bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between inflammatory markers and progression-free survival in patients with advanced EGFR-mutated non-small cell lung cancer under treatment with tirosin kinasa inhibitors: Real-world data from Peru.
Authors: Motta Guerrero Rodrigo , Aliaga Macha Carlos , Carracedo Carlos F. , Runciman Thanya
Published: May 2020

e21568

Background: Tirosine Kinasa Inhibitors (TKI) are the standard treatment in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutation. However, eventually patients will progress to TKI. The aim of this study is to determinate if neutrophil-lymphocyte ratio (NLR), RDW-CV and platelet-lymphocyte ratio (PLR) are associated with progression free survival (PFS). Methods: This is a retrospective observational study of a single patient cohort. Clinical records of advanced NSCLC patients that received TKI as first line therapy in ALIADA cancer center since January 2015 and December 2019 were evaluated. NLR, RDW-CV and PLR were calculated from blood counts before beginning of TKI. The statistical analysis was performed with SPSS version 20 and MINITAB 14. Results: 182 patients were diagnosed with advanced NSCLC and 30% of them harbor a EGFR mutation. 43 patients were finally included, 55.8% were women and mean age was 58 years. The 65% of patients had exon19 deletion, 25% exon21 L858R substitution, 7% exon20 T790 mutations and 3% exon18 G719X substitution. 44% of patients received erlotinib, 38% afatinib and 18% osimertinib. The 61.5% of patients achieved partial response; they had a mean NLR, PRL and RDW-CV of 2.98 (0.93–7.41), 238.59 (101.63–863.01) and 13.8 (12.6–15.5) respectively. 17.3% achieved complete response, with a mean NLR, PRL and RDW-CV of 2.93 (1.22–4.64), 204.37 (109.21–417.46) and 13.7 (12.8–15.4). Finally, 9.6% maintain stable disease; with a mean NLR, PRL and RDW-CV of 4.25 (3.6-4.91), 200.7 (196.4-205) and 14.35 (14.3-14.4). 74% of patients progressed. The mean PFS was 24.33 months (95% CI 16.05 - 32.6). Patients that developed progressive disease and those who did not, had no significant difference in the mean NLR (3.98 vs 3.68, p = 0.706) and mean RDW-CV (14.12 vs 14.3, p = 0.655). However, patients with clinical benefit during TKI had a mean PLR of 163.68, meanwhile patients with progressive disease had a mean PLR of 276.54 (T of Student, p = 0.03). Conclusions: In patients with advanced EGFR mutated NSCLC, a high level of PLR is associated with a lower PFS. It is necessary to carry out studies with a bigger amount of population to validate the PLR as a predictive biomarker. To our knowledge this is the first study that analyzes these characteristics in Latin American population.
Human papillomavirus infection in metastatic lung adenocarcinoma is associated with better outcomes with immune checkpoint inhibitor treatment.
Authors: Rojas Puentes Luis Leonardo , Ruiz-Patiño Alejandro , Mayorga Gonzalez Diana Carolina , Rodríguez July Katherine , Ávila Coy Jenny Mireya , Bravo Espinosa Melissa Andrea , Zatarain-Barron Zyanya Lucía , Arrieta Oscar , Barron Feliciano Barron , Carranza Hernan , Otero Jorge Miguel , Vargas Carlos Alberto , Archila Pilar , Sotelo Rodríguez Diana Carolina , Martin Claudio Marcelo , Pino Luis Eduardo , Rolfo Christian Diego , Rosell Rafael , Cardona Zorrilla Andres Felipe , Recondo Gonzalo
Published: May 2020

e21569

Background: Human papilloma virus (HPV) is associated with the development of several primary tumors. Recent studies have shown that HPV-positive tumors tend to be sensitive to immune checkpoint inhibitors (ICI), owing to the presence of xenobiotic genomes in cancer cells. The objective of this study was to explore this relationship in patients with lung adenocarcinoma. Methods: A retrospective cohort analysis in patients with advanced lung adenocarcinoma treated in a reference center in Bogota, Colombia was conducted. Demographic as well as treatment variables were collected between January 2018 and December 2019. Besides clinical outcomes, HPV infection status was determined by PCR amplification and reverse line hybridization directly on formalin-fixed paraffin-embedded tumor samples. Statistical analyses included stratified survival analysis based on HPV status and response. Results: A total of 133 patients were included. Male predominance (51.1%) with Karnofsky performance scores (KPS) greater than 80, and 19% of prior cigarette exposure (26 patients) was identified in the cohort. HPV positivity was identified in 25.6% of patients (33 cases, [95%CI 17.5-32.2%]), in addition to 29.8% EGFR mutation positivity (29 cases [[95%CI 14.8-28.8%]), 6% ALK positivity (8 cases [95%CI 1.9-10]) and positive PD-L1 expression in 49 samples (36.8% [95%CI 28.6-45%]). In immune checkpoint inhibitor (ICI) exposed patients, HPV+ patients had significantly higher PD-L1 expression compared with HPV- individuals (p < 0.001). In terms of overall survival, ICI treated patients achieved an OS of 27.1 months (95%CI 22.1-NA) and a PFS of 19.4 months (95%CI 18-24.5 months). HPV infection status was associated with prolonged OS (median OS not reached, [95%CI 27.7 months – no reached], p = 0.0089) and better response to ICI (p < 0.001). Conclusions: HPV infection is prevalent in patients with lung adenocarcinoma and is associated with better response to ICIs as well as better survival outcomes. Its identification could serve as a prognostic marker, especially in female non-smoker patients.
Clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine tumors: A population-based analysis.
Authors: Fuentes Harry E , Zhu Mojun , Gile Jennifer , Leventakos Konstantinos , Sonbol Mohamad Bassam , Schild Steven E. , Starr Jason Scott , Halfdanarson Thorvardur Ragnar , Molina Julian R.
Published: May 2020

