bluuebunny/crossref_metadata_2025 huggingface dataset:
Barriers to web-based symptom management systems (web-SyMS).
Authors: Hassett Michael J. , Tramontano Angela , Cronin Christine , Osarogiagbon Raymond U. , Wong Sandra L. , Bian Jessica J , Hazard Hannah W. , Dizon Don S. , Schrag Deborah ,   SIMPRO Investigators
Published: June 2021

6545

Background: Web-SyMS can reduce the burdens of cancer and its treatment. While patients frequently express willingness to use these systems, only a subset actively engages with them. Some patients may lack the tools and confidence needed to benefit from web-SyMS. We sought to characterize these barriers among community-based cancer patients receiving care across six diverse healthcare systems. Methods: We surveyed patients receiving chemotherapy at three healthcare systems (Baptist, TN; Maine Medical, ME; Dana-Farber, MA) and patients recovering from cancer-directed surgery at three healthcare systems (West Virginia University, WV; Dartmouth-Hitchcock, NH; Lifespan, RI). Surveys were conducted as part of a pre-implementation analysis of eSyM – an EHR-embedded web-SyMS that collects, tracks, and manages patient reported outcomes during cancer therapy. Results: Among 563 respondents, access to tech devices (i.e., tablet, computer, or smartphone) was high: 78% reported access to ≥2 devices and only 5% reported access to no devices. However, confidence using tech devices to accomplish online tasks varied: 45% very confident, 38% somewhat confident, 11% little-no confidence. Compared to medical oncology patients, surgery patients were more likely to report being very confident (57% vs. 31%). There were significant differences based on patients’ self-reported tech confidence (Chi-square P<.05 for all values in the table). Conclusions: Low self-reported tech confidence may identify patients who are at high risk for experiencing the burdens of cancer but may be less likely to benefit from web-SyMS. Addressing this barrier is critical to improving outcomes and addressing disparities. Clinical trial information: NCT03850912. [Table: see text]
Impact of cancer on the risk of unplanned 30-day readmissions.
Authors: Qian Alexander , Qiao Edmund , Nalawade Vinit , Kotha Nikhil V. , Voora Rohith S. , Murphy James Don
Published: June 2021

6581

Background: Hospital readmission are associated with unfavorable patient outcomes and increased costs to the healthcare system. Devising interventions to reduce risks of readmission requires understanding patients at highest risk. Cancer patients represent a unique population with distinct risk factors. The purpose of this study was to define the impact of a cancer diagnosis on the risks of unplanned 30-day readmissions. Methods: We identified non-procedural hospital admissions between January through November 2017 from the National Readmission Database (NRD). We included patients with and without a cancer diagnosis who were admitted for non-procedural causes. We evaluated the impact of cancer on the risk of 30-day unplanned readmissions using multivariable mixed-effects logistic regression models. Results: Out of 18,996,625 weighted admissions, 1,685,099 (8.9%) had record of a cancer diagnosis. A cancer diagnosis was associated with an increased risk of readmission compared to non-cancer patients (23.5% vs. 13.6%, p < 0.001). However, among readmissions, cancer patients were less likely to have a preventable readmission (6.5% vs. 12.1%, p < 0.001). When considering the 10 most common causes of initial hospitalization, cancer was associated with an increased risk of readmission for each of these 10 causes (OR range 1.1-2.7, all p < 0.05) compared to non-cancer patients admitted for the same causes. Compared to patients aged 45-64, a younger age was associated with increased risk for cancer patients (OR 1.29, 95%CI [1.24-1.34]) but decreased risk for non-cancer patients (OR 0.65, 95%CI [0.64-0.66]). Among cancer patients, cancer site was the most robust individual predictor for readmission with liver (OR 1.47, 95%CI [1.39-1.55]), pancreas (OR 1.36, 95%CI [1.29-1.44]), and non-Hodgkin’s lymphoma (OR 1.35, 95%CI [1.29-1.42]) having the highest risk compared to the reference group of prostate cancer patients. Conclusions: Cancer patients have a higher risk of 30-day readmission, with increased risks among younger cancer patients, and with individual risks varying by cancer type. Future risk stratification approaches should consider cancer patients as an independent group with unique risks of readmission.
Molecular annotation of extramedullary acute myeloid leukemia to identify prevalence of targetable mutations.
Authors: Ball Somedeb , Knepper Todd C , Deutsch Yehuda Ethan , Bhagat Chirag K , Watts Justin M. , Bradley Terrence J , Samra Wassim , Chan Onyee , Hussaini Mohammad Omar , Sweet Kendra L , Talati Chetasi , Padron Eric , Komrokji Rami S. , Lancet Jeffrey E. , Sallman David Andrew
Published: June 2021

