bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor growth rate (TGR) as an early predictor of outcomes in advanced non-small cell lung cancer treated with PD-1 axis inhibitor.
Authors: He Li-na , Zhang Xuanye , Li Haifeng , Chen Tao , Zhang Li , Hong Shaodong
Published: May 2020

e21560

Background: Tumor growth rate (TGR) signifies percentage change in tumor size per month (%/m). We investigated the association of TGR with outcomes in patients with advanced non-small cell lung cancer (aNSCLC) undergoing anti-PD-1/PD-L1 monotherapy. Methods: We retrospectively reviewed 172 aNSCLC patients treated with anti-PD-1/PD-L1 monotherapy in Sun Yat-Sen University Cancer Center between August 2016 and June 2018. Computed tomography images were reviewed to calculate TGR before treatment (“TGR0”) and upon early treatment (from treatment initiation to the first evaluation; “TGR1”). X-tile software was used to determine cut-off values that maximumly differentiate overall survival (OS). Log-rank tests and Cox regression models were performed for survival analysis. Results: 73 patients with paired TGR0 and TGR1 were included in the testing cohort. The optimal cut-off values of TGR0 and TGR1 were 46.6 %/m and 10.9 %/m, respectively. Patients with higher TGR1 significantly experienced inferior OS versus those with lower TGR1 (HR 2.74, 95% CI 1.34-5.61, P = 0.006). Patients with higher TGR0 tended to have poorer OS, though not statistically significant (HR 1.79, 95% CI 0.84-3.79, P = 0.131). In multivariate analyses, TGR1 remained an independent predictor of OS (HR 2.33, 95% CI 1.12-4.83, P = 0.024). In an external validation cohort (n = 69) enrolling patients with available TGR1 but lacking TGR0 data, TGR1 was also significantly associated with OS (HR 2.73, 95% CI 1.33-5.60, P = 0.006). Conclusions: Higher TGR1 was correlated with inferior outcomes in aNSCLC patients who received anti-PD-1/PD-L1 monotherapy. Larger prospective studies are warranted to identify its added value to RECIST as an early radiological biomarker to predict long-term survival of patients undergoing immunotherapy. [Table: see text]
Evaluation of immune-related adverse events in patients treated with sequential immunotherapy and tyrosine kinase inhibitor treatment in non-small cell lung cancer.
Authors: Baroz Angel Ray , Mambetsariev Isa , Fricke Jeremy , Pharaon Rebecca , Zhao Dan , Koczywas Marianna , Massarelli Erminia , Salgia Ravi
Published: May 2020

e21562

Background: Immune-related adverse events (irAEs) have been frequently observed with non-small cell lung cancer (NSCLC) patients treated with immunotherapy (IO). The severity of irAEs in response to IO treatment may reflect antitumor response. The effect of irAEs with sequential IO and tyrosine kinase inhibitor therapies has not been fully characterized. This study aims to evaluate the irAEs in NSCLC patients who have received sequential IO and TKI treatment. Methods: A retrospective cohort of 387 NSCLC patients previously treated with IO was identified from the City of Hope Thoracic Registry (THOR) from February 2010 to January 2020. Patients had confirmed pathologic disease and received IO and TKI, either on clinical trial or as standard of care. IO-treated patients were classified into two groups: TKI vs non-TKI treated. The non-TKI IO-treated group was used to verify that outcomes are not dependent on the immunotherapy given, but rather TKI therapy. IrAEs were collected from treatment courses and assessed based on the treating physician diagnosis. Results: A total of 63 NSCLC patients received sequential IO and TKI treatment. Histology was nonsquamous in 59 (93.7%) and squamous in 4 (6.3%). Multiple lines of therapies were accounted for in each patient. IO therapies received included nivolumab (n = 30), pembrolizumab (n = 24) and atezolizumab (n = 11). Mostly frequently used TKI therapies were erlotinib (n = 43), osimertinib (n = 25), afatinib (n = 11), crizotinib (n = 10), gefitinib (n = 5), and alectinib (n = 4). IrAEs occurred in 23 patients (36.5%). 22/23 (95.7%) patients who reported irAEs received TKI treatment prior to receiving IO treatment. The most common irAEs were pneumonitis (n = 5), diarrhea (n = 4), fatigue (n = 3) and rash/pruritus (n = 3). Other irAEs included arthralgias & myalgias (n = 2), new onset diabetes (n = 1) and renal insufficiency (n = 1). Conclusions: The severity of irAEs and sequential IO and TKI treatment in NSCLC patients is still not well-defined. Overall and progression-free survival were considered in this cohort. Preliminary data suggested that EGFR-TKI treated patients have low response to immune checkpoint inhibitors, but outcomes vary by allele variation. Further prospective analyses are needed to investigate the correlation of irAEs and survival outcomes with TKI-resistant NSCLC patients treated with IO. Also, treating physician’s diagnosis of irAEs exposed a need to clarify grade and severity of irAEs.
Can polymetastatic disease be arrested using SABR? A dosimetric analysis to inform development of a phase I trial.
Authors: Corkum Mark Thomas , Fakir Hatim , Palma David A. , Nguyen Timothy K. , Bauman Glenn
Published: May 2020

