bluuebunny/crossref_metadata_2025 huggingface dataset:
C-reactive protein (CRP) as a predictive biomarker in lung cancer patients receiving immune checkpoint inhibitors (ICI).
Authors: Ananthula Aneesha , Konda Manojna , Bimali Milan , Safar Ahmad Mazen , Govindarajan Rangaswamy
Published: May 2020

e21645

Background: C-Reactive Protein (CRP) is an acute phase reactant which is elevated in inflammatory conditions and malignancy. Elevated CRP levels are associated with poor prognosis in many cancers and has been reported in patients with melanoma treated with ICI. We examined the association between CRP levels during therapy with ICI in patients with advanced lung cancer and radiological response. Methods: A retrospective study of patients with metastatic lung cancer (stage IV) who were treated with immunotherapy from 2016 to 2019 was conducted. CRP levels were checked at or soon after initiation of therapy and at frequent intervals thereafter. Association between CRP levels and response was determined. Results: 36 patients had initial (at the beginning of therapy, baseline) and subsequent CRP levels recorded during the first course of immunotherapy. Among the 36 patients, 16 (44%) had radiological response or stable disease, and 20 (55%) had radiological progression. The median age was 69 years (range 50 – 89 years); male/female 35/1, Caucasian/African American/other 26/9/1. There was no significant difference in distribution of initial CRP levels between patients with response vs progression as assessed by Kruskal-Wallis test (P-val: 0.20). Logistic regression modeling was employed to examine the association between final CRP level, the last measurement while on ICI therapy (adjusted for baseline CRP level) and odds of observing a response. A unit increase in final CRP level was associated with 4% decrease in odds of observing a response (Odds Ratio, 95% CI: 0.96, 0.92-1.00, P-val: 0.05). Conclusions: Baseline-adjusted final CRP levels were inversely associated with likelihood of observing a response in advanced lung cancer subjects treated with ICI. Further validation in prospective studies is warranted.
Clinical and molecular characteristics of TSC1/2 mutant lung cancer.
Authors: Wang Yanye , Xu Song , Zhao Shikang , Zhu Shuai , Li Xiongfei , Lei Xi , Chen Jun , Chen Gang
Published: May 2020

e21647

Background: Tumor suppressor genes TSC1 and TSC2 inhibit cell growth through inactivation the function of mTORC1. Previous studies have demonstrated that loss of function mutation of either TSC1 or TSC2 gene result in formation of neoplasm in multiple tissues. However, the clinical significance of TSC1 and TSC2 in non-small-cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the clinical and molecular characteristics of TSC1 and TSC2 mutation in NSCLC patients. Methods: We retrieved the clinical and genomic information of 1144 NSCLC from the Pan-Lung cancer dataset through the cBioportal ( www.cbioportal.org) . The cohorts of TSC1 and TSC2 mutant patients were identified. We compared baseline characteristics of patients with the Fisher exact test for categorical data and the Mann-Whitney U test for continuous variables. Overall survival (OS) was estimated with Kaplan-Meier curves, and differences were compared with the log-rank test. Results: Among 1144 patients, 27(2.36%) of them had TSC1 mutation and 40 (3.50%) had TSC2 mutation. Most patients with TSC1 and TSC2 mutations coexisted with other oncogenic gene alterations. TP53 was the most frequent concurrent gene (n = 53), followed with ERBB family genes (n = 24) and KRAS (n = 15). Compared to squamous cell carcinoma, TSC1/2 mutation was slightly more common in adenocarcinoma (53.7% vs 46.3%). 61.2% TSC1/2 mutant patients were male and 88.1% patients had former/current smoking history. Kaplan–Meier analysis showed that the patients harboring TSC1 mutation had a median OS of 14.1 months, whereas patients with TSC2 mutation had a median OS 110.6 months. However, there was not a statistically difference (P = 0.201). Conclusions: TSC1/2 mutation may define a unique population of NSCLC, which often coexists with other oncogenic gene alterations such as TP53 mutation. The function of TSC1/2 mutation and the value of TSC1/2 as therapeutic target in NSCLC are under investigation.
A randomized phase II trial of olaparib maintenance versus placebo monotherapy in patients with chemosensitive advanced non-small cell lung cancer.
Authors: Fennell Dean A. , Lester Jason Francis , Danson Sarah , Blackhall Fiona Helen , Nicolson Marianne , Nixon Lisette Sheena , Porter Catharine , Gardner Georgina Mary , White Ann , Griffiths Gareth Owen , Casbard Angela Claire
Published: May 2020

