bluuebunny/crossref_metadata_2025 huggingface dataset:
TP53/NPM1-mutated acute myeloid leukemia as a molecularly distinct disease entity.
Authors: Scarpa Frank J , Paul Madhuri , Daringer Rachel , Wolfson Wendy A. , Lopez Diaz Fernando , Agersborg Sally , Funari Vincent Anthony , Weiss Lawrence Martin , Blocker Forrest
Published: June 2021

7030

Background: TP53-mutated acute myeloid leukemia (AML) is a distinct disease entity associated with a dismal prognosis. This disease group is distinguishable by its low frequency of SNVs, unremarkable transcriptional signatures, and lower leukocyte and myeloblast counts compared to TP53 wildtype disease. Response to gold-standard hypomethylating agents is typically transient. NPM1 mutations in this disease subset are rare despite the fact that NPM1c has been shown to negatively regulate the tumor suppressive functions of p53 .Methods: Bone marrow, peripheral blood, or FFPE tissue samples from 10,118 patients with suspected myeloid disease were sequenced using a dual DNA/RNA 297 gene myeloid panel. Results were validated in a separate independent dataset using a 54 gene TruSight myeloid panel (N = 2463). FISH/cytogenetic data was analyzed across myeloid disease. Patients with confirmed AML (n = 460) were included in the NGS portion of this study. Statistics were performed using Fisher’s exact test for categorical variables and two-tailed T-test for continuous variables. Results: All TP53-mutated myeloid disease (n = 1282 / 10,118) was associated with fewer co-mutations except DNMT3A (13.4%; n = 172), and complex cytogenetics (36.4%; n = 134/381). TP53+/NPM1+ status across all myeloid disease was not associated with a complex karyotype (7.6% vs 38.5%; 1/13 vs. 133/368, p = 0.02). Among AML patients, NPM1+/TP53+ patients (n = 18) were more co-mutated with DNMT3A (33.3% vs. 10.3%, P = 0.01), FLT3 (33.33% vs. 2.5%, P < 0.0001), IDH1 (27.8% vs. 4.4%, P = 0.002), IDH2 (22.2% vs. 6.4%, P = 0.03); and PTPN11 (22.2% vs. 2.5%, P = 0.003) when compared to TP53+/NPM1- patients. NPM1+/TP53+ AML had more mutations in recurrently mutated genes (4.5 vs 2.1; P < 0.0001) than TP53+/NPM1- AML. Conclusions: TP53+/NPM1+ AML harbors molecular signatures which clearly distinguish it from ordinary TP53-mutated AML, and is more reflective of de novo and NPM1+ AML. Further clinical outcome studies are needed to determine the therapeutic and prognostic implications of this subset, and whether other TP53-mutated patients can be better risk stratified.[Table: see text]
Phenotypes and prognostic factors in adults with Langerhans cell histiocytosis.
Authors: Goyal Gaurav , Acosta-Medina Aldo A. , Hu Marie , Abeykoon Jithma P. , Ravindran Aishwarya , Bennani N. Nora , Davidge-Pitts Caroline , Shah Mithun Vinod , Tobin W. Oliver , Young Jason R. , Ryu Jay H. , Vassallo Robert , Rech Karen , Go Ronald S. ,   Mayo Clinic-University of Alabama at Birmingham Histiocytosis Working Group
Published: June 2021

7049

Background: Langerhans cell histiocytosis (LCH) can manifest as single system (SS) disease, multisystem (MS) disease, or pulmonary LCH (smoking-related). There is a paucity of data on prognostic factors including risk organ (RO) involvement (liver, spleen, and bone marrow) in adult LCH, which we sought to address in this study. Methods: Single-center retrospective study of patients ≥18y diagnosed with LCH from 1998 to 2020. Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were conducted using age, sex, organ involvement, LCH subtype, year of diagnosis, BRAF V600E status, and treatments. Results: We included 219 patients with LCH; median age 43y (range 19-88), females 51%, SS unifocal (23%), SS multifocal (6%), pulmonary (31%) and MS (40%). Commonly involved organs included lung (53%), bone (42%), skin (24%), pituitary (16%), and CNS (12%). BRAF V600E was positive in 40/88 (46%). Median follow-up duration was 6.1y (95% CI, 5.1- 7.1). On univariate analysis, factors associated with worse PFS were bone LCH, RO involvement, multifocal/MS LCH, and radiation therapy alone; those with worse OS included RO involvement, MS disease, BRAF V600E+, and age ≥45y at diagnosis. In multivariate analysis, BRAF V600E and age ≥45y at diagnosis were associated with worse mortality (Table). Median PFS was not reached (NR-NR) for SS unifocal LCH, 5mo (0-12.7) for SS multifocal LCH, 110mo (84.7-135.3) for pulmonary LCH, and 27mo (17.2-36.8) for MS LCH. 5-year OS was 97.4% for SS unifocal LCH, 100% for SS multifocal LCH, 96.1% for pulmonary LCH, and 79.9% for MS LCH. 41 (18.7%) developed a second primary malignancy (SPM), of which 11 were hematologic neoplasms. There was a trend towards a higher prevalence of SPMs in patients with BRAF V600E (28% vs. 17%; p = 0.22). Conclusions: In our large single-center study, PFS for multifocal and MS LCH was worse than SS unifocal or pulmonary LCH. RO involvement was not associated with outcomes in multivariate analysis. Overall prognosis was excellent for all subtypes except MS LCH. BRAF V600E and older age were associated with worse OS. The prevalence of SPMs was very high and needs to be explored further.[Table: see text]
BRAFV600E frequency and impact on outcomes in adults with langerhans cell histiocytosis.
Authors: Acosta-Medina Aldo A. , Abeykoon Jithma P. , Bennani N. Nora , Davidge-Pitts Caroline , Koster Matthew J. , Ravindran Aishwarya , Rech Karen , Ryu Jay H. , Schram Susan M. , Shah Mithun Vinod , Tobin W. Oliver , Vassallo Robert , Young Jason R. , Go Ronald S. , Goyal Gaurav ,   Mayo Clinic - University of Alabama at Birmingham Histiocytosis Working Group
Published: June 2021