e21567

Background: Phase II randomized trials suggest that stereotactic ablative radiotherapy (SABR) improves progression-free and overall survival in patients with oligometastatic cancer, with phase III trials currently testing SABR in up to 10 metastases. Whether SABR could provide similar benefits in polymetastatic disease ( > 10 metastases) is unknown. A critical first step is to determine the feasibility of planning SABR for a large number of metastases throughout the body while maintaining acceptable organ at risk (OAR) doses. Therefore, we sought to evaluate the dosimetric feasibility of using SABR in polymetastatic disease ( > 10 sites) while adhering to OAR constraints to be used in a phase I trial (ARREST). Methods: Five craniospinal CT simulations were utilized to retrospectively contour 24 (n = 2), 30 (n = 2) and 50 (n = 1) tumour targets not present on the initial scan. Standard PTV margins were added based on institutional immobilization practices. OAR constraints from published clinical trial protocols were used. Radiotherapy plans for the highest dose level in our planned phase I trial (30Gy in 5 fractions) were created utilizing a minimum number of isocentres. Plans were created using Raystation (RaySearch Laboratories, Stockholm, Sweden) for delivery on linear accelerators using volumetric modulated arc therapy. Results: The gross tumour volumes (GTVs) ranged from 134.8– 184.2cm3 in our five test cases. The first two cases with 24 GTVs have been planned and were deemed to be clinically acceptable. PTV volumes were 483.0cm3 and 417.4cm3, utilizing five and six isocentres for treatment respectively. Median PTV D95 was 29.7Gy and 29.0Gy, whole body V10 was 21.2% and 17.4%, and V5 was 41.8% and 44.8%. All OAR goals were met, though low-dose conformality was less than traditional SABR treatment plans (R100 of 1.04 and 0.93; R50 of 9.90 and 6.98, respectively). The remainder of the test cases will be presented. Conclusions: In our test cases, planning SABR in polymetastatic disease appears dosimetrically feasible. Our phase I clinical trial (ARREST) is under development, which will evaluate the feasibility and toxicity of delivering SABR in polymetastatic disease in a 3+3 dose escalation study. The starting dose level will be 12Gy in 2 weekly fractions, escalating the dose by adding 6Gy weekly until our target dose of 30Gy in 5 weekly fractions. Our study population will include > 10 sites of disease, all tumour types, and patients must have exhausted standard lines of systemic therapy.
A meta-analysis comparing therapeutic outcomes for anti-EGFR monotherapy to targeted therapy combinations for non-small cell lung cancer.
Authors: Kurup Sonali , Ding Qian , Amissah Felix , Assaad Kaitlin , Chandrasekhara Soniya
Published: May 2020