e21649

Background: Impaired DNA damage response (DDR) is a common feature of cancer, however therapeutic exploitation has been limited to cancers harbouring somatic inactivation of BRCA1/2 which causes homologous recombination deficiency (HRD). We hypothesized that patients (pts) with metastatic non-small cell lung cancer responding to platinum doublet based chemotherapy, might enrich for impaired DDR encompassing HRD, rendering these tumours more sensitive to inhibition of poly-ADP ribose polymerase (PARP) inhibition by olaparib. Methods: PIN was a multicentre double-blind placebo controlled randomised phase II screening trial (alpha and beta = 0.2). Chemonaive pts had advanced (stage IIB/IV) squamous (Sq) or non-sq (NS) NSCLC, ECOG performance status 0-1, no EGFR nor ALK mutation. Prior immunotherapy with a PD1/ PDL1 inhibitor was allowed. If tumour shrinkage was observed after 3 cycles of platinum chemotherapy, pts were randomised 1:1 to olaparib (O, 300mg po bd q21) or placebo (P), which was continued until disease progression or withdrawal. Primary end point was progression free survival (PFS), with a one-sided test for significance. Secondary endpoints were overall survival (OS), response (RECIST v1.1) and safety (CTCAE4.0). Results: 70 pts were randomised to O (32) or P (38) between Aug 2014 and Nov 2017. There was no difference in median dose intensity (% (IQR), O vs P) was 86.4 (64.3-95.7) vs 93.3 (80.2-97.6). Pts receiving O had a longer, but not statistically significant median PFS (weeks (IQR) was O 16.6 (7.1-21.7) vs P 12 (5.6-18.7)); and hazard ratio (HR) was 0.83 (80% CI 0.6-1.15, p = 0.23), using intention to treat (ITT) unadjusted analysis. However, the ITT Cox model, adjusted for smoking history and histology, showed a significantly longer PFS for pts receiving O (HR 0.73 (80% CI 0.52-1.02, p = 0.11)). Pts receiving O also had greater, but not statistically significant OS: median (weeks (IQR) was O 59.4 (38.7-67.9) vs P 31.3 (22.4-58.6)). OS HR was 0.68 (95% CI 0.37-1.26; two-sided p = 0.22). 3 patients were completely withdrawn prior to progression. No complete responses were observed and treatment was well tolerated. Conclusions: Design parameters justifying a Phase III trial (p < 0.2) were met in the adjusted, but not unadjusted PFS analysis, with a trend towards longer PFS and OS in the O arm. We speculate that this signal may be driven by a DDR deficient molecular subgroup. Translational studies are warranted to investigate these possibilities. Clinical trial information: NCT01788332.
Clinical activity and safety profile of dacomitinib in advanced epidermal growth factor receptor-positive non-small cell lung cancer patients with brain metastases.
Authors: Zhang Jinyao , Wang Shouzheng , Yang Ke , Xing Puyuan , Junling Li
Published: May 2020

e21656

Background: Dacomitinib is a second-generation epidermal growth factor receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) which has been shown to be superior to first-generation EGFR TKI, gefitinib in both progression- free survival and overall survival outcomes in EGFR+, non-small cell lung cancer (NSCLC) patients in a Phase III, randomized study, ARCHER 1050. However, the activity of dacomitinib in the central nervous system (CNS) is not known as ARCHER 1050 did not include patients with baseline brain metastases (BM). To our knowledge, this is the first chart review which describes dacomitinib’s activity in the CNS in a real-world setting. Methods: 24 patients who were receiving dacomitinib (30 mg daily) for advanced NSCLC harboring EGFR sensitive mutations, either Exon 19 deletion or Exon 21 L858R substitutions were included in this study. Hospital chart was retrospectively reviewed to identify patients with baseline brain metastases (n = 6). Treatment outcomes of these patients who were presented with baseline brain metastasis were analyzed. Results: Among the 6 patients, median age was 54.5 years (range, 41-74), 4 were male, ECOG PS 0 and 1 were 1 and 5, respectively. All of them had non-squamous NSCLC with asymptomatic BM and 5 with no measurable BM lesion. One patient had dose reduction due to drug-related adverse events. One patient has not reached the 4-week RECIST assessment at data cut-off. The intracranial ORR and DCR among 5 response- evaluable patients with at least one follow-up disease assessment were 40% and 100% (2/5 complete response, 3/5 stable disease). All patients are having ongoing treatment (median follow-up:3-months). Patients experienced low-grade (G1/2) toxicities which are reversible, including diarrhea, rash, paronychia and stomatitis. Conclusions: This chart review suggests, for the first-time, that dacomitinib may have CNS efficacy in patients with untreated EGFR+ NSCLC in the real-world setting. Due to the small number of patients included in this chart review, the findings need to be confirmed in future studies.
Anlotinib plus S-1 for patients with EGFR mutation-negative advanced squamous cell lung cancer with poor performance status after second or more -line treatment.
Authors: Xie Xiaohong , Wang Fei , Liu Ming , Lin Xinqing , Qin Yinyin , Xie Zhanhong , Zhang Jiexia , Ouyang Ming , Zhou Chengzhi
Published: May 2020

e21665

Background: The study aimed to analyze the efficacy and safety of combination regimen of anlotinib and S-1 for Chinese patients with EGFR mutation-negative advanced squamous cell lung cancer (SqCLC) with poor performance status (PS, 2-3) after second-or-more-line treatment. Methods: Clinical data of 32 SqCLC patients with PS scores of 2-3 treated in the First Affiliated Hospital of Guangzhou Medical University between Jan.1, 2018 to Sep.31, 2019 who failed second-or-more-line treatment were analyzed retrospectively. The patients were divided into two treatment groups: anlotinib (12mg) plus S-1 (25mg) combination group and S1 (12mg) monotherapy group. The efficacy and adverse reactions of the two groups were compared. Results: In terms of the short-term efficacy, there was no significant difference in objective response rate (ORR) (16.7% vs 5.0%, p= 0.54), and disease control rate (DCR) (66.7% vs 55.0%, p= 0.713) between the two groups. As for the long-term efficacy, there was no significant difference in progression-free survival (PFS) between the two groups (5.19 ±1.13 months vs 3.17 ±0.42 months, p= 0.062). the overall survival (OS) of patients in the combination group was longer than S1 group (10.0 ±1.14 months vs 6.37 ±0.47 months, p= 0.042). Conclusions: SqCLC patients with higher PS scores still benefit from anlotinib and S-1 combination regimen, even after they failed second-line or above systemic treatment. [Table: see text]
The efficacy and safety of EGFR-TKI combined with chemotherapy in non-small cell lung cancer (NSCLC) patients with EGFR co-mutation with other oncogenic alterations.
Authors: Yu Qitao , Jiang Wei , Zeng Aiping , Qiu Hongtu , Qi Chuang , Zhang Xing
Published: May 2020

