bluuebunny/crossref_metadata_2025 huggingface dataset:
Bortezomib induction prior to autologous hematopoietic cell transplantation (AHCT) for newly diagnosed light chain amyloidosis (AL): A study of 426 patients.
Authors: Cornell Robert F. , Hari Parameswaran , Goodman Stacey , Costa Luciano J. , Fraser Raphael , Estrada-Merly Noel , Kumar Shaji , Qazilbash Muzaffar H. , D'Souza Anita
Published: May 2020

8515

Background: AL is a clonal plasma cell (PC) disorder causing multiorgan dysfunction from amyloid fibril deposition. While bortezomib (B) induction has been used prior to AHCT recently, AHCT without prior induction has been a common practice. The primary objective of this study was to compare outcomes of AL patients who proceeded to AHCT without induction to those receiving pre-AHCT induction with B. Methods: Outcomes of 426 systemic AL AHCT recipients between 2014-2018 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were reviewed. Patients receiving induction with therapy other than B, AHCT occurring > 9 months after diagnosis, no documented AL end-organ involvement, myeloma-defining events and conditioning other than melphalan (MEL) monotherapy were excluded. Multivariate analysis (MVA) was conducted to identify prognostic factors associated with relapse, PFS and overall survival (OS). Results: 286 patients received B induction therapy vs 140 patients receiving no induction. Age, gender, number and type of organs involved, and AL AHCT center volume were similar between the groups. Patients receiving induction had greater PC burden compared with no induction (PC ≥ 10%, 41% vs 11%, p < 0.01). Induction was B, cyclophosphamide and dexamethasone (D) in 83% followed by B, lenalidomide and D (10%) or B+D (7%). Median follow-up was 24.9 months. At 2 years, B induction vs. no induction was associated with 13% (95% CI 10-17%) vs 22% (95% CI 15-30%) relapse risk (p = 0.03); 83% (95% CI 79-87%) vs 74% (95% CI 66-81%) PFS (p = 0.04); 93% (95% CI 90-95%) vs 94% (95% CI 89-97%) OS (p = 0.7). On MVA, the B induction group had improved PFS (HR 0.46, 95% CI 0.3-0.7, p < 0.001) with similar OS (HR 0.6, 95% CI 0.3-1.2, p = 0.1) compared with no induction. Creatinine < 2 mg/dl (HR 0.55, 95% CI 0.3-0.9, p = 0.02) and Karnofsky score ≥90 (HR 0.51, 95% CI 0.33-0.78, p < 0.01) were also associated with improved PFS. MEL dose < 180 mg/m2 was associated with inferior PFS (HR 2.17, 95% CI 1.31-3.61, p < 0.01) and OS (HR 3.6, 95% CI 1.5-8.6, p < 0.01). No deaths were seen in the first 100 days post-AHCT. At last follow-up, 32 deaths occurred, 26 (81%) due to AL. Conclusions: Compared with prior CIBMTR analyses, B induction use has increased in AL AHCT recipients and a higher PC burden was the only clinical determinant. Furthermore, B induction was associated with lower relapse and improved PFS at 2 years with no OS difference despite higher proportion of patients with > 10% PC, which has been associated with poor outcomes.
Pharmacodynamic (PD) responses drive dose/schedule selection of CC-92480, a novel CELMoD agent, in a phase 1 dose-escalation study in relapsed/refractory multiple myeloma (RRMM).
Authors: Wong Lilly , Jiménez Nuñez María Dolores , Bahlis Nizar J. , Vangsted Annette J. , Ramasamy Karthik , Trudel Suzanne , Martínez Joaquín , Mateos Maria-Victoria , Rodríguez Otero Paula , Lonial Sagar , Popat Rakesh , Oriol Albert , Karanes Chatchada , Orlowski Robert Z. , Berdeja Jesus G. , Wang Maria , Lamba Manisha , Pourdehnad Michael , Pierce Daniel W. , Richardson Paul G.
Published: May 2020