e21570

Background: Small molecule inhibitors of epidermal growth factor receptor kinase (EGFR) are approved for EGFR-positive non-small cell lung cancer (NSCLC). Targeted therapies include agents that block tumor-specific molecular targets and thereby interfere with tumor growth and metastasis. This study focuses on a meta-analysis of therapeutic outcomes from phase II and III clinical trials for anti-EGFR monotherapy compared to anti-EGFR therapy in combination with targeted agents. Methods: A literature search was conducted using EMBASE, Pubmed, Scifinder Scholar, clinicaltrials.gov and the Cochrane library for the following terms: “epidermal growth factor receptor kinase”, “combination therapy”, “non-small cell lung cancer”. Eligible studies included patients of advanced stage IV NSCLC and any mutation status that met the predefined inclusion criteria. Data was extracted on trial demographics and therapeutic outcomes including progression-free survival (PFS), survival post progression (SPP), overall survival (OS) and adverse events (AE). Sub-group analysis based on patient mutation status of wild-type (wt) EGFR, mutant EGFR, wt KRAS and mutant KRAS and a correlation analysis between OS, PFS and SPP was conducted. Results: A total of 34 studies were identified that fit the inclusion criteria from 2009-2019. The pooled OS hazard ratio (HR) was 0.94 (95% Confidence Interval (CI): 0.87-1.01); the pooled PFS HR was 0.8 (95% CI: 0.74-0.87). Median OS correlated more closely with median SPP (r2 = 0.97 for monotherapy; r2 = 0.88 for combination therapy) than to median PFS (r2 = 0.90 for monotherapy; r2 = 0.82 for combination therapy), although the linear association between log-HR OS and log-HR PFS had a positive slope (β = 0.31± 0.19). A greater incidence of rash and diarrhea was observed in the combination arm compared to monotherapy. A significant improvement was observed for PFS in wt EGFR patients for combination therapy, pooled PFS HR 0.8 (95% CI: 0.67-0.95). Conclusions: A statistically significant improvement in PFS was observed for anti-EGFR combination regimens compared to anti-EGFR monotherapy. The improvement in OS was not statistically significant for anti-EGFR combination regimens compared to monotherapy.
Phase II trial of clinical activity and safety of ceritinib combined with stereotactic ablative radiotherapy (SABR) in lung adenocarcinoma patients.
Authors: Khan Saad A. , Gerber David E. , Zhu Hong , Hughes Randall S. , Mannala Samantha , Rashdan Sawsan , Dowell Jonathan , Westover Kenneth D. , Saltarski Jessica , Harrah Kasia , Priddy Laurin , Choy Hak , Timmerman Robert D. , Brekken Rolf A. , Sorrelle Noah , Iyengar Puneeth
Published: May 2020

e21571

Background: ALK -targeting drugs and SABR are combined in patients with metastatic cancer, anecdotally yielding clinical benefit. However, the precise impact of the combination and the optimal time to introduce SABR remain unknown. Methods: This completed phase 2 study (NCT02513667) had a primary objective of doubling progression free survival (PFS) for ALK+ lung adenocarcinoma patients by consolidating all remaining disease with SABR, 8-10 weeks after ceritinib initiation. Patients who then progressed could receive repeat SABR as long as they then resumed ceritinib. Patients were divided into ALK-inhibitor naïve vs previously treated cohorts. Oligometastatic disease was NOT a requirement for study entry, CNS disease was permitted. Blood was serially analyzed for variation in 1. blood cfDNA detection of resistance mechanisms 2. flow cytometric analysis of white cell populations. Results: 14 patients were enrolled out of a planned 33; 7 female; 3 hispanic/latino; median age was 53 years (range 31-78); 5 patients had previously received crizotinib. 4 patients stopped ceritinib within 30 days due to toxicity, despite dose reductions or with-food administration. However, all patients still completed initial SABR consistent with protocol time-points. Patients predominantly had thoracic disease irradiated (11/14, 78%). Two patients had only brain metastases treated and 1 had bone only metastases treated. 4 had one fraction SBRT regimens (16-24 Gy per fraction) delivered to disease, 3 had three fraction SBRT regimens (9-11 Gy per fraction) delivered to disease, and 7 had five fraction SBRT or 15 fraction hypofractionated regimens (6 Gy per fraction or 3Gy per fraction, respectively) delivered to disease. Disease control in all irradiated areas was 100%. There was no significant grade 3 or higher toxicity associated with radiation. Broad variability in baseline and serial levels of circulating PMN-MDSC, VEGFR2, FoxP3+, CD56+CD16+ and various T-cell populations showed no clinical correlation. The trial terminated early due to increased use of alternative targeted therapies, thus the primary endpoint was not met. 8 patients had CR/PR/SD as best response. Including those who did not tolerate ceritinib, median PFS was 12 months, max of 31 months with 1 ongoing response. Conclusions: Consolidative SABR after ALK therapy is well tolerated, can be repeated and may prolong PFS compared to drug alone. Ceritinib toxicity meant higher rates of discontinuation but this did not prevent consolidative SABR in any patient. Clinical trial information: NCT02513667.
Concordance of provider treatment patterns with NCCN oncology treatment guidelines (NCCN Guidelines) for metastatic non-small cell lung cancer (mNSCLC).
Authors: Seal Brian S. , Mooradian Meghan , Yong Candice , Schroeder Amy L , Macher Dana , Bekele Biruk , Petrilla Allison
Published: May 2020