e21666

Background: Previous studies indicated primary resistance to EGFR-TKIs might occur in EGFR co-mutation with other oncogenic alterations, including TP53, KRAS, PIK3CA and so on. However, the optimal therapeutic regimens for EGFR co-mutation other oncogenic alterations were still unknown. This respective observation study aimed to evaluate the efficacy and safety of EGFR-TKIs combined with chemotherapy in this sub-population, in order to offer new treatments in clinical practice. Methods: In this retrospectively study, from March 2017 to November 2019 advanced NSCLC patients with EGFR co-mutation with other oncogenic alterations in Medical Oncology of Respiratory, Affiliated Tumor Hospital of Guangxi Medical University were screened for eligibility. All included patients were administrated with EGFR-TKIs combined with platinum-based chemotherapy or EGFR-TKIs monotherapy. The clinicopathological data of the patients, and the efficacy and safety of treatment were accorded for statistic analysis. The Kaplan-Meier method was used to estimate median PFS and OS. For all analyses, p value < 0.05 was considered statistically significant, and confidence interval use 95% confidence level. The primary outcome was Progression-free survival (PFS), and Overall survival (OS), Disease control rate (DCR) and safety profile were considered to be the secondary endpoints. Results: Total 23 patients were enrolled in this retrospectively study. The median age of the combination and monotherapy group was 58.7± 8.8 and 58.9 ± 13.5years, respectively. The frequency of female patients was 53.8% and 40% in monotherapy and combination group, respectively. The median PFS (mPFS) was 5.03 months (95% CI: 1.16- 8.9) and not reach in combination therapy group (P = 0.004). No significantly different in mOS was observed in two groups (P = 0.244). The DCR was 92.3% and 100% in monotherapy and combination group, respectively. In combination group, the common adverse events of grade 1 or 2 were adverse reactions of the blood system and rash (40%). Treatment-related grade 3 or 4 toxicity appeared in 3 patients and no patients harbored treatment-related above grade 4 side effects. No cases of treatment-related death occurred. Conclusions: EGFR-TKIs combined with chemotherapy was effective in NSLCL patients with EGFR co-mutation with other oncogenic alterations and side-effects were tolerable. The outcomes of this study should be confirmed by prospective clinical trials in future.
Different efficacy of osimertinib in pre-TKI treated NSCLC patients with brain metastases harboring EGFR exon 19del and L858R mutant.
Authors: Li Xuanzong , Wang Ruozheng , Zou Bing , Zhang Dai , Yu Jinming , Wang Linlin
Published: May 2020

e21667

Background: Previous studies suggested that the efficacy of osimertinib was better in patients with epidermal growth factor receptor ( EGFR) exon 19 deletion (ex19del) than exon 21 Leu858Arg (L858R). However, the differential clinical outcomes of osimertinib in previous tyrosine kinase inhibitors (TKIs) treated non-small-cell lung cancer (NSCLC) patients with brain metastases (BrMs) according to the two different common EGFR genotypes remains undetermined. Methods: We retrospectively collected EGFR mutant (ex19del and L858R) NSCLC patients with BrMs and received osimertinib treatment between Jan 2016 and Feb 2019 in our hospital. Other eligible standards including Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, osimertinib 80mg monotherapy and neurologic symptoms existing was permitted to enroll in our study. Results: 78 patients with EGFR mutant NSCLC and BrMs were included in the study. EGFR mutation types were ex19del in 55% of patients (43/78) and L858R in 45% of patients (35/78). All of patients received at least one prior EGFR-TKI therapy, among which 46% (36/78) had gefitinib, 49% (38/78) had erlotinib, 19% (15/78) had icotinib. T790M status at osimertinib initiation was positive in 81% of patients (63/78), negative in 4% (3/78), unknown in 15% (12/78). The systemic objective response rate (ORR) was 46%. There was no apparent difference in systemic ORR (49% vs 43%, P = 0.598) between ex19del group and L858R group. The median progression free survival (PFS) and overall survival (OS) were 7.0 (range 4.7-9.3) and 18.8 (range 14.0-23.5) months for all patients. The median PFS in the ex19del and L858R subgroups was 9.1 (range 6.0-12.1) months and 5.3 (range 3.4-7.2) months, respectively ( P = 0.031). The median OS in the ex19del and L858R subgroups was 26.0 (range 13.7-38.3) months and 13.9 (range 7.7-20.2) months, respectively ( P = 0.033). Multivariate analysis identified L858R and ECOG PS 2 as poor independent predictors to the PFS and OS. Conclusions: The efficacy of osimertinib was associated with EGFR genotypes in pre-TKI treated NSCLC patients with BrMs, and L858R maybe an independent bad factor for long-term outcomes of osimertinib.
Patterns of disease progression to checkpoint inhibitor immunotherapy in patients with stage IV non-small cell lung cancer.
Authors: Fei Naomi , Attia Christina , Almubarak Mohammed , Ma Patrick C. , Mattes Malcolm David
Published: May 2020

e21674

Background: The purpose of this study was to assess patterns of disease progression for patients with metastatic non-small cell lung cancer (NSCLC) on checkpoint inhibitor immunotherapy in order to help guide effective use of targeted radiation therapy to sites of gross disease most likely to progress. Methods: This single center, retrospective study included all patients diagnosed with Stage IV NSCLC between June 2015 and February 2019 who received at least 2 cycles of nivolumab, pembrolizumab, or atezolizumab, with or without concurrent chemotherapy. Immune RECIST criteria were used to assess patterns of disease progression, and progression-free survival (PFS), excluding irradiated tumors. Descriptive statistics were used to report baseline patient and tumor characteristics. The Chi square and log-rank tests were used to determine whether any baseline clinical characteristics were associated with progressive disease in initial sites only (vs. new or combined sites), and PFS, respectively. Factors assessed included initial metastatic sites, tumor histology, performance status, PD-L1 expression, untreated primary tumor, history of brain metastasis, number of metastatic sites involved, and use of concurrent chemo-immunotherapy. Results: Among 143 eligible patients with a median follow-up of 11 months, 97 (68%) developed disease progression. Of these, 67 patients (69.1%) progressed only at initial disease site(s), 10 patients (10.3%) progressed only at new disease site(s), and 20 patients (20.6%) progressed in both initial and new sites. Rates of disease progression based on tumor location were higher for liver (64%) and lung metastases (61%) than for other metastatic sites (33-36%) or the primary tumor (24%). Only higher PD-L1 expression ( p= 0.002) and absence of lung metastasis ( p= 0.048) at baseline were associated with improved PFS. No baseline characteristics significantly impacted the probability of initial disease site-only progression, though a trend was observed for untreated primary tumor (72% vs. 56%, p= 0.169). Conclusions: The dominant pattern of disease progression for patients with metastatic NSCLC on checkpoint inhibitor immunotherapy is in the initial sites of disease alone, whereas only 10% of patients progressed in new disease site(s) alone, suggesting a potential role for local radiation therapy as a complementary treatment modality. Pre-treatment patient and tumor characteristics did not predict patients most likely to benefit.
Phase I dose escalation study of immunoconjugate L-DOS47 in combination with pemetrexed/carboplatin in non-squamous non-small cell lung cancer (NSCLC) patients.
Authors: Dowlati Afshin , Belani Chandra Prakash , Simon George R. , Chao Heman , Piha-Paul Sarina Anne
Published: May 2020