e21575

Background: The clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine (NE) tumors is unknown; we therefore conducted a population based analysis to evaluate the implications of brain metastases in these patients. Methods: The NCDB database was queried to identify patients with stage IV bronchopulmonary NE tumors treated between the years of 2004-2012. Patients were split into two groups based on the presence of brain metastases at diagnosis and survival probabilities with multivariate models were performed. Results: A total of 7,725 patients with Stage IV bronchopulmonary NE tumors were identified. The histological subtypes studied in this cohort were NE carcinoma (65.4%), large cell NE carcinoma (30.5%), typical carcinoid (2.8%) and atypical carcinoid (1.3%) . The patients included in this study were mainly white (86.4%) men (56.8%) with a median age of 67 years who had liver (9.5%), bone (6.2%) and brain (5.9%) metastases at diagnosis. The median overall survival (OS) of the cohort was 5.59 (95% CI: 5.4-5.8) months, but when OS was stratified by histological subtype it was significantly better in patients with typical carcinoid (table). In the whole cohort, the median OS did not differ between patients with and without brain metastases (5.55 vs. 5.68; p = 0.24). However, a sensitivity analysis by histology showed that the presence of brain metastases worsen the median OS of patients with typical carcinoid only (15.1 vs 4.6, p = 0.04). An adjusted multivariate analysis restricted to patients with brain metastases showed that administration of systemic chemotherapy (HR:0.5; 95% CI:0.35-0.72, p < 0.001) and resection of distant metastases (HR:0.5; 95% CI:0.29-0.88, p = 0.017) were the two most powerful independent prognostic factors. Conclusions: The presence of brain metastases negatively impact survival of patients with typical carcinoids but not in those with the other histological subtypes included in this study. Staging MRI should be strongly considered at diagnosis in patients with bronchopulmonary NE tumors, due to the sizable proportion of these patients presenting with brain metastases and also due to its prognostic value in a subset of this population. [Table: see text]
Immunotherapy in patients with advanced stage non-squamous (non-Sq) non-small cell lung cancer (NSCLC) with activating genetic mutations: Single institution retrospective study.
Authors: Khaddour Leila , Singh Sunny R K , Rybkin Igor I.
Published: May 2020

e21577

Background: Immunotherapy has dramatically changed the landscape of lung cancer management. However, its efficacy remains controversial in patients with activating mutations. We report retrospective analysis of clinical outcomes of advanced stage NSCLC patients with activating mutations treated with immune checkpoint inhibitors throughout their disease course. Methods: We analyze all adult patients diagnosed with advanced NSCLC in our institution between January 2014 and January 2018, and who had activating mutations in EGFR, MET, or BRAF genes or ALK rearrangement. Patients in both arms must be treated with at least one line of tyrosine kinase inhibitors (TKI). The investigation arm were patients who received immunotherapy at any time during their disease course. The control arm were patients who did not receive immunotherapy. The primary endpoint was overall survival (OS). Secondary endpoints were objective response rate (ORR) and disease control rate (DCR) in the investigation arm. Results: A total of 47 patients met the inclusion criteria: 27 patients received immunotherapy after or before TKI failure, while 20 patients did not receive immunotherapy. Baseline characteristics were similar in both groups. The average age at diagnosis was 65 years and 40% were males. 68% of patients were at stage IV at the time of diagnosis, 43% were never smokers, and 40% had brain metastases. EGFR mutations accounted for 76.6% of alterations, while ALK rearrangement was demonstrated in 17%, MET and BRAF mutations in 4.3% and 2.1% respectively. Among 27 patients in the immunotherapy group, 3 received chemotherapy simultaneously, 11 patients had received prior chemotherapy, while 13 patients were chemotherapy naive. Complete response was achieved in one case. The ORR was 22.2% and DCR was 37%. Targeted therapy was re-introduced in 9 patients after discontinuation of immunotherapy, of whom 3 responded. The median OS was 44 months (95%CI 28.9-59.4) in immunotherapy group versus 35.7 months (95% CI 23.9-47.4) in control group (P-value 0.34). Conclusions: Immunotherapy, as single agent or in combination with chemotherapy, is associated with better OS trend in patients with advanced NSCLC who harbor activation mutations and failed TKI. This effect was not statistically significant. The prospective data in this population is also limited and controversial. More trials are warranted to evaluate the efficacy of immunotherapy in this group.
Improvement in lung cancer survival: Six-year survival analysis of patients diagnosed between 2011 and 2016 in Hungary.
Authors: Bogos Krisztina , Kiss Zoltan , Tamási Lilla , Ostoros Gyula , Dr Szabone Dr Muller Veronika Judit , Bittner Nora , Sarosi Veronika , Vastag Aladar , NAGY-ERDEI ZSOFIA MARIA , Polanyi Zoltan , Daniel Andrea , Nagy Balazs , Horvath Krisztian , Abonyi-Toth Zsolt , Rokszin Gyorgy , Voko Zoltan , Moldvay Judit
Published: May 2020

e21582

Background: Lung cancer is one of the most common cancers worldwide, however, 5-year survival is poor, only 10-20% of pataients survive this period. To date, no long-term study has been conducted to evaluate long-term survival rates in Hungary. Therefore, the objective of our study was to assess the 6-year survival of lung cancer patients (ICD-10 C34) based on a nationwide review of the National Health Insurance Fund (NHIF) database. Methods: Our retrospective, longitudinal study included patients aged ≥20 years who were diagnosed with lung cancer (ICD-10 C34) between 1 January 2011 and 31 December 2016. Screening period was set for 2009-2010. Patients with other cancer-related ICD-10 codes 6 months before or 12 months after lung cancer diagnosis and those who received any anticancer treatment different from lung cancer protocols were excluded. Survival rates were evaluated according to year of diagnosis, patient gender and age, and morphology of lung cancer and main treatment type. Results: 41,854 newly diagnosed lung cancer patients were recorded. Mean age at diagnosis varied between 64.66 and 65.88 years during study period. One- and 5-year crude survival rates for the total population were 42.23% and 17.85%, respectively. Survival was significantly associated with gender, age and type of lung cancer based on statistical association. Female patients (n = 16,362) had 23% better survival (HR: 0.77 CI95% 0.75-0.79; p < 0.001) than males (n = 25,492). The highest survival rates were found in the 20–49 age cohort (5Y = 31.3%) and if the cancer type was adenocarcinoma (5Y = 20.48%). We measured 5.3 % improvement in lung cancer survival between cases diagnosed in 2015-2016 vs. 2011-2012 (HR: 0.947 CI95% 0.92-0.97; p = 0.003). Survival of those lung cancer patients, whom had surgery in first line treatment without adjuvant therapy (3,120) reached 64.18%, those with adjuvant treatment (n = 2,675) 54.47% 5 year survival, while patients with chemotherapy (n = 11,780) had only 7.9% crude survival. Conclusions: Our study provided long-term LC survival data in Hungary for the first time. We found a 6% improvement in survival by the end of the study period in females and in the younger age groups. Survival rates were comparable to – and at the higher end of – rates registered in other East-Central European countries. Better survival rate of females could be attributed to a higher incidence rate of adenocarcinoma in women. Lung cancer patients diagnosed in early stage had 7-8 times better survival than those found in late stage.
Efficacy and safety of SHR-1210 combined with apatinib in first-line treatment for advanced lung squamous cell carcinoma: A phase II study.
Authors: Wang Jinliang , Zhang Zhibo , Yan Xiang , Ma Junxun , Zhang Fan , Song Qi , Zhang Li , Liu Zhefeng , Yang Bo , Wang Lijie , Tao Haitao , Zhang Sujie , Li Xiaoyan , Hu Jie , Li Xiaoting , Wang Jiaqian , Zhi Xiaoyu , Ge Xiangwei , Jiao Shunchang , Hu Yi
Published: May 2020

