bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the incidence of pneumonitis in United States veterans with non-small cell lung cancer receiving durvalumab following chemoradiation.
Authors: Thomas Theodore Seth , Luo Suhong , Knoche Eric Marshall , Sanfilippo Kristen Marie , Keller Jesse W. 
Published: May 2020

9034 Background: Locally advanced, unresectable non-small cell lung cancer is commonly treated with concurrent chemoradiation therapy (CRT). Durvalumab is a PD-L1 immune checkpoint inhibitor (ICI) administered following completion of CRT. Pneumonitis is a known toxicity of ICI therapy. In the landmark PACIFIC study the incidence of pneumonitis in patients receiving durvalumab was 33.9% (any grade) and 3.4% (grade 3/4) compared to placebo 24.8% and 2.6% ( Antonia et al, NEJM 2017). The incidence of pneumonitis is thought to be higher in real-world populations. This study evaluated the incidence of pneumonitis in a cohort of U.S. Veterans. Methods: Durvalumab recipients were identified using VA Informatics and Computing Infrastructure databases. Using pharmacy records we confirmed durvalumab and corticosteroid prescriptions. Clinical information was obtained via the electronic medical record. The primary outcome was the development of pneumonitis. We defined asymptomatic pneumonitis as the presence of new radiographic findings consistent with pneumonitis without documented clinical symptoms. We recorded pneumonitis grade as reflected in clinical documentation. If not specifically graded, we used Common Terminology Criteria for Adverse Events (CTCAE v4.0) to assess severity. Logistic regression analysis evaluated associations between pneumonitis and age, comorbidities, radiation dose and stage. Cox proportional hazards analysis evaluated associations between pneumonitis and risk of death. Results: A total of 123 veterans received durvalumab through 3/31/2019 (with follow up through 11/15/2019). Asymptomatic radiographic infiltrates occurred in 49 (39.8%) patients. There were 26 cases of clinically important pneumonitis Grade 2: 9(7.3%), Grade 3: 14 (11.4%), Grade 4: 2(1.6%), and grade 5: 1 (.08%). Acute hypersensitivity reactions occurred in five (4.1%) patients. Reported reasons for discontinuation of durvalumab included: disease progression [38 (31%)], toxicity [30 (24.3%)], and patient death [1 (1.6%)]. There was no association between age, time from radiation end to durvalumab initiation, radiation dose, smoking history, chemotherapy used or disease stage on development of pneumonitis. Cox analysis did not demonstrate an association between pneumonitis and risk of death. Conclusions: Clinically significant pneumonitis was more frequent in this cohort than reported in prior clinic trial populations. Further studies to identify pneumonitis risk factors are needed.
Contemporary management and associated outcomes of 3,151 patients with stage III non-small cell lung cancer (NSCLC) in a real-world setting: Results of KINDLE, a multicountry observational study.
Authors: Jazieh Abdul Rahman , Onal Huseyin Cem , Tan Daniel Shao-Weng , Soo Ross A. , Prabhash Kumar , Kumar Amit , Huggenberger Reto , Robb Stephen , Cho Byoung Chul 
Published: May 2020

9043 Background: Stage III NSCLC is a heterogeneous disease requiring a multimodality approach. We conducted a global study to characterise the patients (pts), treatment patterns and their associated outcomes for this disease in a real-world setting in the pre-IO era. Methods: KINDLE is a retrospective, multi-country, multi-centre study capturing data on patient and disease characteristics, treatments and outcomes. The study included pts with stage III NSCLC diagnosed between January 1st, 2013 and December 31st, 2017 and with at least 9 months of documented follow-up. Descriptive statistics were used to describe patient demographics, disease characteristics and treatment modalities. Inferential statistics was used to correlate various clinical and treatment variables with progression free survival (PFS) and overall survival (OS). Results: 3151 patients were enrolled at 125 centres in three geographical regions; 1046 pts in Middle East and North Africa, 1874 pts in Asia and 231 pts in Latin America. Median age was 63 years (range 21-92); 76.5% were male; 69.2% with a smoking history; 55.9% were staged as IIIA (AJCC 7th ed.); 53.7% had adenocarcinoma and 36.6% squamous cell, and 31.7% were known to have an EGFR mutation. 21.4% of patients underwent curative surgical resection. First line therapy included more than 25 different regimens, the most common being concurrent chemo-radiotherapy (cCRT) in 29.4%, chemotherapy (CT) alone in 17%, sequential chemo-radiotherapy (sCRT) in 10.4%, and radiotherapy (RT) alone in 8.5%. Median PFS for the whole cohort was 12.5 mos (95% CI; 12.06 – 13.14) and median OS 34.9 mos (95% CI; 32.00 – 38.01). Stage IIIA patients who were eligible for and underwent surgery + CT, had longer OS than patients who did not undergo surgery, receiving other treatments. Non-surgical approaches included CT, RT, and CRT. In stage IIIB, OS was significantly improved for cCRT vs. CT alone (p = 0.0015) or RT alone (p = < 0.0001) or sCRT (p = 0.0216). Improved survival was observed with sCRT compared with RT alone and chemotherapy vs RT alone. Conclusions: KINDLE, a large multi-country observational study, reveals the diversity of treatment practices that exist in stage III NSCLC and provides insights on the outcomes in a real-world setting. The unmet medical need remains high and approaches are required to optimize patient outcomes including implementation of guidelines, physician education and improved access to innovative medicines and quality care.