7024

Background: Extramedullary (EM) involvement, including myeloid sarcoma (MS) and leukemia cutis (LC), is uncommon in patients with acute myeloid leukemia (AML). Mutational landscape of EM-AML is not well characterized, including concordance of sequencing data from EM vs. non-EM site (blood or bone marrow) and the potential for personalized targeted therapy in this patient cohort. Methods: In a multicenter retrospective study, clinical and genomic data were collected on EM-AML patients treated at Moffitt Cancer Center, Memorial Healthcare System, and University of Miami, as well as sequenced cases at a central laboratory. Next generation sequencing (NGS) data come from panels that interrogated 24- 406 genes, with 15 genes covered by all panels, including notably, IDH1, IDH2, KIT, KRAS, NPM1, NRAS, and TP53. Survival estimates using Kaplan-Meier statistics and multivariate analysis with Cox-regression were performed in SPSS (v.26). Results: Our study included 58 patients with EM-AML. Median age at diagnosis was 62 years; 55% of patients were males. In our cohort, 34 (59%) patients had MS, and 19 (33%) had LC. EM-AML was noted during relapse in 60% of evaluable patients (n=45), and 31% had isolated EM disease. Patients with LC had a significantly worse median overall survival (OS) than those with MS (5.7 months vs. 21.9 months, p= 0.008); Pattern of EM involvement (MS vs. LC) remained an independent prognostic factor for OS (p= 0.04) in a multivariate analysis including disease setting (new diagnosis vs. relapse) and ELN risk category. Results of NGS performed during EM presentation were available in 48 patients, 19 of which had NGS data from EM site. Most commonly mutated genes were NRAS on EM site NGS (37%) and NPM1 on non-EM site NGS (28%). Based on EM NGS, 52% patients had a targetable genomic alteration, with 37% mutations in IDH, 21% NPM1, 5% FLT3, and 11% MLL-PTD. Five (two with concurrent M+EM disease) out of nine evaluable patients had significant discordance in targetable mutations between EM and non-EM NGS at EM-AML. Three of four patients who received treatment with IDH1/2 inhibitors based on EM NGS achieved complete response. Conclusions: EM-AML has a distinct molecular architecture with an inferior OS in LC vs. MS patients. We conclude that EM site NGS is critical in patients with EM-AML, as 52% have potentially targetable mutations and could benefit from specific targeted therapies.[Table: see text]
Early results of phase 1 study of JSP191, an anti-CD117 monoclonal antibody, with non-myeloablative conditioning in older adults with MRD-positive MDS/AML undergoing allogeneic hematopoietic cell transplantation.
Authors: Muffly Lori S. , Chin Michelle , Kwon Hye-Sook , Lieber Cara , Smith Steven , Sikorski Robert , Shizuru Judith , Pang Wendy , Artz Andrew S.
Published: June 2021

7035

Background: Myeloablative allogeneic hematopoietic cell transplantation (AHCT) is potentially curative for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but toxicities of conditioning limit its use in older or frail patients. Non-myeloablative (NMA) conditioning achieves better tolerability, at the expense of higher rates of relapse. We have developed a first-in-class monoclonal antibody (mAb), JSP191, which inhibits stem cell factor binding to CD117 (c-Kit), thereby depleting normal and MDS/AML disease-initiating hematopoietic stem cells (HSC). In pre-clinical models, anti-CD117 mAbs potently synergize with low dose total body radiation (TBI) to deplete HSC and facilitate donor cell engraftment. We reasoned that adding JSP191 to a standard NMA conditioning of 2 Gy TBI and fludarabine (Flu) would be safe and result in depletion of measurable residual disease (MRD) in older adults with high-risk MDS/AML entering AHCT. Methods: We report on the first 6 enrolled subjects in our Phase 1 trial (NCT#04429191) of JSP191/TBI/Flu as AHCT conditioning in MDS/AML patients, ≥ 60 years, with MRD detected by cytogenetics (cyto), difference from normal flow cytometry (flow), and/or next-generation sequencing (NGS). Primary endpoints are safety and tolerability of JSP191/TBI/Flu and JSP191 pharmacokinetics. Secondary endpoints include engraftment, donor chimerism, MRD clearance, GVHD, NRM, EFS, and OS at 1 year. JSP191 at 0.6 mg/kg was administered intravenously; serum concentration of JSP191 was used to confirm timing to begin Flu at 30 mg/m2/day x 3 days [Transplant Day (TD)-4, -3, -2] and TBI 2 Gy on TD0. Peripheral blood grafts from HLA-matched related or unrelated donors were administered on TD0 (10-13 days after JSP191). GVHD prophylaxis was tacrolimus, sirolimus, and mycophenolate mofetil. Results: All subjects are still on trial, and there have been no infusion toxicities and no JSP191-related serious adverse events. All subjects engrafted with neutrophil recovery TD+19 to TD+26, and showed ≥94% donor myeloid chimerism in the blood at TD+28. All 3 evaluable subjects with TD+90 follow up showed complete donor (≥95%) total and myeloid chimerism and MRD elimination (Table). Conclusions: These early results are the first to demonstrate that JSP191/TBI/Flu is safe, well-tolerated, and capable of clearing MDS/AML MRD in older adults undergoing NMA AHCT. Clinical trial information: NCT04429191. [Table: see text]
Predictors of hypomethylating agent discontinuation among patients with higher-risk myelodysplastic syndromes.
Authors: Zeidan Amer Methqal , Joshi Namita , Kale Hrishikesh , Wang Wei-Jhih , Corman Shelby , Hill Kala , Salimi Tehseen , Epstein Robert S.
Published: June 2021