e21574

Background: mNSCLC clinical treatment guidelines are rapidly evolving, however, their influence on prescriber use of anti-cancer treatment regimens is not known. This retrospective study evaluated whether US patients with mNSCLC received first line (1LOT), second (2LOT), or third (3LOT) line treatment regimens that were concordant with NCCN Category 1-2A recommendations. Methods: mNSCLC patients who initiated treatment between 2014-2017 were identified using medical and pharmacy claims from the 100% Medicare Fee-for-Service (FFS) Part A/B/D sample and multi-payer Inovalon MORE2 Registry. Claims-based algorithms identified mNSCLC and LOT following diagnosis; patients with other primary cancers or < 6 months follow-up were excluded. Treatment regimens were compared to active NCCN Guidelines at time of treatment to determine if regimen was concordant with Category 1-2A recommendations. Genetic mutation/biomarker status was not available. Results: 6,523 patients with mNSCLC met criteria for analysis (FFS/Medicare Advantage:78.6%; commercial:14.0%, managed Medicaid:7.4%; mean age:69.3 [SD:9.2]). For 1LOT, 81% received platinum-based doublet regimens; most common monotherapy included erlotinib, nivolumab, and pembrolizumab; 18% of 1LOT patients received maintenance therapy. For 2LOT, approximately one-third received nivolumab monotherapy, one-third received platinum-based doublets, and remainder received other regimens. Most common 3LOT included monotherapy nivolumab, pemetrexed, paclitaxel, and docetaxel. NCCN Guidelines concordance varied: 1LOT (90.5%), 2LOT (58.5%), 3LOT (71.9%). Non-concordant regimens included nivolumab as 1LOT and early adoption of platinum agent+(pemetrexed or paclitaxel) in 2LOT, and chemotherapy as 2LOT in anaplastic lymphoma kinase rearrangement-positive or epidermal growth factor receptor mutation-positive disease. Conclusions: In Medicare and non-Medicare patients with mNSCLC, 1LOT closely followed NCCN Guidelines. Most variability was observed in 2LOT where 58.5% regimens were concordant with Category 1-2A recommendations. Non-concordance may be driven by lack of effective second-line regimens and early adoption of innovative therapies.
Genomic correlates and classification of PD-L1 status in non-small cell lung cancer.
Authors: Liang Feng , Liu Sisi , Jiang Ya , Xu Xiuxiu , Ou Qiuxiang , Bao Hua , Wu Xue , Shao Yang , Hu Xingsheng
Published: May 2020

