bluuebunny/crossref_metadata_2025 huggingface dataset:
An open-label, single arm, phase IIa study of bortezomib, lenalidomide, dexamethasone, and elotuzumab in newly diagnosed multiple myeloma.
Authors: Laubach Jacob , Nooka Ajay K. , Cole Craig , O'Donnell Elizabeth , Vij Ravi , Usmani Saad Zafar , Orloff Gregory Joshua , Richter Joshua Ryan , Redd Robert , DiPietro Heidi , Cummings Kristen , Hansen Joshua , Henrick Patrick M. , Bassett Paul , Schachter Haley , Richardson Paul G. , Lonial Sagar
Published: September 2018

8002

Background: Elotuzumab (elo) is approved for use in combination with lenalidomide (len) and dexamethasone (dex) for relapsed and refractory multiple myeloma (MM). This phase 2a study evaluated the efficacy and safety of elo in combination with len, subcutaneous bortezomib (bortez), and dex. Methods: The primary objective of this study was to determine the response rate of newly diagnosed, transplant-eligible MM patients (pts) after four cycles of therapy with elo plus len, bortez, and dex. Pts were newly diagnosed with MM by the revised IMWG criteria. Elo was administered days 1, 8, and 15 of the first two 28 day cycles and days 1 and 11 in cycles 3 and 4. Following cycle 4, pts underwent stem cell mobilization and could then proceed with either autologous stem cell transplant (ASCT) or defer transplant and receive four more cycles of induction therapy with elo plus len, bortez, and dex. Following either ASCT or 8 cycles of induction chemotherapy, pts transitioned to risk-adapted maintenance with elo, len, and dex plus every other week bortez (pts with high-risk cytogenetics, ISS stage II or III) or elo, len, dex (all others). Responses were assessed by the modified Uniform Response Criteria and toxicities graded based on NCI-CTCAE V4. Results: 41 patients with a median age of 60 were enrolled and this analysis encompasses response data from 29 patients. The overall response rate (ORR) after four cycles was 100%, with 24% achieving a complete response (CR), 47% achieving a very good partial response (VGPR), and 29% a partial response (PR). The rate of VGPR or better was 71%. The median number of CD34+ stem cells collected was 10.3 x 10^6. The most frequent grade 3 or higher toxicities included thrombocytopenia (15%) and hypophosphatemia (12%). The rate of grade 3 or higher peripheral neuropathy was 2%. Two pts died while on study, one due to complications of septicemia and the other due to respiratory failure. Conclusions: The combination of elo plus len, bortez, and dex was effective in newly diagnosed, ASCT-eligible patients. The rate of high-grade toxicities was low, although there were two grade 5 events (septicemia and respiratory failure). Clinical trial information: NCT02375555.
Natural history of t(11;14) multiple myeloma (MM).
Authors: Lakshman Arjun , Alhaj Moustafa Muhamad , Rajkumar S.Vincent , Dispenzieri Angela , Gertz Morie A. , Buadi Francis , Lacy Martha , Dingli David , Hayman Suzanne R. , Gonsalves Wilson I. , Kapoor Prashant , Leung Nelson , Lin Yi , Go Ronald S. , Kourelis Taxiarchis , Lust John Anthony , Russell Stephen , Zeldenrust Steven R. , Kyle Robert A. , Kumar Shaji
Published: September 2018

8014

Background: t(11;14) is a standard risk cytogenetic marker in MM. Methods: We reviewed 366 patients with MM who had t(11;14) by FISH and 732 age and period-matched controls without t(11;14), seen at our institution from 2004 to 2014 and outcomes were analyzed using time to first progression or death (PFS1) and overall survival (OS). Results: For the t(11;14) group at diagnosis, the median age was 63.7 yr (range, 22.1-95.4) with 64.5% of patients being male. Eighty nine (24.3%) patients were above 70 yr of age at diagnosis. 33.8%, 40.3% and 25.9% patients belonged to ISS 1, II and III stages respectively. 13% patients had elevated LDH. Monosomy 17 or del 17p were identified in 10.6% patients. The median follow up period was 56.9 months (m) (95% CI: 54.6-62.2) and 209 (57.1%) patients were alive at last follow-up. Among patients receiving proteasome inhibitor (PI)-based, immunomodulator (IMiD)-based, PI+IMiD based or other agent based induction therapy, 71.2%, 70.3%, 90.4% and 37.5% patients respectively attained ≥PR as best response to induction (p < 0.01). During their course, 223 (60.9%) patients underwent stem cell transplant. Median PFS1 and OS were 23.1 (CI: 20.8-27.9) and 78.6 (CI: 66.7-105.9) m respectively. Among the controls, high risk cytogenetics (HRC) was present in 142 (19.4%), and the median OS was 83.8 m (CI: 70.8-97.0) being comparable to t(11;14) group (p = 0.8). For all 1098 patients, using a Cox-proportional hazards model with age > 70 years, induction therapy (novel agent-based vs others), cytogenetics [HRC vs t(11;14) without HRC vs no HRC or t(11;14)], and ISS stage III vs II/I as predictors, age > 70 years [HR-2.2 (CI: 1.8-2.8) and p < 0.01], ISS III vs ISS II/I [HR-1.4 (CI: 1.1-1.8) and p < 0.01] and HRC [HR of 2.1 (CI: 1.6-2.8) vs no HRC or t(11;14) (p < 0.01) and 1.9 (CI = 1.4-2.6) for t(11;14) without HRC (p < 0.01)were associated with reduced OS. The risk for reduced OS did not differ between t(11;14) without HRC, and those without t(11;14) or HRC [HR-1.1 (CI: 0.9-1.4), p = 0.4]. Conclusions: Our study characterizes the outcomes of a large cohort of MM patients with t(11;14) at diagnosis. Advanced age, HRC and advanced stage at diagnosis were associated with worse OS in our cohort. t(11;14) MM without HRC does not differ in outcome compared to non-t(11;14) MM without HRC.
Pembrolizumab (Pembro) plus lenalidomide (Len) and low-dose dexamethasone (Dex) for relapsed/refractory multiple myeloma (RRMM): Efficacy and biomarker analyses.
Authors: Ocio Enrique M. , Mateos Maria-Victoria , Orlowski Robert Z. , Siegel David , Reece Donna Ellen , Moreau Philippe , Rodriguez-Otero Paula , Munshi Nikhil C. , Avigan David , Ghori Razi , Wnek Richard , Mogg Robin , Marinello Patricia Maria , San Miguel Jesus
Published: September 2018

