bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptome-wide mutation discovery in patients in a phase II clinical trial of first-line erlotinib for clinically selected patients with advanced non-small cell lung cancer
Authors: Laskin J. J. , Pugh T. , Jackson C. , Sutcliffe M. , Ionescu D. , Melosky B. , Ho C. , Sun S. , Murray N. , Marra M. 
Published: August 2020

8102 Background: The purpose of this study was to clinically select a population of patients (pts) likely to benefit from erlotinib and to perform extensive genetic profiling of fresh tissue tumour to identify predictive biomarkers. Methods: Treatment was erlotinib 150 mg p.o. daily until disease progression. Eligibility criteria included: stage IIIB/IV NSCLC; no prior chemo; ECOG ≤2; at least 2 of the following 4 criteria: women, never-smokers, Southeast Asian origin, adenocarcinoma and/or BAC. All pts had baseline serum samples and a fresh frozen tumour biopsy. EGFR and KRAS were sequenced using traditional methods to identify known mutations of erlotinib. Transcribed coding regions of all other expressed genes were sequenced to uncover novel mutations and other genetic features. Results: From Sept-06 to Oct-08, 65 pts have been enrolled. Of these 60 have completed at least 8 wks of erlotinib (or progressed before 8 wks). 49F and 11M; 45 never smokers. PS 0/1/2: 10/39/11. 18 Caucasian and 42 Asian. Pathology: 44 ACA; 3 BAC;1 squamous carcinoma; 13 NSCLC NOS. Responses: PR - 21 (35%); SD - 24 (DCR 75%); PD - 10; NE - 5. 85% did not progress at 8 weeks. 19 of 51 (37%) pre-treatment samples had an EGFR mutation. 10 of the 28 pts with response data (24pts still on drug) had a PR and 7 of these had either an LREA deletion or L858R point mutation. 1 of 3 post-treatment samples developed a T790M mutation on erlotinib. 3 of 51 pts have KRAS mutations. Analysis of over 21 Giga basepairs of aligned transcriptome sequencing data from 20 tumour samples has uncovered 1089 putative non-conservative gene mutations of which 15 are seen in multiple tumours: TUBA1C, EPS8L1, ARID4B, RPL22, C20orf52, CCT8, HLA-DRB5, TRIP6, and PLP2 in 4 tumours, C20orf52 and CTSL1 in 5 tumours, and SERF2, TMEM173, and an uncharacterized gene in 6 tumours. Conclusions: Clinical selection of pts enriches the EGFR mutation positive and KRAS mutation negative population and leads to high rates of non-progression. Full tumour RNA analysis identified several recurrent mutations that may describe mechanisms of erlotinib response and resistance. The discovery of novel mutations in multiple pts suggests patterns that may shed light on lung cancer specific behaviour. [Table: see text]
Results of a phase II trial of single-agent amrubicin (AMR) in patients with extensive disease small cell lung cancer (ED-SCLC) refractory to first-line platinum-based chemotherapy: An update
Authors: Ettinger D. S. , Jotte R. , Lorigan P. , Gupta V. , Garbo L. , Conkling P. , Spigel D. , McNally R. , Renschler M. , Oliver J. 