8531

Background: CC-92480 is a novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent under investigation in a first-in-human phase 1 study (NCT03374085) in RRMM patients (pts). In preclinical studies, CC-92480 demonstrated efficient and sustained degradation of Ikaros/Aiolos leading to broad antiproliferative effects and induction of apoptosis in MM cell lines, and enhanced immune stimulatory effects. Methods: Eligible RRMM pts received escalating doses of CC-92480 + dexamethasone. Several dosing schedules were evaluated in parallel; more continuous with 4-day or 7-day breaks and intensive with longer breaks in a 28-day cycle. Peripheral blood and bone marrow aspirates (BMA) were taken before and during treatment at multiple time points. Levels of Ikaros/Aiolos in T cells, and effects on immunomodulation were assessed by flow cytometry. Weekly levels of free light chain (sFLC) and B-cell maturation antigen (sBCMA) were determined in serum during the first 2 cycles of treatment. BMA clots were analyzed by immunohistochemistry for CRBN, Ikaros, Aiolos, ZFP91, c-Myc, and IRF-4. Results: The rate and depth of Ikaros/Aiolos degradation in T cells increased with dose and reached maximal at ≥0.6 mg QD with sustained degradation over 24 hrs. Substrate recovery occurred during drug holidays with faster recovery at lower doses, and reached full recovery with ≥7-day break for all dose levels tested. B cells decreased with increasing dose, and T-cell proliferation was demonstrated at all doses/schedules. Substrate degradation was also evident in bone marrow plasma cells including in the setting of low CRBN levels. In these heavily pretreated, including triple-class-refractory, RRMM pts, CC-92480 dosing periods led to rapid and sustained decreases in sFLC and sBCMA. This was dose and schedule dependent and correlated with plasma exposure; the longer breaks in the intensive schedules led to rapid rebound of these markers, while the more continuous schedules maintained the depth of suppression. Conclusions: PD responses correlated with dose and schedule. PD samplings at multiple time points during treatment allowed dynamic changes and kinetics of each biomarker in all schedules to be followed and to inform next steps. Ikaros/Aiolos degradation and recovery, coupled with changes in sFLC and sBCMA, guided the adjustment of the dosing schedule during dose escalation in order to optimize efficacy and tolerability. The study is ongoing and selection of the recommended phase 2 dose is pending.
Characteristics and outcome of patients with MYD88 wild-type Waldenström Macroglobulinemia.
Authors: Zanwar Saurabh , Abeykoon Jithma P. , Ansell Stephen M. , Paludo Jonas , Gertz Morie A. , Thompson Carrie A. , King Rebecca L. , He Rong , Benanni Nora N , Gonsalves Wilson I. , Nowakowski Grzegorz S. , Muchtar Eli , Warsame Rahma M. , Kyle Robert A. , Kumar Shaji , Kapoor Prashant
Published: May 2020

8550

Background: Waldenström Macroglobulinemia (WM) is a rare lymphoplasmacytic malignancy characterized by the presence of a recurrent point mutation in the MYD88 gene (MYD88L265P) in 80-95% of cases. Patients with MYD88WT genotype comprise a small subset that responds poorly to ibrutinib and other Bruton tyrosine kinase inhibitors. We examined the characteristics and outcome of WM patients with MYD88WT genotype predominantly treated with non-BTK inhibitor based therapies. Methods: Patients with a diagnosis of WM seen at Mayo Clinic, Rochester, between 1996 and 2018 were included. Their characteristics and outcomes were assessed from the time of active disease. Marrow MYD88 genotyping was assessed with an allele specific PCR assay (analytic sensitivity 1%). Categorical and continuous variables were compared using Chi square and Wilcoxon tests, respectively. Time-to-event analyses were performed using Kaplan Meier test. Results: Of 986 patients with active WM, MYD88 genotype data were available in 331 (34 %) patients; 72 (22%) and 260 (78%) patients harbored MYD88WT and MYD88L265P genotypes, respectively. The median follow-up was 5.8 years (95% CI: 5.0-6.5 years) from active WM; 6 years MYD88WT vs 5.4 years for MYD88L265P cohort. Median age was 63 years and 66 years in the MYD88WT and MYD88L265P cohorts, respectively (p = 0.07) with 46% and 53% patients being ≥65 years of age, respectively (p = 0.36). Pre-treatment marrow lymphoplasmacytic (LPL) infiltrate (median 40% for MYD88WT vs 60% for MYD88L265P; p = 0.001) and beta-2 microglobulin (median 3 µg/mL for MYD88WT vs 3.9 µg/mL for MYD88L265P; p = 0.02) were lower in the MYD88WT compared to the MYD88L265P cohort; other laboratory parameters at active disease were comparable. Per IPSSWM prognostic criteria, MYD88WT had fewer patients in the high risk group (18% for MYD88WT vs 42% MYD88L265P; p = 0.03). Patients with MYD88WT had higher likelihood of histological transformation [18% for MYD88WT vs 4% for MYD88L265P; odds ratio 5.8 (95% CI: 2.5-13.5; p < 0.0001)]. Among patients with treatment data available, only 35 (11%) patients received ibrutinib. The 5-year overall survival (OS) from active disease was comparable (85% in MYD88WT vs 82% in MYD88L265P cohort; p = 0.7). Conclusions: MYD88WT genotype in WM is associated with lower marrow LPL infiltration, lower likelihood of high-risk IPSSWM categorization and a higher likelihood of histological transformation in comparison to MYD88L265P mutant subpopulation. MYD88 genotype does not affect the OS from active disease in predominantly non-BTK inhibitor treated patients.
KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer.
Authors: Binkley Michael S , Jeon Young-Jun , Nesselbush Monica , Moding Everett J , Nabet Barzin , Almanza Diego S , Yoo Christopher , Kurtz David Matthew , Owen Susie Grant , Backhus Leah Monique , Berry Mark F. , Shrager Joseph B , Ramchandran Kavitha , Padda Sukhmani Kaur , Das Millie , Neal Joel W. , Wakelee Heather A. , Alizadeh Ash A. , Loo Billy W. , Diehn Maximilian
Published: May 2020

