bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination of metformin and gefitinib as first-line therapy for nondiabetic advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations: A multicenter, randomized, double-blind, placebo-controlled phase II trial.
Authors: He Yong , Li Li , Jiang Liyan , Wang Yubo , Zhao Yizhuo , Zhang Xiaoju , Wu Guoming , Zhou Xiangdong , Sun Jianguo , Bai Jun , Ren Biyong , Tian Kun , Xu Zhi , Xiao Hualiang , Zhou Qi , Han Rui , Chen Hengyi , Wang Haidong , Yang Zhenzhou , Gao Chan
Published: March 2020

9035

Background: Several lines of evidence suggested a role for metformin in sensitizing diabetic NSCLC patients to EGFR tyrosine kinase inhibitors (TKIs). However, data regarding its effects on non-diabetic populations remained scarce. We hereby examined metformin’s first-line use alongside gefitinib in EGFR mutation positive (EGFRm) patients without diabetes. Methods: In this trial (NCT01864681), 224 non-diabetic patients with treatment naïve stage IIIB-IV EGFRm NSCLC were randomly assigned at 1:1 to receive gefitinib plus metformin or placebo. Gefitinib was administered at 250 mg once daily, while metformin/placebo was initiated at 500 mg once daily and then escalated to 1000 mg twice daily over 2 weeks. Dose reduction was permitted for metformin/placebo in case of intolerable toxicity. The primary endpoint was progression-free survival (PFS) rate at 1 year. Secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of interleukin-6 were also subjected to exploratory analysis. Results: Baseline characteristics were well balanced between treatment groups. The median duration of follow-up was 19.15 (IQR 12.99-28.44) months. The estimated 1-year PFS rate was 41.2% (95% confidence interval [CI] 30.0-52.2) in the metformin group versus 42.9% (95% CI 32.6-52.7) in the placebo group (p = 0.6268). Metformin did not increase median PFS (10.3 months vs. 11.4 months), median OS (22.0 months vs. 27.5 months), or ORR (66.0% vs. 66.7%) over placebo. No significant treatment group differences in terms of PFS were detected across subgroups either, including those with elevated levels of interleukin-6. Metformin plus gefitinib shared a similar safety profile with the control group, except for a remarkably higher incidence of diarrhea (78.38% vs. 43.24%). Conclusions: Our study did not show enhanced gefitinib efficacy upon addition of metformin and hence does not support its concurrent use with first-line EGFR-TKI therapy in non-diabetic EGFRm NSCLC patients. Clinical trial information: NCT01864681.
Evaluating the role of race in outcome of advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitor (ICI): Our institutional experience.
Authors: Nazha Bassel , Chen Zhengjia , Goyal Subir , Engelhart Anne , Carlisle Jennifer Wilkinson , Beardslee Tyler , Gill Harpaul , Odikadze Levani , Liu Yuan , Mishra Manoj K. , Behera Madhusmita , Ramalingam Suresh S. , Owonikoko Taofeek Kunle
Published: March 2020

9042

Background: Race-based differences in ICI efficacy for advanced NSCLC have not been studied due to under-representation of patients of minority background in pivotal trials. We systematically explored real-world differences in outcome in our diverse patient population. Methods: This is a retrospective review of clinical outcome of patients with advanced NSCLC treated with single-agent ICI between 2013 and July 2018 at the Winship Cancer Institute of Emory University. We performed univariate and multivariate analyses for overall survival (OS) and progression free survival (PFS) patients according to self-reported race and of OS according to gender and PD-L1 expression levels. Results: We analyzed clinical data from 90 eligible patients: Median age of 68.5 yrs, 51% male, White (W)/Black(B)/Asians(A) made up 62.3%/30.7%/5%; 36.5% had brain metastasis at the time of ICI initiation. The majority (85.9%) had ECOG PS ≤2; ICI was 1st line in 15 (16.9%), 2nd line in 59 (66.3%), 3rd line in 12 (13.5%) and nivolumab was the most commonly used agent (41.1%) followed by atezolizumab (32.2%) and pembrolizumab (26.7%). The median OS for the entire population was not reached (NR) (95%CI: 15.6, NR) while 12-month and 24-month OS rates were 63.8% (52.8%, 72.8%) and 53.1% (40.2%, 64.4%). The median OS, 12-month and 24-month OS rates for W and B respectively, were 23.6 months vs. NR; HR: 1.02 (95%CI: 0.51-2.04), p = 0.9571; 61.8% (47.7%, 73.2%) vs. 59.3% (38.6%, 75.0%) and 46.0% (27.9%, 62.4%) vs. 53.9% (32.8%, 70.9%). The overall response rate was 16.7%; 23.8% vs. 11% for B and W respectively. The median duration of response was comparable at 3.36 months vs. 2.94 months for W and B. The median PFS and 12-month PFS rate for W and B respectively were 5.5 (3.2, 14.8) vs. 3.0 (1.4, 10.7) months, p = 0.1350 and 40.0% (27.1%, 52.5%) vs. 29.6% (14.1%, 47.0%). Conclusions: Real-world analysis of our institutional experience showed no significant racial disparity in advanced NSCLC patients treated with ICI. Larger multi-institutional studies to include other US minority population would make our findings generalizable.
Real-world treatment outcome of advanced Chinese NSCLC EGFR exon 20 insertion patients.
Authors: Wang Yan , Yang Guangjian , Li Jun , Xu Haiyan , Yang Lu , Xu Fei , Yang Yaning , Xia Bing , Zhu Viola Weijia , Qiu Weini , Ou Sai-Hong Ignatius
Published: March 2020