8015

Background: The PD-1 inhibitor pembro blocks interaction of PD-1 with its ligands PD-L1/PD-L2, activating antitumor immunity. Combination of pembro, len, and dex may provide synergistic antitumor activity in RRMM. Methods: Theopen-label, phase 1 KEYNOTE-023 (NCT02036502) study of pembro + len + low-dose dex enrolled patients (pts) with RRMM treated with ≥2 prior therapies (tx). Pts received pembro 200 mg IV Q2W, len 25 mg PO on d1-21, and dex 40 mg PO weekly on each 28-d cycle. Primary end point was safety. ORR was assessed by IMWG 2006. Exploratory biomarker analyses included flow cytometry (FC) (PD-L1, PD-L2 on CD38+CD138+ cells) at screening or predose cycle 1, d 1 bone marrow (BM) aspirate. Absolute and/or relative numbers of circulating immune cells (by FC) and gene expression profile (GEP) (by Nanostring) were evaluated in predose cycle 1, d1 and cycle 2, d1 blood. Results: Median age was 61 y; median (range) prior lines of tx was 4 (1-10); 38 (75%) pts were len-refractory and 27 (53%) pts were double refractory. Most common grade ≥3 tx-related AEs (TRAEs) were neutropenia (33%), thrombocytopenia (18%), and anemia (12%). 2 (4%) pts died (hepatic failure, ischemic stroke) because of TRAEs. Immune-related AEs occurred in 5 (10%) pts. No pneumonitis was reported. For response-evaluable pts, ORR was 50% (20/40; 1 sCR, 14 PR, 5 VGPR); 1 had PD. ORR was 38% (11/29) for len-refractory pts. In 16/32 pts with FC-evaluable BM aspirate with >100 CD38+CD138+ cells, all were PD-L1+, while PD-L2 expression was variable. At cycle 2, d1, frequency of circulating HLA-DR+, central (CD45RO+CCR7-), and effector memory (CD45O+CCR7+) CD8+ T cells significantly increased and naive (CD45RA+) CD8+ T cells significantly decreased; all with multiplicity adjusted P values ≤ 0.01. Conclusions: Pembro + len + low-dose dex has an acceptable safety profile and antitumor activity in pts with RRMM, including len-refractory pts. PD-L1 was expressed in all pts evaluated by FC, whereas PD-L2 expression was variable. Among the pool of circulating T cells in peripheral blood, HLA-DR+ and memory T-cell subset fractions increased after treatment. Clinical trial information: NCT02036502.
Autologous stem cell transplant (ASCT) for newly diagnosed multiple myeloma (MM) in the era of novel agents: A meta-analysis of phase III randomized controlled trials.
Authors: Dhakal Binod , Chhabra Saurabh , Hamadani Mehdi , D'souza Anita , Usmani Saad Zafar , Jackson Jeffrey , Hari Parameswaran
Published: September 2018

8022

Background: Given the unprecedented deep response rates with the novel agent induction, the role of high dose therapy (HDT) followed by ASCT in MM pts. has been questioned, and was re-evaluated in a number of randomized clinical trials (RCTs). Although, the results of most studies suggest the continued benefit of HDT/ASCT, some RCTs suggest no overall survival (OS) benefit. We undertook a systematic review and meta-analysis of phase III randomized RCTs evaluating the role of HDT compared to standard therapy (SDT) in the context of novel agent induction Methods: We searched the PubMed, Scopus and Cochrane Collection of Controlled Trial databases using the term myeloma combined with autologous or transplant or myeloablative or stem cell from 2000-2016. A total of 2480 articles identified, of which 4 large phase III RCTs compared upfront HDT with SDT with novel agents use. Two individuals independently extracted the data. Reported hazard ratio (HR) and survival data were pooled using random effects models (STATA v14, College Station, Tx). Heterogeneity was assessed using I2. Results: Four studies comprising 2421 patients were included (Table 1). One study did not report the HR for death and hence OS analysis was limited to 3 studies. The combined hazard for progression with HDT was 0.55 (95% CI 0.40-0.71) (p < 0.005). The combined hazard for death with HDT was 0.65 (95% CI 0.29-1.0) (p = 0.007). Sensitivity and sub-group analysis showed no difference in PFS (p = 0.06) and OS (p = 0.22) with HDT. Significant heterogeneity was demonstrated by I2 of 71.4% for PFS (p = 0.01) and 68.4% for OS (p = 0.04). Conclusions: Based on our analysis, even in the novel agent era, HDT appears to be beneficial and should be considered standard of care for all transplant eligible MM pts. [Table: see text]
Impact of t(11;14) on outcomes in African American (AA) and non-AA (NAA) patients (Pts) with newly diagnosed multiple myeloma (NDMM): Connect MM registry.
Authors: Gasparetto Cristina , Abonour Rafat , Jagannath Sundar , Durie Brian G. , Shah Jatin J. , Narang Mohit , Terebelo Howard R. , Toomey Kathleen , Hardin James , Wagner Lynne I. , Srinivasan Shankar , Kitali Amani , Flick E. Dawn , Zafar Faiza , Agarwal Amit , Rifkin Robert M.
Published: September 2018