9012

Background: Tumor genotyping in localized non-small cell lung cancer (NSCLC) is not broadly performed due to lack of actionable associations of mutations with treatment or outcome. We sought to identify recurrent mutations in localized NSCLC that are associated with local recurrence (LR) after radiotherapy (RT) or surgery. Methods: We identified consecutive patients with NSCLC treated with chemoradiotherapy (CRT), stereotactic ablative radiotherapy (SABR) or surgery from 2009-2018 at our institution with stage IA1-IIIC NSCLC who had genotyping performed on tumor tissue using a targeted gene panel. Our primary objective was to identify somatic tumor mutations that predicted LR after RT but not surgery. We also performed functional screening assays by expressing open reading frame constructs harboring patient-derived mutations in knock-out cell lines generated by CRISPR-Cas9 and evaluating effects on in vitro radioresistance. Results: We identified 232 consecutive patients with localized NSCLC (87.1% adenocarcinoma, 10.3% squamous, 2.3% other) who received tumor biopsy or resection specimen and underwent tumor genotyping. 47 patients with locally advanced NSCLC received CRT, 50 patients with early stage NSCLC received SABR, and 135 patients with early stage NSCLC underwent surgical resection. Of all recurrent mutations ( > 5% mutation frequency), only mutations in Kelch-like ECH-associated protein 1 ( KEAP1) or Nuclear Factor Erythroid 2-Related Factor 2 ( NFE2L2) genes (K/NMUT) were significantly associated with LR after CRT or SABR, with 2-year LR in the combined RT cohort of 42.4% for K/NMUT versus 12.5% for wildtype (P = 0.005). Furthermore, K/NMUT were present in nearly half of all LR events. Strikingly, there was no significant difference in LR for K/NMUT tumors following CRT versus SABR (P = 0.47). Local recurrence was rare for patients who received surgery (n = 2) and was not associated with K/N mutation status (P = 0.60). Functional evaluation by expression of K/N mutations in knock-out cell lines revealed that LR only occurred in patients with mutations that induced radioresistance (i.e. pathogenic) but not passenger mutations (P = 0.04). In contrast to genotyping, NFE2L2 target gene expression analysis via RNA-seq did not predict LR (P = 0.93). Conclusions: Our findings suggest that KEAP1/NFE2L2 mutations are a predictive biomarker of clinical radioresistance and a dominant cause of LR after RT. Genotyping for KEAP1/NFE2L2 mutations could therefore facilitate treatment personalization in localized NSCLC.
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 .
ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions.
Authors: Piotrowska Zofia , Wang Yating , Sequist Lecia V. , Ramalingam Suresh S.
Published: May 2020