9043

Background: Treatment outcome of advanced EGFR exon20 insertion (ex20ins) patients with 1st- or 2nd-line chemotherapy and EGFR TKIs remains limited. Methods: Retrospective real-world analysis of clinical, molecular, and treatment outcome of a web-based patient registry and hospital chart review. Results: Between 9/13/18-10/22/18, 165 EGFR ex20ins NSCLC patients treated in 99 hospitals from 26 different regions in China were registered. Data cutoff was 12/20/18. EGFR ex20ins were determined by commercial NGS (84%) or PCR (16%). 41 different molecular subtypes of EGFR ex20ins were identified. Ala767_Val769dupASV was the most common (23.0%) followed by Ser768_Asp770dupSVD (17.6%). 61% were females, 77% never-smokers, and CNS mets occurred in 22.4% of patients at time of diagnosis. Median PFS was significantly longer in patients who received 1st-line platinum-based chemotherapy (N = 105) (6.4m; 95% CI:5.7-7.1) vs. EGFR TKI (all generations, N = 23) (2.9m; 95%CI:1.5-4.3; P < 0.001) or vs. EGFR TKI (1G, N = 14) (2.6m; 95%CI:0.8-4.4; P < 0.001). Median PFS was numerically longer in patients who received 2nd-line paclitaxel-based chemotherapy (N = 34) (4.1m; 95%CI:3.3-4.9) versus patients who received 2nd-line EGFR TKIs (N = 18) (2.0m; 95%CI:0.8-3.2; P = 0.342). Patients with CNS mets (N = 21) had shorter median PFS with 1st-line chemotherapy than those without CNS mets (N = 84) (5.5m; 95%CI:0.7-10.3 vs. 6.4m; 95%CI:5.8-7.0; P = 0.694). Patients with CNS mets had numerically shorter median PFS with 1st-line EGFR TKI (N = 7) than those without CNS mets (N = 16) (2.0m; 95%CI:0.8-3.2 vs. 2.9m; 95%CI:2.1-3.7; P = 0.077). Conclusions: Chemotherapy is superior to current approved EGFR TKIs as 1st- or 2nd-line treatment of EGFR ex20ins. Patients with CNS mets had numerically poorer PFS with chemotherapy and EGFR TKI treatment. Targeted therapy against EGFR ex20ins with CNS activity is needed.
Variation in the assessment of immune-related adverse event occurrence, grade, and timing.
Authors: Hsieh David , Watters Mary Katherine , Lu Rong , Xie Yang , Gerber David E.
Published: March 2020

9047

Background: Accurate assessment of treatment toxicity is critical for patient safety, balancing clinical utility, and understanding treatment impact. Given their unpredictability and heterogeneity, immune-related adverse events (irAEs) may be particularly challenging to ascertain. Our objective was to evaluate the agreement between clinicians on the occurrence, grade, and timing of irAEs, and elucidate determinants of discordance. Methods: We performed a retrospective cohort study of 52 patients with cancer treated with immune checkpoint inhibitors at a National Cancer Institute-designated comprehensive cancer center. Two medical oncologist observers used algorithm-driven manual chart review to characterize eight well-described irAEs (adrenal insufficiency, colitis, hepatitis, hyperthyroidism, hypophysitis, hypothyroidism, pneumonitis, rash). Inter-rater agreement for incidence, severity, and timing of irAEs was determined using Cohen's kappa coefficient (κ) and weighted κ with linear weights. Results: The incidence of irAEs ranged from 4-35% for observer 1 and 6-27% for observer 2, while aggregate incidence rates ranged from 8% (hypophysitis) to 40% (pneumonitis). Inter-rater agreement was generally limited for irAE incidence (κ 0.37 [hypophysitis]-0.8 [hypothyroidism]). Weighted κ similarly showed limited or poor agreement for most irAE grades (κ 0.31-0.75). Differences in the assessment of irAE time of onset ranged from 5-188 days. Rates of discordance were greater for grade 1 (39%) and grade 2 (41%) irAEs than for grade 3-4 (20%) irAEs. Multivariable analyses showed that longer therapy duration (OR 4.8, P= 0.02) and a high Charlson Comorbidity Index (OR 4.09, P= 0.03) were significantly associated with discordant irAE assessment. Conclusions: Inter-rater reliability varied among irAEs and consistently showed poor agreement for the incidence, severity, and timing of irAEs. Agreement was greater for irAEs with distinct laboratory-based definitions (eg, hypothyroidism), higher-grade irAEs, and irAEs in patients with fewer comorbidities and shorter immunotherapy duration. These findings have implications in the clinical management of patients receiving immunotherapy and in the reporting of immunotherapy clinical trials.
Circulating free DNA as a prognostic biomarker in patients with advanced ALK+ NSCLC treated with alectinib from the global phase III ALEX trial.
Authors: Dziadziuszko Rafal , Peters Solange , Mok Tony S. K. , Camidge D. Ross , Noé Johannes , Nowicka Malgorzata , Bordogna Walter , Morcos Peter N. , Smoljanovic Vlatka , Shaw Alice Tsang
Published: March 2020

9053

Background: Circulating free DNA (cfDNA) released predominantly by tumors into the blood correlates with tumor load, but correlation with outcomes after ALK inhibitor treatment is poorly understood. Here, we examine the prognostic potential of cfDNA in the phase III ALEX trial of alectinib versus crizotinib in previously untreated patients with advanced ALK+ NSCLC. Methods: Data cutoff was December 1, 2017. Median cfDNA was determined from 276 baseline samples; patients were stratified into ‘≤median’ and ‘ > median’ biomarker-evaluable populations (BEP). Results: Median cfDNA was 11.5ng/mL. Baseline characteristics were mostly balanced between the crizotinib (≤median, n = 72; > median, n = 67) and alectinib (≤median, n = 66; > median n = 71) BEPs. However, the alectinib > median BEP had more active smokers (7.0% vs crizotinib 1.5%), more measurable/non-measurable CNS lesions (47.9% vs 41.8%) and more patients with TP53 short-variant (SV) (44.8% vs 32.8%); the alectinib ≤median BEP had more active smokers (7.6% vs crizotinib 2.8%). Alectinib exposure was not substantially different between relevant BEPs. Higher cfDNA amount was associated with measurable/non-measurable CNS lesions and TP53 SV. Tumor burden positively correlated with normalized cfDNA amount (Pearson correlation 0.204; p < 0.001). Median PFS by investigator in the ≤median BEP was 34.9 months alectinib vs 14.8 crizotinib (HR 0.37, 95% CI 0.22–0.61, p < 0.0001); in the > median BEP it was 14.8 months alectinib vs 8.6 crizotinib (HR 0.43, 95% CI 0.28–0.64, p < 0.0001). Response rates in the ≤median BEP were 82.3% alectinib vs 70.4% crizotinib; in the > median BEP, 70.2% alectinib vs 55.4% crizotinib. Median duration of response in the ≤median BEP was not reached for alectinib vs 21.0 months for crizotinib; in the > median BEP, 33.1 months alectinib vs 7.3 crizotinib. Conclusions: Tumor burden positively correlated with cfDNA amount; patients with ≤median cfDNA at baseline had better prognosis than those with > median cfDNA. Alectinib consistently improved PFS, DOR and ORR versus crizotinib across BEPs, reducing the risk of tumor progression by > 50% compared with crizotinib. Clinical trial information: NCT02075840.
First subsequent treatment after discontinuation of durvalumab in unresectable, stage III NSCLC patients from PACIFIC.
Authors: Planchard David , Cho Byoung Chul , Gray Jhanelle Elaine , Paz-Ares Luis G. , Ozguroglu Mustafa , Villegas Augusto E. , Daniel Davey B. , Vicente David , Murakami Shuji , Hui Rina , Kurata Takayasu , Chiappori Alberto , Lee Ki Hyeong , De Wit Maike , Gu Yu , Wadsworth Catherine , Dennis Phillip A. , Antonia Scott Joseph
Published: March 2020