e21587

Background: PD-1 inhibitors plus chemotherapy is a standard of first-line therapy in advanced lung squamous cell carcinoma (LUSC). Previous preclinical and clinical studies suggested that the combination of anti-PD-1 antibody SHR-1210 and VEGFR-2 inhibitor apatinib significantly improved anti-tumor effects. The aim of this study was to evaluate the efficacy and safety of SHR-1210 in combination with apatinib for advanced LUSC patients as a first-line treatment. Methods: In this phase II study, patients diagnosed with stage IIIB or IV advanced LUSC were enrolled. All patients received SHR-1210 (200mg q2w) and apatinib (250mg po qd) until disease progression or unacceptable toxicity. Treatment efficacy was assessed every 3 cycles (6 weeks). The primary endpoint is progression-free survival (PFS). Secondary endpoints are objective response rate (ORR), disease control rate (DCR), and overall survival (OS), which according to RECIST 1.1. Results: At the primary analysis (data cutoff Feb 10, 2020), 26 advanced LUSC patients had enrolled, and 17 patients of which were evaluable. Baseline characteristics were shown that median age was 67 years, male percentage was 92.3% (24/26), and clinical stage IV percentage was for 57.7% (15/26). The median follow-up time was 3.1 months (range 0.4-13.7 months) in all included patients. No complete response (CR) was reported. Partial response (PR) was achieved in 13 (76.5%) and stable disease (SD) in 4 (23.5%). The ORR and DCR in 17 evaluable patients were 76.5% and 100%, respectively. The most common treatment-related adverse events were hypertension (42.3%), rash (38.5%), hand-foot skin reaction (26.9%), and reactive cutaneous capillary endothelial proliferation (RCCEP) (15.4%). Of 26 patients, 5 experienced a grade ≥3 treatment-related adverse events, including one interstitial pneumonia, one hypertension, one thrombocytopenia, one RCCEP, and one aminotransferase elevation. Three patients (3/26) were reported dead, of which one died due to interstitial pneumonia and the others died of tumor progression. Twelve patients (46.2%) ever suspended treatment or adjusted the dosage of apatinib due to interstitial pneumonia, pyelonephritis, rash, thrombocytopenia, or aminotransferase elevation. Conclusions: The combination of SHR-1210 and apatinib for advanced LUSC patients was well tolerated and effective. This treatment may be a promising method for advanced LUSC as a first-line treatment. Fund Project (No: 2017FC-CXYY-3007) & Project (No: 2017MBD-013). Clinical trial information: ChiCTR1800019329.
BRAF fusion in lung cancer.
Authors: Zhao Jun , Guo Renhua , Ai Xinghao , Liu Lianke , Li Lin , Chen Mingjiu , Pu Xingxiang , Zhang Min , Chen Rongrong , Xia Xuefeng
Published: May 2020

e21598

Background: BRAF was a part of RAS/MAPK pathway, which regulated the proliferation, differentiation, migration, and apoptosis of cells. BRAF V600E was a potential treatment target for non-small cell lung cancer and other tumors. While BRAF fusion was rare in lung cancer. Here we focus on BRAF fusion in lung cancer. Methods: We retrospectively reviewed next-generation sequencing (NGS) results of lung cancers, with or without treatment history. The samples were subjected to NGS using 59 or 1021-gene panel, which enables simultaneously assess snv, indel, rearrangements and cnv variations. Patients with BRAF fusion were collected and used to analysis. Results: We found eighteen lung cancers have BRAF fusion from about twelve thousand patients, 13 are females. The median age at diagnosis was 47-year old (range 28 to 70). Tested samples included 13 tissues, 5 plasma, and 2 pleural effusion. BRAF fusion could occur in different stage, 12 stage Ⅳ and 1 stage Ⅰ, other were unknown. There were 14 lung adenocarcinoma, 1 squamous cell carcinoma and 1 adenosquamous carcinoma, other two patients were unknown. The partner genes of BRAF fusion were distinctly among the patient, TRIM24 was relatively common. The median tumor mutation burden (TMB) was 4.8muts/Mb (range 0 to 15.4), with low TMB-H frequency (10.5%, defined 9 as cutoff value). Seven patients had no system treatment history, and 1 had concurrent EGFR L858R mutation. Nine patients received EGFR-TKI therapy, 1 received ALK-TKI therapy, and 1 received chemotherapy. Among the EGFR-TKI treated patients, 7 received first and third generation TKI sequential therapy, the median TTD (time to discontinue) of TKIs was 26 months (range 17 to 46). The EGFR mutation still exist when EGFR-TKIs resistance, included EGFR primary mutation, T790M, and C797S, concurrent with BRAF fusion. Except for BRAF fusion, there also had other complex resistance mechanism occurred, like HER2 mutation, KRAS mutation, etc. Conclusions: BRAF fusion had low frequency in lung cancer and occurred at different stage during disease development. BRAF inhibitors maybe a potential strategy for BRAF fusion lung cancers. As TKIs resistance mechanism, BRAF fusion is a huge clinical challenge, indicate the importance of further research.
A multi-center phase II study of toripalimab with chemotherapy in patients with EGFR mutant advanced NSCLC patients resistant to EGFR TKIs: Efficacy and biomarker analysis.
Authors: Ren Shengxiang , Zhang Jie , Zhao Yanqiu , Mu Xiaoqian , Zhou Jianying , Bao Zhang , Fan Yun , Xu Yanjun , Shu Yongqian , Guo Renhua , Liu Xiaoqing , Wang Hong , Zhang Helong , Deng Lin , Ma Ningqiang , He Jianxing , Zhang Yalei , Zhou Caicun ,   Shanghai Junshi Biosciences
Published: May 2020

