed to a CPI post TKI had a longer CPI TTF compared to patients who received it prior (Table). In contrast, there was no difference in length of benefit from TKI if it was received pre vs. post CPI (Table). There was also no difference in OS based on sequence of TKI and CPI (p=0.88). Larger sample sizes are needed for analysis of additional driver-stratified cohorts. Conclusions: Patients with oncogenic-driven NSCLC benefited from CPI longer when it was administered after TKI compared to before. Importantly, therapy sequence only affected length of benefit from CPIs and did not affect length of benefit from TKIs. This effect was present in EGFR+ NSCLC, but sample sizes were too small to determine if the same is true for other oncogenic-drivers. Therapy sequence had no impact on OS, indicating the presence of additional clinical, therapeutic, and/or genomic factors contributing to disease progression. Continued research is needed to better understand markers of CPI response in driver+ NSCLC.[Table: see text]
Incidence and heterogeneity of C797S and other EGFR resistance mutations on routine comprehensive genomic profiling (CGP).
Authors: Janne Pasi A. , Lee Jessica Kim , Madison Russell , Venstrom Jeffrey Michael , Schrock Alexa Betzig , Oxnard Geoffrey R. 
Published: June 2021

9101 Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance. There are now a number of therapeutic approaches aimed at overcoming EGFR resistance mutations (muts). We sought to understand the biology of EGFR C797S and other EGFR resistance muts through querying our clinico-genomic database (CGDB). Methods: CGP results from tissue (n = 60,889) or circulating tumor DNA (ctDNA; [n = 9,922]) samples from 70,811 NSCLC patients (pts) were queried for known osi resistance muts in EGFR (C797, L792, G796, L718, G724). Clinical outcomes were evaluated for a cohort of NSCLC pts with osi resistance from the Flatiron Health-Foundation Medicine CGDB, a nationwide de-identified EHR-derived database linked to CGP data. Results: Between 12/2014 and 11/2020, 261 osi resistance mutations in EGFR were detected in 228 samples. The most common were C797S (66%), L718X (14%), G724S (11%), and others (9%). 173 C797S muts were detected in 155 samples (123 ex19del, 30 L858R, 2 other EGFR muts); 100 tissue, 55 ctDNA (median VAF = 7.6%). EGFR T790M co-occurred with C797S muts (96% cis, 3.7% trans) in 118 (76%) samples and decreased over time, occurring in 92% (24/26) of C797S samples tested in 2017 vs 56% (20/36) of samples tested in 2020 (p = 0.002). In 19/155 (12%) samples with C797S (14 ctDNA), multiple changes resulting in EGFR resistance muts were present: 16 samples had > 1 nucleotide changes resulting in C797S (100% trans), 3 samples had other resistance muts (L718Q/V, L792H, L792F) and 3 samples had multiple C797S changes with other resistance muts (C797G, L792H/F + G796S, L718Q + G796S+C797G). 29 pts (14 ctDNA) had C797S with potential off-target resistance (17 PIK3CA muts, 4 BRAF muts, 3 CCDC6- RET fusions, 3 KRAS muts, 2 ERBB2 amplifications (amps), 1 ERBB2 ex16 del, 1 STRN- ALK fusion, 1 FGFR3- TACC3 fusion). In the CGDB, 527 EGFR-mut NSCLC pts had documented receipt of osi. Pre and post osi-treated specimens were available for 19 of these pts (12 ex19del, 6 L858R, 1 G719A/S768I). Heterogeneous acquired resistance mechanisms were observed in the post-osi specimen, including 2 CCDC6- RET fusions, 2 MET amps, 2 BRAF fusions, BRAF V600E, and secondary EGFR muts (C797S, L704F, L718V). 161/527 pts had a documented line of therapy after osi discontinuation and most frequently received platinum doublet + immunotherapy (27%) or platinum doublet alone (23%); 17 (11%) pts received another EGFR tyrosine kinase inhibitor. 214/527 had documented osi progression and median post-progression survival was 11.8 months. Conclusions: Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition. EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.
Genomic markers associated with hyperprogression in patients with lung cancer treated with immune checkpoint inhibitors.
Authors: Tadesse Eyob ale , Heslin Kayla , Hendawi Mohamed , Peterson Luke , Wolf Frank M. , Brown Thomas D. , Thompson Michael A. 