9054

Background: In the phase 3 PACIFIC trial of unresectable, stage III NSCLC patients (pts) without progression after concurrent chemoradiotherapy (cCRT), durvalumab (durva) significantly improved PFS and OS with similar safety compared to placebo (pbo). We performed exploratory analyses to characterize first subsequent treatment (Tx) after discontinuation of durva. Methods: Pts with WHO PS 0/1 and any tumor PD-L1 status were randomized (2:1) 1–42 days after ≥2 cycles of platinum-based cCRT to durva 10 mg/kg IV or pbo Q2W up to 12 months, stratified by age, sex and smoking history. Pts were classified by the use or not of first subsequent Tx and category of first systemic Tx (platinum doublet CT [PDCT], single-agent CT [SCT], immunotherapy [IT] or targeted therapy [TT]). Results: As of Mar 22, 2018, 216/476 (45.4%) and 153/237 (64.6%) in the durva and pbo arms, respectively, had a RECIST-based PFS event per BICR (5.7% and 8.4% due to death). 195 (41.0%) and 128 (54.0%) received first subsequent Tx, most of which were systemic Tx (158 [33.2%] and 109 [46.0%]): PDCT (16.4% and 19.0%), SCT (8.6% and 8.4%), IT (4.2% and 13.5%) or TT (3.8% and 5.1%); 7.8% and 8.0% received RT only. Time to first subsequent therapy or death (TFST) was longer with durva vs pbo (HR 0.58; 95% CI 0.47–0.72; median 21.0 vs 10.4 months). Baseline characteristics of pts with or without first subsequent Tx were similar, and similar across durva or pbo arms. Among pts with systemic Tx, baseline characteristics (including pre-cCRT PD-L1 status) were generally similar, except pts on TT, more of whom were EGFR+ (70.0% vs 0–6.6% of other systemic Tx groups) with commonly associated phenotypes (more females, Asians, non-smokers and non-squamous pts). Best overall response to first systemic Tx will be presented. Conclusions: Due to longer PFS and fewer progression events with durva vs pbo, fewer pts on durva required subsequent Tx and, per TFST, much later. With the exception of IT, use of each subsequent Tx was similar between the durva and pbo arms with PDCT the most common. Baseline characteristics were similar for pts with or without first subsequent Tx and pts who received first systemic Tx, except for pts who received TT, as expected due to their molecular profile.
Real-world practice patterns and impact of PD-L1 expression testing in patients with advanced non-small cell lung cancer.
Authors: Leapman Michael , Presley Carolyn J , Zhu Weiwei , Soulos Pamela R. , Adelson Kerin B. , Boffa Daniel J. , Gross Cary Philip
Published: March 2020

9059

Background: Several tests measuring programmed cell death ligand 1 (PD-L1) expression are available to select patients with advanced non-small cell lung cancer (aNSCLC) for PD-1 axis therapy including FDA approved companion diagnostics (CoDx), as well as complementary (CyDx) and laboratory developed tests (LDTs). However, it is unknown how rapidly PD-L1 expression testing has become adopted, which type of tests are used, or whether testing affects first-line therapy. Methods: We retrospectively reviewed the Flatiron Health electronic health record-derived database, reflecting real-world care at community oncology practices in the U.S. We evaluated trends in the use of PD-L1 expression testing within 12 months of diagnosis. Among patients diagnosed after FDA approval of PD-L1 testing prior to first-line therapy (Oct 2016), and without other identifiable driver mutations, we used multivariable logistic regression to examine the association between PD-L1 testing and receipt of first-line PD-1 axis therapy. We further examined the association between PD-L1 expression result (using overall reported status or % staining) and choice of first-line therapy. Results: We identified 49,546 patients with aNSCLC from 2011 through the third quarter of 2018. The use of PD-L1 expression testing increased from 7.0% in 2015 to 70.6% in 2017 (p < 0.01). Among those receiving testing, the proportion of patients receiving CoDx increased from 29.9% in 2015 to 73.0% in 2017 with corresponding reductions in CyDx and LDTs. PD-L1 expression testing was associated with use of PD1-axis therapy in the first-line (OR = 2.92, 95% CI 2.59-3.30). Among 4,942 treated patients diagnosed after Oct 2016, those with ≥50% staining more frequently received first line PD-1 axis therapy (82.9%) than those with intermediate (35.5%) or low (25.8%) positive staining; conversely, patients with ≥50% were less likely to receive chemotherapy alone or combination with PD-1 axis therapy. Conclusions: PD-L1 expression testing was rapidly adopted following FDA approval of companion diagnostic testing for aNSCLC. Although the results of PD-L1 expression testing inform the choice of first-line therapy, a substantial proportion of patients are not tested prior to first line treatment.
Therapeutic and prognostic impacts of specific gene alterations for squamous cell lung cancer: A result of nationwide genome screening in Japan (LC-SCRUM-Japan).
Authors: Kato Terufumi , Matsumoto Shingo , Umemura Shigeki , Yoh Kiyotaka , Nishino Kazumi , Daga Haruko , Tsubata Yukari , Ebi Noriyuki , Miyamoto Shingo , Shingyoji Masato , Hashimoto Shigeki , Nakagawa Taku , Hara Satoshi , Goto Koichi
Published: March 2020