9513

Background: EGFR exon 20 insertions (ins20), which comprise 4-10% of EGFR-mutant NSCLC, are generally refractory to first- and second-generation EGFR TKIs. While the clinical activity of the third-generation EGFR TKI osimertinib against EGFR ins20 is unknown, preclinical studies suggest its favorable therapeutic window may allow for inhibition of EGFR isn20 at clinically-achievable doses (Hirano, Oncotarget 2015). We report the results of EA5162, a single-arm, phase II study of osimertinib 160 mg in NSCLC pts with EGFR ins20 (NCT03191149). Methods: Pts with advanced NSCLC with an EGFR ins20 mutation identified by any local, CLIA-certified tissue assay were treated with osimertinib 160 mg daily until progression, intolerable toxicity or withdrawal. At least one prior line of therapy was required; stable, asymptomatic brain metastases were allowed. The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival. The estimated sample size was 19 patients. Results: 21 pts were enrolled between 4/2018 and 7/2019 (median age 65; 15 female, 6 male; median 2 prior therapies); 1 patient did not meet eligibility criteria due to laboratory studies obtained 1 day out of window. As of 1/21/20, 6 pts remain on treatment. Among the 20 eligible pts, the best response was PR in 4 pts and CR in one pt, for a confirmed ORR of 25%; 12 (60%) pts had SD. The median PFS was 9.7 months (95% CI, 4.07, NA), median duration of response (DOR) was 5.7 months (95% CI, 4.73, NA.) Grade > 3 treatment-related adverse events (TRAE) observed in > 1 pt included anemia (n=2), fatigue (n=2), prolonged QT interval (n=2.) One pt had grade 4 respiratory failure, there were no grade 5 TRAEs. One pt discontinued study treatment due to grade 3 anemia. Conclusions: Osimertinib 160mg daily is well-tolerated and showed clinical activity in EGFR ins20-mutant NSCLC with a response rate of 25%, disease control rate of 85%, and mPFS of 9.7 months. The adverse events with osimertinib 160 mg QD in this cohort were consistent with other reports of this regimen; grade 3 rash and diarrhea were not observed. Clinical trial information: NCT03191149 .
PREDICT1: An observational study for identifying blood biomarkers associated with clinical benefit from carboplatin and pemetrexed (CbP) treatment in patients with non-squamous (NS) non-small cell lung cancer (NSCLC) (CJLSG1201).
Authors: Hase Tetsunari , Yanagisawa Kiyoshi , Fukatsu Asuki , Kimura Tomoki , Kojima Eiji , Abe Takashi , Imaizumi Kazuyoshi , Horio Yoshitsugu , Oguri Tetsuya , Yamamoto Masashi , Ogasawara Tomohiko , Sugino Yasuteru , Morise Masahiro , Nakatochi Masahiro , Ando Masahiko , Kondo Masashi , Saka Hideo , Saito Hiroshi , Hasegawa Yoshinori , Takahashi Takashi ,   Central Japan Lung Study Group, Chubu Regional Consortium for Advanced Medicine
Published: May 2020

9524

Background: At present, platinum-doublet chemotherapy or in combination with an immune check point inhibitor are standard treatment for patients with metastatic or recurrent NSCLC which lacks somatic gene alterations. Although CbP is one of the commonly used treatment options for NS-NSCLC, its clinical utility is limited due to lack of optimal biomarkers. Methods: Chemotherapy-naïve patients with pathologically proven advanced or recurrent NS-NSCLC received carboplatin (area under the curve = 5-6, at investigator’s discretion) plus pemetrexed (500 mg/m2) every 3 weeks followed by maintenance pemetrexed until disease progression. Blood samples were collected before treatment for proteomic analysis using mass spectrometry (MS). A classifier was constructed based on both an objective response assessed by radiologist independent of attending physicians in accordance with RECIST v1.1 and expression profiles of protein in a training cohort. The constructed classifier was then assessed with a validation cohort evaluating prediction accuracy of good responder, progression free survival (PFS) and overall survival (OS). Results: Of 244 patients with NS-NSCLC in a training cohort, proteomic profiles in blood from 96 patients who responded or progressed after treatment with CbP were analyzed to develop a classifier based on weighted voting. Details of the classifier will be presented at the 2020 ASCO Annual Meeting. The classifier was then applied to validation cohort (n = 94), and we successfully identified patients who benefit from the treatment (55 in good MS group) or not (39 in poor MS group). The objective response rate of the good MS group was significantly higher than that of the poor MS group (30.9% vs. 5.1%; p = 0.0018). The good MS group showed a significantly improved survival compared to the poor MS group (median PFS, 6.0 m vs. 2.3 m; hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.09-0.27; p < 0.001; median OS, 25.7 m vs. 5.1 m; HR, 0.18; 95% CI, 0.1-0.34; p < 0.001). Conclusions: In the present study, we successfully developed and validated a predictive classifier using proteomic analyses with blood samples collected from patients before treatment with CbP, suggesting the clinical utility of the classifier in selecting NS-NSCLC patients for treatment with CbP. Clinical trial information: UMIN000008476 .
RELAY study of erlotinib (ERL) + ramucirumab (RAM) or placebo (PL) in EGFR-mutated metastatic non-small cell lung cancer (NSCLC): Biomarker analysis using circulating tumor DNA (ctDNA) in Japanese patients (pts).
Authors: Nishio Kazuto , Sakai Kazuko , Seto Takashi , Nishio Makoto , Garon Edward B. , Reck Martin , Goto Koichi , Kato Terufumi , Nakanishi Yoichi , Takahashi Toshiaki , Yamamoto Nobuyuki , Kiura Katsuyuki , Ohe Yuichiro , Tamura Tomohide , Visseren-Grul Carla M , Hozak Rebecca R. , Wijayawardana Sameera R. , Enatsu Sotaro , Nakagawa Kazuhiko
Published: May 2020