7043

Background: Real-world studies have shown that persistence with intravenous (IV) and subcutaneous (SC) hypomethylating agents (HMAs) among patients (pts) with higher-risk myelodysplastic syndromes (MDS) is poor, with over one-third of treated pts receiving <4 cycles or having a ≥90-day gap in therapy, despite recommendations for at least 4-6 cycles to elicit response in absence of progression/unacceptable toxicity. Survival outcomes have also been shown to be worse, and direct medical costs higher, among HMA non-persistent vs persistent pts. We explored factors associated with early discontinuation of HMA therapy in this population. Methods: This was a retrospective cohort study among pts from the 2010-2016 SEER-Medicare linked database with a diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) from 2011-2015. Included pts had to have received HMA therapy and have ≥12 months’ continuous follow-up after diagnosis. Discontinuation was defined as stopping HMA therapy before 4 cycles. Multivariable logistic regression was used to assess predictors of HMA discontinuation. Results: In total, 664 pts with RAEB and treated with HMAs were included. Overall, 193 (29%) discontinued before 4 cycles; of these, 91 (47%) discontinued after 1 cycle, 57 (30%) 2 cycles, and 45 (23%) 3 cycles. Compared with pts continuing for ≥4 cycles, pts discontinuing before 4 cycles were generally older and more likely to be single/separated/divorced/widowed, have more comorbidities, and have poor performance status (PS) (Table). These trends were most pronounced among pts discontinuing HMA therapy after only 1 cycle vs ≥4 cycles (Table). In multivariable analysis, age 71-75 vs ≥80 y (odds ratio [OR] 0.556, p=0.017) and poor PS (OR 1.585, p=0.019) remained significant predictors of HMA discontinuation. Among treatment-related factors, the most statistically significant association with HMA discontinuation was observed for GCSF use (OR 0.453, p<0.001). Number of pills/day was not a predictor of HMA discontinuation (OR 1.009, p=NS). Conclusions: In this real-world study, almost one-third of RAEB pts treated with IV/SC HMAs discontinued before 4 cycles, with almost half of these pts discontinuing after only 1 cycle. Predictors of HMA discontinuation included older age and poor PS. Novel approaches are needed to improve persistence with HMA therapy, particularly among these higher-risk groups.[Table: see text]
Outpatient practice pattern and remote patient monitoring for axicabtagene ciloleucel CAR-T therapy in patients with aggressive lymphoma.
Authors: Bansal Radhika , Paludo Jonas , Holland Adam , Megan Spychalla , Alli McClanahan , Hathcock Matthew , Alkhateeb Hassan , Dingli David , Wang Yucai , Kenderian Saad , Kumar Shaji , Shah Mithun Vinod , Mustaqeem Siddiqui , Warsame Rahma M. , Villasboas Jose Caetano , Bennani Nabila Nora , Johnston Patrick B. , Ansell Stephen M. , Haddad Tufia C. , Lin Yi
Published: June 2021

7554

Background: Chimeric antigen receptor T-cell therapy (CAR-T) are commonly administered inpatient due to concern for early onset cytokine release syndrome (CRS), especially with axicabtagene ciloleucel (axi-cel). We report Mayo Clinic Rochester experience for hospital-based outpatient (HBO) management of patients (pts) receiving axi-cel and identify opportunities for improvement. HBO is closely integrated with inpatient practice and includes the same specialty trained clinical team. It is the first point of contact 24/7 for pts and triage evaluations. Lymphodepletion chemotherapy and CAR-T infusion is given on HBO followed by daily monitoring till day 8 and thereafter, as clinically needed until admission criteria is met. Methods: We retrospectively analyzed database of pts who received axi-cel between 1/2018 and 1/2021. After 06/2020, remote patient monitoring (RPM) tools were implemented to collect patient-reported neurologic symptoms and vital signs via bluetooth-enabled devices 4 times daily through month 1. Adverse data trends are addressed by the HBO team. Results: Among 72 recipients, 89% received their cells outpatient; 8% remained outpatient for the entire month. CRS and neurotoxicity incidence were comparable to those reported from CIBMTR. Median time to first admission was 2 days (Table). Use of bridging therapy, increased CRP and LDH were associated with early admission (≤3 days). Median time to tocilizumab, steroid, oxygen support, vasopressor was 4 days after admission. Half of HBO visits required intervention such as blood transfusions, IV medications through the first month. Nine pts had enrolled in RPM to date; with 8 having evaluable data. With 4 scheduled entries/day, a median of 1 entry/day was skipped and 2 entries/day were answered incompletely. An average of 57 additional unscheduled entries were generated per pt. Among a median of 373 (range 91-522) readings per pt over the first month, 4% (2%-20%) of the readings generated alerts. An average of 4 alerts were seen within 48 hours prior to admission. Data including additional subjects will be presented at ASCO meeting. Conclusions: We report a feasible outpatient care model for management of axi-cel recipients with safe outcomes. Clinical characteristics associated with more aggressive disease are associated with likelihood of early admission. Early RPM experience suggest use of digital tools could improve monitoring compliance and may predict evolution to symptoms requiring escalation of care.[Table: see text]
Phase Ib trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-β signaling pathway.
Authors: Malek Ehsan , Hwang Sunjin , Caimi Paolo Fabrizio , Metheny Leland L. , Tomlinson Benjamin Kent , Cooper Brenda W. , Boughan Kirsten M. , Otegbeye Folashade , Gallogly Molly , Driscoll James Joseph , De Lima Marcos J.G.
Published: June 2021