9060

Background: Various gene alterations occur during the development of squamous cell lung cancer (SqLC), but specific gene alterations for SqLC and their clinical significance remain unknown. Methods: In a nationwide genome screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer patients for genetic alterations using a next-generation sequencing (NGS) system, Oncomine Comprehensive Assay, and have established a large-scale clinico-genomic database. Results: Since February 2013 to December 2018, a total of 6692 lung cancer patients (686 SqLCs, 5360 non-squamous non-small cell lung cancers [Non-sq] and 646 small cell lung cancers [SCLCs]) had been enrolled in the LC-SCRUM-Japan. The success rate of the NGS assay was 91%. Of 639 SqLCs analyzed, 274 (48%) had potentially targetable gene alterations, including 77 NFE2L2 (encoding NRF2) mut, 50 PIK3CA mut, 46 FGFR1 amp, 40 EGFRmut/amp, 36 PTEN mut, 23 KRAS mut, 6 AKT1 mut, 6 MET ex14skip, 5 ALK fusions, 2 FGFR3 fusions. Among the alterations detected, NFE2L2 mut and FGFR1 amp were significantly frequent in SqLC than Non-sq or SCLC (NFE2L2, 12.1% vs. 1.0% vs. 1.3%; p < 0.001, and FGFR1, 7.2% vs. 1.1% vs. 3.4%; p < 0.001). In advanced SqLC patients who received platinum-containing chemotherapies, the median progression-free survival (mPFS) was significantly shorter in NFE2L2-mutated patients (NRF2-type) than NFE2L2/FGFR1-negative patients (nonNF-type) (3.8 [95%CI, 2.9-5.1] vs. 4.5 [95%CI, 3.8-5.4] months, p = 0.03), and similarly, the mPFS of FGFR1-amplified patients (FGFR1-type) (3.5 months [95%CI, 1.5-4.9]) tended to be shorter than that of nonNF-type (p = 0.07), although the response rates were equivalent among the three types. NRF2-type also showed shorter overall survival (OS) than nonNF-type (median OS, 10.4 [95%CI, 6.9-22.3] vs. 16.6 [95%CI, 13.6-21.7] months, p = 0.10). Therapeutic efficacy of nivolumab or pembrolizumab was not different among these types in the current follow-up data. Conclusions: Our large scale genome screening identified specific gene alterations for SqLC and the alterations were associated with a less efficacy of chemotherapy and worse prognosis, suggesting the need for the development of genotype-directed therapeutic strategy for SqLC patients.
Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase II clinical trial–Updated report on progression-free and overall survival.
Authors: Michels Sebastian Yves Friedrich , Franklin Jeremy , Massuti Bartomeu , Sebastian Martin , Schildhaus Hans-Ulrich , Felip Enriqueta , Grohe Christian , Rodriguez-Abreu Delvys , Bischoff Helge , Carcereny Enric , Corral Jesús , Dingemans Anne-Marie C. , Insa Amelia , Reck Martin , Rothschild Sacha , Smit Egbert F. , Provencio Mariano , Büttner Reinhard , Rosell Rafael , Wolf Juergen
Published: March 2020

9066

Background: ROS1 rearrangements are found in 1% of non-small cell lung cancer (NSCLC) patients. Early clinical trials in the US and East Asia have proven the therapeutic efficacy of crizotinib in this subset of patients. EUCROSS is the first prospective European trial to evaluate the acitivity of crizotinib in ROS1-positive lung cancer. Here we present an updated analysis of the investigator-assessed progression-free survival (PFS) and overall survival (OS). Methods: EUCROSS is a multi-centre, single arm phase 2 trial (NCT02183870). Key eligibility criteria: ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation). Treatment with crizotinib was initiated at a dose of 250 mg twice daily. Primary endpoint of the trial: investigator-assessed objective response rate (ORR) in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1). Key endpoints of this report: updated PFS and OS and updated molecular characterization of tumour tissue. Results: Thirty-four patients received treatment with crizotinib and were included in the intention-to-treat analysis. Four patients were excluded from the primary endpoint analysis due to violation of eligibility criteria (response-evaluable set, N = 30). Median follow-up period was 44.9 months. At the time of data cut-off for this report 19 patients (63%) discontinued treatment due to progression or death. Investigator ORR was 70% (95% CI, 51–85; 21/30), disease control rate was 90% (95% CI, 73.5-97.9; 27/30) and median PFS was 19.4 months (95% CI, 10.1-31.2). Median OS was not reached, but 24-months-OS probability was 66% (95% CI, 48.3-82.9). Tissue of 18 patients was available for hybrid-capture-based sequencing. Co-occurring genetic aberrations were found in 61% (11/18). TP53 mutations were most frequent (28%; 5/18). PFS (24-months probability, TP53-mut. 0% vs. TP53 wild-type (wt) 61%; p = 0.0219) and OS (24-months, TP53-mut. 40% vs. TP53 wt 83%; p = 0.015) were significantly shorter in TP53-mutant patients. Differences in OS and PFS stratified by number of prior treatment lines (0-1 vs. > = 2), brain metastases (yes vs. no) or CD74-rearrangement ( CD74- ROS1 vs. other fusion type) status were not significant. Conclusions: Updated PFS and OS results show that crizotinib is highly effective in ROS1-rearranged lung cancer. Co-occurring TP53 mutations were associated with a significantly worse outcome. Clinical trial information: NCT02183870.
Whole exome sequencing (WES) of non-small cell lung cancer (NSCLC) for tumor mutational burden (TMB) analysis and long-term benefit to immune checkpoint inhibitors (ICIs).
Authors: Felip Enriqueta , Navarro Alejandro , Callejo Ana , Martinez Marti Alex , Cedres Susana , Pardo Nuria , Ros Javier , Assaf Juan David , Pedrola Anna , Viaplana Cristina , Sansano Irene , Jimenez Jose , Nuciforo Paolo , Sansó Miriam , Dienstmann Rodrigo , Amat Ramon , Mancuso Francesco M , Vivancos Ana
Published: March 2020