e21618

Background: Immune checkpoint blocker (ICB) monotherapy showed a lack of response in advanced NSCLC patients with EGFR mutations. This Phase II study aimed to evaluate the efficacy and safety of toripalimab, a humanized PD-1 mAb plus platinum doublets chemotherapy in EGFR mutant advanced NSCLC patients, who developed resistance to 1st/2nd generation of EGFR TKIs and without T790M mutation. Methods: Patients received toripalimab (240 or 360 mg) intravenously combined with carboplatin (AUC = 5) and pemetrexed (500mg/m2) on day 1, Q3W, for up to 6 cycles, followed by toripalimab and pemetrexed maintenance until disease progression or unacceptable toxicity. Efficacy was evaluated every six weeks according to RECIST v1.1. PD-L1 expression (JS311 assay) and co-mutation status by whole exome sequencing were further analyzed. Results: From Apr 2018 to March 2019, 40 patients were enrolled from 8 centers in China. The median age was 57 years with 53% female, 57.5% EGFR exon19 deletion and 42.5% L858R mutation. By the cutoff date of Jan 2, 2020, 20 partial response and 15 stable disease were observed (ORR 50% and DCR 87.5%) with a median DOR of 7.0 months. The median PFS was 7.0 months and the median OS was still not reached. 52.6% (20/38) patients were PD-L1+ (TPS≥1%) and had numerically higher ORR (60% vs 39%, p= 0.33) and longer PFS (median 8.3 vs 5.7 months, p= 0.61) than PD-L1- patients. Co-mutations analysis revealed common genetic alternations including TP53 (79%), RB1 (18%), ERBB2 (15%), PIK2CA (12%), CDKN2A (12%), HDAC9 (12%) and MET (9%). Patients with TP53 co-mutation responded significantly better in ORR than TP53 wild type patients (62% vs 14%, p= 0.04) . Most frequent TRAE included leukopenia (78%), neutropenia (70%), anemia (70%), ALT elevation (48%), AST elevation (48%) and nausea (48%). Grade 3+ TRAE occurred in 55% patients, including neutropenia (43%), leukopenia (20%) and anemia (13%). Dose delay due to TRAE occurred in 40% patients while 10% patients discontinued treatment due to TRAE. Conclusions: Toripalimab in combination with chemotherapy showed promising anti-tumor activity with a manageable safety profile for advanced NSCLC patients with EGFR mutations refractory to TKI therapies. Patients with PD-L1+ tumor biopsy or TP53 co-mutation preferentially responded to the combination. A randomized phase III trial is ongoing to further validate the finding in this study (NCT03924050). Clinical trial information: NCT03513666.
Real-world outcomes after second-line treatment in non-small cell lung cancer (NSCLC) patients treated with immunotherapy.
Authors: Marmarelis Melina Elpi , Hwang Wei-Ting , Yang Yu-Xiao , Ciunci Christine Agnes , Singh Aditi Puri , Aggarwal Charu , Cohen Roger B. , Langer Corey J. , Mamtani Ronac , Bauml Joshua
Published: May 2020

e21620

Background: In patients (pts) with advanced non-small cell lung cancer (NSCLC), national guidelines recommend against retrial of immunotherapy (IO) if there is disease progression on IO in the 1st-line (1L). However, optimal 2nd-line (2L) therapy after 1L IO remains unclear and there is significant practice variation. We compared outcomes of 2L approaches after 1L IO or chemoimmunotherapy (chemoIO). Methods: This retrospective cohort study utilized the Flatiron Health EHR-derived de-identified advanced NSCLC database. The study population included pts with disease progression on 1L IO or chemoIO and who subsequently received 2L therapy. Pts with targetable alterations were excluded. We defined the exposure by type of 2L therapy (IO, chemoIO, chemo). Multivariate covariates included age, sex, race, 1L progression-free survival (PFS) and PDL1 level. Median overall survival (mOS) and median real-world PFS (mPFS, based upon abstraction of clinician documentation) times were estimated from Kaplan-Meier curves. A multivariate Cox proportional hazard model computed hazard ratios (HRs) to assess the effectiveness of 2L treatment. Results: 532 NSCLC pts received 1L IO and a 2L therapy, of which 393 (74%) received 1L IO and 139 (26%) received 1L chemoIO. Among 1L IO patients, 2L therapies included chemo (315 (80%)), IO (39(10%), 18/39 (46%) switched IO), and chemoIO (39(10%)). Among 1L chemoIO patients, 2L therapies included: chemo (121 (87%)), IO (8(6%), 6/8 switched IO) and ChemoIO (10 (7%), 8/10 changed chemo used). All pts who received 2L ChemoIO continued the same IO agent. Demographics were well balanced between 2L groups except for higher PDL1 level in the IO-based groups and older age in the IO alone group. There was no statistically significant difference in mPFS or mOS between 2L IO and non-IO containing regimens (Table), nor were there differences among patients switching IO agents in the 2L (multivariate p interaction = 0.2 (PFS), 0.06 (OS)) (Table). Conclusions: Despite national guidelines against this practice, a small proportion of pts in routine care receive 2L IO-based therapies after disease progression on 1L IO or chemoIO. We found similar outcomes between IO and non-IO based 2L therapies after progression on 1L IO or chemoIO. [Table: see text]
IMpower110: Clinical safety in a phase III study of atezolizumab (atezo) monotherapy (mono) vs platinum-based chemotherapy (chemo) in first-line non-small cell lung cancer (NSCLC).
Authors: Jassem Jacek , Herbst Roy S. , de Marinis Filippo , Cadranel Jacques , Csőszi Tibor , Isla Dolores , Chen Gongyan , Syrigos Konstantinos N. , Cortinovis Diego , Hida Toyoaki , Mocci Simonetta , Phan See , Enquist Ida , Patel Hina , Villalobos Monette , Wen Xiaohui , Deng Yu , Kuriki Hiroshi , Spigel David R. , Giaccone Giuseppe
Published: May 2020