7050

Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAFV600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAFV600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAFV600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAFV600E. Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAFV600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAFV600E mutation. Increasing age was associated with BRAFV600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAFV600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAFV600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAFV600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAFV600E and non- BRAFV600E patients ( p= 0.167). However, patients with BRAFV600E had a worse 3-year OS compared with non- BRAFV600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAFV600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAFV600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAFV600E and high-risk or multisystem disease.[Table: see text]
Preliminary safety and efficacy of PBCAR0191, an allogeneic, off-the-shelf CD19-targeting CAR-T product, in relapsed/refractory (r/r) CD19+ NHL.
Authors: Shah Bijal D. , Jacobson Caron A. , Solomon Scott , Jain Nitin , Vainorius Monika , Heery Christopher Ryan , He Fiona C. , Reshef Ran , Herrera Alex Francisco , Akard Luke Paul , Sauter Craig Steven
Published: June 2021

7516

Background: Although autologous CD19-directed CAR T products have demonstrated unprecedented efficacy in chemorefractory patients, manufacturing failure or delays remain important barriers to care, limiting utility for those with more rapidly growing disease and/or impaired T cell fitness. Here, we present an update to preliminary safety, efficacy, and correlative data for the subjects dosed with at least 3 x 106 CAR-T+ cells/kg, or equivalent, of PBCAR0191, an off-the-shelf allogeneic CAR T product. Methods: Subjects were required to have evaluable CD19+ r/r NHL, adequate organ function, 2+ prior treatment regimens, and no active GvHD, CNS disease, infections or active medical issues. Prior stem cell transplant and/or CAR-T therapy were allowed. All subjects were lymphodepleted prior to administration of PBCAR0191with either standard (sLD; 30/500mg/m2/day x 3 days fludarbine/cyclophosphamide) or enhanced (eLD; 30 x 4 days and 1000mg/m2/day x 3 days flu/cy) lymphodepletion. Correlative laboratory samples were taken at baseline and while patients remained on study for CAR T cell expansion, persistence, response to treatment and safety assessments. Results: As of February 2021, 13 subjects were evaluable meeting these criteria. Demographics, baseline disease characteristics, and prior therapy data are presented in the table. Median time from eligibility confirmation to PBCAR0191 infusion was 6.5 days (1 day to start LD). To date, most adverse events (AE) reported were mild, with no cases of GvHD or Grade ≥3 CRS/ ICANS. PBCAR0191 related serious AEs were reported for 31% (4/13) of the subjects and 1 subject (9%) died of Febrile neutropenia on day 42 after treatment. Infections and cytokine release related AEs occurred at higher frequency in the eLD group. Efficacy of PBCAR0191 in 13 NHL subjects with available 28 day follow up is presented in the table. Peak PBCAR0191 expansion was increased 56-fold and was associated with CR rate of 71% in eLD group versus 33% in sLD group. Duration of response assessment is ongoing. Conclusions: PBCAR0191 has demonstrated dose and LD-dependent cell expansion kinetics with encouraging anti-tumor activity. Host-versus-graft rejection may have a role in depth and durability of response. CR rates with PBCAR0191 are preliminarily comparable to those observed with autologous CAR T in this population. Updated response durability assessment will be presented at the time of the meeting. Clinical trial information: NCT03666000. [Table: see text]
Survival trends in chronic lymphocytic leukemia in the era of oral targeted therapies in the United States: SEER database analyses (1985 to 2017).
Authors: Alrawashdh Neda , McBride Ali , Persky Daniel O. , Sweasy Joann , Erstad Brian , Abraham Ivo
Published: June 2021

7524

Background: The survival of chronic lymphocytic leukemia (CLL) patients has progressively improved after the approval of new targeted therapy for first-line treatment and relapsed disease. We performed a corresponding analysis from the U.S. population-based SEER database (1973–2017) to explore the trend of survival and the effect of advanced CLL treatment on overall survival in CLL patients. Methods: Data were extracted from SEER*Stat for all patients 15 years or older with a primary diagnosis of CLL with or without subsequent cancers. A period analysis was performed to estimate the 5- and 10-year relative survival rates for patients diagnosed (dx) during different calendar periods from 1985 to 2017, based on gender and age at time of diagnosis (15–44, 45–54, 55–64, 65–74, 75–84, 85 years or older). A mixture cure model was used to examine the proportion of long-term survivors per gender and age category among CLL patients diagnosed between 1985 and 2015. Cox proportional hazard modeling was used to calculate the hazard ratios (HRs) of death adjusted for gender and age at diagnosis for two cohorts: (a) diagnosed in 2000–2003 and followed to 2012; (b) 2004–2007 and followed to 2015. Results: For males, the 5-year age-adjusted relative survival rate improved progressively from 72.0% (dx 1985-1989) to 88.2% (dx 2010-2014); for females, from 76.8% (dx 1985-1989) to 90.8% (dx 2010-2014). The corresponding 10-year age-adjusted relative survival rates were 47.3% (dx 1985-1989) and 72.5% (dx 2005-2009) for males; and 58.2% (dx 1985-1989) and 78.7% (dx 2005-2009) for females. The table below shows the proportions of long-term survivors for the 1985–2017 cohort as estimated in the mixed cure model. The HRs (95%CI) of death for cohort (b) in comparison to cohort (a) were 0.58 (0.43–0.78), 0.58 (0.48–0.70), 0.57 (0.49–0.67), 0.68 (0.54–0.85); and 0.83 (0.68–1.02) for age categories of 45–54, 55–64, 65–74, 75–84, and 85 years or old. Conclusions: Survival is significantly improved by calendar period among patients diagnosed after 2004 and treated in the era of advanced therapies. Females and younger patients had a higher probability of long term survival. Future studies should consider such covariates as treatment type, disease stage and genetics.[Table: see text]
Herpes zoster in chronic lymphocytic leukemia: Effect of vaccination and treatment.
Authors: Antao Nirav , Chilkulwar Abhishek R. , Luo Suhong , Carson Kenneth Robert , Sanfilippo Kristen Marie , Schoen Martin W.
Published: June 2021