9071

Background: ICIs have significantly changed the therapeutic landscape of advanced NSCLC. As such, characterizing predictive markers of long-term clinical benefit is a critical objective. TMB quantification using targeted gene panels associates with long-term response to ICIs in NSCLC patients (Rizvi H ASCO 18). Although TMB quantified by targeted NGS correlates with that of WES, caution may be needed when using smaller panels. Methods: Here we analyzed WES of tumors and matched normal tissue from 67 NSCLC patients including 42 treated with ICIs. We correlated TMB with clinico-pathological features and outcomes. TMB was categorized as high vs. low according to the upper quartile of cohort distribution. Results: The median TMB was 2.68 non-synonymous variants (nSNVs)/Mb, ranging from 0 to 15.6 nSNVs/Mb, with upper quartile at 5.42 nSNVs/Mb. TMB was higher for smoker/current smoker (median 3.51) compared to never smokers (median 0.94, p = 0.0048) but no differences were seen in elderly ( > 70 years) vs. young patients or across histologies (squamous, adeno and other) and stages at diagnosis. In patients treated with ICIs, median TMB was 5.44 for those achieving complete response, 3.87 for patients with partial response and 2.42 for patients with progressive disease (PD) (p = 0.04). Moreover, improved clinical outcomes were associated with higher TMB (Table). In patients treated with ICIs, TMB as continuous variable had an impact on progression free survival (PFS) (p = 0.03). Median PFS was 22.3 months (mo) (14-not reached) for those with high TMB and 6.4 mo (3-16) for those with low TMB (HR 0.34, 0.13-0.9, p = 0.03). Median overall survival was not reached for those patients with high TMB and 32 mo (22-43) for those with low TMB (HR 0.29, 0.1-0.86, p = 0.02). Conclusions: High TMB correlates with long-term ICI benefit in NSCLC patients. Mutations in individual genes potentially linked to long-term benefit or resistance to ICIs will be presented. [Table: see text]
First-in-human phase 1 study of the antibody-drug conjugate (ADC) SAR408701 in advanced solid tumors: Dose-expansion cohort of patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC).
Authors: Gazzah Anas , Cousin Sophie , Boni Valentina , Ricordel Charles , Kim Tae Min , Kim Jin-Soo , Helissey Carole , Gardeazabal Itziar , Chadjaa Mustapha , Allard Aurore , Yoruk Semra , Barlesi Fabrice
Published: March 2020

9072

Background: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types. This Phase 1, open-label, dose-escalation, dose-expansion study (NCT02187848) investigated SAR408701, a DM4 conjugated ADC targeting CEACAM5, in pts with advanced solid tumors. During dose escalation, maximum tolerated dose (MTD) of SAR408701 was 100 mg/m2 IV once every 2 weeks in 14-day cycles. Interim analysis of an ongoing expansion cohort in pts with NSQ NSCLC with CEACAM5 expression in ≥ 50% of the tumor cell population is reported. Methods: SAR408701 was administered at MTD. Primary endpoint: overall response rate (ORR; expansion phase). Secondary endpoints include safety and pharmacokinetics (PK). Tumor assessments were performed every 4 cycles (8 weeks). Results: As of Aug 2, 2018, 22 pts with NSQ NSCLC (21 adenocarcinoma; 1 not yet reported) received SAR408701 at MTD. Median age: 60 years; male: 72.7%; ECOG PS (n = 21): 0 = 38.1%, 1 = 61.9%. Median number of prior anticancer therapies for advanced disease was 3; 66.7% (14/21) received ≥ 3 lines; 59.1% had prior anti-tubulin-based treatments. Pts received a median of 6.5 cycles. 15 pts discontinued due to progressive disease and 1 due to an adverse event (AE; peripheral neuropathy); 6 pts remain on study. ORR was estimated at 22.7% (5/22 pts; 90% CI 11.5–39.9); 40.9% had stable disease. Most frequently occurring all-grade treatment-emergent AEs (TEAEs) were corneal events (40.9%; including keratitis 22.7% [1 Grade 3] and keratopathy 18.2%), dyspnea (31.8%; 5 Grade ≥ 3), asthenic conditions (31.8%) and diarrhea (27.3%). 6 pts had ≥ 1 dose modification due to a TEAE. PK analysis was performed in 14 pts at Cycle 1; mean Cmax, AUC, clearance and t1/2z were 53.1 µg/mL, 297 µg.day/mL, 0.685 L/day and 6.19 days, respectively. Conclusions: In pts with advanced NSQ NSCLC and CEACAM5 expression in ≥ 50% of tumor cells, SAR408701 had a favorable safety profile. Interim analysis of 22 pts achieved the predefined boundary for efficacy (≥ 4 of 30 pts). These data support further development in NSQ NSCLC. Funding: Sanofi Clinical trial information: NCT02187848.
Nintedanib plus docetaxel in lung adenocarcinoma patients (pts) following treatment with immune checkpoint inhibitors (ICIs): Preliminary efficacy and safety results of the non-interventional study VARGADO.
Authors: Grohé Christian , Blau Wolfgang , Gleiber Wolfgang , Haas Siegfried , Mueller-Huesmann Harald , Schulze Mathias , Atz Judith , Kaiser Rolf
Published: March 2020