e21623

Background: IMpower110 evaluated atezo mono in PD-L1–selected, chemo-naive patients (pts) with nonsquamous (nsq) or squamous (sq) NSCLC. At the interim analysis, IMpower110 met its primary OS endpoint, with a statistically significant and clinically meaningful improvement for atezo vs chemo in TC3 or IC3 wild-type ( EGFR/ALK-negative) pts. We report on the safety profile of atezo vs chemo in IMpower110. Methods: 572 pts with stage IV nsq or sq NSCLC, PD-L1 expression ≥ 1% on TC or IC and ECOG PS 0-1 were randomized 1:1 to receive atezo (1200 mg IV q3w) or chemo (4 or 6 21-day cycles). In the chemo arm, nsq pts received cisplatin (cis) 75 mg/m2 or carboplatin (carbo) AUC 6 + pemetrexed (pem) 500 mg/m2 IV q3w; sq pts received cis 75 mg/m2 + gemcitabine (gem) 1250 mg/m2 or carbo AUC 5 + gem 1000 mg/m2 IV q3w. Safety was assessed in all treated pts (safety evaluable [SE] population [pop]), regardless of PD-L1 expression or EGFR/ALK status. AEs were summarized per MedDRA v22.0 and severity graded per NCI CTCAE v4.0. Immune-mediated AEs (imAEs) were defined per a sponsor-specified list of terms, regardless of whether the events led to systemic glucocorticoid, endocrine therapy, or other immunosuppressants use. Results: At data cutoff (Sep 10, 2018) within the ITT pop, treatment (tx) was ongoing in 90 (atezo: 31.6%) and 25 (chemo: 8.7%) pts, with 13.7 mo of follow-up. Within the SE pop (atezo: n = 286, chemo: n = 263), atezo pts had longer tx exposure (5.3 mo) vs chemo pts (pem, 3.5 mo; gem, 2.6 mo; carbo, 2.3 mo; cis, 2.1 mo). Atezo had a favorable safety profile vs chemo (table); safety data were consistent with data from a pooled atezo mono pop. imAEs occurred in 40.2% (atezo) and 16.7% (chemo) of pts and were Grade (Gr) 3-4 in 6.6% and 1.5%, respectively. Conclusions: Atezo was better tolerated than chemo and imAEs were generally low grade. Overall, the safety experience with atezo mono in IMpower110 was consistent with its known safety profile; no new safety signals were identified. Clinical trial information: NCT02409342. [Table: see text]
IMpower150: Exploratory efficacy analysis in patients (pts) with bulky disease.
Authors: Jotte Robert M. , Batus Marta , Bernicker Eric , Copur Mehmet Sitki , Kirshner Eli , Koh Han A. , Kozloff Mark , Sabbath Kert D. , Subramanian Janakiraman , Yu Wei , Nowicki Michael , Bara Ilze , Finley Gene Grant
Published: May 2020

e21637

Background: In the Ph 3 IMpower150 study (NCT02366143), 1L treatment (tx) with atezolizumab (A) + bevacizumab (B) + carboplatin + paclitaxel (CP; ABCP) significantly improved PFS and OS vs B + CP (BCP) in pts with chemotherapy-naive metastatic (met) nsq NSCLC. As pts with high tumor burden or large size (bulky disease) have poor survival outcomes, an exploratory analysis was conducted to determine whether pts with bulky disease in IMpower150 could derive benefit from ABCP. Methods: 1202 pts (ITT population) were randomized 1:1:1 to ABCP, atezo + CP (ACP) or BCP arms. Doses were given q3w: A, 1200 mg; B, 15 mg/kg; C, AUC 6 mg/mL/min; P, 200 mg/m2. Disease burden subgroups (high or low) were defined using the 3rd quartile of the sum of the longest diameter (SLD) of the target lesions or median number (no.) of met sites at baseline (BL). Exploratory efficacy analyses included PFS, OS, ORR, time to response (TTR) in these subgroups; safety was also assessed. Outcomes are reported for pts enrolled in the ABCP vs BCP arms. Results: Per 3rd quartile SLD (108 mm), 91 ABCP and 85 BCP pts had high disease burden. Per median no. of met sites (median = 2), 210 ABCP and 190 BCP pts had high disease burden. BL characteristics were generally balanced between ABCP and BCP in high disease burden subgroups. With a minimum follow-up of 32.4 mo (data cutoff: Sep 13, 2019), ABCP showed improved OS, PFS and ORR vs BCP in pts with high and low disease burden (Table). High disease burden did not impact TTR. The safety profile of ABCP was comparable between ITT-WT (no EGFR or ALK alterations) pts and high disease burden subgroups. Conclusions: A tx effect for OS, PFS and ORR was seen in pts with and without bulky disease when ABCP vs BCP was compared, regardless of the method used to define “bulky”; TTR was not affected in high disease burden pts. ABCP had a comparable safety profile in bulky disease and ITT-WT pts. ABCP may be a 1L tx option for pts with nsq NSCLC who have high disease burden. Clinical trial information: NCT02366143. [Table: see text]
Cancer cachexia syndrome in the prediction of outcome in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs): Results from a single-institution, prospective, observational study.
Authors: Mavroudis Dimitrios , Rounis Konstantinos , Makrakis Dimitrios , Georgiou Alexandra , Galanakis Nikolaos , Papadaki Chara , Vamvakas Lampros , Tsigkas Alexandros-Pantelis , Kontogianni Meropi , Gioulbasanis Ioannis , Agelaki Sofia
Published: May 2020