9527

Background: The phase III RELAY study (NCT02411448) showed significantly improved progression-free survival (PFS) for RAM+ERL vs PL+ERL in 449 pts with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4 mo, HR 0.591 [95% CI 0.461–0.760], p<.0001). To understand baseline genetic mutations and treatment-emergent (TE) resistance mechanisms, this exploratory liquid biopsy substudy examined biomarkers in ctDNA from participating Japanese pts by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). Methods: Plasma samples were collected at baseline, during treatment (Cycle 4, 13, and every 6 cycles to Cycle 53) and post-study treatment discontinuation (30-day follow-up [30d FU]). Mutations were assessed at baseline and 30d FU by NGS (Ion AmpliSeq Colon and Lung Cancer panel). EGFR mutations and MET and ERBB2 copy number (CN) were assessed at all time points by ddPCR. Baseline markers were analyzed in pts with any detectable baseline mutation (to confirm ctDNA presence; NGS N=84, ddPCR N=74). TE mutations were analyzed in pts with any detectable mutation at baseline and 30d FU (NGS N=26, ddPCR N=28). Among these pts, 81% and 57% for NGS and ddPCR, respectively, had progressed by 30d FU. Results: By plasma NGS, baseline EGFR activating mutations (exon 19 deletion or exon 21 [L858R] mutation) were detected in 83.3% of pts. Common co-occurring baseline mutations were TP53 (42.9%), PTEN (7.1%) and KRAS (6.0%). Baseline TP53 mutation rate was higher in men vs women (p=.02). No difference in PFS was detected by baseline TP53 status (interaction predictive p=.45, prognostic p=.33). TE mutations were detected in EGFR (including T790M), FGFR3, KRAS and TP53. Slightly higher rates of TE KRAS (p=.03) and TP53 (p=.07) mutations were detected in RAM+ERL than in PL+ERL. TE total EGFR mutations (p=.65) or TE T790M (p=.69) did not differ by arm. By ddPCR, baseline EGFR activating mutations were detected in all pts. T790M was detected at baseline in 2/37 pts/arm (5.4%) and was TE in 6/11 (55%) RAM+ERL pts and 7/17 (41%) PL+ERL pts. There was a trend (p=.054) for greater ERBB2 CN in RAM+ERL vs PL+ERL at Cycle 4. MET CN decreased slightly at Cycle 4 in both arms (significant in PL+ERL, p=.003). Biomarker levels by ddPCR across all time points will be presented. Conclusions: Though limited by sample size and likely inconsistent tumor shedding, this exploratory study identified potential differences in TP53, KRAS, ERBB2 and MET by demographics, treatment and/or time. Clinical trial information: NCT02411448 .
Effect of performance status on survival with pembrolizumab monotherapy in advanced non-small cell lung cancer (NSCLC).
Authors: Sehgal Kartik , Bindal Poorva , Koshy Anita Geevarghese , Gill Ritu R. , McDonald Danielle C , Rangachari Deepa , Costa Daniel Botelho
Published: May 2020