e21578

Background: Programmed cell death 1 (PD-L1) is the first FDA-approved predictive biomarker for non-small cell lung cancer (NSCLC) patients treated with PD-(L)1 blockade therapy. Herein, we aim to identify potential anti-PD-L1 treatment-related biomarkers through evaluating the correlation between the PD-L1 expression level, clinical characteristics, and the mutational profile of a large Chinese NSCLC cohort. Methods: Genomic profiling of tumor biopsies from a total of 808 Chinese NSCLC patients, including 651 adenocarcinomas (ADCs) and 157 squamous cell carcinomas (SCCs), was performed using next-generation sequencing by targeting 425 cancer-relevant genes. Immunohistochemical analysis was used to evaluate PD-L1 protein expression using PD-L1 antibodies including DAKO 22C3 ( N= 695) and DAKO 28-8 ( N= 113), respectively. Results: The PD-L1 positive ( > 1%) rate was 49.2% in ADCs and 52.9% in SCCs, respectively. PD-L1 expression (22C3) was associated with the male gender( p< 0.01) and lymph node metastasis ( p= 0.048) in ADCs but not in SCC patients. PD-L1 expression (22C3) was inversely correlated with KRAS wildtype ( p< 0.001) and EGFR exon 19 deletion( p< 0.01) in ADC, while it was negatively associated with TP53 oncogenic mutations ( p= 0.049) in SCC. Copy number variation analysis revealed that MDM2 amplification ( p= 0.027), 1q gain ( p= 0.012), and 5q deletion ( p< 0.01) negatively correlated with PD-L1 expression, whereas PD-L1 and PD-L2 amplification ( p< 0.001 and p< 0.0001) were positively associated with PD-L1 expression in ADCs. In SCCs, PD-L1 expression (22C3) was negatively associated with copy number gain in EGFR ( p= 0.040), MDM2 ( p= 0.044), 14q ( p= 0.032), and 20q ( p= 0.026), along with PTPRD loss (p = 0.015) and 19p deletion (p = 0.025). However, it was positively associated with 9p amplification ( p< 0.01) and 13q deletion ( p= 0.019). Plus, KIF5B- RET ( p= 0.006) appeared to be inversely related to the PD-L1 expression levels (22C3) in ADCs alone. In addition, these predicted biomarkers were used to delineate the receiver operating characteristic (ROC) calculation to discriminate between PD-L1 low and high (22C3, 50%) with an AUC score of 0.779. Lastly, PD-L1 expression (28-8) did not show significant correlation with any detected oncogenic mutations, but negatively correlated with NKX2-1 gain ( p= 0.0379) and 9q deletion ( p= 0.0379) in ADCs. Conclusions: This study revealed the correlation between PD-L1 protein expression, clinical features, and mutational traits in NSCLC patients, and provided a classifier for PD-L1 expression prediction.
Comparison of outcomes with pembrolizumab monotherapy (P) versus combination with chemotherapy (P+C) in advanced non-small cell lung cancer (NSCLC).
Authors: Sehgal Kartik , Gill Ritu R. , Bindal Poorva , Koshy Anita Geevarghese , McDonald Danielle C , Rangachari Deepa , Costa Daniel Botelho
Published: May 2020

e21579

Background: P and P+C are standard-of-care (SOC) treatment options for advanced NSCLC. However, they have not yet been directly compared in clinical trials. Methods: We conducted a retrospective cohort study of patients with advanced NSCLC who initiated treatment with SOC P±C at our center from 2/11/16 to 10/15/19 (data cutoff 1/15/20). Patient demographic, clinicopathologic, therapeutic and outcomes data were extracted. All radiographic scans were independently evaluated by a thoracic radiologist using iRECIST. Survival time was defined from the start of P±C. Kaplan-Meier and Cox proportional hazards model were utilized. Results: Of 103 patients with median follow up of 17.7 months, 74 (71.8%) had received P, while 29 (28.2%) had received P+C. In PD-L1 tumor proportion score (TPS) unselected population, there were no significant differences in age, sex, smoking status, driver mutation, tumor mutational burden (TMB), line of therapy, ECOG performance status (PS) or immune-related adverse events (irAE) between P and P+C groups. 71.6% in P vs 13.8% in P+C had PD-L1 TPS ≥50% (p < 0.001). There were no significant differences between the two groups in objective response rate (ORR), disease control rate (DCR), unadjusted progression-free survival (PFS) or unadjusted overall survival (OS) (Table). Multivariable adjustment for confounding factors between P+C vs P revealed no differences in OS [hazard ratio (HR) for death, 1.53, 95% CI 0.55 – 4.25] or PFS [HR for progression/death, 1.75, 95% CI 0.63 – 4.91]. Further stratification into PD-L1 TPS ≥50% and < 50% showed no significant differences between P+C vs. P in adjusted OS [HR for death, TPS < 50%- 1.54 (95% CI 0.59 – 4.03); TPS ≥50%- 0.71 (95% CI 0.11 – 4.52)] or PFS [HR for progression/death, TPS < 50%- 1.58 (95% CI 0.72 – 3.48); TPS ≥50%- 0.64 (95% CI 0.06 – 6.93)]. ECOG PS and development of irAE influenced OS in all groups, while TMB was relevant in PD-L1 ≥50% only. Conclusions: Our study shows no significant differences in outcomes with P vs P+C in advanced NSCLC in a real-world setting, albeit with limitations of single-center design, limited sample size, different line settings and lack of disease burden stratification. Ongoing phase III trials comparing front line P vs P+C will definitively address the long-term clinical benefits -if any- of combining cytotoxic chemotherapy with anti-PD-1 drugs. [Table: see text]
A retrospective study evaluating clinical and molecular predictors of duration of response (DoR) to immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Ibrahim Yahya , Sankar Keerthana , Kim Seongho , Haddad Amy , Mamdani Hirva
Published: May 2020