8023

Background: t(11;14) is a common cytogenetic abnormality historically associated with standard-risk and generally favorable MM outcomes, but has shown poor prognosis in some retrospective analyses. Connect MM is a prospective, US, observational, multicenter registry that collects data on management and natural history of NDMM pts in clinical practice. The impact of t(11;14) on survival outcomes was assessed in AA and NAA pts. Methods: Adult NDMM pts who completed induction and were tested for t(11;14) by FISH/cytogenetics were grouped by race (AA vs NAA). Endpoints were PFS and OS. Kaplan-Meier analyses were adjusted for differences in cohort, age, ISS stage, transplant intent, t(4;14), hemoglobin, platelets, calcium, creatinine, and diabetes history. Data cutoff was Jul 7, 2016. Results: 3011 pts were enrolled in 2 cohorts (Cohort 1: n = 1493, Sep 2009–Dec 2011, median follow-up = 39.3 mos; Cohort 2: n = 1518, Dec 2012–Apr 2016, median follow-up = 16.4 mos). Of 1539 (52%) pts tested for t(11;14), 363 (24%) were t(11;14)-positive, including 53 (26%) of 205 AA and 310 (23%) of 1334 NAA pts. First-line bortezomib exposure was similar across groups. A trend of shorter PFS was observed in AA pts with t(11;14) vs AA without t(11;14) (Table). AA pts with t(11;14) had significantly higher risk of death compared to those without t(11;14) and higher rate of early mortality than NAA pts. No differences in PFS or OS were noted in NAA pts with or without t(11;14). For OS, the interaction between race and t(11;14) status was statistically significant ( P= 0.004). Conclusions: In Connect MM, the effect of t(11;14) on OS was significantly different between AA and NAA pts. t(11;14) was associated with poorer survival outcomes in AA pts, and thus, may be a risk factor for poor prognosis. Additional analyses will be conducted to elucidate the role of induction treatment, transplant and maintenance in AA and non-AA pts with t(11;14). Clinical trial information: NCT01081028. [Table: see text]
MOR202 with low-dose dexamethasone (Dex) and in combination with pomalidomide/dex and lenalidomide/dex in relapsed or refractory multiple myeloma (RRMM): Interim analysis of a phase I/IIa dose-escalation study.
Authors: Raab Marc , Chatterjee Manik , Goldschmidt Hartmut , Agis Hermine , Blau Igor W. , Einsele Hermann , Engelhardt Monika Martha , Ferstl Barbara , Gramatzki Martin , Röllig Christoph , Weisel Katja C. , Jarutat Tiantom , Weinelt Dominika , Winderlich Mark , Boxhammer Rainer , Peschel Christian
Published: September 2018

8024

Background: CD38 is a type II transmembrane glycoprotein expressed by MM cells. MOR202, a human IgG1 CD38 monoclonal antibody, has shown high single-agent activity in preclinical models of MM and synergy in combination with immunomodulatory drugs (IMiDs), lenalidomide (LEN) and pomalidomide (POM). Methods: This interim analysis of a multicenter phase I/IIa study reports safety and efficacy data from RRMM patient (pt) cohorts treated with clinically relevant doses of MOR202 (2-hour IV infusion; 4, 8 and 16 mg/kg q1w) + Dex (≤40 mg), or at 8 or 16 mg/kg q1w with an IMiD/Dex. Primary objectives were to evaluate the safety, maximum tolerated dose (MTD) and recommended phase II dose of MOR202. Results: As of January 2017, 79 pts had been treated, including 44 in clinically relevant cohorts: 18 received MOR202 + Dex, 15 MOR202 + LEN/Dex and 11 MOR202 + POM/Dex. Pts had received a median of 3, 2 and 3 prior treatment lines, respectively. The MTD of MOR202 was not reached. Combinations were generally well tolerated, with grade ≥3 adverse events (AEs) mainly hematological; 2 pts discontinued due to a MOR202-related AE (one grade 4 thrombocytopenia; one grade 3 acute kidney failure). Infusion-related reactions (all grade 1 or 2) were seen in only 3/44 (7%) pts, and mainly occurred during the first infusion. In the MOR202 + Dex cohort, 5/17 (29%) evaluable pts (receiving at least 1 cycle of treatment) had a response, including 3 with partial responses (PRs) and 2 with very good PRs (VGPRs). Responses were also seen in 11/13 (85%, 8 PRs, 3 VGPRs) evaluable pts in the MOR202 + LEN/Dex cohort and 5/9 (56%, 2 complete responses, 3 PRs) in the MOR202 + POM/Dex cohort. Longest response duration was 17 months (MOR202/Dex). Preliminary analysis showed preservation of high CD38 levels on MM cells under MOR202 therapy. Conclusions: In heavily pretreated pts with RRMM, a 2-hour infusion of MOR202 administered at up to 16 mg/kg with Dex or in combination with an IMiD/Dex, showed a favorable safety profile, including excellent infusion tolerability. Promising preliminary efficacy and long-lasting tumor control was seen. Clinical trial information: NCT01421186.
Factors predicting organ response in light chain amyloidosis (AL).
Authors: Sidana Surbhi , Tandon Nidhi , Dispenzieri Angela , Gertz Morie A. , Buadi Francis , Lacy Martha , Dingli David , Fonder Amie L. , Hayman Suzanne R. , Hobbs Miriam A. , Gonsalves Wilson I. , Hwa Yi Lisa , Kapoor Prashant , Kyle Robert A. , Leung Nelson , Go Ronald S. , Lust John Anthony , Russell Stephen J. , Rajkumar S. Vincent , Kumar Shaji
Published: September 2018

8048

Background: Organ response (OR) in AL is often delayed and difficult to predict early. Methods: We retrospectively analyzed 1308 patients (pts) with newly diagnosed AL from 2006 – 2015 to determine factors which could predict for OR. Results: Median age was 64 years (yr) and Mayo Stage was: 1 (22%); 2 (23%); 3 (25%); 4 (31%). Organ involvement was: cardiac (74%, n=932); renal (59%, n=738), liver (16%, n=205); gut (24%, n=310) and autonomic (12%, n=152). 59% (n=765) had > 1 organ involved, including 43% (n=567) with > 1 critical organ (heart, kidney, liver) involved. Treatment was: ASCT based (28%, n=330, N=1186), bortezomib based (24%, n=281), alkylator based (33%, n=392), others (5%, n=54) and none (10%). In evaluable pts, VGPR or better rates were: 53% at 6 months (m) (N=625), 72% at 12 m (N=465) and 57% overall (N=688). Table 1 lists OR at various time points. Complete OR in all involved critical organs was seen in: 51% (n=308, N=600), partial response (at least 1 OR when >1 organ involved) in 12% (n=73) and none in 37% (n=219). Complete OR was associated with better overall survival (OS) than partial or no OR (median OS: not reached vs 42 m vs 29 m; P <0.0001). In multivariate model the following variables at baseline or 1 yr mark were predictive of complete OR: lower Mayo Stage (p=0.01), fewer critical organs involved (p=0.007), higher baseline GFR (p=0.03), female sex (Complete OR 60% vs 47%; p=0.04) and VGPR at 1 yr (Complete OR 70% vs. 36%; p <0.0001). Other factors included in the model were age (p=0.9), bilirubin (p=0.1) and transplant (p=0.2). All aforementioned factors were significant in univariate analysis. Conclusions: Achievement of response in all involved critical organs is associated with better survival in AL pts than partial or no OR. Various baseline factors and VGPR at 1 yr can predict for achieving complete OR, with 70% pts who achieve VGPR at 1 yr having a complete OR. [Table: see text]
Salvage guideline for local-regional failure after stereotactic ablative radiotherapy for early-stage non-small cell lung cancer.
Authors: Brooks Eric , Sun Bing , Zhao Lina , Komaki Ritsuko , Liao Zhongxing X. , Jeter Melenda , O'Reilly Michael , Welsh James William , Gomez Daniel Richard , Nguyen Quynh , Antonoff Mara , Hahn Stephen M. , Heymach John , Rice David C. , Chang Joe Y.
Published: September 2018