AFT-16: Phase II trial of atezolizumab before and after definitive chemoradiation (CRT) for unresectable 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 , Gandhi Mayank , Schulze Katja , Brockman JaneMichelle Michelle , Wang Xiaofei F. , Gao Junheng , Vokes Everett E. , Stinchcombe Tom 
Published: May 2020

9045 Background: A minority of the > 40,000 patients (pts) diagnosed with stage III NSCLC annually in the US are cured by CRT, more recently followed by adjuvant immune checkpoint inhibitors (ICI). PD-L1 blockade with CRT may attenuate tumor-related immunosuppression via depletion of regulatory T cells and clonal expansion of effector T cells. Further, CRT may expose otherwise hidden antigens that present additional targets to the reconstituting immune system. Adjuvant ICI has improved survival. Whether ICI before CRT will further improve outcomes is unknown. Methods: This Alliance Foundation Trials (AFT) study evaluated safety and efficacy of atezolizumab before and after CRT. 4 cycles of atezolizumab 1200 mg IV q 21 days with restaging after cycles 2 and 4 were followed by carboplatin and paclitaxel (C/P) weekly with 60 Gy radiation and C/P consolidation followed by atezolizumab for 1 year of therapy. Primary endpoint is disease control rate (DCR) (complete response + partial response (PR) + stable disease (SD)) at 12 weeks (wks). Secondary endpoints include overall response rate, progression-free survival, overall survival, safety and quality of life assessed by EORTC QLQ-30. Correlatives include PD-L1 and tumor mutation burden as predictive biomarkers. Tumor tissue was obtained at study entry; plasma and immune cells were isolated at multiple timepoints. Results: 64 pts with stage III NSCLC, performance status (PS) 0-1, no active autoimmune disease or significant organ dysfunction enrolled at 13 Alliance sites from 11/2017 to 7/2019. 62 pts received ≥ 1 dose of atezolizumab and are included in the primary analysis; median age 63.9 years (38.1-86.5), 51.6% female, 77.4% white, 61.3% former smokers, 56.5% PS 0. DCR at 12 wks was 77.4% (80% confidence interval 69.2-84.3%) (30.7% PR, 46.8% SD). 54 pts reported adverse events (AEs) during induction, mostly grade (gr) 1. There were 13 serious AEs, most unrelated to study treatment; 1 gr 3 anaphylactic reaction, 1 gr 3 colitis, and 1 gr 4 Guillain-Barre syndrome were attributable to atezolizumab. Baseline PD-L1 status was available for 49 pts. DCR was 82.4% for pts with PD-L1 negative and 90.9% for pts with PD-L1 positive tumors. Conclusions: Atezolizumab prior to and following CRT for stage III unresectable NSCLC was well tolerated with an encouraging 12-wk DCR. Analysis of secondary endpoints is ongoing. Further study of induction ICI therapy is warranted in patients with unresectable stage III NSCLC. Support: AFT, Genentech; Clinical trial information: NCT03102242.
Non-pneumonitis immune-mediated adverse events (imAEs) with durvalumab in patients with unresectable stage III NSCLC (PACIFIC).