7527

Background: Patients with Chronic Lymphocytic Leukemia (CLL) are susceptible to infections due to impaired humoral immunity as a complication of the disease, treatments received and age at diagnosis. Herpes zoster (HZ) is a painful, vesicular rash from reactivation of varicella-zoster virus that is common in immunocompromised patients. While HZ vaccines can reduce both varicella-zoster reactivation and post-herpetic neuralgia, vaccination rates are low. The aim of this study is to determine the effect of vaccination on rates of HZ infection in patients with CLL. Methods: We identified patients diagnosed with CLL between September 1999 and October 2015 using Veterans Administration Central Cancer Registry (VACCR). Pharmacy records were used to identify patients who received treatment for CLL and HZ. HZ events were defined as patients with International Classification of Diseases 9th Revision (ICD-9) codes for HZ infection (053) or prescriptions of acyclovir or valacyclovir at a dose of 1500 mg/day or higher or famciclovir at a dose of 1000 mg/day or higher without a diagnosis of Herpes simplex or Bell’s palsy, or an ICD-9 code and prescription above. Cox proportional hazards regression model was used to assess the association between vaccination as a time-varying exposure and developing HZ while controlling age at CLL diagnosis, co-morbidity score, and receipt of first and second line chemotherapy. The study was approved by the St. Louis VA Medical Center institutional review board. Results: A cohort of 7155 patients with CLL was identified using VACCR. 2640 patients (36.9%) and 1161 patients (16.2%) received first and second line chemotherapy respectively. Mean age at first chemotherapy was 69.5 years. We detected 1115 cases of HZ (15.6%) using ICD-9 codes, prescriptions or both. 615 patients (8.6%) received HZ vaccinations. Patients with HZ were younger (mean 68.0 vs. 69.8 years, p < 0.001), had similar co-morbidities, and were more likely to get treatment for CLL (58.1% vs. 33.0%, p < 0.001). Using a time-varying analysis, there was a trend for HZ vaccine to decrease the risk of developing HZ (HR 0.71, 95% CI 0.49-1.04, p = 0.082). When adjusting for age and co-morbidity, patients with CLL treated with first line chemotherapy had a higher risk of HZ (HR 2.34, 95% CI 2.02-2.71, p < 0.001) compared to those never receiving therapy. Second line chemotherapy increased risk of HZ (HR 1.32, 95% CI 1.13-1.55, p < 0.001) beyond first line treatment. Conclusions: HZ is prevalent in patients with CLL and affects younger patients who require chemotherapy. The risk of developing HZ increases in recipients of first and second line chemotherapy. In the time-varying analysis, there was a trend towards decreased infection in patients who received HZ vaccination. Further studies in a more modern cohort that assess infection risk using a larger vaccinated group with the newer and more effective HZ vaccine are warranted.
NVG-111, a novel ROR1xCD3 bispecific antibody for non-Hodgkin lymphoma.
Authors: Granger David , Gohil Satyen , Barbarulo Alessandro , Baccaro Annalisa , Muczynski Vincent , Chester Kerry , Germaschewski Fiona , Batten Toby , Brown Kathryn , Cook Sarah , O'Donovan Kieran , Jasani Parag , Nathwani Amit C. , Phillips Peter
Published: June 2021

7549

Background: Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a type I transmembrane protein is highly expressed on an array of haematological and solid tumours. NVG-111 is a humanised, tandem scFv ROR1xCD3 bispecific antibody previously shown to elicit potent killing of tumour cells in vitro and in vivo by engaging a membrane-proximal epitope in the Wnt5a-binding Frizzled domain of ROR1 and redirecting T cell activity. The in vitro potency and pharmacodynamic responses to NVG-111 were assessed to support progression to a first-in-human study. Methods: The potency of NVG-111 in vitro was determined by evaluating the concentration response for cytotoxicity, T cell activation, and cytokine release in co-cultured Jeko-1 and unstimulated human T cells. Comparative data were generated for the marketed CD19xCD3 bispecific antibody, blinatumomab. Potency data for NVG-111 were used together with allometric scaling from murine PK studies to inform planned clinical doses. Results: NVG-111 demonstrated T cell-dependent cytotoxicity, T cell activation and levels of cytokine release similar in potency to blinatumomab. Cytotoxic responses of both NVG-111 and blinatumomab were more potent than T cell activation and cytokine release. Dose response curves for NVG-111 showed a decrease in activity beyond the concentration of maximal response (ie “hook effect”). We hypothesise this is due to receptor saturation, inhibiting synapse formation. NVG-111 has progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), the drug given as add-on to ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax. Phase 1 includes escalating doses of 0.3 to 360 µg/day via continuous infusion over 3 cycles (each 21 days on, 7 days off) to establish safety, PK, pharmacodynamics (PD) and recommended phase 2 dose (RP2D). Predicted exposure at 0.3 µg/day is ̃EC20 for cytotoxicity in vitro and below the lowest EC10 for cytokine release. PD biomarkers in the study include systemic cytokines. Phase 2 will study efficacy and safety of the RP2D in CLL and MCL, with primary endpoint complete response rate; other efficacy endpoints include minimal residual disease and progression free survival. Conclusions: NVG-111 shows potent T-cell mediated lymphoma cell cytotoxicity in vitro at concentrations well below those associated with extensive cytokine release. NVG-111 is in an ongoing Phase 1/2 study and may present a novel option for adoptive immunotherapy in patients with non-Hodgkin lymphoma and potentially other cancers. Clinical trial information: 2020-000820-20. [Table: see text]
IL-1 receptor antagonist for prevention of severe immune effector cell-associated neurotoxicity syndrome.
Authors: Oliai Caspian , Crosetti Anna , De Vos Sven , Eradat Herbert , Mead Monica Diane , Larson Sarah Marie , Tsai Steven , Liu Annabel , Khachatrian Gina , Hannigan Christopher , Yamada Reiko E. , Rokni Neiki , Timmerman John
Published: June 2021