8501

Background: Up to 1 in 7 patients receiving stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) will develop local-regional recurrence. While SABR is the pillar of treatment for medically inoperable patients, little is known about outcomes and management for this potentially curable, local-regionally recurrent patient group. Methods: We present the first long-term results for the largest group of salvaged patients with local-regional recurrence after SABR. 772 patients with clinically early-stage I-II NSCLC were treated with SABR (50 Gy in 4 or 70 Gy in 10 fractions) between 2004-2014 at our center. Patients with isolated local recurrence (LR, n = 34) or regional recurrence (RR, n = 41) were analyzed and compared to patients with no recurrence (NR, n = 569). Results: Median time to LR or RR after SABR was 14 months. Salvage was performed in 79.4% of LR and 92.7% of RR patients. Salvage consisted of surgery (20% LR, 2% RR), re-irradiation (24% LR, 17% RR), radiofrequency ablation (15% LR), chemotherapy (15% LR, 26% RR), and chemoradiation (6% LR, 44% RR) based on a standard multi-disciplinary decision approach (Figure 1). 5-year OS was 37.1% for LR and 39.1% for RR patients. Of LR and RR patients, those receiving salvage had significantly better 5-year OS compared to those not receiving salvage (45.2% LR, 42.9% RR, 0% no salvage; p = 0.009). 5-year OS for salvaged patients was not statistically different from patients with NR (53.5% NR, p = 0.466). 5-year lung-cancer specific survival was 51% for LR and 55.1% for RR patients. Subsequent DM occurred in 20.5% of LR and 29.3% of RR patients at a median of 8.4-10.3 months. No salvaged patient experienced grade 5 toxicity. Conclusions: Patients with local or regional recurrence after SABR have excellent outcomes with salvage therapy, with no statistical difference in 5- year OS between LR and RR patients salvaged after SABR, and patients with no recurrence. Because a standard multidisciplinary approach was applied to any LR or RR patient after SABR, a novel treatment algorithm is generated. We offer a much needed management guide for thoracic oncologists treating patients who local-regionally recur after SABR.
A nationwide genomic screening project for small cell lung cancer in Japan (LC-SCRUM-Japan).
Authors: Murakami Haruyasu , Umemura Shigeki , Shinoda Masahiro , Shingyoji Masato , Ogawa Yukari , Takeda Koji , Nosaki Kaname , Okamoto Norio , Aono Hiromi , Hara Satoshi , Kuyama Shoichi , Sato Akiko , Kanaji Nobuhiro , Okimoto Tamio , Kataoka Yuki , Matsumoto Shingo , Udagawa Hibiki , Yoh Kiyotaka , Tsuchihara Katsuya , Goto Koichi
Published: September 2018

8518

Background: Recent genomic studies of small-cell lung cancer (SCLC) have identified promising therapeutic strategies for this highly lethal form of cancer. Thus, we established a nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) to identify SCLC patients harboring targetable genomic alterations for the development of novel targeted therapies. Methods: The samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: As of December 2016, 133 institutions were participating and 295 patients had been enrolled. The median age was 69 years (range, 14-90 years). Two hundred seventeen (74%) were male and most patients (93%) were smokers. Among 268 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 198 (74%) /82 (31) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 10 (4%) /13 (5) /4 (1) of cases, respectively. The NGS analysis also showed that 62 (23%) of cases had at least one targetable genomic alterations, including 7 EGFR activating mutations (3%), 6 KRAS activating mutations (2%), and 8 FGFR1 copy number gains (3%). No case was positive for ALK or ROS1 fusions. Never-smokers (71% vs. 5%, p<0.001) were significantly frequent in the EGFR type compared to the others. The KRAS type showed significantly poor progression free survival (PFS) of the first-line chemotherapy compared to the others (median PFS 1.2 vs. 6.1 months, respectively; p<0.001). Mutations in the PI3K/AKT/mTOR pathway were detected in 22 (8%) of the tumors: 10 PIK3CA mutations (4%), 9 PTEN inactivating mutations (3%) and 3 TSC2 inactivating mutations (1%). Among them, a case with PTEN mutation was enrolled in the investigator initiated phase II study of gedatolisib named “EAGLE-PAT” (UMIN 000020585). Conclusions: We identified a series of targetable genomic alterations in SCLC. This nationwide screening system is helpful for identifying targetable genomic alterations and their clinical features, contributing to the development of novel targeted therapies for this disease. Updated screening results will be presented at the 2017 ASCO Annual Meeting.
Analysis of circulating tumor DNA in localized lung cancer for detection of molecular residual disease and personalization of adjuvant strategies.
Authors: Chaudhuri Aadel , Chabon Jacob J. , Lovejoy Alexander F. , Newman Aaron M. , Stehr Henning , Azad Tej D. , Carter Justin N. , Merriott David J. , Liu Chih Long , Kurtz David Matthew , Dudley Jonathan C. , Padda Sukhmani Kaur , Shrager Joseph B , Neal Joel W. , Wakelee Heather A. , Loo Billy W. , Alizadeh Ash A. , Diehn Maximilian
Published: September 2018