Published: August 2020

8103 Background: Amrubicin (AMR), a third-generation synthetic anthracycline and potent topoisomerase II inhibitor, is approved in Japan for the treatment of lung cancer. Patients (pts) with SCLC, who are refractory to first-line chemotherapy or progress within 3 months (mos) of treatment completion, are less likely to respond to additional chemotherapy and have an expected median survival of 3–5 mos. Here, we investigate the efficacy and safety of single-agent AMR in the treatment of Western pts with refractory ED-SCLC. Methods: In this phase II trial, pts with ED-SCLC refractory to prior 1st-line platinum-based chemotherapy (defined as progression (PD) while on therapy or relapse within 90 days of treatment completion) and ECOG performance status (PS) ≤2 were eligible. Patients were treated with intravenous AMR 40 mg/m2/day x 3 days every 21 days until PD or intolerable toxicity. The primary endpoint was response rate (ORR, by RECIST), with a goal to demonstrate an ORR ≥18% (point estimate). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: In all, 75 pts were enrolled with a median age of 63 years (range 43–88), 52% female, 17% PS 2. Response to 1st-line therapy was 5% complete remission (CR), 36% partial remission (PR) and 28% PD. Median time from completion of 1st-line therapy to PD was 1.3 mos. Sixty-nine pts received AMR for a median of 4 cycles (range 1–12). Six pts died or discontinued before receiving treatment. The primary endpoint was met with an ORR of 21% (16/75, 95% confidence interval [CI] 13.6% - 31.9%), including CR in 1 pt (1%) and PR in 15 pts (20%). Stable disease was achieved in 40% of pts. Two pts with PD as best response to 1st line chemotherapy achieved a PR. Median OS was 6.0 mos (95% CI 4.8–7.1 mos). Median PFS was 3.2 mos (95% CI 2.4–4.0 mos). The most common grade 3 or 4 adverse events were neutropenia (65%), thrombocytopenia (39%), and leukopenia (35%). Seven (10%) patients experienced febrile neutropenia. Dose reductions were required in 26 patients (38%). Conclusions: AMR shows promising activity, with an ORR of 21%, and an acceptable safety profile in patients with refractory ED-SCLC, and warrants further study in these pts. [Table: see text]
Phase II study of RAD001 (everolimus) in previously treated small cell lung cancer (SCLC)
Authors: Kotsakis A. P. , Tarhini A. , Petro D. , Flaugh R. , Vallabhaneni G. , Belani C. P. , Friedland D. , Argiris A. 
Published: August 2020

8107 Background: Everolimus (E) is an oral inhibitor of mammalian target of rapamycin (mTOR), a novel target for anti-cancer therapy that plays a central role in the PI3K/AKT signaling pathway and other pathways that mediate tumor growth, proliferation, and angiogenesis. E has shown preclinical activity in SCLC cell lines and xenograft models. Methods: Eligibility included SCLC with disease progression after up to 2 prior chemotherapy regimens, ECOG performance status (PS) 0–2, and adequate bone marrow, liver, and kidney function. Patients (pts) were treated with E 10 mg, orally, once daily. Primary endpoint was the disease control rate (DCR), i.e. complete response (CR), partial response (PR) and stable disease (SD), after 2 cycles of E (6 weeks) in pts who received at least 1 cycle. A 2-stage design was followed. PI3K/AKT signaling pathway molecular biomarkers (AKT, pAKT, PTEN, P-S6, p-4E- BP1) will be evaluated on baseline tumor tissue. Results: 40 pts were enrolled; 14 males/26 females; median age 64 years (44–80); PS 0: 17, PS 1: 23; prior chemotherapy status: 1 prior regimen/sensitive relapse (i.e. relapse >60 days from completion of first-line chemotherapy): 23 pts; 1 prior regimen/refractory: 4 pts; 2 prior regimens: 13 pts. 28 pts (70%) received ≥ 2 cycles of E, 7 (18%) 1 cycle and 5 (12%) did not complete the first cycle of E due to adverse events or early progression. Best response in 35 evaluable patients: 1 (3%) PR, 8 (23%) SD and 26 (74%) progression; DCR at 6 weeks was 26% with a duration of disease control of 2.7–6.3 months; median progression-free survival 1.4 months; and median overall survival 5.5 months. No grade 4 toxicity was seen. Grade 3 toxicities included thrombocytopenia (2), neutropenia (2), infection (1), pneumonitis (1), fatigue (1), elevated transaminases (1), hyperglycemia (1), diarrhea (1), and acute renal failure due to dehydration from diarrhea and poor oral intake (1). Conclusions: E is well tolerated but has limited single-agent antitumor activity in unselected patients with pretreated SCLC. [Table: see text]
R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by autologous stem cell transplantation: CORAL study
Authors: Gisselbrecht C. , Glass B. , Mounier N. , Gill D. , Linch D. , Trneny M. , Bosly A. , Shpilberg O. , Ketterer N. , Moskowitz C. , Schmitz N. 