9533

Background: Pembrolizumab (P) is now widely used as standard of care (SOC) in advanced NSCLC. We sought to identify prognostic factors influencing survival with it in a real-world setting. Methods: We conducted a retrospective cohort study of with advanced NSCLC patients who initiated treatment with SOC P monotherapy at our center from 2/11/16 to 10/15/19 (data cutoff 1/15/20). Patient demographic, clinicopathologic, therapeutic and outcomes data were extracted. Survival time was defined from start of P. Cox proportional hazards and logistic regression were utilized. Results: Of 74 patients with median follow up of 83.9 weeks, 30 (40.5%) were alive at cutoff. Patient characteristics at start of therapy were: 36 (48.6%) female, median age 68.5 yr (range 33-87), 10 (13.5%) with symptomatic brain metastases; 54 (72.9%) treatment-naïve, 29 (39.2%) with ECOG performance status (PS) ≥2. Tumor characteristics were: 53 (71.6%) with PD-L1 tumor proportion score (TPS) ≥50%, median PD-L1 TPS 75% (range 1-100), tumor mutational burden (TMB) tested in only 37 (50%) patients, median TMB 8 mut/mB (range 1-62). Any grade immune-related adverse events (irAE) occurred in 33 (44.6%) patients, while 16 (21.6%) received systemic steroids. Median survival was 43.3 wks (95% CI 29-104.1). Multivariable regression showed ECOG PS of ≥2 as the strongest risk factor for death (Table). We next evaluated differences in characteristics of patients who were alive vs dead within 12 wks of starting P, by which initial response assessments are completed in routine practice. ECOG PS was the only significantly different baseline variable, even after multivariable adjustment (p = 0.002). Conclusions: ECOG PS of ≥2 is a poor prognostic risk factor associated with P monotherapy in advanced NSCLC. Though comprising a clinically significant subset of patients in real-world, they were not included in landmark trials (KEYNOTE-024 & 042). Prospective evaluation is warranted. [Table: see text]
Interaction between CAF and CD8+ T cells in non-small cell lung cancer affects prognosis and efficacy of immunotherapy.
Authors: Zheng Xinlong , Zeng Dongqiang , Peng Wenying , Li Pansong , Li Lifeng , Gao Xuan , Zhou Zhipeng , Bai Jing , Li Junhui , Ding Jianming , Wang Deqiang , Zheng Suya , Miao Qian , Jiang Kan , Wu Biao , Long Feng , Li Chao , Xu Haipeng , Yin Yi , Gen Lin
Published: May 2020

9536

Background: Cancer-related fibroblasts (CAFs) are important components of the tumor microenvironment (TME) and play a key role in tumor progression. There is growing evidence that CAF levels in tumors are highly correlated with treatment response and prognosis. However, the effect of CAFs on immunotherapy response remains unknown. Methods: RNA-seq and clinical data were downloaded from TCGA and GEO. The SVA package ComBat function was used to remove batch effects. The ssGSEA algorithm was used to assess the level of cell infiltration in each sample. OS (overall survival) and DFS (disease free survival) were analyzed using the Kaplan–Meier method. GO enrichment analysis was used to assess the biological processes of subgroup differential genes. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and subclass mapping were used to predict the clinical response to immune checkpoint blockade. Results: We evaluated the infiltration abundance of 24 types of immune cells and fibroblasts in 1768 NSCLC samples and found that almost all IMFRs (immune cells / fibroblasts) are beneficial to the prognosis. This phenomenon is called “CAFs-mediated immune resistance pattern (CMIRP)”. We evaluated the infiltration abundance of 24 types of immune cells and fibroblasts in 1768 NSCLC samples and found that almost all IMFRs (immune cells / fibroblasts) are beneficial to the prognosis. This phenomenon is called “CAFs-mediated immune resistance pattern (CMIRP)”. The prognosis according to CD8+ T cells was not strong, but CD8+ T cells / fibroblasts (CFR) were significant protective prognostic factors [n = 1588; hazard ratio (HR), 0.66; 95% confidence interval (CI), 0.56–0.78; P < 0.001]. Multivariate analysis revealed that the CFR was an independent prognostic biomarker. The TCGA pan-cancer cohort confirmed the widespread presence of CMIRP in cancer. We further defined the CFR high and CFR low subgroups. CFR high samples were enriched with immune activation pathways including T cell activation, cytolysis, and antigen presentation, while CFR low was associated with immunosuppression including activation of transforming growth factor β, epithelial-mesenchymal transition, and angiogenesis pathways. Finally, we combined TIDE and submap to speculate that CFR is a potential prognostic marker of immunotherapy for NSCLC. Conclusions: We proposed the term “CMIRP” to shed light on a more accurate assessment of immune status. CFR is a potential marker for prognosis and predictive efficacy of immunotherapy in NSCLC.