8519

Background: Identifying localized non-small cell lung cancer (NSCLC) patients with residual disease following curative intent therapy is difficult due to normal tissue changes caused by surgery or radiation and an inability to detect microscopic disease. Analysis of circulating tumor DNA (ctDNA) might enable identification of molecular residual disease (MRD) and personalization of adjuvant treatment approaches but has not been explored in lung cancer. Methods: We applied CAPP-Seq, an ultra-sensitive next-generation sequencing based ctDNA quantitation method, to pre- and post-treatment blood samples from a cohort of 41 patients treated with chemoradiation, radiotherapy or surgery for stage I-III primary lung cancer. Detection of ctDNA at a single MRD time-point within 4 months of treatment completion was compared with surveillance by cross-sectional imaging. Furthermore, we developed an approach for identification of tumor mutation burden based on mutations detected in plasma, leveraging whole exome sequencing data from 1,177 NSCLCs sequenced by TCGA. Results: Median follow-up time was 35 months. Pre-treatment ctDNA was detected in 38 (93%) patients and 19 (46%) had detectable post-treatment ctDNA MRD. MRD+ patients displayed significantly inferior 3-year freedom from progression (0% vs. 92%; HR 38; P < 0.0001) and 3-year overall survival (8% vs. 75%; HR 12; P < 0.0001) than MRD- patients. Detection of ctDNA MRD had positive and negative predictive values for disease progression of 100% and 93%, respectively. Furthermore, we non-invasively identified activating EGFR mutations or high mutational burden (≥5 CAPP-Seq non-synonymous mutations, corresponding to > 200 non-synonymous mutations per exome or > 4 single nucleotide variants per megabase of exome) in 47% of patients with detectable ctDNA MRD, suggesting potentially favorable responses to TKIs and immune checkpoint inhibitors, respectively. Conclusions: Our results indicate that ctDNA analysis accurately detects MRD in localized lung cancer patients and could facilitate personalized adjuvant treatment at early time-points when disease burden is minimal.
Phase 1/2 study of veliparib (V) combined with carboplatin (Cb) and etoposide (E) in patients (pts) with extensive-stage disease (ED) small cell lung cancer (SCLC) and other solid tumors: Phase 1 results.
Authors: Atrafi Florence , Groen Harry J.M. , Byers Lauren Averett , Garralda Elena , Lolkema Martijn P. , Sangha Randeep S. , Viteri Ramirez Santiago , Chae Young Kwang , Camidge D. Ross , Gabrail Nashat Y. , Waskiewicz Tina , Hu Beibei , Xu Tu , Nuthalapati Silpa , Hoening Elizabeth , Komarnitsky Philip , Calles Blanco Antonio
Published: September 2018

8530

Background: The majority of SCLC cases are diagnosed as ED, for which there is a poor prognosis and no curative treatment (Tx). V, a potent PARP inhibitor, has been shown in preclinical studies to enhance the antitumor activity of platinum-based agents and E against SCLC. The presented phase 1 dose-escalation (NCT02289690) evaluated V combined with Cb/E. Methods: Pts (≥18 years) with ED SCLC or other advanced/metastatic solid tumors with ≤1 line of prior cytotoxic therapy and ECOG performance score 0/1 were included. This study followed a 3+3 design. V starting dose and schedule were 80 mg BID PO administered on days (D) –2 to 5 in combination with Cb AUC 5 mg/mL•min administered on D 1 and E 100 mg/m2 administered on D 1 to 3 via intravenous infusion in 21-D cycles. V schedules of D –2 to 12 and continuous dosing were also explored. Primary objectives were to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for V combined with Cb/E, and to evaluate the pharmacokinetic (PK) interaction between V and E. Results: Thirty-nine pts (n = 24 ED SCLC; n = 15 other solid tumors) with median age of 62 years (range 43–79) received study Tx. Most common adverse events (AEs; ≥40%) were nausea (54%), fatigue (51%), alopecia (46%), and anemia (44%); grade 3/4 AEs (≥30%) were decreased neutrophil count, neutropenia (31% each), and anemia (26%). Dose-limiting toxicity occurred in 1 pt (n = 1 grade 3 fatigue) at V 240 mg BID D –2 to 5. The MTD was not reached; RP2D for V was set at 240 mg BID on D –2 to 12 based on long-term tolerability. Continuous dosing of V 240 mg BID with Cb/E resulted in unacceptable Cb/E dose delays due to hematologic toxicity. Coadministration of V (80 to 240 mg BID) with Cb/E exhibited dose-proportional kinetics with no impact on the E PK. Confirmed responses: ED SCLC 63% (15/24 pts) across all dose levels and in 83% (5/6) at RP2D; other tumor types: 13% (2/15) across all dose levels. Conclusions: V + Cb/E had an acceptable safety profile in pts with ED SCLC, with an RP2D of 240 mg BID D –2 to 12. Coadministration of V with Cb/E had no effect on E PK. Responses were seen across all dose levels. A phase 2 study of V with Cb/E in ED SCLC is ongoing. Clinical trial information: NCT02289690.
Expansion study of ADI-PEG 20, pemetrexed and cisplatin in patients with ASS1-deficient malignant pleural mesothelioma (TRAP).
Authors: Phillips Melissa , Szyszko Teresa , Hall Peter , Cook Gary J. R. , Khadeir Ramsay , Steele Jeremy P. C. , Spicer James F. , Feng Xiaoxing , Hategan Mirela , Rashid Sukaina , Johnston Amanda , Bomalaski John S. , Shamash Jonathan , Pacey Simon , Sheaff Michael , Szlosarek Peter Wojciech
Published: September 2018