7566

Background: Progress in chimeric antigen receptor (CAR) T-cell therapy has included reduction in life-threatening toxicity. Rates of severe cytokine release syndrome (CRS) have declined from 50% in early trials to 7% in the most recent real-world experience. However, rates of severe immune effector cell-associated neurotoxicity (ICANS) associated with axicabtagene ciloleucel (Axicel) remain unchanged. IL-1 is a major driver of ICANS pathophysiology that is produced upstream of IL-6. The IL-1 receptor antagonist, Anakinra, can prevent neurotoxicity in animal models when given at fever onset. We present our early experience of the first 13 participants enrolled into a phase II trial evaluating Anakinra to prevent severe ICANS (NCT4205838). Methods: This investigator-sponsored trial included adults eligible for standard-of-care Axicel for large B-cell lymphoma after ≥2 lines of intensive chemoimmunotherapy. Participants received Anakinra 100 mg SQ q6h x 12-36 doses until ICANS returned to grade ≤1. The trigger to initiate Anakinra was any grade ICANS or grade ≥3 CRS in the absence of ICANS. A protocol modification, made after the first 3 participants were treated, changed the trigger for Anakinra to grade ≥2 CRS. In addition to Anakinra, all participants received standard-of-care interventions for CRS and ICANS. The primary objective is to estimate the efficacy of Anakinra in preventing severe ICANS (grade ≥3) according to ASTCT 2018 consensus grading. Results: To date, 13 participants have been enrolled, and 7 met criteria to initiate Anakinra and received the first dose prior to severe ICANS. Median age was 56 years (range, 23-84 years). Of the 7 participants whom received Anakinra prior to severe ICANS, only 1 of 7 (14%) developed grade 3 ICANS. The most common adverse event was injection site reaction, which peaked at grade 2. There were no unexpected toxicities. Once the protocol was amended to initiate Anakinra for grade ≥2 CRS (N = 4), no participant developed severe ICANS, and only one participant met the institutional standard to receive corticosteroids (Table). Conclusions: Anakinra is feasible to initiate in the non-prophylactic setting in patients at increased risk for severe ICANS. These early results demonstrate potential to reduce severe ICANS associated with Axicel to a rate similar to other CAR T-cell products, and to reduce corticosteroid use. Further enrollment to the pre-planned sample size of N=36 is required to demonstrate statistical efficacy. Serum IL-1 analysis is also ongoing. Clinical trial information: NCT4205838. [Table: see text]
Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial.
Authors: Tada Hirohito , Mitsudomi Tetsuya , Yamanaka Takeharu , Sugio Kenji , Tsuboi Masahiro , Okamoto Isamu , Iwamoto Yasuo , Sakakura Noriaki , Sugawara Shunichi , Atagi Shinji , Takahashi Toshiaki , Hayashi Hidetoshi , Okada Morihito , Yoshioka Hiroshige , Inokawa Hidetoshi , Takahashi Kazuhisa , Higashiyama Masahiko , Yoshino Ichiro , Nakagawa Kazuhiko ,   West Japan Oncology Group
Published: June 2021

8501

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor is a standard of care for EGFR mutation-positive, untreated metastatic non-small cell lung cancer (NSCLC). However, the efficacy and safety of adjuvant gefitinib for patients with completely resected lung cancer harboring EGFR mutation over cisplatin-based adjuvant chemotherapy were not known in 2011 when this study was initiated. Methods: From September 2011 to December 2015, we randomly assigned 234 patients with completely resected, EGFR mutation-positive (exon 19 deletion or L858R), stage II–III NSCLC to receive either gefitinib (250 mg, once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) (cis/vin) every 3 weeks for four cycles. The primary endpoint was disease-free survival (DFS) according to a central review in the intent-to-treat (ITT) population. Results: Two patients in the gefitinib arm withdrew consent and were excluded from the ITT population. No treatment-related deaths were seen in the gefitinib arm, but three treatment-related deaths were reported in the cis/vin arm. Median duration of follow-up was 71 months. Median DFS was numerically longer in the gefitinib arm (36 months) than in the cis/vin arm (25.2 months). However, Kaplan-Meier curves began to overlap around 5 years after surgery, and no significant difference in DFS was seen, with a hazard ratio (HR) of 0.92 (95% confidence interval (CI), 0.67–1.28; P = 0.63). Overall survival was also not significantly different (median not reached in either arm). Five-year survival rates for gefitinib and cis/vin arms were 78.0% and 74.6%, respectively, with an HR for death of 1.03; 95%CI, 0.65–1.65; P = 0.89. Exploratory subset analysis revealed that patients ³70 years old in the gefitinib arm (n = 19/27 with G to cis/vin) survived longer than those in the cis/vin arm (HR 0.31; 95%CI, 0.10–0.98; P = 0.046). Conclusions: Adjuvant gefitinib appeared to prevent early relapse, but did not significantly prolong DFS or OS in patients with completely resected stage II–III, EGFR-mutated NSCLC. The apparent non-inferiority of DFS/OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for cis/vin adjuvant therapy. Clinical trial information: UMIN000006252.
Early detection of lung cancer using cfDNA fragmentation.
Authors: Mathios Dimitrios , Johansen Jakob Sidenius , Cristiano Stephen , Medina Jamie , Phallen Jillian , Richter Larsen Klaus , Bruhm Daniel , Niknafs Noushin , Nielsen Hans J. , Meijer Gerrit A. , Andersen Claus Lindbjerg , Bojesen Stig Egil , Scharpf Robert , Velculescu Victor E.
Published: June 2021