e21644

Background: Cancer cachexia syndrome (CCS) is a multifactorial inflammatory syndrome affecting a large subset of patients (pts) with NSCLC which in preclinical models negatively impairs antitumor immunity. We conducted a prospective, observational study to investigate the effect of CCS and sarcopenia on the efficacy of ICIs in NSCLC. Methods: CCS was defined as weight loss of > 5% in the last 6 months or any degree of weight loss > 2% in combination with BMI < 20% or baseline skeletal muscle index at the level of the 3rd lumbar vertebra consistent with sarcopenia. Skeletal muscle index was calculated using slice-o-matic tomovision software in the abdominal CT scan before starting ICIs. Results: 83 pts were included in the analysis. Median follow up was 9.5 months. Median age was 66 years, 61.4% had non-squamous histology, 20.5% received ICIs as first and the remaining as second-line therapy. 20.5% of pts experienced partial response (PR), 31% had stable disease (SD) and 48.2% had disease progression (PD). Median progression-free survival (PFS) was 4.4 months and median overall survival (OS) was 10.33 months. 43.4% of the whole group were categorized as having CCS, whereas 63.3% of 30 pts evaluated using tomovision had sarcopenia. CCS negatively affected response rates (p = 0.003) but not response duration (p = 0.266). CCS was associated with reduced PFS (2.46 vs 5.77 months, p = 0.006) and OS (4.8 vs 14.53 months, p = 0.001). In the multivariate analysis, CCS independently predicted for shorter OS (HR = 2.01; CI: 1,14-3,54; p = 0.014). Sarcopenia was also associated with reduced OS (5.4 vs 17.9 months, p = 0.012). Analysis on the whole pt population will be presented at the conference. Conclusions: CCS is associated with lower response rates and independently predicts for shorter OS in pts with NSCLC treated with ICIs. Further research on CCS could better define its role as a potential biomarker and a research platform for maximizing immunotherapy efficacy.
Camrelizumab in the treatment of patients with advanced lung cancer: A multicenter, prospective, cohort study.
Authors: Wang Rong , Ji Mei , Shi Meiqi , Hua Dong , Liu Lianke , Lu Kaihua , Shen Hua , Chen Meng , Cai Wei , Chen Bi , Gao Chao , Yu Changhua , Shu Yongqian
Published: May 2020

e21650

Background: Camrelizumab is a humanized PD-1 monoclonal antibody. The efficacy of camrelizumab monotherapy or combined with chemotherapy in the treatment of advanced NSCLC had been demonstrated with promising anti-tumor activity in previous studies. However, in the real-world clinical practice, the activity of camrelizumab in patients with advanced lung cancer is poorly characterised. We sought to analyse the antitumour activity and toxicity of camrelizumab in advanced lung cancer to explore benefit subgroups and optimal treatments. Methods: This is a multicentre, prospective cohort study of advanced lung cancer in Jiangsu province, China. Eligibility required patients with histologically confirmed advanced lung cancer who couldreceive treatment regimen based on camrelizumab. No other restrictive inclusion criteria were applied. Data were captured with electronic uniform database templates to ensure consistent data collection. Primary endpoint is progression-free survival (PFS), Secondary endpoints are adverse events (AE), objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: 97 pts with advanced lung cancer were enrolled from August 7, 2019 to December 20, 2019. Median age was 64, male 82.5%, adenocarcinoma 50.5%, squamous carcinoma 29.9%, SCLC 14.4%. 30.9% were treated as first-line therapy, 24.7% were second-line treatment, 44.4% were third-line and above treatment. Treatment regimens included camrelizumab monotherapy 13.4%, combination chemotherapy 52.6%, combination anti-angiogenic therapy 24.7%. 52 pts were accessable for efficacy analysis. 11 (21%), 37(71%), and 6(8%) patients showed partial response (PR), stable disease (SD), and progression disease (PD), respectively. The ORR, DCR was 21.2%, 92.3%. 72 pts had experienced the safety assessment. This was an early stage of data analysis, PFS has not yet reached. Major AE was reactive cutaneous capillary hyperplasia (RCCEP) (20/72), no Grade≥3 RCCEP occurred. Other common AEs were eutrophil count decreased (14/72), nausea (12/72), fatigue (11/72), white blood cell decreased (10/72). No treatment-related deaths occurred. Conclusions: This Real-world research showed current treatment status of advanced lung cancer and provides preliminary evidence for camrelizumab treating with advanced lung cancer, and we expect follow-up data to provide more clues. Clinical trial information: ChiCTR1900026089.
PD-L1, brain metastases, and survival among patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.
Authors: Feisal James , Balakrishna Pragathi , Itani Aleena , King Caleb , Acharya Pawan , Vesely Sara , Aljumaily Raid
Published: May 2020

e21655

Background: PD-L1 expression is predictive of response to treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICI) among patients with metastatic non-small cell lung cancer (mNSCLC). Brain metastases (BM) are common in patients with mNSCLC and carry significant morbidity. While the use of ICI has significantly improved survival for mNSCLC, it is unclear if patients with brain metastases have the same survival benefit. Methods: In this retrospective study, we reviewed data from all patients treated at our center with mNSCLC who had PD-L1 testing from 2015-2019. Patients with another active malignancy were excluded. Descriptive statistics were calculated using proportions and means using SAS v9.4. We examined the relationship between PD-L1 level ( < 50% vs ≥50%) and BM at diagnosis among patients with mNSCLC using chi-square analysis. We then compared overall survival (OS) and progression free survival (PFS) among mNSCLC patients with and without BM at diagnosis treated with ICI using Kaplan-Meier plots followed by log rank tests. Results: 141 mNSCLC patients with PD-L1 results were identified. 71 (50.4%) were female. Mean age was 63. 71 (50.4%) were current smokers, 53 (37.6%) were former smokers. Histology included 111 (78.7%) adenocarcinoma, 19 (13.5%) squamous cell carcinoma, and 11 (7.8%) other or mixed types. 19 (13.5%) had KRAS mutation, 13 (9.2%) had EGFR mutation, 1 had ALK rearrangement, 3 had ROS1 rearrangement, and 2 had BRAF mutations. 86 (61.0%) were PD-L1 high (≥50%). 57 (40.4%) had BM at diagnosis. Patients with high PD-L1 had a higher rate of BM at diagnosis (47.3% vs 36.0%), but this trend was not statistically significant (p = 0.18). There were significantly more current smokers among those with BM at diagnosis than those without BM (p = 0.01). Among patients treated with first line ICI (n = 78), median OS was 26.5 months for those without BM and 12.2 months for those with BM at diagnosis, although this difference was not significant (p = 0.11). Median PFS was 8.9 months for patients without BM and 8.6 for those with BM (p = 0.58). Conclusions: While a higher proportion of patients with high PD-L1 had BM at the time of metastatic diagnosis, this trend was not significant. Among patients treated with ICI, survival for those with or without BM at the time of diagnosis was not significantly different. Our observations may be limited by the number of patients.
Do herbal drinks augment the cytotoxic effect against different cancer cells? Are they potent stimulators of innate and acquired immunity?
Authors: Adnan Israa , Talib Wamidh
Published: May 2020