8553

Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) cells are sensitive to arginine deprivation with pegylated arginine deiminase (ADI-PEG20), which also potentiates the cytotoxic effect of pemetrexed (PEM). In the phase I dose-escalation TRAP study (NCT02029690) we showed that ADI-PEG20 with first-line PEM and cisplatin (CIS) chemotherapy (ADIPEMCIS) produced a 100% disease control rate (DCR) in patients (pts; n = 9) with ASS1-deficient thoracic cancers, with no additional toxicity (Beddowes et al 2017). Here, we present the TRAP expansion cohort experience in MPM. Methods: Good performance (ECOG 0-1) MPM pts with non-resectable disease and measurable by modified RECIST, were enrolled in a phase I TRAP expansion cohort at the maximum tolerated dose (MTD) of ADIPEMCIS, using tumoral ASS1 loss as a selection biomarker. PEM (500mg/m2) and CIS (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for a maximum of 6 cycles with maintenance ADI-PEG20 in responding pts. Primary endpoint was tumor response rate (modified RECIST), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We measured plasma arginine and citrulline concentrations, ADI-PEG20 antibodies, and biopsied patients on progression to explore resistance mechanisms. Results: 31 ASS1-deficient MPM pts (median age 67) were enrolled (11 epithelioid, 10 biphasic and 10 sarcomatoid) out of 92 screened pts. Plasma arginine decreased with a reciprocal increase in plasma citrulline. The partial response rate was 35.5% (95% CI 19.2%-54.6%) with a DCR of 93.5% (95% CI 78.6%-99.2%). Median PFS was 5.6 months (95% CI 4-6) and median OS was 10.1 months (95% CI 6.7-17.7). 10/31 pts (32.3%) experienced grade 3/4 treatment-related toxicities, the most common being neutropenia (16.1%). Upregulation of ASS1 expression was observed in 2/3 biopsies on progression. Conclusions: The ADIPEMCIS regimen is active in ASS1-deficient MPM pts, including non-epithelioid disease. Based on these data the ATOMIC-meso phase 2/3 trial has opened comparing ADIPEMCIS versus PEMCISPlacebo, focusing on pts with non-epithelioid MPM. Clinical trial information: NCT02029690.
Progression after the next line of therapy (PFS2) and updated OS among patients (pts) with advanced NSCLC and PD-L1 tumor proportion score (TPS) ≥50% enrolled in KEYNOTE-024.
Authors: Brahmer Julie R. , Rodriguez-Abreu Delvys , Robinson Andrew George , Hui Rina , Csõszi Tibor , Fülöp Andrea , Gottfried Maya , Peled Nir , Tafreshi Ali , Cuffe Sinead , O'Brien Mary , Rao Suman , Hotta Katsuyuki , Leiby Melanie A. , McLean Jessica , Shentu Yue , Rangwala Reshma A. , Reck Martin
Published: September 2018

9000

Background: In KEYNOTE-024 (NCT02142738), pembrolizumab (pembro) was superior to chemotherapy (chemo) as first-line (1L) therapy for advanced NSCLC with PD-L1 TPS ≥50% and no sensitizing EGFR mutations or ALK translocations. After a median follow-up of 11.2 mo, HR was 0.50 for PFS by independent central radiologic review ( P< 0.001) and 0.60 for OS ( P= 0.005). Here we present PFS2 and updated OS. Methods: 305 pts were randomly assigned to pembro 200 mg Q3W (n = 154) or investigator (INV)-choice platinum-doublet chemo with optional pemetrexed maintenance for nonsquamous histology (n = 151). Pts in the chemo arm could cross over to pembro upon PD. Poststudy anticancer therapy and INV-assessed outcomes were collected. Kaplan-Meier PFS2 and OS were calculated in all allocated pts. PFS2 was defined as time from randomization to PD per INV after start of 2L+ therapy or death, whichever occurred first; pts alive and without 2L+ PD were censored at last known survival. Kaplan-Meier OS was defined as time from randomization to death. There was no adjustment for multiplicity (cutoff: Jan 5, 2017). Results: 2L+ therapy was received by 48 (31.2%) pts in the pembro arm and 97 (64.2%) in the chemo arm, including 80 pts who crossed over from chemo to pembro per protocol and 14 pts who received anti–PD-1 therapy outside of crossover. 56 (36%) 1L pembro pts were on 1L pembro therapy or in follow-up as of data cutoff. Updated median OS and PFS2 results are in the Table. Conclusions: Fewer pembro pts received 2L+ therapy vs chemo pts because of the significant improvement in PFS observed for pembro in the 1L setting. Median PFS2 was substantially improved for pembro (not reached [NR]) vs chemo (8.6 mo). Updated OS with median follow-up of 19 mo maintained consistent superiority of 1L pembro, despite increased crossover from 1L chemo. Clinical trial information: NCT02142738. [Table: see text]
Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomized phase III OAK study.
Authors: Gandara David R. , Von Pawel Joachim , Sullivan Richard N. , Helland Aslaug , Han Ji-Youn , Ponce Aix Santiago , Rittmeyer Achim , Barlesi Fabrice , Kubo Toshio , Park Keunchil , Goldschmidt Jerome H. , Gandhi Mayank , Yun Cindy , Yu Wei , Matheny Christina , He Pei , Sandler Alan , Ballinger Marcus , Fehrenbacher Louis
Published: September 2018

9001

Background: Cancer immunotherapy (CIT) can have a positive impact on OS that exceeds response rate or PFS effects, termed post progression prolongation of survival (PPPS). This effect can also result from unconventional CIT response due to tumor immune infiltration or delayed response, reducing reliability of RECIST v1.1 (RECIST) PD as an indicator of treatment failure. In the primary analysis (N = 850) of OAK, a study of atezo vs docetaxel (doc) in 2L/3L NSCLC, OS favored atezo (HR 0.73; 95% CI: 0.62, 0.87), despite similar PFS between arms (HR 0.95; 95% CI: 0.82, 1.10). Here we evaluate clinical benefit from TBP, defined by post PD tumor regression, OS and safety. Methods: Patients (pts) received atezo 1200 mg IV q3w until PD or loss of clinical benefit per investigator or doc 75 mg/m2 IV q3w until PD per RECIST. No crossover was allowed. Primary outcome measure: OS. Atezo TBP pts were evaluated for post PD tumor change and for safety pre and post PD. OS from time of PD per RECIST was evaluated in both arms (data cutoff, July 7, 2016; minimum follow-up, 19 mo). Results: Among 332 atezo pts with PD, 51% (n = 168) continued atezo TBP; 7% (12/168) achieved subsequent response in target lesions (≥ 30% reduction from new baseline at PD); 49% (83/168) had stable target lesions (best change between +20% and −30%). mOS was 12.7 mo (95% CI: 9.3, 14.9) post PD for pts on atezo TBP (Table). Atezo TBP was not associated with increased safety risk. Conclusions: This is the first report from a Phase III study of CIT in NSCLC to evaluate post PD OS in pts continuing treatment beyond RECIST PD. Atezo TBP was associated with high frequency of stable or decreased target lesions, mOS > 1 year and a tolerable safety profile, all supporting prolonged treatment benefit consistent with PPPS. NCT02008227 Clinical trial information: NCT02008227. [Table: see text]
Efficacy and safety results from AvaALL: An open-label, randomized phase III trial of standard of care (SOC) with or without continuous bevacizumab (Bev) treatment beyond progression (PD) in patients (pts) with advanced non-small cell lung cancer (NSCLC) progressing after first-line Bev and chemotherapy (chemo).
Authors: Bennouna Jaafar , De Castro Javier , Dingemans Anne-Marie C. , Griesinger Frank , Grossi Francesco , Langer Corey J. , Ohe Yuichiro , Syrigos Konstantinos N. , Thatcher Nick , Das-Gupta Ashis , Donica Margarita , Smoljanovic Vlatka , Gridelli Cesare
Published: September 2018