8039

Background: Immunosuppression and osteoclast activation are two hallmarks of the bone marrow environment in Multiple Myeloma (MM). Corticosteroids have been used historically as part of anti-myeloma regimens due to their anti-plasma cell activity, however they potentially could suppress immune system and activate osteoclast further; therefore there is an unmet need for corticosteroid-free approaches in the era of emerging anti-cancer immunotherapy modalities. There is an abundance of Transforming Growth Factor-beta (TGF-β), a crucial cytokine in suppression of immune system as well as catabolic bone remodeling, in the MM microenvironment. Vactosertib (Vacto) is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model. Here, we report the phase Ib trial of Vacto in combination with pomalidomide (Pom) without any corticosteroids (NCT03143985). Methods: pts with relapsed MM with at least two lines of therapies enrolled on a 3 + 3 dose escalation design and received Vacto, 60 mg/d, 120 mg/d, 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The primary objectives of the study was to assess safety and recommended phase 2 dose. Vacto tablets, taken once or twice daily for 5 days followed by 2 days without treatment, is administered in 28-day cycles, until progression of disease or intolerable toxicity. Results: 15 pts were enrolled on the study (Table). The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt, one episode of grade III renal failure that took less than 7 days to get back to baseline on another patient, sinus bradycardia that reversed to sinus rythem and an Afib that was rate controlled with beta blocerks. No grade IV non-hematologic AE was observed. Three pts had grade III hematologic AE, no grade IV hematologic AE. Three out of 15 pts experienced progression of disease (PFS-6: 80%). Conclusions: The phase Ib data shows safety of this agent in combination with Pom. The efficacy assessment (PFS-6: 80%) is higher than the historical control (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Clinical trial information: NCT03143985. [Table: see text]
Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis.
Authors: Spicka Ivan , Moreau Philippe , Martin Thomas G. , Facon Thierry , Martinez Gracia , Oriol Albert , Koh Youngil , Lim Andrew , Mikala Gabor , Rosiñol Laura , Yağci Münci , Cavo Michele , Risse Marie-Laure , Asset Gaëlle , Macé Sandrine , Van De Velde Helgi , Yong Kwee
Published: June 2021

8042

Background: A prespecified interim efficacy analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d) (Isa-Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (HR 0.531; 99% CI, 0.318–0.889; P= 0.0007), with a clinically meaningful increase in minimal residual disease negativity (MRD-) (29.6% vs 13.0%) and complete response (CR) (39.7% vs 27.6%) rates, and a manageable safety profile. This subgroup analysis of IKEMA examined efficacy and safety in pts with high-risk cytogenetics [t(4;14), del(17p), and t(14;16)] and/or gain(1q21). Methods: Pts with 1–3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n = 179) or Kd (n = 123). High-risk cytogenetics was assessed by central laboratory analysis and defined as ≥1 of the following: del(17p): 50% cutoff; t(4;14) or t(14;16): 30% cutoff. Assessment of gain(1q21) was prespecified as ≥3 copies: 30% cutoff. Results: Of the randomized pts, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk cytogenetic abnormality (CA); 26.3% (Isa-Kd) and 25.2% (Kd) had isolated gain(1q21). The addition of Isa to Kd improved PFS for pts with ≥1 high-risk CA and standard-risk pts (Table); pts with t(4;14) (HR 0.549; 95% CI, 0.232–1.301) had a more pronounced treatment effect than pts with del(17p) (HR 0.837; 95% CI, 0.281–2.496). A clear PFS benefit with Isa-Kd was also seen for pts with isolated gain(1q21) and gain(1q21) combined with other high-risk CA (Table). The trend toward improved CR, ≥very good partial response (VGPR), and MRD- rates with the addition of Isa was more pronounced in pts with gain(1q21) than in pts with high-risk CA alone. Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd vs Kd, but the incidence of serious and fatal TEAEs was similar with both arms for high-risk pts (Table). Conclusions: The addition of Isa to Kd improved PFS in pts with high-risk CA and disease response in pts with gain(1q21) isolated or combined with high-risk CA, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA population. Isa-Kd is a potential new treatment option for the difficult-to-treat subgroup of pts with RMM and high-risk cytogenetics. Funding: Sanofi. Clinical trial information: NCT03275285. [Table: see text]
AFT-16: Phase II trial of neoadjuvant and adjuvant atezolizumab and chemoradiation (CRT) for stage III non-small cell lung cancer (NSCLC).
Authors: Ross Helen J. , Kozono David E. , Urbanic James John , Williams Terence Marques , DuFrane Carter , Bara Ilze , Schulze Katja , Brockman Jane Michelle , Wang Xiaofei F. , Gao Junheng , Vokes Everett E. , Stinchcombe Tom
Published: June 2021

8513

Background: A minority of the approximately 40,000 US patients diagnosed annually with stage III NSCLC can be cured by concurrent CRT. Standard adjuvant immune checkpoint inhibitors (ICI) improve outcome for those patients who complete CRT with good performance status (PS) and without disease progression, but most patients diagnosed with unresectable stage III NSCLC will not meet the criteria for adjuvant ICI. AFT-16 investigated safety and efficacy of neoadjuvant and adjuvant atezolizumab as a strategy that may allow more patients to benefit from ICI. Methods: Eligible patients received 4 cycles (cy) of atezolizumab 1200 mg IV q 21 days followed by CRT with 60 Gy + weekly carboplatin and paclitaxel (CP), CP consolidation and adjuvant atezolizumab to complete 1 year of therapy (17 cy). The primary endpoint of disease control rate at 12 weeks (wks) has been reported. Secondary endpoints reported here include overall response rate, safety, and progression-free and overall survival (PFS, OS) measured from the start of induction therapy. Correlative science data and quality of life endpoints will be reported elsewhere. Results: 64 patients with unresectable stage III NSCLC, PS 0-1 and no active autoimmune disease or significant organ dysfunction were enrolled at 13 Alliance for Clinical Trials in Oncology sites from 11/2017 to 7/2019. 62 patients who received at least one dose of atezolizumab are included in this analysis. Median age was 63.9 years (range 38.1-86.5). Patients were 51.6% female, 77.4% white, 88.7% current & former smokers and 56.5% PS 0. All patients are off study treatment. Mean cycles of treatment received was 9 (1-17). 46 patients were alive at median follow up 24.1 mo (range 3 – 34.1 mo). PFS at 12 and 18 mo from start of induction atezolizumab was 66% (95%CI 55-79) and 57% (95%CI 45-71) respectively. Median PFS was 23.7 mo (95%CI 13.2-NE). OS at 18 mo was 84% (95%CI 75-94). Median OS is not yet estimable. Atezolizumab was well tolerated. One grade (gr) 4 Guillain-Barre syndrome and 1 each gr 3 pneumonia, pneumonitis and colitis were attributable to neoadjuvant atezolizumab. The remaining 9 severe adverse events were unrelated to ICI. Conclusions: Atezolizumab prior to and following CRT for stage III unresectable NSCLC was well tolerated with encouraging PFS and OS without unexpected safety signals. Analysis of correlative endpoints and quality of life are ongoing. Further study of induction atezolizumab is warranted in patients with unresectable stage III NSCLC. Support: https://acknowledgments.alliancefound.org ; Clinical trial information: NCT03102242.
Different exposure duration of adjuvant icotinib in stage II-IIIA non-small cell lung cancer patients with positive EGFR mutation (ICOMPARE study): A randomized, open-label phase 2 study.
Authors: Lyu Chao , Wang Rui , Li Shaolei , Yan Shi , Wang Yuzhao , Chen Jinfeng , Wang Liang , Liu Yinan , Guo Zhanlin , Wang Jia , Pei Yuquan , Yu Lei , Wu Nan , Chen Jun , Liu Yanheng , Li Shanqing , Han Bing , Ding Lieming , Mao Li , Yang Yue
Published: June 2021