e21657

Background: The herbal drinks are highly prevalent in the Middle East and are consumed in large quantities as daily drinks. Few studies have evaluated the biological activities of the herbal drinks produced from some plants.The current study aims to evaluate the anticancer and immunomodulatory activities of five herbal drinks consumed in the Middle East. These drinks are Palestinian Zhourat, Lebanese Zhourat, Lemon and Ginger combination, Wild Thyme, and Marjoram. Methods: The selected herbal drinks as concentrated water extracts were tested separately for: A. Anti-cancer effect on the cell lines (MCF-7, MDA-MB231, HCT-116, A549, and Vero-normal cells) by assessing: - Antiproliferation activities using MTT assay. Apoptosis (using the caspase-3 assay) and vascular endothelial growth factor (VEGF) expression (using ELISA kit) for the most potent antiproliferative extract. B. Immunomodulatory effect by evaluating: - Splenocytes proliferation using the mitogen proliferation assay. Phagocytosis activity using the nitro blue tetrazolium assay. - Pinocytosis function using the neutral red method. Results: The Lemon and Ginger combination was the most potent against MDA-MB231, MCF-7 and A549l cell lines with IC50 3.5,4, 6.5mg/ml, respectively. Lemon and Ginger combination and Wild thyme separately showed high apoptosis induction and angiogenesis suppression on the MDA-MB231cell line at concentrations 3.5 and 4.4 mg/ml for both extracts, respectively. Wild thyme was the most potent stimulant lymphocyte proliferation (with index 4.7), and Marjoram has the highest percentage (314.4%) in phagocytosis activity, while moderate stimulation by Zhourat was noted. Lemon and Ginger combination, Wild thyme, Marjoram, and the Lebanese herbal drink "Zhourat" were the most active extracts in stimulating pinocytosis with absorbance value 0.5745,0.4645,0.461,0.4575 nm, respectively. Meanwhile, the Palestinian herbal drink "Zhourat" had a moderate effect. Conclusions: The consumption ofthe mentioned herbal drinks has various Anti-cancer and immunomodulatory effects. Lemon and ginger combination exhibits the most potent anticancer activities. Wild thyme and marjoram are potent stimulators of innate and acquired immunity. The result achieved in this study is very optimistic and encouraging to be considered for further clinical trials.
Comparison of treatment outcomes in patients with metastatic lung cancer who did or did not develop EGFR T790M mutation.
Authors: Wang Zhen , Sandler Jason , Shieh Kevin , Mo Lan , Huang Yiwu , Solomon William B. , Becker Kevin Douglas , Xu Yiqing
Published: May 2020

e21658

Background: First-line treatment of lung cancer patients with EGFR mutation with early generation tyrosine kinase inhibitors (TKIs) renders a median progression-free survival (mPFS) of 11 months (m), and for the patients who subsequently develop the T790M mutation, osimertinib provides an additional mPFS of 10 m. First-line treatment with osimertinib showed mPFS of 18.9 m and none developed T790M at the time of progression (FLAURA trial). We hypothesized that the mPFS for patients who developed T790M mutation might be longer than those who did not and the prognosis and outcome might be different between these two groups. Methods: This is a retrospective study on patients who were diagnosed with metastatic, EGFR-mutated NSCLC and treated at Maimonides Cancer Center between 1/1/2011 and 9/30/2019. Patients were divided into two cohorts: those who did not develop T790M mutation (group 1), and those who did (including 1 patient who had de novo mutation, group 2). Results: Fifty-six patients were identified, with median age of 70 years (range 40-93). All patients had adenocarcinoma. Thirty-nine (70%) were Chinese. There were 31 (55%) exon 19 deletion, 22 (39%) L858R, 1 E709A, 1 G719S and 1 de novo T790M mutations. Forty-five patients (80%) never developed T790M (group 1), 10 (18%) did and 1 had primary mutation (group 2). The median time to developing T790M mutation was 22 m. In group 1, 8 patients received first-line osimertinib, while other 37 received erlotinib (23), gefitinib (4) and afatinib (10). Among the 37 patients, 12 were switched to osimertinib in subsequent lines, 5 due to toxicity and 7 due to progression. In group 2, 8 patients received osimertinib at identification of T790M and 1 for de novo mutation. At 22 m median follow up, the mPFS for group 1 was 14 m (95% CI 9.3-19); the mPFS for group 2 was 21.6 m (95% CI 7.4-49.1) up to the time of identification of T790M, and 31.2 m (95% CI 4.9-45.4) until disease progression after osimertinib. The mPFS of the entire cohort was 17.1 m (95% 11.1-25.9), and mOS was 22.0 m (95% 15.6-29.6). The mOS was 19.0 m (95% CI 11.4 – 25.2), and 39.9 m (95% CI 13.3 – 62.1) for group 1 and 2 respectively. Conclusions: Patients who developed the T790M mutation appeared to have a longer PFS than those who did not and the mean duration to detection of T790M was 22 m. The development of T790M may confer a slower growth pattern and longer PFS. This question should be further explored in larger studies.
LP-300 as a potential first-in-class combination agent with tyrosine kinase inhibitors (TKIs) in non-smoker lung adenocarcinoma.
Authors: Kulkarni Aditya , Parker Aulma , Jair Kamwing , Petluru Pavankumar , Chen Xinghai , Kochat Harry , Hausheer Frederick H. , Kathad Umesh , Bhatia Kishor , Barnhart Kerry , Sharma Panna
Published: May 2020