8519

Background: Lung cancer incidence and mortality are increasing worldwide despite more effective treatments. This is primarily due to the late stage of diagnosis when treatments are less effective. Although large randomized trials have demonstrated a significant decrease in lung cancer mortality through screening of high-risk individuals with chest low dose computed tomography (LDCT), LDCT has made little impact in the community, mainly due to lack of accessibility. There is therefore an unmet clinical need for development of cost-effective and easily implemented tests for early lung cancer detection. Methods: We have previously shown that altered genome-wide fragmentation of cell free DNA (cfDNA) is a common characteristic of many cancers. In this study, we leverage this knowledge to increase the sensitivity of lung cancer detection by interrogating characteristics of the size distribution of cfDNA fragments across the genome using machine learning methods. The approach we present, called DELFI (DNA evaluation of fragments for early interception) generates a score that reflects the presence of tumor-derived DNA in plasma based on a multi-feature genomic analysis that assesses millions of cfDNA fragments for tumor-derived genomic and epigenomic changes in a small amount of blood (2-4 mls) via inexpensive low coverage (1-2x) whole genome sequencing. We applied this methodology in a prospectively collected cohort of 365 individuals under investigation for lung cancer and we prospectively validated it in a separate case-control cohort of patients with newly diagnosed early stage lung cancer as well as individuals without cancer (n=427). Results: These analyses revealed high performance for detection of early and late stage disease (Table). When DELFI was used as a prescreen for LDCT it increased specificity from 58% with CT imaging alone to 80% using the combined approach. The DELFI score was significantly associated with T and N stage in lung cancer cases (p<0.0001) as well as with overall survival (p=0.003). In a multivariable analysis including age, histology and stage, DELFI score was an independent prognostic factor of overall survival (HR=2.53; p=0.0003). Finally, we determined that genome-wide fragmentation profiles can be used to distinguish small cell lung cancer from non-small cell lung cancer with high accuracy (AUC 0.98). Conclusions: These findings provide key insights into cfDNA fragmentation in patients with cancer and a new and easily accessible avenue for non-invasive diagnosis and molecular profiling of lung cancer.[Table: see text]
Minimal residual disease (MRD) in patients with resected stage I NSCLC: Results of the prospective adjuvant IFCT-0703 trial.
Authors: Vasseur Damien , Jovelet Cécile , Cozic Nathalie , Mazieres Julien , Barlesi Fabrice , Bennouna Jaafar , Gervais Radj , Moreau Lionel , Berard Henri , Molinier Olivier , Moro-Sibilot Denis , Souquet Pierre Jean , Amour Elodie , Morin Franck , Zalcman Gerard , Soria Jean-Charles , Westeel Virginie , Lacroix Ludovic , Besse Benjamin
Published: June 2021

8526

Background: MRD aims to detect circulating biomarkers of micrometastatic disease and ultimately predict recurrences. The IFCT-0703 randomized phase II trial failed to show a benefit of 6 months adjuvant pazopanib (P) vs. placebo after resection of stage I NSCLC (7th TNM edition). The outcome of pts based on their MRD status has been evaluated. Methods: Blood samples were collected in EDTA tubes (Becton Dickinson Company) after surgery (T0), after 3 months (T3) of P or placebo and at the end of treatment (T6). Plasmas were obtained after double centrifugation of total blood. Total nucleic acid was extracted using the Maxwell RSC LV plasma kit (Promega) according to the manufacturer’s protocol. Samples were quantified using the QuBit dsDNA HS Assay kit on a QuBit 3.0 flurometer (Thermo Fisher Scientific). Molecular analysis was performed by next generation sequencing using the Oncomine Lung cfDNA Assay (ThermoFisher Scientific). Two MRD definitions were tested : 1) high level of DNA in the blood or 2) any mutation detected by the standard bioinformatic pipeline was considered present, whatever the allelic fraction. Results: 143 pts were randomized in 29 centers between March 2009 and August 2012, 71 and 72 in the placebo and P arms respectively. Among the 119 pts with evaluable T0 samples, 27 pts recurred and 14 died. Median DNA concentration ([DNA]) was 6.6 ng/ml and an increase of [DNA] of 10 ng/ml was found prognostic of poor DFS and OS, HR=1.4, 95%CI [1.14-1.72], p=0.0016 and HR=1.62, 95%CI [1.15-2.30], p=0.0057 respectively. In 81 pts with available T0-T6 samples, [DNA] variation had no different impact on DFS and OS, in the P arm and the placebo arm. ctDNA mutations (ctDNA+) were detected in 31/119 pts. ctDNA+ were more frequent in samples with high DNA quantity (p=0.0002). Genes mutated at T0 were TP53 in 16, NRAS in 6, MAP2K1 in 2, KRAS in 1, EGFR in 5, BRAF in 1, ALK in 2. 29 pts had 1 mutation, 2 had 2 mutations. DFS and OS were similar between pts with or without ctDNA+ : HR= 1.038 (95%CI 0.438-2.456, p=0.93) and 1.193 (95% CI 0.367-3.882, p=0.77) respectively. Among 27 pts with ctDNA+ at T0 and available sample at T6, 23 had no more mutations at T6. Two pts had a ctDNA+ only at T6 (not at T3), one of them had a recurrence at 7 months. Conclusions: Post-operative ctDNA mutations are found in 26.0% of the pts but their positivity had no impact on DFS or OS. In contrast, DFS and OS were poorer in pts with increased plasma DNA concentration. ctDNA mutations status do not recapitulate the complexity of MRD characterization. NGS will be performed on matched tissues in order to refine MRD definition. Clinical trial information: NCT00775307.
Prognostic value of SUVmax on FDG-PET/CT before and after stereotactic body radiotherapy (SBRT) on recurrence and survival in early-stage non-small cell lung cancer (NSCLC).
Authors: Deshpande Saarang , Podder Tarun Kanti , Zhang Yuxia , Zheng Yiran , Grubb William , Kharouta Michael , Linden Philip Aaron , Biswas Tithi
Published: June 2021