8521

Background: EGFR-TKI has been widely used in the treatment for advanced non-small cell lung cancer (NSCLC). Previous studies, such as the EVIDENCE study and the ADAURA study, have confirmed that patients with EGFR-mutated NSCLC could benefit from adjuvant EGFR-TKI treatment. However, the optimal duration time of adjuvant EGFR-TKIs has not been clearly defined. Methods: In this multicenter, randomized, phase 2 trial, eligible patients with II-IIIA stage EGFR mutation-positive NSCLC after R0 resection were randomized in 1:1 to receive adjuvant icotinib for 1 year (group A) or 2 years (group B). The primary endpoint was disease-free survival (DFS). Results: Between September 2013, and September 2018, 109 patients from 8 centers were enrolled in this study, among whom 55 were randomized to group A and 54 to B. As of August 24, 2020 (data cutoff), the median follow-up was 44.1 months (95%CI 37.1-49.9), 31 (56%) of 55 patients in the 1-year group and 25 (46%) of 54 patients in the 2-year group had DFS events. The median DFS was 48.92 months (95%CI 33.15, 70.11) in 2-year group and 32.89 month (95%CI 26.61, 44.78) in 1-year group, respectively. 2-year icotinib significantly prolonged DFS (HR 0.521, 95%CI 0.278, 0.976; p = 0.039). OS events were observed in 20 patients, the OS was not mature yet. Icotinib was re-given for 32 patients with disease recurrence or metastasis as first-line treatment, objective response occurred in 66.7% of 30 patients with measurable disease. Treatment-related adverse events were recorded in 41 of 55 (75%) patients in 1-year group and 36 of 54 (67%) patients in 2-year group, and grade 3 or 4 treatment-related adverse events occurred in 4 (7%) of 55 patients in the 1-year group versus 3 (6%) of 54 in the 2-year group, respectively. No treatment-related deaths or interstitial lung disease were reported. Conclusions: 2-year adjuvant treatment with icotinib resulted in a significantly lower risk of recurrence than 1-year adjuvant icotinib in patients with stage II-IIIA NSCLC positive EGFR mutations and was not associated with increased toxic effects. Clinical trial information: NCT01929200.
Modeling the cost-effectiveness of adjuvant osimertinib in resected EGFR-mutant non-small cell lung cancer patients.
Authors: Lemmon Christopher , Zabor Emily Craig , Pennell Nathan A.
Published: June 2021

8527

Background: Adjuvant Osimertinib (Osi) was recently approved for resected EGFR-mutant non-small cell lung cancer (NSCLC) based on disease free survival (DFS) benefits from the ADAURA trial. Prior studies of adjuvant EGFR inhibitors yielding DFS benefits have lacked an overall survival (OS) benefit, leading to debate over early clinical implementation given the associated drug costs. This study aims to evaluate the cost-effectiveness (CE) of Osi in this setting. Methods: We constructed Markov models using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of the use of 3 years of adjuvant Osi versus placebo in the ADAURA patient population of stage IB to IIIA NSCLC patients over a 10-year time horizon. All patients entering the progressive disease (PD) state were assigned for re-treatment with Osi. Cost and utility values were derived from Medicare reimbursement data and literature (Table). A CE threshold of 3 times the GDP per capita was used. Deterministic sensitivity analyses were performed to assess the impact of a range of OS benefit, as the impact of adjuvant Osi on OS has not yet been reported. Results: The incremental cost-effectiveness ratio (ICER) for adjuvant Osi was $317,119.90 per QALY gained. Initial costs of Osi are higher in the first 3 years, but become lower than the placebo group in year 4 onward, with similar costs after year 7. Costs due to PD are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2,388, $379,047, and $502,937, respectively in the placebo group, compared to $505,775, $255,638, and $800,697, respectively in the Osi group. QALYs were higher in the Osi arm throughout. Sensitivity analysis using incremental OS gains reaches the CE threshold of $195,000 between 25-30% OS benefit of Osi over placebo. A 50% discount to the Osi annual cost yielded an ICER of $115,419. Conclusions: 3 years of adjuvant Osi is more cost-effective than placebo if one is willing to pay $317,119 more per QALY gained, with most costs accruing in the first 3 years as drug cost. This strategy became cost-effective with an OS benefit between 25-30% over placebo. Discount to Osi annual costs improves the ICER significantly. True cost-effectiveness of adjuvant Osi will require further study due to immaturity of ADAURA OS data and model limitations.[Table: see text]
Elderly patients with unresectable stage 3 NSCLC treated with definitive chemoradiation with or without durvalumab: Safety and outcomes.
Authors: Ryan Malcolm Isaiah , Weiss Jessica , Fares Aline Fusco , Tsao Ming Sound , Liu Geoffrey , Bradbury Penelope Ann , Leighl Natasha B. , Shepherd Frances A. , Sacher Adrian G. , Lau Sally C. M.
Published: June 2021