Published: June 2021

9105 Background: Immune checkpoint inhibitor (ICI) therapy has become a mainstay of non-small cell lung cancer (NSCLC) treatment. However, not all patients (pts) benefit with a subset paradoxically experiencing accelerated tumor growth while on ICI. Hyperprogression (HP) refers to accelerated tumor growth on ICI with worsening clinical status. Various gene alterations may be associated with HP including MDM2/MDM4 amplifications, EGFR alterations, and STK11/LKB1 mutations. Kato et al. (doi: 10.1158/1078-0432.CCR-16-3133 ) showed HP in 6/6 pts with MDM2/MDM4 amplification and in 2/10 pts with EGFR alterations. This report describes HP in pts with NSCLC treated with ICIs in a large health system. Methods: Pts with NSCLC treated with ICIs from Jan 2012 to Jan 2021 at Advocate Aurora Health were reviewed after IRB approval. Pts with NSCLC histology (ICD diagnosis codes and/or manual chart review), ICI treatment, and molecular testing were identified via the real world data integrated within the Syapse Learning Health Network platform. Additional chart review to ascertain HP was performed, and molecular results were analyzed. HP criteria include: 1) time-to-treatment failure < 2 months (from start to discontinuation of ICI for any reason), 2) > 50% increase in tumor burden by RECIST, 3) spread of the disease to a new organ between baseline and first radiologic evaluation or clinical deterioration, and 4) ECOG PS ≥ 2 during the first 2 months of treatment. Based on the number of criteria fulfilled, HP = > 3, Progression = 1-2, and non-progressor = 0. Pts with and without HP were compared using Chi-squared and Fisher Exact tests. T-tests were performed for continuous variables. Results: Out of 7,078 NSCLC pts, 1,389 (20%) were treated with ICI including atezolizumab (40 pts, 3%), durvalumab (17 pts, 1%), nivolumab (167 pts, 12%), pembrolizumab (190 pts, 14%), and multiple ICIs (12 pts, 1%). Of those pts treated with ICIs, molecular testing was performed in 427 (31%). 98 of 427 pts (23%)had HP and an additional 86 pts (20%) had progressive disease without meeting the definition of HP. Biomarker associations with HP are shown in the table. By tumor gene alterations, HP was seen in pts with: EGFR (20/60), STK11/LKB1 (16/25); and MDM2/4 (4/7). Conclusions: EGFR, STK11/LKB1, and MDM2/4 gene alterations were all statistically significantly associated with HP. Clinical and molecular predictors of HP need to be explored in order to optimize selection of pts for ICI therapy.[Table: see text]
Population-based impacts of new therapies on outcomes for stage IV non-small cell lung cancer.
Authors: Rittberg Rebekah , Bucher Oliver , Xue Lin , Aurangzeb Zeb , Banerji Shantanu Otto , Dawe David 
Published: June 2021

9120 Background: Over 15 years, diagnostic and therapeutic algorithms for Stage IV non-small cell lung cancer (NSCLC) have dramatically progressed. While clinical trials demonstrate overall survival (OS) advantages, population level impact remains uncertain. Here we evaluate real world, population-based outcomes for Stage IV NSCLC to assess impact of changing therapies on referral, treatment patterns and OS, which may help explain ongoing stigma/nihilism. Methods: A retrospective cohort analysis was completed to evaluate de novo Stage IV NSCLC diagnosed in Manitoba from 2006 to 2015. We evaluated treatment received (not seen by specialist, saw a specialist but did not receive therapy, radiation therapy (RT) only, and systemic therapy (mutation unknown and known)) and treatment era of diagnosis (2006-2009, 2010-2013 and 2014-2015). Multivariable logistic regression assessed systemic therapy predictors. Kaplan-Meier curve and Cox proportional hazard models evaluated OS. Results: 3,601 patients were diagnosed with Stage IV NSCLC, 53% male. Only 21% received systemic therapy, mean age of 62. Within the cohort, 973 (27%) patients did not see a specialist, 610 (17%) saw a specialist but did not receive therapy, 1248 (35%) only received RT, and 771 (21%) received systemic therapy (17% mutation status unknown and 4% known). Younger patients and those with confirmed histology were more likely to see a specialist and receive treatment, each (p < 0.001). Patients who received systemic therapy had lower comorbidity and higher income quintile, each (p < 0.001). Median OS did not differ between treatment era with median OS of 3.0, 2.9 and 2.8 months for 2006-2009, 2010-2013 and 2014-2015 respectively, p = 0.082. When survival analysis was restricted to patients who received systemic therapy, median OS improved by era to 10.9, 11.2 and 15.6 months respectively, p = 0.001. Variables found to be independently associated with survival included treatment type, age, sex and comorbidity. Conclusions: Improved systemic therapy and molecular testing has improved OS for patients who receive systemic therapy. However, due to the large proportion of Stage IV NSCLC patients who never receive systemic therapy we do not see improved survival at a population level between treatment eras.