Authors: Naidoo Jarushka , Vansteenkiste Johan F. , Faivre-Finn Corinne , Özgüroğlu Mustafa , Murakami Shuji , Hui Rina , Quantin Xavier , Broadhurst Helen , Newton Michael , Dennis Phillip A. , Antonia Scott Joseph 
Published: May 2020

9048 Background: The phase 3 PACIFIC trial established durvalumab (durva) after chemoradiotherapy (CRT) as SoC for pts with unresectable stage III NSCLC. We report exploratory analyses to characterize non-pneumonitis (np) imAEs that occurred with durva in PACIFIC. Methods: PACIFIC was a double blind trial of pts without disease progression after platinum-based concurrent CRT (≥2 cycles). Pts were randomized 2:1 to receive durva 10 mg/kg or placebo (pbo) IV q2w for ≤12 months, stratified by age, sex and smoking history. We characterized the time to onset, duration, and management/outcomes of np imAEs and their association with (1) baseline pt/disease factors and (2) AEs (excluding all-cause pneumonitis). Results: Of 709 treated pts, 19% and 11% experienced imAEs and np imAEs of any grade, respectively; proportionally more had np imAEs with durva (71/475; 15%) vs pbo (5/234; 2%). Thyroid disorders (54/475; 11%), rash/dermatitis (9/475; 2%), and diarrhea/colitis (5/475; 1%) were the most common np imAEs with durva; rash/dermatitis had the shortest time to onset (Table). Among durva treated pts with np imAEs, 11% had grade 3/4 np imAEs, 41% had np imAEs that resolved, and none had fatal np imAEs; interventions included endocrine replacement therapy (73%), systemic corticosteroids (34%), high dose corticosteroids (16%), and discontinuation (10%). There were no apparent differences in baseline factors between pts with or without np imAEs. Durva had a broadly manageable safety profile irrespective of the occurrence of np imAEs. However, a higher proportion of durva treated pts with vs without np imAEs experienced all-cause, grade 3/4 events (41% vs 29%); none were fatal (excl. pneumonitis). Conclusions: Np imAEs occurred infrequently in PACIFIC, but were more common with durva vs pbo; thyroid disorders and rash/dermatitis were the most common np imAEs. Of durva treated pts with np imAEs, 11% experienced np imAEs of grade 3/4. Overall, np imAEs were broadly manageable and did not lead to high rates of discontinuation, and no association with baseline factors was seen, suggesting this should not deter use of durva in eligible pts. Clinical trial information: NCT02125461. [Table: see text]
A gentle therapy: Weekly epirubicin, as second-line treatment in elderly patients with malignant pleural mesothelioma (MPM).
Authors: Bollina Roberto , Belloni Paolo , Pelliccione Michela 
Published: May 2020

9053 Background: MPM is a rapidly progressive tumor with a poor prognosis. Treatment options are limited for patients (pts) with PMP who experience disease progression after first-line pemetrexed-based chemotherapy (CT). This retrospective study wants to evaluate, in the age of immunotherapy, whether a gentle CT can be used as second line of treatment in elderly pts, above all maintaining quality of life (safety and tolerability ) and improving progession free survival (PFS ). Currently second-line CT is increasingly use, because many elderly pts are fit at the progression of the disease. No standard second/further line CT exist for MPM after failure of first-line pemetrexed based CT. The purpose of the study is to evaluate the clinical activity of weekly epirubicin as second-line CT in elderly with MPM. Methods: From July 2015 to March 2019, in Medical Oncology Dept. of ASST Rhodense 98 pts were elegible for analysis. Pts had histologically confermed unresectable MPM. Histology was epithelioid in 86 pts, sarcomatoid in 7 and biphasic in 5 pts. A Carboplatin(AUC4)-pemetrexed doublet was administered in 70 pts and 28 received gemcitabine as single agent how first line. A quality of life questionnaire was administered to each pt and geriatric comprehensive assessment (GCA) was performed. Epirubicin ( E ) was always administered with a schedule at 20 mg/msq day 1,8,15 every 28 until disease progression or intolerance. The primary endpoint was PFS, and secondary endpoints were the overall response rate (ORR) and QofL an overall survival (OS). Results: Of the 98 elegible pts, 71 was males, and 27 was female . Median age: 78 (range 72-86) PS: 0/1/2 was respectively in 32%, 60% and 8% of pts. A median of 5 cycles of E (range 2 -16) was delivered; 3% of pts required dose modification. PFS was of 7 months (range 3-16) . ORR was as follow: 0 CR, 18 PR (17%), 44 SD (44%) and PD occurred in 36 pts (39%). OS was 11 months (range 5-22). No life threatening event occurred. No grade 3-4 toxicities were observed . Liver toxicity grade 1-2in 10 pts (10%), thrombocytopenia grade 1 in 9 pts (9%), neutropenia grade 1-2 in 40 pts (40%), fatigue grade 2 in 33pts (32%), nausea grade 1 in 20 pts (20%). The analitical and stratified data will be exposed. Conclusions: Also in the era of immunotherapy, a simple treatment, E in weekly schedule has demonstrated to be a gentle therapy with a possibility to treat in second line, pre-treated elderly pts with MPM in progression after first line therapy, with an acceptable profile . Now this schedule could be considered as a safe and standard secon-line CT in elderly pts.