9004

Background: The role of treatment with Bev beyond PD is unclear in the multiline treatment strategy of advanced NSCLC.AvaALL(NCT01351415), a multinational, open-label, randomized phase III trial, assessed continuous Bev and SOC beyond first PD (PD1) in pts with NSCLC following first-line treatment with platinum-based chemo plus Bev. Here we present efficacy and safety data from AvaALL. Methods: Pts with NSCLC who received 4–6 cycles of chemo + Bev and ≥2 cycles of maintenance Bev were randomized after PD1 to second-line SOC therapy (docetaxel, pemetrexed or erlotinib) ± Bev. After second PD (PD2) and third PD (PD3), pts received third-line or fourth-line SOC ± Bev treatment, respectively. Primary endpoint was overall survival (OS). Secondary endpoints were OS rates (6, 12, and 18-months [mos]), progression-free survival (PFS) from PD1 to PD2/from PD2 to PD3, overall response rate (ORR), disease control rate (DCR), and safety. Data cut-off: 24 Jun 2016. Results: Overall, 485 pts were randomized (n = 475 treated). Pt characteristics were well balanced between the two arms. Bev plus chemo resulted in a median OS of 11.9 mos versus 10.2 mos for SOC alone (HR 0.84, 90% CI 0.71–1.00; p = 0.1016; 387 OS events). The primary endpoint was not met (416 OS events were required, at 10% two-sided significance level). OS rates were 10% higher in the Bev arm vs SOC alone at 6-, 12- and 18-mos. Median PFS2 was 4.9 mos with Bev vs 3.8 mos with SOC (HR 0.85, 90% CI 0.72–1.00; p = 0.0907). PFS3 was significantly improved (3.5 mos for Bev, 2.4 mos for SOC; HR 0.65, 90% CI 0.51–0.84; p = 0.0047). ORR and DCR were slightly higher in the Bev arm versus the SOC arm (ORR 9.7% vs 6.7%; DCR 86.2% vs 79.3%, respectively). No new safety signals were identified. Grade ≥3 adverse events were reported in 78.2% of Bev pts and 61.6% of SOC pts. Conclusions: Although the primary endpoint was not met, efficacy data suggest a positive trend for continued Bev plus SOC after PD1 compared with SOC alone. No cumulative safety signals were identified. Clinical trial information: NCT01351415.
Safety of retreatment with immunotherapy after immune-related toxicity in patients with lung cancers treated with anti-PD(L)-1 therapy.
Authors: Santini Fernando Costa , Rizvi Hira , Wilkins Olivia , van Voorthuysen Martine , Panora Elizabeth , Halpenny Darragh , Kris Mark G. , Rudin Charles M. , Chaft Jamie E. , Hellmann Matthew David
Published: September 2018

9012

Background: Anti-PD(L)-1 therapy is generally well tolerated, but immune-related adverse events (irAEs) can occur. No data currently exists to guide decisions related to considering re-treatment following an irAE. Methods: Patients (pts) with lung cancer treated with anti-PD(L)-1 (+/- anti-CTLA-4) between 4/2011 to 5/2016 who had a treatment delay of at least one week were identified. Those in whom delay was a result of a definite irAE were included, and subsequent treatment details and outcomes were captured. Pts with an irAE concurrent with disease progression were excluded. Results: Among 482 pts treated, 71 (14.7%) had treatment delay related to an irAE. Most events were Grade 2 (38/71, 54%) or Grade 3 (30/71, 42%), and predominantly included pneumonitis (21%), colitis (17%), rash (14%), or hepatitis (13%). 32 pts (45%) were permanently discontinued after the irAE and 39 (55%) were later retreated with anti-PD(L)-1 therapy. In retreated pts, the same irAE recurred in 10/39 (26%), a new irAE occurred in 9/39 (23%), and 20/39 (51%) had no subsequent irAE. The rate of recurrent/new irAEs was similar in those with Grade 3 compared to Grade 2 irAEs (p = 1.0), but were more common following initial irAE that occurred early ( < 3 months) compared to later (≥3 months) in treatment course (16/24 [67%] vs 3/15 [20%], p = 0.0079). The rate of recurrent/new irAE was 33% (2/6) in those with pneumonitis, 40% (2/5) with rash, 57% (4/7) with colitis, and 80% (4/5) with arthralgia. Recurrent/new irAEs were successfully managed with immunosuppression in 17/19 (90%) pts. However, 2 pts died, both related to a new irAE different from the one initially experienced. Of the pts retreated, 3 (8%) had onset of objective response to anti-PD(L)-1 therapy following resumption of treatment. Conclusions: In pts who develop irAEs and improve, re-treatment with anti-PD(L)-1 therapy was associated with recurrent or new irAEs in half of pts, and was more common in early-onset irAEs. The majority of the pts with recurrent/new irAEs were managed successfully, but two deaths occured. Few objective responses occurred following retreatment.
A phamacoeconomic analysis of personalized dosing versus fixed dosing of pembrolizumab in first-line PD-L1 positive non-small cell lung cancer.
Authors: Goldstein Daniel A. , Gordon Noa , Davidescu Michal , Leshno Moshe , Steuer Conor Ernst , Patel Nikita , Stemmer Salomon M. , Zer Alona
Published: September 2018