Analysis of patterns of care and benefit of thoracic radiotherapy for patients with stage IV NSCLC in the immunotherapy-era from a national hospital-based registry.
Authors: Kharouta Michael , Gross Andrew Jonathan , Kelley Kevin , Choi Serah , Biswas Tithi 
Published: June 2021

9123 Background: Metastatic non-small cell lung cancer (mNSCLC) has classically been treated with platinum-doublet chemotherapy. Recent studies have established immunotherapy as an integral part of therapy for mNSCLC without targetable mutations. There are limited data on the role of consolidative thoracic radiotherapy (TRT) for patients with mNSCLC in the immunotherapy-era. A secondary analysis of KEYNOTE-001 showed significant improvement in overall survival in patients who received radiotherapy with pembrolizumab compared to patients not previously receiving radiotherapy. Methods: We queried the National Cancer Database (NCDB) for patients with metastatic presentation, stage IVA/IVB non-small cell lung cancer between the ages of 18-90 years treated between 2012-2017 with a combination of chemotherapy, immunotherapy, and thoracic radiotherapy. Patients with unknown treatment status, follow up time, or vital status were excluded. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between treatment groups utilizing log-rank testing. A 3:1 nearest-neighbor propensity-score matching was performed utilizing clinical and demographic covariates to reduce the impact of potential confounders of overall survival on the probability of receipt of TRT. Cox proportional hazards regression was used to identify predictors of overall survival. Results: A total of 81,382 patients were identified that met inclusion criteria. The median age was 68 (18-90) years. The majority of patients (n = 51,681, 64%) had chemotherapy, while 7,929 (10%) patients received immunotherapy, and 15,984 (20%) received TRT. The median follow-up was 6.18 (range 0-76.9) months. For the entire cohort of patients receiving immunotherapy, 2 year OS was 29.4% with TRT compared to 32.7% without. Following propensity matching by age, sex, race, and comorbidity score, a total number of 4,264 patients receiving immunotherapy were matched. The 2 year OS was 27.7% in patients receiving TRT and immunotherapy vs. 22.2% in patients with immunotherapy alone (p = 0.004). On multivariable analysis receipt of TRT was a significant predictor of OS after adjustment for age, race, comorbidity score, sex, and median income (p = 0.0003, HR 0.87, 95% CI 0.80 - 0.94). For patients receiving BED10 > 39 Gy (equivalent to 30 Gy in 10 fractions), 2 year OS was significantly improved at 37.0% vs 18.1% (p < 0.0001). Conclusions: In patients with mNSCLC, the addition of TRT to immunotherapy is associated with improved overall survival at 2 years. Receipt of a higher BED10 is associated with further improved survival. Selection of mNSCLC patients receiving immunotherapy for TRT approaching definitive doses warrants further investigation. Data from prospective, randomized trials may better elucidate this benefit and identify a potential mechanism.
TMB and BRAF mutation status are independent predictive factors in stage IIIC/D/IV melanoma patients receiving adjuvant PD-1 antibodies.
Authors: Forschner Andrea , Eckardt Julia , Martus Peter , Armeanu-Ebinger Sorin , Ossowski Stephan , Bonzheim Irina , Eigentler Thomas , Amaral Teresa Maria Santos , Flatz Lukas , Garbe Claus , Schroeder Christopher 
Published: June 2021

9524 Background: High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant PD-1 antibodies. Methods: We systematically evaluated all melanoma patients who started adjuvant PD-1 antibody therapy at our center between March 2018 and September 2019 to identify predictive factors for outcome. The median follow-up time from start of adjuvant anti-PD-1 therapy was 22 months. Tumor and normal tissue of all stage IIIC/D/IV patients and of stage IIIA/B patients with relapse were sequenced using a 700 genes panel. Predictive factors for relapse and RFS were identified using univariate and multivariate logistic and Cox regression analysis. RFS was estimated by the Kaplan-Meier method. TMB high was defined as the top 20 % of the cohort, corresponding to TMB values ≥ 20 Var/Mb. Results: A total of 165 patients were included in this study. According to AJCC 8th the initial tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48 %), N = 85 stage IIIC/D/IV (52 %). 72/165 patients (44 %) suffered a relapse, 44/72 (61 %) with loco regional and 28/72 (39 %) with distant metastases. Sequencing results were available from 79 / 85 patients with stage IIIC/D/IV. Here we present the results of this cohort. TMB low (OR 17.46, 95%CI 4.03-75.55; p < 0.0001) or absence of BRAF V600E/K mutation (OR 4.13, 95%CI 1.36-12.53; p = 0.012) were statistically significant, independent predictive factors for relapse. Also, with regard to RFS, BRAF mutation status and TMB were statistically significant and independent predictive factors. In the table below we display results for the combined variables. Patients with BRAF V600E/K mutation and TMB high had the best outcome. Conclusions: We identified TMB high as positive predictive marker in stage IIIC/D/IVmelanoma patients with adjuvant PD-1 antibody therapy. In tumors with BRAF V600E/K mutation and concurrent low TMB, adjuvant targeted therapy with BRAF- and MEK-inhibitors may be an alternative. This is also supported by the data on adjuvant dabrafenib and trametinib, which showed a greater advantage in patients with low TMB, presumably due to less tumor heterogeneity.[Table: see text]
Patterns and management of progression on first-line ipilimumab combined with anti-PD-1 (IPI+PD1) in metastatic melanoma (MM) patients.