Peritoneal mesotheliomas characterized by less cell-cycle alterations and more TRAF7 alterations than malignant pleural mesotheliomas.
Authors: Offin Michael , Egger Jacklynn V. , Cercek Andrea , Nash Garrett Michael , Ladanyi Marc , Zauderer Marjorie Glass 
Published: May 2020

9059 Background: While peritoneal mesotheliomas (PM) are clinically distinct from malignant pleural mesotheliomas (MPM) it is unknown if genetic alterations reflect these differences. Here we report the molecular alterations and clinicopathologic characteristics of a prospectively collected PM cohort as compared to MPM. Methods: Patients with PM (n = 59) and targeted next generation sequencing (NGS; MSK-IMPACT) from January 2014 to January 2019 were assessed and followed through February 2020. Germline variants were analyzed in consented patients. NGS was compared to patients with MPM (n = 194) assessed in the same time interval. Results: Median age at diagnosis was 61 (range: 20-77), 56% were women (n = 33), and 92% had epithelioid histology (n = 54). 66% had ascites (n = 39) and 24% developed extra-abdominal metastases (n = 14; including lung, pleura, and mediastinum). 68% (n = 40) underwent surgical debulking and 80% (n = 47) had infusional therapy (median lines: 3) including platinum/pemetrexed (n = 38), EPIC (n = 22), HIPEC (n = 15), and immunotherapy (n = 16). The median overall survival (OS) from diagnosis was 5.4 years (median follow up 3.5 years). The median tumor mutation burden (TMB) was 1.8 mut/Mb (range: 0-14.9) in PM vs 2.0 mut/Mb (range: 0-31.5) in MPM (p = 0.049). More patients with PM had TRAF7 alterations than in MPM (5/59 vs 3/194; p = 0.02) while fewer had CDKN2A/ CDKN2B (4 vs 55; p = 0.0004). All patients with TRAF7 altered PM had well-differentiated papillary epithelioid histology. There was no difference in the prevalence of other common alterations such as BAP1 (32 vs 98; p = 0.66), NF2 (12 vs 55, p = 0.24), SETD2 (11 vs 24; p = 0.28), and TP53 (9 vs 28; p = 0.84) in PM vs MPM respectively. Patients with BAP1-altered PM had shorter OS (4.6 vs 9.8 years; HR 2.6, 95% CI 1.1-6.4; p = 0.04) while TRAF7-altered PM had improved OS (not reached vs 4.8 years; HR 0.3, 95% CI 0.1-0.9; p = 0.04) compared to wild type. 13% (4/30) of patients with PM had pathogenic variants on germline NGS ( POT1 I78T, MUTYH R109Y, BAP1 E402*, APC I1037K). Conclusions: NGS confirms the distinct biology of PM compared to MPM. Specifically, the former shows fewer cell cycle ( CDKN2) alterations compared to MPM. In contrast to MPM, BAP1 alteration was associated with shorter survival. As previously described, we found enrichment of TRAF7 in well differentiated papillary epithelioid PM associated with improved survival but notably some TRAF7 alterations were identified in poorly differentiated MPM. Consistent with other reports, the prevalence of germline alterations was 13%.
The impact of adjuvant therapy for non-metastatic thymic carcinoma: An analysis of the surveillance, epidemiology, and end results (SEER) database.