Published: August 2020

8509 Background: Salvage chemotherapy followed by high dose therapy and autologous stem cell transplantation (ASCT) is the standard of treatment for chemosensitive relapses in diffuse large B cell lymphoma. This intergroup trial compared the association rituximab, ifosfamide, etoposide, carboplatinum, R-ICE and rituximab dexamethasone aracytine and cisplatinum R-DHAP. Methods: DLBCL CD 20+ in first relapse or pts refractory after first line therapy were randomized between R-DHAP and R-ICE. Responding patients received BEAM and ASCT and were randomized between observation or maintenance with rituximab for 1 yr. Results: Intent to treat analysis was made on the first 396 pts randomized in 11 countries (R ICE:202; R DHAP:194): median age 55 yrs.; 225 relapses >12months, 166 refractory/early relapses; 244 pts with prior exposure to rituximab; Stage 3–4: 240 pts; elevated LDH: 198 pts; secondary IPI 0–1: 226 pts/ 2–3:149 pts. Patients with prior exposure to rituximab had more refractory disease and adverse prognostic factors. The overall response rate was 63%, with 38% complete remission. There was no difference in response rate between R-ICE 63.5% (CI 56–70%) and R-DHAP 62.8% (CI 55–69%), and in mobilization adjusted response rate. ASCT was performed in 206 pts. 90 SAE were reported in the R-ICE arm and 120 in the R-DHAP with 14 deaths. Factors significantly affecting response rate (p<.0001) were: refractory/relapse < 12 months:46 % vs 88 %, secondary IPI >1:52% vs 71% and prior exposure to rituximab:51% vs 83%. There was not significant difference between R-ICE and R-DHAP for 3 yr EFS (26% vs 35% p=0.6) and OS (47% vs 51%, p=0.5). Three yrs EFS was affected by: prior treatment with rituximab, 21% vs none 47% (p<.0001); early relapse< 12 m 20% vs >12m 45% (p <.0001); secondary IPI 2–3: 18% vs 0–1: 40% (p=.0001). In Cox model, all these parameters were significant (p<.0001) for EFS, PFS and OS but not the treatment arm. Longer follow up is necessary to evaluate the second randomization. Conclusions: There was no difference between R-ICE and R-DHAP. In pts without adverse prognostic factors a response rate > 80% was observed. However, early relapses/ refractory pts to upfront rituximab-based chemotherapy have a poor response rate and prognosis. [Table: see text]
Lenalidomide, bortezomib, pegylated liposomal doxorubicin hydrochloride, and dexamethasone in newly diagnosed multiple myeloma: Initial results of phase I/II MMRC trial
Authors: Jakubowiak A. J. , Hofmeister C. C. , Campagnaro E. L. , Zimmerman T. M. , Schlossman R. L. , Lonial S. , Reece D. E. , Kaminski M. S. , Anderson K. C. , Richardson P. G. 