8547

Background: Recently, it has been demonstrated that the addition of durvalumab after chemoradiation (CRT) in unresectable stage 3 non-small cell lung cancer (NSCLC) significantly improves overall survival (OS). The benefit of CRT in elderly patients is considered controversial given its increased toxicity. As such, CRT followed by durvalumab in elderly patients may be underutilized despite its demonstrated superiority. The practice pattern at our center is to offer curative treatment unless clearly contraindicated. We sought to investigate the outcomes of elderly patients treated with CRT +/- durvalumab at our center. Methods: We conducted a review of all stage 3 NSCLC patients treated with CRT between 2018 and 2020. Patients were analyzed based on age: < 70 years, ≥70 years. Endpoints evaluated were treatment patterns, toxicity, progression free survival (PFS) and overall survival (OS). Results: We identified 115 stage 3 patients: 44 patients ≥70 years (70-89) and 71 patients < 70 years (34-69). Patients were fit: ECOG 0-1 (98%/97%), mean Charlson comorbidity index (CCI) (1.1/0.9) in elderly vs young patients; p > 0.05. All other baseline characteristics including PD-L1 expression were similar. The chemotherapy regimens (platinum in combination with etoposide, paclitaxel or pemetrexed), dose intensity (97% vs 97%) and percentage of planned cycles received (91% vs 96%) were similar. There were 2 treatment related deaths from CRT among the younger cohort and none in the elderly patients. At the completion of CRT, 75% of elderly and 72% of young patients received durvalumab. Clinician/patient preference was the most common reason for not receiving consolidation durvalumab in older patients (55% vs 25%). The median time to starting durvalumab was 43 days in the elderly and 37 days in young patients (p = 0.19). Durvalumab was well tolerated in the elderly and incidence of grade ≥3 immune-related adverse events was 9% compared to 6% in young patients; p = 0.68. The durvalumab completion rates were 30% in elderly and 24% in young patients; p = 0.22. Median PFS was similar between elderly and young patients (17.9 vs 10.6 months respectively; p = 0.07), even after adjusting for the CCI (HR 0.60; p = 0.07). The 24- and OS rates are also similar (p = 0.93): 77% in elderly and 77% in young patients. Conclusions: Definitive CRT followed by durvalumab can be safely delivered in elderly patients ≥70 years with comparable outcomes. The non-significant trend towards better PFS in elderly patients suggests that only select fit patients are being referred for treatment. In conclusion, all patients should undergo comprehensive oncologic assessment to determine if curative intent treatment can be delivered to avoid undertreatment of elderly patients.
The impact of a genomic sequencing classifier (GSC) on clinical decision making in patients with a high-risk lung nodule.
Authors: Sethi Sonali , Oh Scott , Chen Alexander , Bellinger Christina , Lofaro Lori , Tom Jennifer , Johnson Marla , Huang Jing , Bhorade Sangeeta Maruti , Kennedy Giulia
Published: June 2021

8549

Background: Current guidelines recommend that patients who have lung nodules with high risk of malignancy (ROM) ( > 65%) should undergo surgical and other ablative therapies. However, prior studies have shown that clinicians may opt for more conservative management in these high-risk patients. Percepta Genomic Sequencing Classifier (GSC), a RNA-seq based classifier derived from bronchial epithelial cells to assess risk of lung cancer, was designed to risk stratify lung nodules by both down classifying ROM as a “rule -out“ test with high sensitivity as well as up-classifying ROM as a “rule- in” test with high specificity for malignancy. This study assesses the impact of up-classification of high ROM to very high- risk (ROM > 90%) by Percepta GSC in increasing the number of ablative therapies recommended for high-risk lung nodules. Methods: This prospective randomized decision impact survey included 37 patients from the AEGIS I/ II cohorts and the Percepta Registry who were undergoing work up of a lung nodule and had a high ROM that was up-classified to very high ROM by Percepta GSC. 97 physicians assessed 10 randomly assigned patient cases. They then responded to a survey designed to test the hypothesis that including a Percepta GSC result will increase the recommendation for surgical or other ablative therapy in very high- risk patients as well as their level of confidence of this recommendation. Physicians were first presented with the patient’s clinical information without Percepta GSC and then with Percepta GSC. Results: 97 physicians provided a total of 682 evaluations of 37 patients. In this study, the recommendation for surgical or other ablative therapy increased from 19/341 (5.6%) prior to the Percepta GSC result to 157/341 (46%) after the Percepta GSC result (odds ratio of 4.76, p-value < 0.001). The number of extremely confident recommendations increased from 72/341 (21%) without Percepta GSC to 106/341 (31%) with Percepta GSC. Significantly more physicians had increased confidence in their recommended next step post-Percepta GSC when collapsing the confidence level responses into increased confidence (n = 93) and decreased confidence (n = 44) (p-value = 0.002). Conclusions: Percepta GSC had a quantifiable impact on clinical decision making. It increased the number of surgical and other ablative therapies recommended when patients were re-classified from high to very high- risk of lung cancer with a higher confidence in the recommended next step. By up-classifying nodules from high to very high ROM, Percepta GSC will improve the likelihood and timeliness of appropriate therapies and assist clinicians more effectively manage patients to improve patient outcomes.
Pooled analyses of immune-related adverse events (irAEs) and efficacy from the phase 3 trials IMpower130, IMpower132, and IMpower150.
Authors: Socinski Mark A. , Jotte Robert M. , Cappuzzo Federico , Nishio Makoto , Mok Tony S. K. , Reck Martin , Finley Gene Grant , Yu Wei , Patel Hina , Paranthaman Nindhana , Bara Ilze , West Howard
Published: June 2021