8539

Background: Stereotactic body radiotherapy (SBRT) is the standard of care in medically inoperable early-stage non-small cell lung cancer (NSCLC). Assessment of FDG-PET/CT before and after SBRT may stratify risk of disease recurrence and survival outcomes. Methods: Patients with T1-2N0M0 NSCLC who underwent PET/CT prior to SBRT (50-60 Gy over 3-5 fractions) between 2012 and 2019 were retrospectively identified. Pre-SBRT SUVmax and change in SUVmax at 3 and 6 months after SBRT were assessed as predictors of local control (LC), progression-free survival (PFS), and overall survival (OS). Optimal cutoff points for comparison were determined by receiver operator characteristic (ROC) analysis. Survival analyses were performed with Kaplan-Meier estimates with log rank testing, and Cox proportional hazards models including age, sex, T stage, histology, and performance status. Results: Out of 163 patients identified, 71 (43.6%) underwent repeat PET/CT within 6 months of SBRT completion. Median follow-up was 19 months (range 1 – 94 months). For the whole cohort, 1-year and 2-year LC, PFS, and OS were 95.0% and 80.3%, 75.9% and 47.7%, and 87.1% and 67.0%, respectively. Pre-SBRT SUVmax greater than 12.3 had an aHR of 2.80 (95% CI 1.3 – 6.2, p = 0.011) for PFS. A cutpoint of 12.6 for pre-SBRT SUVmax had an aHR of 3.00 (95% CI 1.6 – 5.8, p = 0.003) for OS. Pre-SBRT SUVmax did not significantly predict LC. A 3-month SUVmax decrease of at least 45% was associated with improved LC (aHR = 0.15, 95% CI 0.02 – 0.91, p = 0.018). At 6 months following SBRT, a cutoff point of a 53% decrease in SUVmax was associated with better LC (p = 0.038). Change in SUVmax was not significantly associated with PFS or OS at either time point. Performance status significantly predicted PFS and OS in all models. No other factors were significant. Conclusions: Pre-treatment SUVmax cutoffs can predict PFS and OS in early-stage NSCLC. At both the 3- and 6-month time points following SBRT, cutoff values for change in SUVmax can stratify risk of local recurrence.[Table: see text]
Multiomics analysis reveals high-immune infiltration in tumor-adjacent lung tissues affects the prognosis of stage I NSCLC.
Authors: Ying Lisa , Su Dan , Chunliu Zhang , Tian Yiping , Bai Jing , Wang Canming , Fang Jianfei , Futreal Andrew , Zhang Jianjun
Published: June 2021

8540

Background: Along with the wide application of low-dose spiral CT in lung cancer screening, a large number of resectable patients with lung cancer are identified, especially stage I Non-Small Cell Lung Cancer (NSCLC). However, their prognosis varies greatly and 5-year recurrence rate of stage I NSCLC is around 30%. Therefore, it is crucial to explore the potential mechanism of recurrence of early NSCLC. Methods: Eighty-seven patients with stage I NSCLC were enrolled from April 2008 to July 2015, including 79 squamous carcinoma and 28 adenocarcinoma. Frozen tumor tissues and paired tumor-adjacent lung tissues were collected to employ targeted panel sequencing, RNA sequencing and TCR repertoire sequencing. Results: Ninety-five non-silent mutations were detected in tumor-adjacent lung tissues with a median tumor mutation burden of 1.5/Mb, significantly lower than that in tumor tissues (11/Mb), p < 0.05. 42 mutations were specifically detected in the adjacent normal tissues, enriching in the immune response pathways. Comparing with paired tumors, tumor-adjacent lung tissues were found more favorable immune infiltration including higher immune cell activity like CD8+ T cell (0.50 vs 0.43, p < 0.0001), up-regulated immune-associated pathways, higher TCR clonality (0.19 vs 0.18, p < 0.05), less loss of heterozygosity (LOH) of human leukocyte antigen (HLA) (6.25% vs 50%, p < 0.0001) and observed predicted neoantigens expression (1 vs 128, p < 0.01). However, more shared viral-associated TCRs in tumor and tumor-adjacent tissues were found using the GLIPH algorithm. Prognostic analysis showed patients with higher overlap of TCR in tumors and tumor-adjacent lung tissues were prone to recur in five years. Furthermore, patients with higher immune infiltration in tumor-adjacent lung tissues had favorable outcomes than those with lower immune infiltration (HR: 0.37 for DFS, p < 0.05, HR: 0.31 for OS, p < 0.05), irrelevant of the infiltration level in tumor tissues. Conclusions: Immune microenvironment in tumor-adjacent lung tissues plays important roles in progress of stage I NSCLC.
The efficacy of PD-1 antibody sintilimab on ground glass opacity lesions in patients with early-stage multiple primary lung cancer (CCTC-1901, NCT04026841).
Authors: Cheng Bo , Cheng Bo , Li Caichen , Zhao Yi , He Jianxing
Published: June 2021