Published: August 2020

8517 Background: Three-drug combinations with lenalidomide (Revlimid, Rev) and bortezomib (Velcade, Vel) are highly active in previously untreated multiple myeloma (MM). Among the most active are RVD (Revlimid, Velcade, Dexamethasone) and VDD (Velcade, Doxil, Dexamethasone) with ≥ PR rate of 100% and 93%, and a CR/nCR rate of 44% and 40%, respectively. Pre-clinical evaluations suggest that adding pegylated liposomal doxorubicin hydrochloride (Doxil, Dox) to RVD (RVDD) may have higher activity. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of RVDD, assess safety and evaluate efficacy of this 4-drug regimen in newly diagnosed MM. Methods: Four dose levels are being evaluated: Rev 15–25 mg (days 1–14), Vel 1.3 mg/m2 (days 1, 4, 8, 11), dexamethasone (Dex) 20/10 mg (cycles 1–4/5–8; days of and after Vel), Dox 20 and 30 mg/m2 (day 4), with dose assignment for patients (pts) according to the TITE-CRM algorithm. Eight 21-day cycles are planned with 38 pts to be treated at the MTD in phase II. Pts who achieve ≥ PR can proceed to autologus stem cell transplant (ASCT) after ≥ 4 cycles, while all others receive 21-day maintenance cycles with Rev (days 1–14), Vel (day 1 and 8), and Dex (days of and after Vel) at the doses tolerated by the end of initial treatment. Results: The study has enrolled 23 pts to date. Four pts received level 1 (Rev/Dox 15/20), 11 pts level 2 (Rev/Dox 20/20, and 8 pts level 3 (Rev/Dox 25/20). Nineteen pts are evaluable for toxicity after completion of a median of 4 cycles (range 1–8). Two pts developed DLT at dose level 2, consisting of grade (G) 3 asymptomatic neutropenia and G3 elevation of transaminase. The MTD has not been reached. Overall, toxicities have been manageable with no additional G3 hematologic events. There have been 4 additional G3 non-hematologic events including one case each of pneumonia, DVT, fatigue, and hypotension. After a median of 12 (range 3–24) weeks of treatment, preliminary response rates by modified EBMT/UC in 19 evaluable pts are: 95% ≥ PR, 47% ≥ VGPR, 26% CR/nCR. Conclusions: RVDD is well tolerated in newly diagnosed MM and appears highly active with an overall response (≥ PR) of 95%. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. [Table: see text]
Bone marrow microenvironment (ME) associated genes identified prior to all altered 48 hours after bortexomib test-dose application and prognosis of multiple myeloma (MM) treated with total therapy 3 (TT3)
Authors: Qu P. , Haessler J. , Barlogie B. , Shaughnessy J. 
Published: August 2020

8520 Background: Total Therapy 3 (TT3) incorporated bortezomib (BOR) to co-target ME that plays an important role in MM progression and drug resistance. Consenting patients received a BOR test dose of 1mg/m2 to determine whether ME alterations induced 48hr post-BOR could clarify the drug's in-vivo mechanism of action in the context of achieving MM control. Methods: Bone marrow biopsies were obtained at baseline (BL) prior to and 48hr after BOR (PB) in 70 of 303 patients receiving TT3a (training set) and in 45 of 177 patients enrolled in TT3b (test set). Among 608 ME genes distinguishing BL and PB training samples, 58 were identified as being significantly linked to short event-free survival (EFS). A summary score was computed based on the percent change of these 58 genes (PB-ME-S). Additionally, 20 ME genes were selected whose BL expression predicted OS, arriving at a BL score (BL-ME-S). Results: Applying the PB-ME-S score, 3-yr OS and EFS estimates were 96% and 96% among the 49 patients with low PB-ME-S and 50% and 38% in the 21 with high PB-ME-S (both p<0.0001). Follow-up is too short to validate the PB-ME-S model in the test set of 45 patients in TT3b. The BL-ME-S distinguished OS and EFS in the training set of 70 patients, with 3-yr OS and EFS estimates of 92% and 91% among the 50 patients with low and 54% and 45% in the 20 patients with high BL-ME-S (both P<0.0001). These data were validated in 113 patients with only BL-ME data: 3-yr OS and EFS were 90% and 85% among the 89 patients with low as opposed to 70% and 55% among the 14 patients with high BL-ME-S (p=0.001, p=0.002). TT3 survival was independently significantly affected by PB-ME-S (OS: HR=12.74, p=0.002; EFS: HR=14.32, p<0.001) and BL-ME-S (EFS: HR=3.10, p=0.045), whereas the univariately significant role of BL-PC-S for both endpoints could not be confirmed on multivariate analysis. Conclusions: To our knowledge, this is the first report documenting a validated prognostic role of ME for cancer survival. Key genes shared by both PB-ME-S and BL-ME-S models are involved in endothelial and mesenchymal stem-cell signaling, the details of which will be reported at the meeting. [Table: see text]
The multi-institutional myeloma group clinico-genomic risk stratification system: A blinded validation
Authors: Tuchman S. A. , Chng W. , Anguiano A. , Barry W. T. , Zhan F. , Gasparetto C. , Fonseca R. , Shaughnessy J. D. , Potti A. 