Authors: Pires Da Silva Ines , Versluis Judith M. , Ahmed Tasnia , Johnson Douglas Buckner , Soon Jennifer , Allayous Clara , Gerard Camille Lea , Mangana Joanna , Klein Oliver , Zimmer Lisa , Robert Caroline , Vitale Maria Grazia , Yeoh Hui-Ling , Michielin Olivier , Lebbe Celeste , Sandhu Shahneen Kaur , Blank Christian U. , Carlino Matteo S. , Menzies Alexander M. , Long Georgina V. 
Published: June 2021

9533 Background: First line IPI+PD1 induces long-term response in 36% of MM patients (pts); however, the majority of pts will progress and may require further treatment, which is yet to be established. We studied the patterns of progressive disease (PD) on 1st line IPI+PD1, and the management and outcomes in MM pts. Methods: Demographics, disease characteristics, nature of PD, subsequent treatments and outcomes were examined in MM pts with PD on 1st line IPI+PD1. Multivariable analyses (MVA) identified factors associated with patterns of PD: innate resistance (IR) = PD as best response or stable disease (SD) < 6 mo; acquired resistance (AR) = PD after initial response or SD ≥ 6 mo. Results: 310 MM pts from 14 melanoma centres were included; 208 (67%) had PD during and 102 (33%) after ceasing IPI+PD1. Overall med. progression-free survival (mPFS) was 2.8 mo (CI 95% 2.7 – 3.0); 187 pts (60%) had IR (mPFS 2.2 [2.1 – 2.5]), 112 pts (36%) had AR (mPFS 8.5 [7.2 – 10.2]) and 11 pts (4%) had pseudoprogression, i.e. PD followed by response without changing treatment (mPFS 2.7 mo [1.4 – NA]). On MVA, pts with ECOG PS ≥ 1 were more likely to have IR vs AR; and within IR pts, those with head & neck primary melanomas and lung metastases were more likely to have PD < 1.5 mo. Most pts with IR (68%) had PD in multiple sites, while 61% AR pts had PD in a single site. Brain was most common site of single organ PD; 49% of IR and 41% of AR. Med. follow-up from PD was 32.7 mo (28.1 – 36.8). After PD, 61 pts (20%) had best supportive care (26% of IR and 11% of AR pts). 259 pts (80%) received further treatment: 39% IR pts had systemic treatment (ST) only and 27% had ST + local; 31% AR pts had ST only and 39% had ST + local. Of 200 pts (65%) who had ST(+/-local), 54% had 1 line of ST and 46% had ≥ 2; 1st line ST (ST1) was BRAF/MEKi in 36% of pts, PD1 in 32%, IPI+PD1 in 7%, investigational drugs in 11%, chemotherapy in 9% and others in 5%. ORR in IR pts was lower than in AR pts for every type of ST1 (see Table). Med. OS from PD was 11.4 mo (CI 95% 9.6 – 16.1); IR 6.4 mo (CI 95% 5.6 – 10.2) and AR 26.1 mo (CI 95% 17.1 – NA). Conclusions: These data suggest longer OS from PD for AR vs IR pts independent of ST type. BRAF/MEKi, rechallenge with PD1+/-IPI and investigational drugs showed activity after PD on IPI+PD1, while chemotherapy has no role in this context.[Table: see text]