9002

Background: PD-L1/PD-1 inhibitors have transformed the treatment (tx) of advanced NSCLC. Evidence suggests that the occurrence of irAEs with these agents may predict improved outcomes in cancers such as NSCLC. Atezolizumab (atezo; anti–PD-L1) has shown efficacy and tolerability in NSCLC and is currently approved in the 1L and 2L+ settings. The Ph 3 IMpower130, IMpower132 and IMpower150 trials evaluated atezo + chemo ± bevacizumab (bev) as 1L tx of NSCLC. We explore the association between irAEs and efficacy in these trials. Methods: Each trial enrolled tx-naive patients (pts) with nonsquamous stage IV NSCLC. Pts were randomized to: carboplatin (carbo) + nab-paclitaxel alone or with atezo in IMpower130; carbo or cisplatin alone or with atezo in IMpower132; atezo (A) + bev (B) + carbo + paclitaxel (CP), ACP or BCP in IMpower150. Data were pooled (data cutoffs: Mar 15 2018 [IMpower130]; May 22 2018 [IMpower132]; Sep 13 2019 [IMpower150]) and analyzed by tx (atezo-containing vs control) and irAE status. A time-dependent Cox model and landmark analyses at 1, 3, 6 and 12 mo were used to control for immortal bias. Study protocols required atezo tx interruption/discontinuation for grade (Gr) ≥3 irAEs. Results: 2503 pts were included in the analysis (atezo, n = 1577; control, n = 926). In both arms, baseline characteristics were generally balanced between pts with irAEs (atezo, n = 753; control, n = 289) and without irAEs (atezo, n = 824; control, n = 637). Any-Gr irAEs occurred in 48% (atezo) and 32% (control) of pts; Gr 3-5 irAEs occurred in 11% (atezo) and 5% (control). The most common irAEs (atezo vs control) were rash (28% vs 18%), hepatitis (lab abnormalities; 15% vs 10%) and hypothyroidism (12% vs 4%). Median time to onset of first irAE was 1.7 (atezo) vs 1.4 mo (control). OS HRs (95% CI) from the time-dependent Cox model between pts with vs without irAEs were 0.69 (0.60, 0.78) in the atezo arm and 0.82 (0.68, 0.99) in the control arm; after excluding rash (perceived as the least specific irAE), OS HRs (95% CI) were 0.75 (0.65, 0.87) and 0.90 (0.71, 1.12), respectively. OS landmark data are in the Table. Conclusions: In this exploratory pooled analysis, pts with irAEs had longer OS vs pts without irAEs in the atezo-containing and control arms per the time-dependent Cox model and landmark analyses; this trend remained for the atezo arm after excluding rash. Landmark analyses suggest that in the atezo arm, pts with Gr 1/2 irAEs had the longest OS and pts with Gr ≥3 irAEs had the shortest OS, potentially due to tx interruption/discontinuation. Clinical trial information: NCT02367781; NCT02657434; NCT02366143. [Table: see text]
Final OS analysis from the phase III j-alex study of alectinib (ALC) versus crizotinib (CRZ) in Japanese ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC).
Authors: Yoshioka Hiroshige , Hida Toyoaki , Nokihara Hiroshi , Morise Masahiro , Kim Young Hak , Azuma Koichi , Seto Takashi , Takiguchi Yuichi , Nishio Makoto , Kumagai Toru , Hotta Katsuyuki , Watanabe Satoshi , Goto Koichi , Satouchi Miyako , Kozuki Toshiyuki , Nakagawa Kazuhiko , Mitsudomi Tetsuya , Yamamoto Nobuyuki , Yoshimoto Takuya , Tamura Tomohide
Published: June 2021

9022

Background: The primary analysis of the J-ALEX (JapicCTI-132316) study for the ALK-inhibitor naïve ALK+ NSCLC demonstrated superior progression-free survival (PFS) in Japanese patients randomized to the ALC, compared with those assigned in the CRZ (HR 0.34, 99.7% CI 0.17–0.71, stratified log-rank p<0·0001) by the Independent Review Facility (IRF) (Hida et al., Lancet 2017). The final PFS and 2nd overall survival (OS) interim analysis (IA) data were subsequently reported (Nakagawa et al., Lung cancer 2020). Here, we report the final OS data. Methods: ALK+ NSCLC (by IHC and FISH or RT-PCR) patients were randomized 1:1 either to receive ALC (Japanese approved dose 300 mg BID, n = 103) or CRZ (250 mg BID, n = 104). Stratification factors included ECOG PS, treatment line, and clinical stage. The primary endpoint was PFS according to the blinded IRF. Secondary endpoints included OS, objective response rate, and safety. Results: After a median follow-up of 68.6 months in the ALC arm and 68.0 months in the CRZ arm, death events occurred in 40.8% and 39.4% in the ALC and the CRZ arms, respectively. Five-year survival rates for patients in the ALC and CRZ arm were 60.85% and 64.11%, respectively. The final OS HR was 1.03 (95%CI 0.67-1.58), however, median OS was not reached in either arm. Of note, patients in the CRZ arm tended to have their treatment switched earlier than those in the ALC arm (median time to treatment-switch: 12.3 months vs. NE). Most of the patients (78.8%) in the CRZ arm received ALC as a 1st subsequent therapy, whereas only 10.7% of patients in the ALC arm received CRZ. Conclusions: In this final J-ALEX OS analysis, prolongation of OS in the ALC arm was not observed compared to the CRZ arm. However, OS result may be substantially confounded since 78.8% of the patients in the CRZ arm received ALC as initial, subsequent therapy. Clinical trial information: 132316.
Anti PD-(L)1 in KRAS mutant advanced nsclcs: A meta-analysis of randomized controlled trials.
Authors: Landre Thierry , Justeau Gregoire , Assié Jean-baptiste , Chouahnia Kader , Taleb Chérifa , Chouaid Christos , Duchemann Boris
Published: June 2021