Published: August 2020

8521 Background: Several clinical and molecular prognostic factors (e.g, International Staging System [ISS] stage, plasma cell labeling index, genomic models) exist for multiple myeloma (MM). We hypothesized that exploiting gene signatures representative of oncogenic pathway deregulation (i.e., Ras, Myc, etc.), would improve MM prognostication and also aid with the identification of novel therapeutic targets. Methods: Using a discovery cohort (n=47) of patients with MM and corresponding gene expression data, we built upon current molecular risk-stratification and devised a Bayesian genomic (“metagene”) model for prognosis. We validated that model in an independent patient cohort (n=207). Finally, we incorporated ISS staging and clinical variables to construct a combined Clinico-Genomic Risk Stratification System. We further validated the combined model in a separate cohort (n=72), in a blinded manner. Results: Using gene signatures predictive of oncogenic pathway activation in the discovery cohort, we identified specific patterns (metagenes) of signaling pathway activation with prognostic relevance. In an independent validation cohort, this metagene-based model accurately predicted event free survival (EFS) independently of ISS (multivariate hazard ratio [HR] 3.4 for ISS stage, and 5.4 for the metagene model, p=0.002). Using multivariate risk modeling, we incorporated ISS staging and the metagene model into a Clinico-Genomic System and successfully stratified the validation cohort into three groups (low, intermediate, and high risk) with markedly different EFS (HR 4.2 for intermediate risk and 14.0 for high risk vs. the low risk cohort, p<0.0001). In an additional blinded validation, the Clinico-Genomic System again accurately predicted median overall survival (68.7 [low risk] vs 24.7 [intermediate risk] vs 18.7 months [high risk], p<0.0001); more accurately than either ISS or other reported genomic models. Conclusions: A combined Clinico-Genomic Risk Stratification System, building on patterns of oncogenic pathway activation and ISS staging system, improves upon current prognostic models in MM and identifies novel pathway targets for future therapeutic consideration. No significant financial relationships to disclose.
Expression of programmed death ligand 1 (PD-L1) by non-Hodgkin's lymphomas (NHL) and effect on tumor-associated T cells
Authors: Andorsky D. J. , Yamada R. , Steward K. , De Vos S. , Said J. , Timmerman J. 