e21680

Background: L-DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, consists of urease conjugated to an anti-CEACAM6 camelid monoclonal antibody. The antibody serves as a targeting agent to deliver urease to tumor sites, while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells. An additive cytotoxic effect of L-DOS47 and pemetrexed/carboplatin has been observed against the A549 human lung adenocarcinoma cell line. L-DOS47 has been shown in a previous phase I clinical trial to be safe and well tolerated at doses up to 13.55 µg/kg. The current phase I study was designed to define the maximum tolerated dose of L-DOS47 in combination with pemetrexed/carboplatin. Methods: Stage IV (TNM M1a and M1b) histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤1) received up to four cycles of L-DOS47 in combination with standard of care doses of pemetrexed/carboplatin. L-DOS47 was administered weekly over 21 days in each treatment cycle. Seven planned dosing cohorts (0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 μg/kg) employed a standard 3+3 design for the first two and the last two cohorts, and an accelerated 1 + 2 design for the middle three cohorts. Dose levels of L-DOS47 were escalated following a review of safety data by the Trial Steering Committee. Results: Fourteen (14) patients were enrolled across 6 dosing cohorts before recruitment was halted. Median age was 65.1 years, with 50.0% male and 78.6% Caucasian. 57.1% of patients had an ECOG score of 0, and 42.9% had an ECOG score of 1. The maximum tolerated dose (MTD) could not be determined as none of the patients experienced a dose limiting toxicity (DLT). 50.0% of patients experienced at least one treatment emergent adverse event (TEAE) assessed as study drug-related, with 14.3% of patients experiencing at least one grade 3/4 drug-related toxicity. Of 12 patients evaluable for efficacy, 5 patients (41.7%) had a partial response (PR), 4 patients (33.3%) experienced stable disease (SD) and 3 patients (25.0%) had progressive disease (PD). The objective response rate is 41.7%. The clinical benefit rate is 75.0%. Conclusions: L-DOS47, in combination with pemetrexed/carboplatin, appears to be well tolerated with promising anti-tumor activity against non-squamous NSCLC. Clinical trial information: NCT02309892.
3rd-line anaplastic lymphoma kinase (ALK) inhibitors (ALKi) in advanced non-small cell lung cancer (aNSCLC): Real-world comparison to non-ALKi therapy.
Authors: Maimon Natalie , Dudnik Elizabeth , Rottenberg Yakir , Popovits-Hadari Noa , Asna Noam , Wollner Mira , Zer Alona , Gottfried Maya , Mishaeli Moshe , Rovitsky-Gelis Yulia , Lobachov Anastasiya , Onn Amir , Urban Damien , Moskovitz Mor Tal , Bar Jair ,   Israel Lung Cancer Group
Published: May 2020

e21685

Background: ALKi represent the standard 1st- and 2nd -line treatment (Tx) for ALK+ aNSCLC patients (pts). The value of ALKi in the 3rd-line setting is unclear. We retrospectively assessed the real-world impact of a 3rd -line ALKi vs. non-ALKi Tx in ALK+ aNSCLC pts. Methods: Consecutive ALK+ aNSCLC pts were identified in the working databases of 7 Israeli oncology centers; pts receiving any systemic Tx beyond 2 different ALKi were selected for the comparative analysis. Pts whose immediate next Tx line (post-2nd-ALKi) was a 3rdALKi (Group (Gr) A) were compared to pts whose immediate next Tx line (post-2nd-ALKi) was non-ALKi Tx (Gr B), in terms of overall survival (OS) and time to next Tx line (TNT). Results: 158 consecutive ALK+ aNSCLC pts diagnosed in January 2011 - March 2019 were included, median follow up from diagnosis of aNSCLC was 41 months (mo) (IQR 8-45). Median OS from aNSCLC diagnosis was 56 mo (95% CI 36-66). Post-2nd-ALKi line was a 3rd ALKi for 23 pts (Gr A) and a non-ALKi Tx for 10 pts (Gr B). 7 of Gr B (70%) received ALKi as a later line Tx. Median OS after initiation of post-2nd-ALKi Tx was 27 mo (95% CI, 7-NA) for Gr A vs. 16 mo (95% CI, 7-NA) for Gr B; p-non-significant (NS) with or without adjustment for sex, age, brain metastases. TNT on post-2nd-ALKi Tx was 6 mo (95% CI, 2-27) for Gr A vs. 2.5 mo (95% CI, 0-NA) for Gr B; p-NS. Conclusions: Following progression on a 2ndALKi, OS and TNT were numerically higher for pts receiving a 3rd ALKi, but statistically NS. Extensive exposure of pts in the non-ALKi Tx Gr to an ALKi at a later stage might have impacted these results. Further studies are required to identify patients likely to benefit from ALKi after progressing on 2 or more ALKi Tx lines. [Table: see text]
Platinum-based chemotherapy (chemo) with CS1001, an anti-PD-L1 antibody, for first-line advanced non-small cell lung cancer (NSCLC): Preliminary results from phase Ib cohorts of CS1001-101 study.
Authors: Zhou Qing , Zhang Qingyuan , Xu Nong , Zhao Yanqiu , Miao Zhanhui , Shen Lin , Gao Quanli , Pei Zhidong , Xia Teddy , Wang Jingru , Dai Hangjun , Guo Rong , Yang Jianxin , Wu Yi-Long
Published: May 2020