9013

Background: In October 2016 pembrolizumab became the new standard of care for first-line treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death ligand 1 in at least 50% of cells. The FDA recommended dose is 200mg every three weeks. Multiple studies have demonstrated equivalent efficacy with weight-based doses between 2mg/kg to 10 mg/kg. The objective of this study was to compare the economic impact of using personalized dosing (2mg/kg) versus fixed dosing (200mg) in the first line setting of mNSCLC. Methods: We performed a budget impact analysis from the US societal perspective to compare fixed dosing with personalized dosing. We calculated the target population and weight of patients that would be treated with pembrolizumab annually in the first-line setting. Using survival curves from the KEYNOTE 024 trial with Weibull extrapolation we estimated the mean number of cycles that patients would receive. Using the Medicare average sales price we calculated the difference in cost between personalized and fixed dosing. Results: Our base case model demonstrates that the total annual cost of pembrolizumab with fixed dosing is US$ 3,440,127,429, and with personalized dosing it is US$ 2,614,496,846. The use of personalized dosing would lead to a 24% annual saving of US$ 825,630,583 in the United States. Conclusions: Personalized dosing of pembrolizumab may have the potential to save approximately 0.825 billion dollars annually in the United States, likely without impacting outcomes. This option should be considered for the first-line management of PD-L1 positive advanced lung cancer.
Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.
Authors: Gangadhar Tara C. , Schneider Bryan J. , Bauer Todd Michael , Wasser Jeffrey S. , Spira Alexander I. , Patel Sandip P. , Balmanoukian Ani Sarkis , Bauml Joshua , Schmidt Emmett V. , Zhao Yufan , Jones Mark M. , Tarhini Ahmad A.
Published: September 2018

9014

Background: ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of epacadostat (a potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus pembrolizumab (E + P) in patients (pts) with advanced tumors. We report preliminary efficacy and safety outcomes for the phase 1/2 NSCLC cohort. Methods: Adult pts with prior platinum-based therapy (tx) and no prior checkpoint inhibitor tx were eligible. Phase 1 dose-escalation tx was E (25, 50, 100, 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 cohort expansion. Efficacy was evaluated by tumor proportion score (TPS [% viable tumor cells, PD-L1 staining]: < 50% and ≥50%) and by prior lines of tx in RECIST 1.1 evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: As of 29OCT2016,43 pts (phase 1, n = 12; phase 2, n = 31) were evaluated. Median age was 65 years, 58% of pts were women, 12% were EGFR-positive, and 23% were KRAS-positive. Most pts had a history of smoking (84%), ≤2 prior lines of tx (84%), and no prior TKI tx (93%). For the 40 efficacy-evaluable pts, ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. PD-L1 TPS test results were available in 28/40 efficacy-evaluable pts. ORR and DCR for pts with TPS ≥50% and ≤2 prior tx were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for pts with TPS < 50% and ≤2 prior tx, ORR and DCR were 35% (6/17; all PR) and 53% (9/17; 3 SD). Among the 40 efficacy-evaluable pts, 12/14 responses were ongoing (range, 1+ to 519 days) at data cutoff. PFS and biomarker analyses are ongoing. Across all 43 pts, most frequent TRAEs were fatigue (19%), arthralgia (9%), and increased AST (9%); 16% of pts had grade ≥3 TRAEs, and increased lipase (asymptomatic) was the only grade ≥3 TRAE that occurred in > 1 pt (n = 2). Two pts discontinued due to TRAEs (grade 3 increased AST, grade 2 increased ALT [n = 1]; grade 2 brain edema [n = 1]). Conclusions: E + P was generally well tolerated and associated with promising responses in pts with NSCLC. A phase 3 NSCLC study is planned. Clinical trial information: NCT02178722.
Osimertinib compared to docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small cell lung cancer.
Authors: Nie Keke , Zhang Zhongfa , Zou Xiao , Zhang Chunling , Zhuang Xingjun , Yu Zhuang , Lan Ketao , Ji Youxin
Published: September 2018

9017

Background: Osimertinib, an oral irreversible EGFR tyrosine kinase inhibitor, had promising results in patients with EGFR T790M resistance mutation of non-small-cell lung cancer (NSCLC). This study compared efficacy and toxicities of osimertinib versus docetaxel -bevacizumab as third-line treatment in EGFR T790M mutated NSCLC. Methods: In this phase 3, open-label, three-center study, we randomly assigned previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients who had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum genetic test. Patients were randomly assigned in a ratio of 1:1 to receive oral osimertinib (80mg/day) or receive intravenous infusion docetaxel (75mg/m2) and bevacizumab (7.5mg/kg) until disease progression or unacceptable toxic effects. Docetaxel -bevacizumab group patients might crossover to osimertinib group after disease progression. The primary end-point of this study was progression-free survival and the secondary end-point were response rates, toxicities and OS. Results: A total of 147 patients were treated. Among them, 74 enrolled in the osimertinib group and 73 in the docetaxel-bevacizumab group. The median progression-free survival was 10.20 months and 2.95 months in the osimertinib group and docetaxel -bevacizumab group respectively (Hazard ratio 0.23; 95% confidence interval, 0.12 to 0.38; P < 0.0001). The overall response rate and disease control rate was 61.6% or 87.6% in osimertinib group 8.3% or 43.0% in docetaxel-bevacizumab group respectively. The median overall survival time was not reached. The main grade 3 or 4 toxic effects were diarrhea (2.7%) and interstitial lung disease (1.2%) in the osimertinib group and alopecia (15.1%), anorexia (12.3%), neutropenia (9.6%) and nausea (8.6%) in docetaxel -bevacizumab group. Conclusions: Response rate and progression-free survival of osimertinib group were superior to docetaxel-bevacizumab group in third-line treatment of EGFR T790M positive NSCLC. There was no survival difference between patients with EGFR 19 Del-T790M mutation and EGFR L858R-T790M mutation. Clinical trial information: NCT02959749.