Authors: O'Neal Richard Lee , Vsevolozhskaya OIga , Hao Zhonglin 
Published: May 2020

9071 Background: Thymic Carcinoma is a rare malignancy with an aggressive clinical course. While the importance of surgery in the non-metastatic setting has been well defined, the optimal role of radiation and/or systemic therapy in this setting remains controversial. This study utilized the Surveillance, Epidemiology, and End Results (SEER) database to investigate the impact of adjuvant therapy on overall survival in patients with thymic carcinoma. Methods: We identified adults in the SEER database with thymic carcinoma diagnosed between 1989 to 2015 for analysis. As the primary treatment for non-metastatic thymic carcinoma is surgery, we excluded patients who did not have surgery as a component of their treatment Patients were categorized into Masaoka-Koga stage groups (I-IIa, IIb, III, and IV). Kaplan-Meier estimates of 10-year OS and multivariate Cox proportional hazards regression analyses were performed. Results: 515 patients met the inclusion criteria, of which 125 were stage I-IIa, 46 were stage IIb, 191 were stage III, and 143 were stage IV. A multivariate analysis was performed, adjusting for age, sex, race, and tumor size. When compared to surgery, no statistical improvement in survival was seen with adjuvant radiation or chemotherapy in stage I-IIa or IIb thymic carcinoma. In stage III disease, standard of care surgery was compared with adjuvant radiation (hazard ratio 0.69 (95% confidence interval 0.29 – 1.63], p = 0.39), adjuvant chemotherapy (hazard ratio [HR] 0.84 [95% confidence interval 0.28 – 2.53], p = 0.76), and adjuvant chemo-radiotherapy (HR 0.40 [0.18 – 0.93], p = 0.03). On Kaplan-Meier analysis, triple therapy (surgery + chemo-radiotherapy) was also associated with a marked improvement in 10-year overall survival at 55.3%, compared to 39.8%, 23.9%, and 20.8% (adjuvant radiation, adjuvant chemotherapy, and surgery alone, respectively). Conclusions: This study finds that in stage III thymic carcinoma, surgery followed by chemo-radiotherapy is associated with improved overall survival compared to single or dual-modality treatments. Because of the rarity of this disease, there are no large randomized studies evaluating the most appropriate treatment modalities, therefore this data may assist with clinical decision making in non-metastatic thymic carcinoma.
Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01.
Authors: Smit Egbert F. , Nakagawa Kazuhiko , Nagasaka Misako , Felip Enriqueta , Goto Yasushi , Li Bob T. , Pacheco Jose Maria , Murakami Haruyasu , Barlesi Fabrice , Saltos Andreas Nicholas , Perol Maurice , Udagawa Hibiki , Saxena Kapil , Shiga Ryota , Guevara Ferdinand M. , Acharyya Suddhasatta , Shahidi Javad , Planchard David , Janne Pasi A. 
Published: May 2020

9504 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a phase I trial, patients (pts) with HER2-mutated NSCLC who received T-DXd had a confirmed objective response rate (ORR) of 72.7% (8/11) (Tsurutani et al, WCLC 2018). DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase II study of T-DXd in pts with non-squamous NSCLC overexpressing HER2 or containing a HER2-activating mutation. We report data for the cohort with HER2 mutations after a median follow-up of 8.0 mo (range, 1.4-14.2 mo). Methods: Pts were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR (complete response [CR] + partial response [PR]) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety. Results: At data cutoff (25 Nov 2019), 42 pts (64.3% female) had received T-DXd. Median age was 63.0 years (range, 34-83 years; < 65 y, 59.5%); 45.2% had central nervous system metastases; ECOG performance status was 0 in 23.8% of pts and 1 in 76.2%. HER2 mutations were predominantly in the kinase domain (90.5%). Most pts (90.5%) had prior platinum-based chemotherapy and 54.8% had anti–PD-1 or –PD-L1 treatment; median number of prior treatment lines was 2 (range, 1-6). Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of pts remained on treatment. Confirmed ORR by ICR among the 42 pts was 61.9% (95% CI, 45.6%-76.4%); median DOR was not reached at data cutoff; 16 of 26 responders remained on treatment at data cutoff; DCR was 90.5% (95% CI, 77.4%-97.3%); estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo). All pts (42/42) had treatment-emergent adverse events (TEAEs); 64.3% were grade ≥ 3 (52.4% drug-related), including decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (all grade 2, no grade ≥ 3) and 1 case of grade 1 ILD is pending adjudication. TEAEs led to dose interruption in 25 pts (59.5%), dose reduction in 16 pts (38.1%), and treatment discontinuation in 10 pts (23.8%). Conclusions: T-DXd demonstrated promising clinical activity with high ORR and durable responses in pts with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies. Clinical trial information: NCT03505710 .