e21687

Background: Immuno-oncology (IO) monotherapy or combination with platinum-based chemo is the current standard of care for pts with PD-L1 expression ≥ 50% and EGFR, ALK, ROS1, BRAF negative advanced NSCLC in China. CS1001-101 phase Ib study is to evaluate the efficacy and safety of CS1001, anti-PD-L1 mAb, in pts with solid tumors or lymphomas. Here we present the results of 2 cohorts: CS1001 plus platinum-based chemo for 1L advanced NSCLC. Methods: Pts with non-squamous (nsq)-NSCLC received 4-6 cycles of CS1001 (1200 mg, IV, Q3W), carboplatin (AUC = 5), and pemetrexed (500 mg/m2), followed by maintenance therapy with CS1001 and pemetrexed. Pts with squamous (sq)-NSCLC received CS1001 (1200 mg, IV, Q3W), carboplatin (AUC = 5), and paclitaxel (175 mg/m2), followed by maintenance therapy with CS1001. Results: By July 1st, 2019, 21 nsq-NSCLC and 20 sq-NSCLC pts were treated, with a median treatment duration of 135 and 109 days, respectively. 15 nsq-NSCLC pts remained on the study and 6 discontinued CS1001, 5 due to progressive disease (PD). 17 sq-NSCLC pts remained on the study and 3 discontinued CS1001, 2 due to adverse events (AEs). 10 had partial response (PR) in each cohort, leading to a response rate of 47.6% (nsq) and 58.8% (sq). The median duration of response (mDoR) and median progression-free survival (mPFS) were not reached (Table). In nsq-NSCLC cohort, 18 (85.7%) had CS1001-related AEs and 6 (28.6%) had G≥3 TRAEs. irAEs occurred in 5 pts with the most frequent ones being aspartate aminotransferase (AST) increased (4, ≤G2) and alanine aminotransferase (ALT) increased (3, ≤G2). 18 (90.0%) sq-NSCLC pts had CS1001-related AEs and 5 (25%) had G≥3 TRAEs. irAEs occurred in 3 pts with the most frequent ones being rash (2, ≤G2). AEs that led to CS1001 withdrawn only occurred in 2 sq-NSCLC pts, which were not related to CS1001. Conclusions: The combination of CS1001 and platinum-based chemo regimen demonstrated promising anti-tumor activity with a tolerable safety profile. The results of this study support further evaluation of CS1001 and platinum-based chemo in 1L NSCLC. Currently, a randomized phase III study (NCT03789604) of this treatment regimen in pts with chemo-naive advanced NSCLC is recruiting pts in China. Clinical trial information: NCT03312842. [Table: see text]
Anti-PD-1 antibody monotherapy or anti-PD-1 antibody combination with chemotherapy treated non-small cell lung cancer (NSCLC) patients with EGFR mutation: A retrospective analysis.
Authors: Yu Shaorong , Hu Ran , Shi Meiqi
Published: May 2020

e21691

Background: Anti-PD-1/PD-L1 antibody has been approved as first- or second-line therapy in non-small cell lung cancer (NSCLC) patients and modified the management of patients with locally advanced or metastatic NSCLC. However, anti-PD-1 treatment shows less effective in patients with EGFR mutation than in those without driver gene mutation. To determine the activity of anti-PD-1 antibody in EGFR mutant NSCLC, we retrospectively evaluated response patterns among EGFR mutant NSCLC patients. Methods: We identified 58 patients with EGFR mutation who were treated with anti-PD-1 monotherapy or anti-PD-1 antibody combined with chemotherapy from March 2018 to December 2019. All of patients have received more than one treatment regimen including EGFR-TKI treatment. Objective response rates (ORR) were assessed using RECIST v1.1. Results: A total of 58 patients including 53 cases of lung adenocarcinoma, 4 cases of squamous cell carcinoma and 1 case of adenosquamous carcinoma were analyzed. Among them 26 patients received nivolumab treatment, 9 patients with pembrolizumab treatment, 9 patients with sintilimab treatment, 8 patients with JS001 treatment and 6 patients with camrelizumab treatment. Seven patients received anti-PD-1 monotherapy and the other 51 patients received anti-PD-1 combined chemotherapy. The main chemotherapeutic drugs contain docetaxel, pemetrexed, paclitaxel and paclitaxel-albumin. ORR was observed in 6 out of 58 (10%) patients. The disease control rate was 50% (29/58). The median PFS was 2.82 months. All six patients who achieved PR were received anti-PD-1 combined chemotherapy. Four patients died during treatment with anti-PD-1 therapy and we can’t confirm if these were due to cancer progress or immune related tumor hyperprogression. The adverse events were immune related pneumonia (two cases with grade 2 and one case with grade 3) and immune related hepatitis (one case with grade 2). Conclusions: Anti-PD-1 antibody combined chemotherapy seems showed moderate effect on NSCLC patients with EGFR mutation who have received anti-EGFR therapy.
Clinical outcomes between patients with and without RET fusions in advanced/metastatic non-small cell lung cancer in the United States.
Authors: Sireci Anthony , Hess Lisa M. , Han Yimei , Zhu Yajun Emily , Bhandari Naleen Raj , Martinez Ricardo
Published: May 2020