e21581

Background: ICI with/without chemotherapy has become the standard of care for the treatment of advanced NSCLC. Little is known about the clinical and molecular predictors of DoR to these agents. We previously reported clinical predictors of DoR to ICI in NSCLC patients (pts). Here we report the correlation of molecular alterations with DoR and clinical/molecular characteristics of super responders (DoR ≥ 2yr) to ICI. Methods: A retrospective chart review of pts with advanced NSCLC treated with ICI based therapy between 2015-2018 at Karmanos Cancer Institute was conducted. Clinical, tumor, and molecular characteristics data were collected. DoR was grouped into: < / = 6 weeks, > 6weeks-6months, > 6mo-1yr, > 1yr, and super responders. Results: Of 147 pts, 68% had adenocarcinoma, 61% received prior radiation, 21% had brain metastasis (mets), 26% developed irAEs, 33% were on statin, 27% were on aspirin, 83% were current or former smokers, 55% had right sided primary tumor, ICI was 1st line treatment (tx) in 20% and 2nd line tx in 52%. Overall median DoR was 168 days (95% CI, 132-231 days). Pts with right sided primary tumors and those who received ICI as 1st line tx had longer DoR (p = 0.012 and p = 0.017; respectively). Other aforementioned covariates, including brain mets, had no significant relationship with DoR. Molecular profile (MP) of 592 genes was available for 57 (38.8%) pts. PD-L1 ≥50%, CDKN2A and NOTCH1 mutations were associated with statistically significant longer DoR. Mutations/alterations in EGFR, ALK, ROS1, MET, RET, HER2, KRAS, STK11 and TP53 did not appears to have an impact on the DoR, although some of the analysis was limited because of very small number of pts. Of the 10 super responders, majority had adenocarcinoma, received prior radiation and were current/former smokers. Two had brain mets. Most did not have concurrent use of anti-inflammatory agents (statin or ASA). Only 2 of the super responders had MP available with negative NOTCH1 and CDKN2A mutations. Conclusions: Receiving ICI as 1st line of therapy and having right sided primary tumors predicted longer DoR. Presence of brain mets did not adversely affect the DoR. Super responders were more likely to have adenocarcinoma, prior radiation therapy, and current/former smoking history. PD-L1 expression ≥ 50%, CDKN2A, and NOTCH1 were associated with longer DoR. Presence of actionable genomic alterations, STK11, KRAS and TP53 did not appear to impact DoR to ICI.
Circadian variation in nivolumab efficacy in patients with advanced non-small cell lung cancer.
Authors: Karaboué Abdoulaye , Bisseux Laurence , Pavese Ida , Collon Thierry
Published: May 2020