8545

Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have been proven its significant efficacy on advanced non-small cell lung cancer (NSCLC). However, it remains unknown and is of great interest whether the PD-1 antibody affects early-stage lung cancer. Here, we reported the preliminary efficacy and safety outcomes of sintilimab on these early-stage GGO lesions in patients (pts) with multiple primary lung cancer in the CCTC-1901 study, the first trial evaluating PD-1 antibody in preinvasive or low invasive lung cancer worldwide. Methods: This single-center, phase II, Simon's two-stage design trial included pts who had a pathological diagnosis of resected lung cancer and at least one unresectable GGO lesion suspicious malignant which evaluated by a multidisciplinary team's consensus. The enrolled pts received 4 cycles of intravenous sintilimab 200 mg every 3 weeks. The primary endpoint is the objective response rate (ORR) of unresectable GGO lesions. For persistent GGO lesions that did not respond to treatment, either observation or second operation was taken. Also, immune biomarkers (T/B/NK subpopulation etc.) were monitored during treatment to validate the immune activity. Results: A total of 36 pts were included, with median age 59.5 (53.5-69), 66.7% females, 80.6% never smokers. All resected lesions were adenocarcinomas, of which 52.8% were EGFR mutated. 49 unresected GGOs (pure 11[22.4%], mixed 38[77.6%]) were defined as target lesions from 36 enrolled pts, with a mean size of 13.20±5.06 mm. The ORR (RECIST v1.1) was 5.6% (2/36, 1 PR and 1 CR); none of the pts had PD. Additionally, 3 non-target lesions (unresected solid lesions) from 3 included pts showed PR after the treatment of sintilimab, and the rest lesions (target or non-target) of 31 pts performed SD. Grade 1-2 fatigue (13, 36%), rash (13, 36%) and arthralgia (8, 22%) were the most common treatment-related adverse events (TrAEs), and no grade 3-5 TrAEs occurred. The proportion of CD8+ T-cell and the ratio of CD8+/CD4+ in 5 patients who showed PR of unresected lesions were significantly higher compared to those with SD lesions at baseline (CD8+ 36.6% vs 24.6%, p < 0.01; CD8+/CD4+ 1.09±0.18 vs 0.64±0.22, p < 0.01). Conclusions: This study is the first to confirm that PD-1 antibody sintilimab has immune-related antitumor activity on GGO-featured lung cancer and could be well tolerated among pts with early-stage lung cancer. Clinical trial information: NCT04026841.
NRG-RTOG 1106/ACRIN 6697: A phase IIR trial of standard versus adaptive (mid-treatment PET-based) chemoradiotherapy for stage III NSCLC—Results and comparison to NRG-RTOG 0617 (non-personalized RT dose escalation).
Authors: Kong Feng-Ming Spring , Hu Chen , Ten Haken Randall , Xiao Ying , Matuszak Martha , Hirsh Vera , Pryma Daniel A. , Siegel Barry A. , Gelblum Daphna Y. , Hayman James , Robinson Clifford Grant , Loo Billy W. , Videtic Gregory M.M. , Faria Sergio , Ferguson Catherine , Dunlap Neal E. , Kundapur Vijayananda , Paulus Rebecca , Bradley Jeffrey D. , Machtay Mitchell
Published: June 2021

8548

Background: NRG-RTOG 0617 (R0617) found that non-personalized dose escalation of radiotherapy (RT) with concurrent chemotherapy was deleterious. NRG-RTOG 1106/ACRIN 6697 (R1106) studied adaptive chemoradiotherapy, using tumor and patient individualized RT dose intensification simultaneously with field reduction, based upon mid-treatment FDG-PET. Methods: The control arms of both studies used 60 Gy (+ weekly carboplatin/paclitaxel). The investigational arm of R0617 used 74 Gy in 37 fractions, with no field/dose adaptation, while R1106 used mid-treatment FDG-PET (after ̃40 Gy) to design an individualized dose adaptive RT plan with daily-fraction size 2.2 to 3.8 Gy (up to 80.4 Gy/30 fractions), based upon a model of isotoxic lung risk. Nearly all (93%) patients had IMRT. No patients had consolidation immunotherapy. The primary endpoint for R1106 was local-regional-progression freedom (LRPF) assessed by central review. Other endpoints reported here were survival, toxicity, and institution-defined local/regional control. Results: From 2012-2017, 127 patients were enrolled to R1106 (43 in the standard and 84 in the adaptive arms), with a median follow-up of 3.6 years. The median actual RT dose in the adaptive arm was 71 Gy (Q1-Q3 68-76 Gy). The 2-year LRPF was 59.5% versus 54.6% (p=0.66) for standard versus adaptive RT; the 3-year survival rates were 49.1% versus 47.5% (p=0.80). An exploratory analysis of 2-year in-field local primary tumor control and local-regional tumor control (institution-assessed) were 58.5% and 55.6% for standard RT, and 75.6% and 66.3% for adaptive RT, respectively. As shown in the table, there were no significant differences in cardiac or esophageal adverse events between the two arms; the adaptive RT arm had more Grade 3+ respiratory events (23.8% versus 14.3%). Conclusions: NRG-RTOG1106 did not meet its primary endpoint of demonstrating improved LRPF. Unlike R0617, there was no suggestion of a detrimental effect of adaptive dose-intensified RT on survival and cardiac events. Studies to refine personalized RT, especially in the immunotherapy era, should be considered. Outcome comparison between R0617 and R1106. Clinical trial information: NCT01507428. [Table: see text]
A phase II trial of abemaciclib in patients with p16ink4a negative, relapsed mesothelioma.
Authors: Fennell Dean Anthony , King Amy , Mohammed Seid , Branson Amy , Greystoke Alastair , Moody Sam , Hutka Margaret , Dawson Alan G. , Darlison Liz , Scotland Molly , Bhundia Vina , Bajaj Amrita , Morgan Bruno , Nicholson Adrian , Brookes Cassandra , Gaba Aarti , Wells-Jordan Peter , Richards Catherine Jane , Thomas Anne
Published: June 2021