e21693

Background: Fusions involving the REarranged during Transfection ( RET) gene are known oncogenic drivers in non-small cell lung cancer (NSCLC). The patient profile is distinct from a genomically-unselected population of NSCLC patients and may lead to the potentially confounded conclusion that RET fusion-positive patients have a better prognosis. This study characterized clinical outcomes in patients with RET fusion-positive NSCLC versus those without when correcting for known demographic differences. Methods: The Flatiron ClinicoGenomics Database, electronic medical record data linked to Foundation Medicine, Inc genomic test results, was used to identify individuals diagnosed with advanced or metastatic NSCLC who initiated anti-cancer systemic therapy between JAN2011 and JUN2019 in the US. Follow up data were available through JUN2019. Patients were considered RET+ if a fusion was reported and RET- if no fusion was reported. Baseline characteristics and tumor response were compared using Fisher’s exact, chi-squared or t-tests; unadjusted and adjusted COX models were used to compare progression-free survival (PFS) and overall survival (OS). Results: There were 5,807 eligible patients with NSCLC; 46 (0.8%) and 5,761 (99.2%) were RET+ and RET-, respectively. Patients with RET+ tumors were significantly younger (63 vs 67 yrs), better performance status, less likely to have smoking history (37% vs 82%), more likely to have non-squamous tumors (98% vs 76%) (all p < 0.05), and less likely to have ALK, ROS1, KRAS or BRAF alterations, which were each 0% in the RET+ group. There were no differences in total lines of therapy received; treatment regimens were comparable. In unadjusted analyses, patients with RET+ tumors had no significant differences in tumor response (p = 0.17) or PFS (p = 0.06) but significantly better OS outcomes (p = 0.005) from the start of first-line therapy. After adjusting for all available baseline covariates, survival outcomes were not significantly different between RET- and RET+ groups (PFS hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 0.86, 1.78, p = 0.26; OS HR = 1.53, 95% CI = 0.95, 2.44, p = 0.08). Conclusions: Patients with RET fusion-positive NSCLC have different baseline characteristics than patients without these fusions. The unadjusted differences in OS between groups appear to be driven by baseline demographic features and not the presence of the RET fusion, however further research is needed. Conclusions are limited by the rarity of RET fusions in NSCLC and subsequent small sample size.
Two-year survival with nivolumab in previously treated, advanced non-small cell lung cancer: A pooled analysis of real-world patients from France, Germany and Canada.
Authors: Sebastian Martin , Audigier-Valette Clarisse , Butts Charles Andrew , Debieuvre Didier , Dixmier Adrien , Gröschel Andreas , Gutz Sylvia , Juergens Rosalyn A. , Labbe Catherine , Moro-Sibilot Denis , Perol Maurice , Schumann Christian , Juarez-Garcia Ariadna , Lakhdari Khalid , Penrod John R. , Pettersson Filippa , Reynaud Dorothee , Waldenberger Daniela , Allan Victoria , Barlesi Fabrice
Published: May 2020

e21714

Background: Data from clinical studies demonstrate a long-term survival benefit of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC) patients with overall survival (OS) at two-years of 27%, however real-world data are limited. We report OS in patients pooled from two prospective multi-centre observational cohort studies in France (EVIDENS, NCT03382496) and Germany (ENLARGE, NCT02910999) and a third retrospective registry of patients treated through expanded access to nivolumab in Canada. Methods: Individual patient data from each cohort were pooled and harmonised in eligibility criteria and variable definitions. Included patients had locally advanced or metastatic (stage IIIB/IV) NSCLC, received nivolumab after at least one prior systemic therapy and had no other concurrent primary cancers. OS was estimated from nivolumab initiation until death or censoring using Kaplan-Meier method. Equality of survival distributions across cohorts was measured using log-rank test. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated from unstratified Cox proportional hazards regression models to explore survival among subgroups. Data on bone and liver metastases, PD-L1 and safety were available and analysed for France and Germany only. Results: Data from 2582 patients (48% France; 34% Germany; 18% Canada) were pooled. Baseline characteristics were: median age 66 years, 64% male, 82% ECOG 0-1, 69% 1 prior line of therapy, 68% non-squamous histology, and 18% with brain metastases (treated or untreated). Median follow-up was 8 months. No difference in OS was observed between countries. The 2-year OS was 28% (95%CI 25-31) for all patients, 26% (95%CI 21-31) for squamous histology and 29% (95%CI 26-33) for non-squamous histology. Bone metastases (HR 1.42; 95%CI 1.26-1.60; P= < .0001) and liver metastases (HR 1.60; 95%CI 1.39-1.85; P= < .0001) were associated with shorter survival, while ECOG PS 0-1 (HR 0.61; 95%CI 0.52-0.71; P= < .0001) and PD-L1 positivity (HR 0.75; 95%CI 0.60-0.93; P= < .0001) were associated with prolonged survival. Rates of any grade and grade 3/4 treatment-related adverse events (TRAE) were 32% and 7% respectively. Conclusions: In this three-country pooled analysis of nivolumab in previously treated advanced NSCLC, real-world overall survival at 2-years was consistent with pivotal nivolumab trials overall and in subgroups. Rates of grade 3/4 TRAEs were comparable, but events of lower grade may be underreported in the real world.
Peripheral blood biomarkers associated with outcome in non-small cell lung cancer patients treated with nivolumab and durvalumab monotherapy.
Authors: Wu Lin , Jiang Meilin , Peng Wenying , Pu Xingxiang , Chen Bolin , Li Jia , Xu Fang , Xu Li , Xu Yan , Wang Jingyi
Published: May 2020