9074

Background: The treatment landscape of non-targetable advanced NSCLC pts has changed considerably following the introduction of ICIs. Data are scarce regarding optimal treatment choice and treatment sequence for pts who progressed on ICI. Methods: VARGADO (NCT02392455) is a prospective non-interventional study investigating the efficacy and tolerability of the oral triple angiokinase inhibitor nintedanibplus docetaxel in pts with advanced lung adenocarcinoma after first-line chemotherapy. The present analysis focused on its clinical activity in pts who received nintedanib plus docetaxel in 3rd line following progression on ICIs in 2nd line. Results: 25 pts whose disease has progressed on previous ICI therapy received subsequently nintedanib plus docetaxel. Median age was 59 years (range: 45 – 76); 17/25 pts (68.0%) were men, 17/25 pts (68.0%) were ECOG PS0/1, and 24/25 pts (96.0%) were current or former smokers. 1st line chemotherapy included pemetrexed (18/25 pts, 72.0%), cisplatin (15/25 pts, 60.0%), carboplatin (12/25 pts, 48.0%), bevacizumab (8/25 pts, 32.0%), vinorelbine (4/25 pts, 16.0%), paclitaxel (2/25 pts, 8.0%), and docetaxel (1/25 pts, 4.0%). 2nd line treatment included nivolumab (18/25 pts, 72.0%) and pembrolizumab (6/25 pts, 24.0%). Under nintedanib and docetaxel, 9/20 pts (45.0%) showed a partial response, and 7/20 pts (35.0%) showed stable disease, resulting in a DCR of 80.0% (16/20 pts). Median PFS was 5.5 months (95%CI 2.5 – 8.2). Treatment emergent adverse events (TEAEs) grade ≥3, serious TEAEs, and TEAEs leading to discontinuation occurred in 15/25 pts (60.0%), 13/25 pts (52.0%), and 9/25 pts (36.0%), respectively. Conclusions: Nintedanib, in combination with docetaxel, showed clinically meaningful efficacy and an acceptable safety profile in advanced lung adenocarcinoma pts following chemotherapy and ICIs. These findings support the use of nintedanib plus docetaxel as a therapeutic option in lung adenocarcinoma pts progressing under ICI therapy. Clinical trial information: NCT02392455.
Randomized multicenter phase II trial evaluating the sequencing of PD-1 inhibition with pembrolizumab (P) and standard platinum-based chemotherapy (C) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) (AFT-09).
Authors: Hensing Thomas A. , Wang Xiaofei F. , Gao Junheng , Stinchcombe Tom , Knopp Michael V. , Dudek Arkadiusz Z. , Graziano Stephen L. , Patel Jyoti D. , Faller Bryan , Dragnev Konstantin H. , Kozono David E. , Vokes Everett E.
Published: March 2020

9088

Background: KEYNOTE-024 established single-agent P as a 1st-line option for pts with metastatic NSCLC without targetable alterations and PD-L1 tumor proportion score (TPS) ≥ 50%. KEYNOTE-189 and 407 established concurrent C + P as a treatment option irrespective of PD-L1 expression. In this randomized phase II selection trial, we explored sequencing of C and P in this pt. population. Methods: Eligible pts were randomized 1:1 to (arm A) C (carboplatin (AUC 6) + pemetrexed 500 mg/m2 (non-squamous) or paclitaxel 200 mg/m2 (squamous)) x 4 cycles followed by P 200 mg x 4 cycles, or the reverse sequence (arm B) of P x 4 cycles followed by C x 4 cycles. After 8 cycles, pts on both arms were eligible to receive maintenance P for up to 24 months. Primary endpoint was objective response rate (ORR) per RECIST 1.1 by independent review. Secondary endpoints included progression free survival (PFS) per RECIST 1.1 and overall survival (OS). Efficacy endpoints were also evaluated by PD-L1 expression. Results: 89 pts (47 arm B & 42 arm A) were enrolled and are included in the analysis (PD-L1 TPS 0/1-49%/≥50% = 24 pts (34%)/25 pts (36%)/21 pts (30%)). There was no significant difference in ORR (36% vs 38%, p = 0.829), median PFS (2.7 vs 5.5 months (mo), HR 1.25, 95% CI 0.77-2.02, p = 0.363) or OS (13.1 vs 19.8 mo, HR 1.25, 95% CI 0.69-2.25, p = 0.4573), arm B (Px4→C) vs arm A (Cx4→P). Multivariable Cox regression analysis demonstrated significant interaction between treatment and PD-L1 TPS ( < 50% vs ≥ 50%) for PFS (HR 6.76, 95% CI 2.14-21.35, p = 0.0011) and a trend for OS (HR 5.02, 95% CI 0.92-27.55, p = 0.0632), arm B vs arm A. Incidence of grade ≥3 adverse events was 71% for arm A and 65% for arm B. No new safety signals were observed. Conclusions: In pts with stage IV NSCLC and PD-L1 TPS ≥ 50% there was an observed improvement in PFS and OS in favor of C followed by P vs P x 4 followed by C. Given small # of pts and trial design, this observation should be considered hypothesis-generating, but supports further exploration of sequential C + P in this setting. Support:Merck Sharp & Dohme Corp.; https://acknowledgments.alliancefound.org Clinical trial information: NCT02591615.
A phase II study of bemcentinib (BGB324), a first-in-class highly selective AXL inhibitor, with pembrolizumab in pts with advanced NSCLC: OS for stage I and preliminary stage II efficacy.
Authors: Felip Enriqueta , Brunsvig Paal , Vinolas Nuria , Ponce Aix Santiago , Carcereny Costa Enric , Dómine Gomez Manuel , Trigo Perez Jose Manuel , Arriola Edurne , Campelo Rosario Garcia , Spicer James F. , Thompson Jonathan Robert , Ortega Granados Ana Laura , Holt Robert J , Lorens Katherine , Lorens James B. , Shoaib Muhammad , Siddiqui Abdul , Schmidt Emmett V. , Chisamore Michael Jon , Krebs Matthew
Published: March 2020