e21660

Background: Lung cancer in non-smokers (LCINS) is the seventh leading cause of death among solid tumors. LCINS is more frequent in women, and the histological incidence of adenocarcinoma is higher among non-smokers. The mutation pattern by smoking status in non-small cell lung cancer (NSCLC) is distinct with genomic alterations in EGFR, MET and ROS1 being more frequent in non-smokers. Non-smoking status is the strongest clinical predictor of benefit from the EGFR TKIs. Lantern Pharma is developing LP-300/Dimesna, a non-toxic, well-tolerated, water-soluble disulfide as a combination therapy agent potentially indicated in female never-smokers with adenocarcinoma. Retrospective subgroup analyses of prior phase 3 trial data showed substantial overall survival benefit for LP-300 in combination with standard chemotherapy in patients with advanced NSCLC, especially in the female non-smoker adenocarcinoma subgroup (13.4 months in control arm to 27 months in treatment arm). Purpose of this work conducted at BioNumerik Pharmaceuticals was to determine if LP-300 modulates activity of selected receptor tyrosine kinases relevant to non-smoker NSCLC. Methods: In vitro luminescence-based kinase assays were used to evaluate the effect of LP-300 and LP-300-derived mesna-disulfide heteroconjugates, Erlotinib, and Crizotinib, in combination and as single agents, on EGFR, MET, and ROS1 kinase activity. Results: LP-300 inhibited WT EGFR kinase and MET kinase. LP-300 had a time-dependent inhibitory effect on ROS1 kinase activity. LP-300 and LP-300-derived mesna-disulfide heteroconjugates stimulated Erlotinib-mediated inhibition of WT and T790M EGFR. T790M EGFR is normally insensitive to Erlotinib but when LP-300 was used with Erlotinib, inhibition was more prominent. LP-300 also stimulated Crizotinib-mediated inhibition of MET kinase and displayed time-dependent stimulation of Crizotinib-mediated inhibition of ROS1 kinase. Conclusions: LP-300 is a multi-targeted modulator of enzymatic activities of EGFR, MET and ROS1, and potentiates the activity of Erlotinib and Crizotinib. EGFR family members contain conserved extracellular structures that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR and potentially downregulate EGFR-dependent proliferative signaling in cancer cells. We propose LP-300 as a Disulfide Bond Disrupting Agent (DDA) that may complement existing EGFR-targeted agents functioning through alternate mechanisms.
Preclinical evaluation of SIM1803-1A, a small molecule Trk/ROS1 dual inhibitor for wild and mutate NTRK/ROS1 fusion solid malignancies.
Authors: Wang Jianfei , yu xiaohong , Zhu Shunwei , Chen Qingying , Sun Jikui , Xia Yuanfeng , Zhang Yang , Chan Chi-Chung , Li Jian , Chen Shuhui
Published: May 2020

e21663

Background: Fusions and rearrangements of NTRK1/2/3 and ROS1 genes are oncogenic drivers in multiple solid malignancies. Drugs targeting tyrosine kinases TrkA/B/C and ROS1, such as larotrectinib and entrectinib, are proven highly efficacious in diverse adult and pediatric tumor types (ORR > 75%). However, the treatment-related drug resistance, including S.F. mutations, G.K. mutations and DFGx mutations, has been identified in clinical trials. The use of second generation of TKI, such as repotrectinib to against these acquired resistance mutations, has been explored in clinical trials and reported unsatisfied efficacy in patients under acceptable dosages, which might due to its broader inhibition of multiple kinases. Here we report a novel potent Trk/ROS1 dual inhibitor SIM1803-1A, targeting both the wild type and multiple clinical mutations of Trk and ROS1 with clean selectivity profile and expected in vitro and in vivo efficacy for wild and mutant NTRK/ROS1 fusion solid tumors. Methods: Kinase inhibiting potency was determined with Reaction Biology kinase assays. Kinase selectivity was screened on Eurofins Kinase Profiler panel. Cellular anti-proliferative potency was evaluated on relevant fusion cell lines. Antitumor efficacy was evaluated in the related CDX and PDX mice models shown in results. Results: SIM1803-1A displayed high kinase inhibiting potency with IC50 3.64/1.24 /4.45 nM on TrkA( WT/G595R/G667C) kinase, 0.07/5.03/5.68 nM on TrkC( WT/G623R/L686M), and 0.08/0.10 nM on ROS1( WT/G2032R) respectively. A clean selectivity profile was also identified in 112 enzymes from TK and TKL family at 0.5 µM. The proliferation inhibition IC50 of SIM1803-1A in following cell lines were: 0.3 nM on KM12 TPM3-NTRK1, 2.2/0.9/5.7/5.6 nM on Ba/F3 LMNA-NTRK1( WT/F589L/G595R/G667A), 2.9/6.2 nM on Ba/F3 ETV6-NTRK3( WT/G623R), and 7.3/15.0 nM on Ba/F3 SLC34A2-ROS1(WT/G2032R) respectively. SIM1803-1A showed high antitumor efficacy in the subcutaneous colon cancer KM12 TPM3-NTRK1 CDX model with 68% and 80% TGI at 1 and 3 mg/kg (bid) dosing, and similar high efficacy in the subcutaneous NSCLC LU-01-0414 SDC4-ROS1 PDX model with 60% and 74% TGI at 1 and 3 mg/kg (bid) dosing. Conclusions: Collectively, these studies have shown SIM1803-1A is a potent Trk/ROS1 dual inhibitor with better safety potentially from improved kinase selectivity. SIM1803-1A is currently at IND submission stage and represents a promising clinical candidate for the treatment-naïve and acquired-resistance NTRK/ROS1 fusion-positive malignancies.