e21732

Background: Selecting patients that potentially benefit from immune checkpoint inhibitors (ICIs) is critical. Programmed death ligand-1 (PD-L1) protein immunohistochemical expression on cancer cells or immune cells and Next generation sequencing based tumor mutational burden (TMB) are the hot spots in studies on ICIs, but there is still confusion in the testing methods. Due to blood samples are much easier for clinical application, many potential peripheral biomarkers have been proposed. This study identify blood parameters that associated with outcome of non-small cell lung cancer (NSCLC) patients with ICIs monotherapy. Methods: Data of 76 NSCLC patients were analyzed retrospectively. To assess the connection between survival and peripheral blood markers measured before and after treatment, we utilized COX regression model survival analysis and receiver operating characteristic (ROC) curve to assess the markers. Results: In the nivolumab cohort, the optimal cutoff for predicting 11 month overall survival (OS) were 168.13 and 43g/L in Plateletto-lymphocyte ratio (PLR) and albumin, respectively. When patients are grouped with PLR and albumin the cut-offs, a significant difference in SD-PR vursus PD rate were found between high and low groups, separately. which was not found when grouped by PD-L1 expression. Patients with high PLR ( > 168.13) or low albumin ( < = 43g/L) before ICI had a significantly raised hazard of progression, separately (for PLR, P = 0.006; for albumin, P = 0.033) and of death (for PLR, P = 0.014; for albumin, P = 0.009) compared with those patients who had low PLR or albumin level. More importantly, we found that higher PLR ( > 168.13) after the fourth cycle of ICIs was also an prognostic biomarker, which significantly correlated with shorter OS in both Nivolumab (P = 0.046) and durvalumab cohort (P = 0.028). Conclusions: PLR and albumin may help the stratification of high progression and death risk group in advanced NSCLC patients treated with nivolumab and durvalumab monotherapy.
Efficacy and safety of apatinib plus docetaxel for non-squamous non-small cell lung cancer with bone metastases.
Authors: Zang Aimin , Sun Guoguo ,   ASCO Authors' Group
Published: May 2020

e21741

Background: The skeletal system is one of the most common distant sites of metastatic non-small cell lung cancer (NSCLC) which may lead to skeletal-related events (SREs). Bone metastasis can reduced quality of life. Vascular endothelial growth factor receptor (VEGFR)-targeted therapy is effective against bone metastasis in animal models. Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), which is inhibits tumor angiogenesis. Therefore, we aimed to investigate the efficacy and safety of apatinib plus docetaxel for NSCLC with bone metastases. Methods: Eligible patients of NSCLC with bone metastases who received first-line platinum-based chemotherapy. Treated with apatinib (500 mg, qd, orally) plus docetaxel (60mg/m2, q3w, iv) and zoledronic acid (4mg, q3w, iv). Treatment was continued until disease progression or unacceptable toxic effects. Results: Between July 2017 and June 2019, 10 patients were enrolled. All patients available for efficacy and safety evaluation. the objective response rate (ORR) was 50% and the disease control rate (DCR) was 80%. The median progression-free survival (PFS) was 6.5 months, The proportions of patients with SREs were 20%. The most common Grade 1 or 2 adverse events included hypertension (30%, 3/10), fatigue (30%, 3/10), digestive tract reaction (30%, 3/10), leukopenia (20%, 2/10). Conclusions: Apatinib plus docetaxel prolonged PFS and reduced the incidence of SREs, with acceptable toxic effects. The therapeutic regime may be an option for NSCLC with bone metastases. Clinical trial information: NCT03127319.
Randomized phase II study of nivolumab (N) alone versus with pegilodecakin (PEG) in combination with N in patients (pts) with post-platinum immunotherapy-naive stage IV non-small cell lung cancer (NSCLC) and no or low PD-L1 expression (CYPRESS 2).
Authors: Jotte Robert M. , Goldschmidt Jerome H. , Schneider Jeffrey Gary , Shum Merrill Kingman , Berz David , Seneviratne Lasika C. , Socoteanu Matei P. , Hung Annie , Hozak Rebecca R. , Chao Bo H. , Nemunaitis John J.
Published: May 2020

e21744

Background: Nivolumab (N) is an immune checkpoint inhibitor (CPI) approved to treat post-platinum NSCLC as monotherapy. PEG in combination with N has demonstrated promising efficacy in NSCLC pts in a phase I trial (IVY; NCT02009449; Naing et al., 2019 Lancet Oncol), providing rationale for this randomized phase II trial (CYPRESS 2). Methods: CYPRESS 2 was an open label phase II trial, for ECOG 0-1, PD-L1 negative or low (TPS 0-49%), Stage IV NSCLC pts, without known EGFR/ALK mutations. Pts were randomized 1:1 to arm N (240 mg every 14-days or 480 mg every 28-days as decided by investigator) v. arm PEG+N (received N as above + PEG daily of 0.8 mg if weight ≤80kg and 1.6mg if weight > 80 kg). Pts were stratified by tumor histology and smoking history and must have no prior history of cancer or CPI therapy. Primary endpoint was ORR (per RECIST v 1.1 per investigator). Secondary endpoints included PFS, OS, and safety. Exploratory endpoints included immune activation biomarkers (baseline and change from baseline), assessed by immunoassay. Results: As of Aug 28, 2019, 52 pts were randomized to PEG+N (n=27) or N (n=25). Median follow-up time was 11.6 months. The following results were found for PEG+N versus N: ORR 14.8% v. 12.0%, mPFS 1.9 v. 1.9 months with HR = 1.01 (95% CI [0.52, 1.95]), mOS 6.7 v. 10.7 months with HR = 1.87 (95% CI [0.77, 4.53]). Gr ≥3 treatment related adverse events (TRAEs) for PEG+N versus N were 70.4% vs. 16.7%. Gr 3 TRAEs of ≥10% incidence included anemia (40.7% v. 0%), fatigue (18.5% v. 0%), and thrombocytopenia (14.8% v. 0%). In PEG+N arm, increased circulating IL-18, Granzyme B, FasL, and IFNg levels and decreased TGFb levels were observed on treatment. Conclusions: Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway. Despite evidence of biological effect, adding PEG to N did not lead to improvement in ORR, PFS, or OS in post-platinum advanced NSCLC with no or low PD-L1 expression. PEG+N arm demonstrated expected safety profile but overall higher toxicity compared to nivolumab alone. Clinical trial information: NCT03382912.
A phase I trial of nab-paclitaxel/bevacizumab (AB160) nano-immunoconjugate therapy for unresectable stage IV malignant melanoma (MM): MC1371 (NCT02020707).
Authors: Block Matthew Stephen , Suman Vera J. , Nevala Wendy Kay , Finnes Heidi Diann , Schimke Jill , Strand Carrie , Dimou Anastasios , Kottschade Lisa A. , Yan Yiyi , Reid Joel M. , Hocum Craig , Markovic Svetomir , McWilliams Robert R.
Published: May 2020