9098

Background: AXL is an RTK implicated in epithelial-to-mesenchymal transition and as a resistance mechanism to multiple therapies including anti-PD1. Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy in the pre-clinical setting. Methods: This is a Phase II single-arm, two-Stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously treated, IO naïve pts (n = 48 in total) with Stage IV lung adenocarcinoma. The primary endpoint was ORR according to RECIST 1.1 with pre-defined minimum requirement for 18% RR in the first Stage (n = 24) to proceed to Stage 2. Secondary endpoints included DCR, PFS, OS and safety. Tumour biopsies were analysed for PD-L1 (22C3 pharmDx), AXL, and infiltrating immune cells. Results: Stage 1 completed enrolment in Apr ‘18. As of Feb ‘19, 38 pts (24 and 14 in Stage 1 and 2, respectively) have been dosed with the combination; median age 66 (range 39-79) yr, 59% male, all previously received one prior line of platinum-based chemotherapy or a licensed EGFR/ALK-directed therapy. The most common TRAEs (occurring in > 15% of pts) were transaminase increases (37%), diarrhoea (29%), and asthenia (17%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments. At time of writing, Stage 1 had met the efficacy threshold to proceed to Stage 2 with continued enrolment. Among 29 pts evaluable for response 7 PRs were reported (24%). For AXL positive pts (10/21 with available biopsies), ORR was 40%. PD-L1 status was known for 5 responders: 4 pts (80%) were PD-L1 negative or weakly positive. In Stage 1, mPFS was 4.0 months (95% CI 1.9 – NR) and 5.9 months in AXL positive pts (n = 10; 3.0 - NR). mOS was not mature. Conclusions: Overall, bemcentinib in combination with pembrolizumab was well tolerated and promising clinical activity was seen, particularly in pts with AXL positive disease. Updated results will be reported at the meeting, incl 12-month OS for Stage 1 and preliminary efficacy of Stage 2. Clinical trial information: NCT03184571.
Immune-checkpoints inhibitors in metastatic non small cell lung cancer with rare histology.
Authors: Signorelli Diego , Ferrara Roberto , Proto Claudia , Lo Russo Giuseppe , Imbimbo Martina , Galli Giulia , De Toma Alessandro , Pagani Filippo , Randon Giovanni , Fucà Giovanni , Trevisan Benedetta , Ganzinelli Monica , Zilembo Nicoletta , Fabbri Alessandra , De Braud Filippo G. , Garassino Marina Chiara , Prelaj Arsela
Published: March 2020

9106

Background: Immune-checkpoints inhibitors (ICIs) have clearly improved prognosis of metastatic lung squamous carcinoma and adenocarcinoma, while their benefit remains uncertain in patients (pts) with rare NSCLC histotypes (RH). The study aim was to evaluate ICIs efficacy in RH. Methods: We retrospectively collected data from consecutive metastatic NSCLC pts treated with ICIs at our Institution from 4/2013 to 12/2018. Objective response rate (ORR) and disease control rate (DCR) were assessed. Fisher’s exact test was used to compare ORR and DCR in RH versus not-RH (NRH). Univariate and multivariate survival analyses were estimated by Kaplan-Meier and Cox progression hazard models. Results: Of 268 pts, 31 (11.6%) had RH: 16 sarcomatoid, 7 pulmonary enteric adenocarcinoma, 4 large cell neuroendocrine carcinoma and 4 adenosquamous carcinoma. In RH group, median age was 67 years old (range 41-81), most were males (71%) and smokers (90.3%); ECOG PS was: 0 (16.1%), 1 (67.8%) and 2 (16.1%). PD-L1 < 1%, 1-49%, ≥50% and unknown expression were reported in 22.6%, 19.3%, 35.5% and 22.6% pts, respectively. Twelve pts received ICIs as first and 19 as second or further-line. ORR was 22.6% in RH, 20.3% in NRH (p = 0.81); DCR was 35.5% in RH, 53.1% in NRH (p = 0.08). After a median follow-up of 20 months (m) (95% CI 4.0 – 36.7 m), median progression-free survival (PFS) was 2.6 m (95% CI 1.9-3.3 m) in RH vs 2.6 m in NRH (95% CI 2.1 – 3.0 m); median overall survival (OS) was 4.6 m (95% CI 0.03-12.0 m) in RH vs 9.2 m (95% CI 7.4 – 10.9 m) in NRH. No statistically significant differences were seen between the two groups (p = 0.729 for PFS, p = 0.601 for OS). At multivariate analyses adjusted for age, sex, smoke, PS, PD-L1 status, line of therapy and histotype (RH vs NRH), only low PS and first line treatment showed better PFS and OS (p < 0.001 and p = 0.003, respectively) in overall population. Conclusions: Our analysis, limited by the small and heterogeneous RH sample size, reported no significant differences between RH and NRH in terms of ORR, DCR and survival. However, looking at OS and DCR data, RH seem to have worse outcome. Correlation between histotype and pts characteristics and survival analyses in a larger cohort of ICIs treated NSCLC pts is ongoing. Specific prospective trials are needed to evaluate ICIs role in RH.
Fast-progression (FP), hyper-progression (HPD) and early deaths (ED) in advanced non-small cell lung cancer (NSCLC) patients (pts) upon PD-(L)-1 blockade (IO).
Authors: Ferrara Roberto , Mezquita Laura , Texier Matthieu , Lahmar Jihene , Audigier-Valette Clarisse , Tessonnier Laurent , Mazieres Julien , Brosseau Solenn , Leroy Laura , Duchemann Boris , Lefebvre Corentin , Veillon Remi , Westeel Virginie , Champiat Stephane , Planchard David , Remon Jordi , Gazzah Anas , Soria Jean-Charles , Caramella Caroline , Besse Benjamin
Published: March 2020