Published: August 2020

8526 Background: PD-L1 is expressed on antigen presenting cells and inhibits activation of T cells through its receptor, PD-1. PD-L1 is aberrantly expressed on epithelial malignancies and may prevent an effective host anti-tumor immune response. The role of PD-L1 in NHL is unknown. Methods: PD-L1 expression was analyzed in 16 NHL cell lines by flow cytometry (FC) and in 111 lymphoma specimens by immunohistochemistry (IHC) (n=92) or FC (n=19). In functional studies, irradiated anaplastic large cell lymphoma (ALCL) cells were co-cultured with allogeneic T cells in the presence of anti-PD-L1 blocking antibody, and IFNγ secretion and thymidine incorporation was used to assess T cell function and proliferation. To further test tumor-T cell interactions, malignant ascites from a patient with ALK+ ALCL and peripheral blood mononuclear cells from a patient with leukemic mantle cell lymphoma, both containing PD-L1-expressing tumor cells and tumor-associated T cells, were stimulated with phytohemagglutinin (a polyclonal T cell activator) and incubated with anti-PD-L1 antibody. Levels of 16 inflammatory cytokines were measured as an assessment of T cell activity. Results: All 9 B cell lymphoma lines were negative for PD-L1, while all 5 ALCL cell lines were strongly positive. One T-cell ALL line was positive, and one peripheral T cell lymphoma was negative. Strong PD-L1 staining was detected by IHC in all 14 ALCL specimens and in 83% of diffuse large B cell lymphomas (DLBCL) analyzed (n=35). Activity of allogeneic T cells co-cultured with irradiated ALCL cells, as measured by IFNγ secretion and proliferation, was markedly enhanced in the presence of anti-PD-L1 blocking antibody. In the autologous setting using cultures of ALCL and mantle cell lymphoma specimens containing host T cells, secretion of inflammatory cytokines by tumor-associated T cells, including GMCSF, IFNγ, IL-1, IL-6, IL-8, TNFα, and MIP1α, were increased by incubation with anti-PD-L1 antibody. Conclusions: PD-L1 is highly expressed in ALCL and in a majority of DLBCL. Blockade of tumor-associated PD-L1 promoted activation of adjacent T cells. PD-L1 may play a role in thwarting an effective anti-tumor immune response and represents an attractive target for lymphoma immunotherapy. No significant financial relationships to disclose.
A phase II multicenter study of CNTO 328, an anti-IL-6 monoclonal antibody, in patients (pts) with relapsed or refractory multiple myeloma (MM)
Authors: Voorhees P. M. , Manges R. F. , Somlo G. , Lentzsch S. , Jagannath S. , Sonneveld P. , Frank R. C. , Zweegman S. , Wijermans P. W. , Thomas S. 
Published: August 2020

8527 Background: Relapsed/refractory MM constitutes a specific and unmet medical need with poor overall response and survival. Interleukin-6 (IL-6) plays an important role in MM cell proliferation, survival, and corticosteroid resistance and previous studies have shown clinical benefit from anti-IL-6 therapy. We therefore evaluated the combination of CNTO328, a chimeric monoclonal antibody with high affinity for human IL-6, and dexamethasone (dex) in pts with relapsed/refractory MM. Methods: Pts were treated with 6 mg/kg CNTO328 IV Q2 weeks. Oral dex (40mg) was given once daily, days 1–4, 9–12, and 17–20 for a max of 4 cycles; and on days 1–4 for subsequent cycles. Inclusion criteria were > 2 prior lines of systemic therapy, creatinine clearance >20 ml/min, platelets >50,000/mm3, and neutrophils >1000/mm3. Primary endpoint was overall response with secondary endpoints of time to progression, incidence of AEs and SAEs. Results: Thirty-nine pts received at least 1 infusion of CNTO328 in combination with dex - median age 66 yrs (range 43–89), median disease duration 4.2 yrs (1–13), median lines of prior therapy 5 (2–9) including bortezomib (100%), IMIDs (87%), and ASCT (59%). The median duration of therapy was 3.3 months (0.5–21+). Of the 36 pts who were evaluable, the overall response rate (CR+PR+MR) using EBMT criteria was 31% (7PR, 4MR). An additional 4 uMR and 4 SD lasting ≥3 months have been reported. PRs were durable; 6 out of 7 pts had responses ranging from 3 months to up to more than 1 year (with 1 still ongoing for more than 1 year). Duration of MRs ranged from 2–5 months. Responses were seen in pts relapsing after and refractory to at least one other prior treatment including bortezomib, IMIDs, or steroids. Median time to disease progression (PD) was 3.7 months (0.3–18+). Main reasons for treatment discontinuation were PD (24) and AEs (6). Hematologic toxicities Grade ≥ 3 were common though not dose-limiting. Three pts had Grade ≥ 3 infections considered reasonably related to CNTO328. Conclusions: CNTO 328 in combination with dex shows promising preliminary activity in this heavily pretreated patient population with an acceptable safety profile. Further investigation is ongoing. No significant financial relationships to disclose.