9025

Background: KRAS comprise the most frequently found oncogene driver mutation in non-small cell lung cancer (NSCLC), accounting for 20-25% of these patients. Single-agent Anti PD-(L)1 clinical efficacy against KRAS mutant NSCLC is a topic of debate. Methods: This meta-analysis examined randomized-trial data comparing first-or second line Anti PD-(L)1 +/- chemotherapy (CT) vs CT alone for KRAS mutant advanced NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK). Results: We analyzed 3 trials in first line (IMPOWER-150, KEYNOTE-189 and KEYNOTE-042), as well as 3 trials in second line (OAK, POPLAR and CHECKMATE-057) including 1313 NSCLCs (386 KRAS mutant and 927 KRAS wild-type tumor). Anti PD-(L)1 +/- CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49-0.72]; p < 0.00001) and PFS (0.58 [0.43-0.78]; p = 0.0003) compared to CT alone in KRAS mutant NSCLCs. Survival benefits occured in both first and second line. Survival benefits observed in KRAS wild-type NSCLCs were (0.87 [0.76-0.99]; p = 0.03) and (0.79 [0.56-1.11]; p = 0.17) respectively. OS benefit in KRAS mutant was significantly superior compared to OS benefit in KRAS wild-type (p = 0,001). Conclusions: Anti PD-(L)1 (+/- CT) appears superior to CT alone both for mutant and wild-type KRAS in advanced NSCLCs for OS and PFS with higher magnitude of benefit in KRAS mutated group for OS.
Efficacy and safety of pan-ErbB inhibitor pyrotinib combined with antiangiogenic agent apatinib for HER2-mutant or amplified metastatic NSCLC: A phase II clinical study.
Authors: Yang Guangjian , Xu Haiyan , Yang Lu , Zhang Shuyang , Xu Fei , Li Hongshuai , Yang Yaning , Ai Xin , Wang Yan
Published: June 2021

9035

Background: Tumor angiogenesis could be induced by activation of HER2 receptor, and currently, there is lack of clinical evidence of anti-HER2 tyrosine kinase inhibitors (TKIs) combined with antiangiogenic therapy for HER2-mutant or amplified non-small cell lung cancer (NSCLC). We conducted a study to explore the efficacy and safety of a pan-ErbB inhibitor pyrotinib combined with apatinib for metastatic NSCLC patients harboring HER2 amplification or activating mutations. Methods: This was a single-center, single-arm phase II study with Simon’s optimal two-stage design. Metastatic NSCLC patients with ECOG scores of 0-1 and harboring primary HER2 amplification, exon 20 insertion or activating missense mutations who had failed to prior chemotherapies or anti-HER2 TKIs were eligible to be enrolled. All patients received oral pyrotinib (400mg once daily) combined with apatinib (250mg once daily) therapy. The primary endpoint was objective response rate (ORR), and second endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR), overall survival (OS) and safety. Results: Between March 5, 2019, and December 1, 2020, 33 metastatic NSCLC patients with HER2 alterations were enrolled, including exon 20 insertions (A775_G776insYVMA, 20/33; P780_Y781insGSP, 6/33; other variants, 2/33), missense mutations (3/33), and primary HER2 amplification (2/33). Seventeen patients (51.5%) were pretreated with first-line platinum-based chemotherapies or anti-HER2 TKIs, and the remaining had received at least 2 lines of prior therapies (range, 2-6). At the last follow-up time January 23, 2021, the overall ORR and DCR were 45.5% (15/33) and 93.9% (31/33), respectively. The median PFS was 6.8 (95%CI: 5.4-8.2) months. The median DoR and OS were 5.3 (95%CI: 0-11.8) and 12.9 (95%CI: 8.6-17.2) months, respectively. The mPFS was significantly longer in patients who received second-line pyrotinib combined with apatinib therapy than those in third- or above-line settings (9.8 vs. 5.3 months, P = 0.018, HR = 0.281 [95%CI: 0.098-0.807]). Although pyrotinib combined with apatinib therapy showed similar ORRs in patients with presence (46.2%, 6/13) or absence (45.0%, 9/20) of brain metastases, and those in second-line (47.1%, 8/17) or above-line settings (43.8%, 7/16). Common treatment-related adverse events (AEs) were grade 1-2, mainly including diarrhea (90.9%), hypertension (72.7%), asthenia (63.6%), anorexia (54.5%) and nausea (51.5%). Grade 3 AEs were diarrhea (3.0%) and hypertension (9.1%). No grade 4 or 5 AE or treatment-related deaths were reported. Conclusions: Pyrotinib combined with apatinib showed potent anti-tumor activity and acceptable safety profile in metastatic NSCLC with HER2 amplification or activating mutations. Clinical trial information: ChiCTR1900021684.