8558

Background: Genetically stratified therapy for malignant mesothelioma (MM) is lacking. MMs frequently harbour loss of chromosome 9p21.3 locus (CDKN2A) associated with shorter survival. CDKN2A encodes the tumour suppressor p16ink4a, an endogenous suppressor of CDK4 and CDK6. Genetic reconstitution of p16ink4a into CDKN2A suppresses MM in preclinical models, underpinning the rationale for targeting of CDK4/6 in p16ink4a negative MM. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis as arm 2 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST2). Methods: Patients with histologically confirmed MM (pleural or peritoneal) were molecularly screened by immunohistochemistry for p16ink4a, BAP1, BRCA1, and PDL1 (Dako 22C3). Patients with p16ink4a negative MM were eligible. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Abemaciclib (Ab) 200mg bd po daily in q21 day cycles. Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Results: Between November 2019 and March 2020, 26 patients with p16ink4a negative MM received at least one dose of Ab. The median age of pts was 67 (range, 64-74) years, 89% were male, 80.8% epithelioid, 84.6% ECOG PS1, > 1 prior systemic therapy 62%. All patients received at least one cycle with 27% completing 6 cycles. No dose reductions occurred in 53.9% of pts. DCR12w: 54% (95% confidence limit (CI), 36% – 71%), DCR24w: 23% (95%CI, 9% – 44%). Best responses (within 24w): partial - 15% (95%CI, 4- 35%), one occurring after 18 weeks; stable disease - 53.8% (33.4 – 73.4%); progression - 7.7% (0.9 – 25.1%). Adverse events (any cause): ≥ grade 3 toxicities affected 5.7% of pts. Conclusions: MiST2 met its primary endpoint, warranting further clinical evaluation of Ab. Whole exome sequencing of the cohort is ongoing to explore genomic correlates of de novo and acquired resistance. Clinical trial information: NCT03654833.
Efficacy and safety analysis of anlotinib combined with etoposide plus cisplatin/carboplatin as first-line therapy for extensive-stage small cell lung cancer (SCLC): The final results from a phase II single-arm trial.
Authors: Kong Tiandong , Chen Lu , Duan Fangfang , Hou Xiaoxia , Wang Liuyan , Zhou Hanli , Wang Lanrong , Hu Shanshan , Liu Danna
Published: June 2021

8560

Background: In recent years, the therapeutic regimens of extensive-stage small cell lung cancer (ES-SCLC) have progressed a lot. The most significant clinical studies include IMpower133 and CASPIAN. However, the relevant results showed that the combination of PD-L1 monoclonal antibody and EC regimen chemotherapy as first-line treatment of small cell lung cancer have a median PFS (progession-free survival) of about 5 months, which is comparable to that of simple chemotherapy. Therefore, the EP/EC is still the standard treatment for extensive-stage small cell lung cancer. Meanwhile, we noticed that anlotinib (multi-target small molecule oral VEGF inhibitor) has a curative effect on patients with extensive-stage SCLC as a third-line or above treatment in the ALTER 1202 study in China. Therefore, we tried to add anlotinib to the first-line treatment with EP/EC regimen in patients with ES-SCLC to observe the efficacy and safety. Methods: Eligible ES-SCLC pts (18̃75 years old, initial treatment, no obvious heart, liver and kidney dysfunction) were received anlotinib (12mg QD from day 1 to 14 of a 21-day cycle) + etoposide(100mg/m2, d1̃3 of a 21-day cycle)+CBP (AUC = 4̃5,d1,Q3W) or DDP (70̃75mg/m2, d1,Q3W) for 4̃6 cycles, then anlotinib maintenance (12mg QD from day 1 to 14 of a 21-day cycle) until the disease progresses or intolerable adverse reactions occur. During the treatment, dose reduction of anlotinib was permitted, which could be reduced to 10mg or 8mg if it was intolerable. The main observation endpoints were ORR, PFS and adverse events. Results: Between January 2019 and August 2020, a total of 20 patients with extensive-stage SCLC were enrolled in the study, with an average age of 66.2 ± 8.1(45-75) years old, 17 males (85%) and 3 females (15%). The median PFS was 10 months (95% CI: 7.809-12.191), median OS was 15 months (95%CI:10.639-19.361), ORR (objective remission rate) was 90% and DCR (disease control rate) was 100%. The most common grade 3 or 4 adverse events related to the trial regimen included: neutropenia was 10/20 (50.0%), thrombocytopenia was 5/20 (25.0%), anemia, nausea and fatigue were all 2/20 (10%), hypertension, transaminase elevation and hoarseness were all 1/20 (5%). Conclusions: Anlotinib combined with EP/EC regimen has better PFS, OS, ORR and DCR for the initial treatment of extensive-stage SCLC, and a manageable safety profile. A randomized, controlled phase III clinical study will be conducted to confirm this conclusion. Clinical trial information: ChiCTR2000035043.