e21585

Background: Despite efficacy of human checkpoint inhibitors, only 20 to 30% of treated patients present long term benefits. Circadian variations of the delivery of nivolumab to patients with advanced non-small-cell lung cancer (NSCLC) are proposed here as a factor potentially influencing the efficacy. Methods: A total of 1318 courses of nivolumab were administered in 57 consecutive patients with advanced NSCLC from September 2015 to December 2019 in Medical Oncology Unit of Montfermeil hospital. Percentage of total dose per patient delivered before and after 12:00 pm was computed and corelated to objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: Twenty eight patients (49%) received ≥ 50% of their treatment before 12:00 pm (morning group) and 29 patients (51%) after 12:00 pm (afternoon group). ORR was 53.6% in morning group and 31.0% in afternoon group; p = 0.083. Both PFS and OS were significantly longer in morning group as compared to afternoon group. Median PFS was 18.6 months [95%CL, 8.6 – 28.7] and 3.5 months [2.9 – 4.1] in morning and afternoon group respectively; p < 0.001. After a maximum follow-up of 48 months, median OS was not reached in morning group whereas it was 14.4 months [0.0 – 29.5] in afternoon group; p = 0.004. Conclusions: The significant difference in the efficacy of nivolumab between morning and afternoon group is indirect evidence of the influence of circadian rhythm on the metabolism of this checkpoint inhibitor. The application of this finding in clinical practice should allow an increase of nivolumab efficacy in patients with advanced NSCLC.
Genomic heterogeneity of multifocal NSCLC.
Authors: Chen Mingjiu , Ma Haitao , Yu Haoda , Chen Chen , Dai Pingping , He Zhiyi , Li Pengcheng , Zhang Yan , Guan Yan-Fang , Xia Xuefeng , Yang Ling , Yi Xin
Published: May 2020

e21595

Background: Distinguishing multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) remains a common diagnostic dilemma but critical for developing a therapeutic strategy. Methods: In this study, we analyse genomic features of 584 tissue samples from 258 NSCLC patients with > 1 surgically-resected tumor. NGS was performed using panels of 1021/59 genes. Results: Among 80 patients with definite diagnosis, 23 patients (46 tumors) were diagnosed with IPM. And 57 patients (145 tumors) were MPLC, consisting of 53 synchronous and 3 metachronous tumor pairs. Among 23 IPM tumor pairs, we identified at least one shared somatic mutation. By contrast, 93%(53/57) MPLC tumor pairs exhibited entirely unique mutation profiles in each tumor. Of 57 MPLCs, 4(7%) had no driver alteration ( EGFR, KRAS, BRAF, ALK, ERBB2, MET Exon 14). 9(16%) had a driver in only one of the tumors. In the remaining 44 MPLCs, 40 had unique driver mutation in each tumor. 50%(20/40) had distinct EGFR mutations, the most common combination was L858R and delins in exon 19. Specifically, 8(20%) patients resided ≥3 unique driver mutations simultaneously. This observation indicated that multiple lesions in the same individual can be driven by distinct molecular events. In contrast, 21 available IPM tumor pairs shared the same driver mutation. Pathogenic germline mutations were also analysed. Two were found in 2 MPLCs, involving PLAB2 and BLM, which were both null variants. While there were no pathogenic germline mutations found in IPMs. Regarding the MSI status, all samples from either MPLCs and IPMs displayed MSS, unexpectedly. To further verify the findings above, the remaining 393 samples with uncertain diagnosis were classified into group M (no shared mutation, 218 samples /97 patients) and I (≥1 shared mutation, 175 samples/81 patients). We find the similarity results among all available patients, driver mutation profiles exhibited completely unique and multiple in group M and fully consistent in group I. Conclusions: Taken together, our analyses indicated that the genomic heterogeneity of multifocal NSCLC may be a potential strategy for differentiating IPM and MPLC. This may hold implications for prioritizing therapeutic strategies.
Artificial intelligence model to predict slow progression for advanced non-small cell lung cancer (aNSCLC) patients receiving second-line therapies.
Authors: Charest Francois , Heilbroner Samuel P , Rudeen Karl , Chawla Jitesh , Suryadevara Somasekhar , Narayanan Babu
Published: May 2020