e22020

Background: The combination of nab-paclitaxel (NP) and bevacizumab (BEV) in patients with MM has shown promising clinical activity. AB160 is a 160 nm nano-immunoconjugate of NP nanoparticles non-covalently coated with BEV for targeted delivery into high VEGF expressing tissues. Preclinical data showed that AB160 improved tumor targeting/ tumor inhibition more than NP followed by BEV. Methods: A 3+3 phase I trial was conducted in patients (pts) with MM who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. Dose level 1 (DL1) was 125 mg/m2 NP /50 mg/m2 BEV. Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥ 2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Tumor evaluations (RECIST) were conducted every 8 weeks. Treatment continued until progression or intolerability. Results: 21 pts (11 ♀) aged 36-78 years old were enrolled. One of the first 3 pts on DL1 developed a G2 colonic perforation; this was considered a DLT. One of the next 3 pts on DL1 had a DLT: G4 neutropenia. Of the 3 pts on DL-1 (100 mg/m2 NP/40 mg/m2 BEV), 2 had no DLTs and 1 died of sepsis after C1D1 dose. Enrollment was suspended until an amendment modifying the eligibility criteria was approved by the IRB. The trial reopened. One of the 4 pts on DL-1 and 1 of the 5 pts on DL1 had a DLT: G3 pain and G3 fatigue, respectively. Enrollment ended after 2 of the 3 pts on DL2 (150 mg/m2 NP/ 60 mg/m2 BEV) developed G4 neutropenia. Thus, MTD is DL1. A median of 3 cycles was administered. Treatment ended due to progression (9), intolerability (9), refusal (2) and death (1). There were no objective tumor responses. Common G3-4 toxicities were: neutropenia (33%) and thromboembolic events (19%). Conclusions: AB160 was found to have insufficient clinical benefit in patients with previously treated MM to justify further development. However, parallel phase I testing in gynecologic cancers suggests clinical benefit (abstract #300225). Clinical trial information: NCT02020707.
Methylated DNA marker panel for metastatic melanoma: Discovery and tissue validation.
Authors: Meves Alexander , Taylor William R. , Bamlet William R , Mahoney Douglas W. , Doering Karen A , Burger Kelli , Foote Patrick H. , Quattrocchi Enrica , Lehman Julia S. , Ahlquist David A. , Kisiel John B.
Published: May 2020

e22024

Background: Disease surveillance in high risk melanoma patients using PET/CT is recommended every 6 months, an algorithm that is extremely expensive and often difficult to access. Biomarkers capable of detecting recurrence and low volume metastasis have application in tools to improve the cost effectiveness of surveillance. Towards this long term goal, our aim was to discover melanoma-specific methylated DNA markers (MDMs). Methods: Candidate MDMs were identified by reduced representation bisulfite sequencing of selected age- and sex-balanced snap frozen metastatic melanoma, benign control skin and white blood cells. Sequences were filtered for highest methylation difference, lowest control methylation background ( < 1%), and highest discrimination by variance inflated logistic regression. Using formalin-fixed tissues, the top 32 MDMs were further evaluated in metastatic melanoma from 35 patients, primary melanoma from 26 patients, and 73 control samples (47 benign precursor lesions or normal skin, and 26 healthy buffy coat samples to assess for background DNA in circulation). Candidate markers were blindly assayed by quantitative methylation specific PCR. After normalization by within sample ACTB level, random forest modeling with cross-validation identified marker combinations with greatest predictive accuracy. Results: On receiver operator characteristics analyses of individual marker candidates, areas under the curve (AUCs) ranged from 0.43 to 0.97. Median AUC was 0.835. At 100% specificity, a cross-validated panel of five MDMs (see Table), yielded a sensitivity of 33/35 cases (94.3%; 95% CI, 86.6-100%) for metastatic melanoma and 22/26 cases (84.6%; 95% CI, 70.7-98.5%) for primary melanoma. Furthermore, none of the 5 markers were detected in normal buffy coat samples. Conclusions: A panel of five novel MDMs assayed on tissue and undetectable in normal buffy coat achieves very high discrimination between melanoma and benign control tissues. This panel can be assessed in blood or other bodily fluids for application in melanoma surveillance. [Table: see text]
Efficacy and safety of apatinib in patients with recurrent or refractory melanoma.
Authors: Wang Zibing , Yuan Shumin , Zhang Xiaojie , Huang Hao , Gao Quanli
Published: May 2020

e22026

Background: The prognosis of patients with metastatic malignant melanoma is very poor, a fact that is partly due to its high resistance to conventional chemotherapies. The objectives of this phase II trial were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma. Methods: This was a single arm, single center phase II trial. The primary endpoint was progression free survival (PFS), and the second endpoints was objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Eligible patients received at least one prior line of therapy for advanced melanoma and experienced recurrence. Apatinib was given daily at a dose of 500 mg orally. This study was registered at ClinicalTrials.gov , number NCT03383237 . Results: A total of 17 patients were included in the final analysis. The median PFS was 4.5 months. There were two major objective responses, for a response rate of 11.8%. Thirteen patients had a stable disease, for a DCR of 88.2%. The median OS was 11.5 months. The most common clinically significant grade 3 or 4 toxicities included hypertension (n = 1) and canker sore (n = 1). No treatment-related death occurred. Conclusions: Apatinib showed antitumor activity as a second or above line therapy in patients with malignant melanoma. The toxicity was manageable. Clinical trial information: NCT03383237.