9107

Background: HPD was described in 13.8% of NSCLC pts upon single-agent IO and correlated with high metastatic burden and poor prognosis. Other progression (PD) patterns as FP and ED within 12 weeks have been reported respectively in 4.7% and 5.6% of atezolizumab treated NSCLC pts. Whether FP/ED and HPD are different or overlapping patterns is currently unknown. Methods: We analyzed FP, ED and HPD in a multicentric (8 centers) retrospective cohort of IO treated NSCLC pts (11/2012-04/2017). Eligibility criteria required 2 CT scans before and one after IO start. HPD was defined as RECIST v 1.1 PD at first CT scan and a variation per month of tumor growth rate (TGR upon IO – TGR before IO) > 50%. ED was defined as deaths due to disease PD within 12 wks of IO start. FP was defined as ≥ 50% increase in the sum of long diameters within 6 weeks (wks) from baseline. The associations between PD patterns and pts’ characteristics were performed using Fisher or t-student tests. Median overall survival (mOS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: Out of 406 NSCLC pts, 46% were ≥65 years, 72% had non-squamous NSCLC, > 90% received single agent IO in ≥2 line. 56 (13.8%) were HPD by TGR analysis. Among 72 pts (18%) who performed a CT scan within 6 wks after IO start, 6 (8.3%) were FP. These 6 FP pts were also classified as HPD by TGR analysis, while the other 50 (89%) of 56 HPD pts were not FP. The rate of PD in ≥ 3 sites (54% vs 0%, p = 0.002), the rate of liver PD (62% vs 5%, p = 0.002), the baseline tumor burden (BTB) (mean 176± 26 mm vs 55 ± 6 mm, p < 0.0001) and the TGR upon IO (mean 439± 119% vs 216 ± 41%, p = 0.03) were significantly higher in FP pts compared to HPD pts who were not FP. At 4.4 months of median follow-up, FP pts had significantly worse mOS compared to HPD pts not FP [0.7 months (95% CI 0.6,0.8) vs 1.6 months (95% CI 1.1, 2.1); p = 0.02]. Of 406 IO treated pts, 46 (11%) were ED within 12 wks, and 21 (46%) of ED pts had also HPD by TGR analysis. Conclusions: FP and ED are not a surrogate of HPD. FP occurs in a small subgroup (11%) of HPD and correlates with more aggressive features (PD in ≥3 sites, liver-PD, high BTB, high TGR upon IO) and worse OS. ED within 12 wks overlapped with HPD for only 46% of pts.
Treatment with FLAG followed by second allogeneic stem cell transplant for relapsed acute myeloid leukemia and myelodysplastic syndrome.
Authors: Pham Brian , Hoeg Rasmus , Hariharan Nisha , Alvarez Kathyryn , Rosenberg Aaron Seth , Jonas Brian Andrew , Tuscano Joseph M. , Abedi Mehrdad
Published: March 2020

e18503

Background: There is no standard treatment for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) relapsing after allogeneic stem cell transplant (SCT). Options include combination chemotherapy, withdrawal of immunosuppression, donor lymphocyte infusion (DLI), and second SCT. Previous studies have used fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG) or second SCT separately for salvage therapy. Our institution uses FLAG followed by SCT from the same donor (FLAG/SCT) in this setting. We report a retrospective study of FLAG/SCT in MDS and AML patients relapsed after SCT. Methods: Patients who received FLAG/SCT for treatment of relapsed AML or MDS between 2009 and 2018 were identified using the bone marrow transplant database at University of California Davis. Their baseline characteristics and outcomes were determined using the electronic medical record. Descriptive statistics and Kaplan-Meier survival analysis were used to describe patients, rates of graft-versus-host disease (GvHD) and estimate survival times. Results: Nineteen patients received FLAG/SCT for AML (n=18) and MDS (n=1). Median time to relapse from first SCT was 145 days (range 41 to 960 days). Prior to FLAG/SCT, 17 patients had medullary relapse (median bone marrow blasts 27%; range 7-85%). Two patients had extramedullary relapse. Eighteen (94.7%) patients achieved complete remission (CR) after FLAG/SCT. Median follow-up time was 354 days from the first day of FLAG/SCT (range 7 to 2144 days). Six patients (31.6%) relapsed with median time to relapse of 334 days (range 78 to 679 days) after treatment. Overall survival at 2 years was 52.5%. Causes of death were relapsed AML (n=4; 21.1%), infection (n=4; 21.1%) complications of GvHD (n=3,15.8 %), and brain herniation (n=1, 5.3%). Acute GvHD grade I-IV and new onset chronic GvHD occurred in thirteen (68.4%) and eight patients (42.1%), respectively. Conclusions: FLAG/SCT for AML and MDS relapsing after SCT resulted in a high remission rate. The overall survival of over two years suggests that the second SCT augmented the graft versus leukemia effect. The GvHD rate increased after second SCT, but the rate and severity were manageable. FLAG/ SCT is a reasonable option for relapsed AML and MDS after SCT.
Clinical value of event-free survival (EFS) in acute myeloid leukemia (AML).
Authors: Maiti Abhishek , Kantarjian Hagop M. , Popat Vinita , Blanco Carlos , Velasquez Miguel , Garcia-Manero Guillermo , Konopleva Marina , Verstovsek Srdan , Andreeff Michael , Borthakur Gautam , Kadia Tapan M. , Daver Naval Guastad , Pemmaraju Naveen , Dinardo Courtney Denton , Pierce Sherry A. , Wierda William G. , Kornblau Steven Mitchell , Ravandi Farhad , Cortes Jorge E.
Published: March 2020

e18513

Background: EFS is not considered a robust end-point for AML trials. We hypothesized that rather than a surrogate for overall survival (OS), improvement in EFS may be valuable due to patients (pts) staying in remission and thus decreasing health care utilization (HCU). Methods: In this retrospective study we identified AML pts treated on frontline therapy trials at our institute from 2003-2013 with EFS ≥2 months (mo) and OS of 12-36 mo. We captured the amount of HCU from diagnosis till death, including number of clinic and emergency room (ER) visits, hospitalizations, consultations, blood product transfusions, invasive procedures, laboratory and imaging studies. Linear regression and product-moment correlation were used to determine the relation between these parameters and EFS. Results: Among 337 pts meeting inclusion criteria, the median age was 65 years, 30% had adverse risk AML, 47% received intensive chemotherapy (IC) and 27% received hypomethylating agents (HMA). The median EFS was 10.8 mo. Increasing EFS led to statistically significant decline in HCU for all patients regardless of OS and the correlations were stronger for pts achieving a complete remission (CR, Table). These observations held true across European LeukemiaNet risk groups, younger and older pts, and those receiving IC, HMA, and non-IC, with or without other agents. Conclusions: In newly diagnosed AML, improvement in EFS is correlated with decrease in all HCU irrespective of OS duration. [Table: see text]