e21596

Background: There are ongoing efforts to understand and predict exceptional response to existing cancer therapies, but few clinical characteristics of these patients are known. We trained a machine learning model using the Concerto HealthAI database of oncology EMR data that includes clinical data from CancerLinQ Discovery to predict slow progression, a proxy for exceptional response, in aNSCLC in the second line setting. Methods: We trained an XGBoost model to predict patients with a progression free survival (PFS) greater than 180 days from the start of second line therapy (index date). This cutoff approximately determines the top 20% of PFS values in our database (median PFS = 86 days). Patients were included from the study if they (1) were pathologically confirmed aNSCLC without other primary cancer diagnoses and (2) started their second-line therapy between 2013 and 2017. Patients were labeled as slow progressors if they (1) had no evidence of progression or death within 180 days of index and (2) were evaluated for progression for at least 180 days post-index. The model considered data up to 120 days prior to index date. Risk factors in the model included demographics, vitals, common labs, common medical conditions, ECOG performance status, stage, histology, prior cancer treatment patterns, prior progression/response assessments, and medication history. Feature importance was evaluated using SHapley Additive exPlanations (SHAP). Results: 2205 patients met selection criteria of the study. Of these, 420 were labeled as slow progressors. 1776 patients were used for model training and 429 were set aside for model validation. The final model was able to predict slow progression with an AUCROC of 0.75 (F-score 0.48, precision 0.39, recall 0.6). The performance compares favorably to that of a logistic regression model (0.66 AUCROC). Top features that indicated slow progression included a low number of prior progression events or regimens, absence of metastatic disease, lower stage/t-stage/ECOG, absence of COPD, previous treatment with an EGFR inhibitor, normal Alk-Phos/WBC (versus elevated), absence of tachycardia, and a normal BMI (versus low). Conclusions: Machine learning and real world-data provided promising results in predicting slow progression in aNSCLC and may be useful in discovering novel drivers of favorable response.
Biological predictors of third-line treatment outcomes in patients with advanced non-small cell lung cancer.
Authors: Vassias Antonios , Vassos Dimitrios , Grapsa Dimitra , Bakakos Petros , Rovina Nikoletta , Syrigos Konstantinos N.
Published: May 2020

e21597

Background: The introduction of molecularly-guided targeted therapies and immunotherapy in routine oncology practice has led to significant survival increases in a subset of patients with advanced-stage non-small cell lung cancer (NSCLC). Nevertheless, the ultimate prognosis of these patients remains grim, and their overall therapeutic management challenging, particularly beyond the first-line treatment setting. We herein aimed to assess outcomes of third-line treatment in real-world patients with NSCLC, and to investigate potential correlations of clinicopathological and laboratory fearures with survival data. Methods: The medical records of 111 patients with advanced NSCLC, diagnosed and treated at the Oncology Unit of Sotiria Athens General Hospital between January 1, 2015 and December 31, 2018, were retrospectively reviewed. Eligible patients were those who had received more than two cycles of third-line treatment. Clinicopathological and laboratory features of patients, including baseline levels of complete blood count parameters evaluated immediately before administration of third-line therapy, were recorded and correlated with progression-free and overall survival. Results: The majority of patients had lung adenocarcinoma (54.1%) and stage IV disease (64,9%). Progression-free survival rates at 3 and 6 months were 59% and 20, respectively. Risk of disease progression was 35% lower in adenocarcinoma, as compared to other histological subtypes. Increased haematocrit and reduced white blood cell count levels were independently correlated with decreased risk of disease progression [HR (95% CI): 0,95(0,91-1,00); p = 0,044 and HR (95% CI):.1,05(1,00-1,11); p = 0,048, respectively]. Furthermore, higher white blood cell count and platelet count levels were independent predictors of decreased survival [HR (95% CI): 1,05 (1,01-1,1); p = 0,018 and HR (95% CI): 1,02(1-1,04); p = 0,018, respectively]. Conclusions: Haematocrit, white blood cell count and platelet count, recorded immediately before initiation of third-line therapy, may represent independent predictors of survival parameters in patients with advanced NSCLC.
CONCORDANCE study: An observational, multicenter, prospective study to evaluate concordance of detecting EGFR mutations by circulating tumor-free DNA versus tissues biopsy in NSCLC.
Authors: Prabhash Kumar , Biswas Bivas , Khurana Sachin , Batra Ullas , Biswas Ghanashyam , Advani Suresh Hariram , Mohapatra P , Rajappa Senthill J , Sharma Ajay , Patil Shekar , Dattatreya Palanki Satya , Almel Dr.Sachin , Goyal Gautam , Roy Rakesh , Warrier Narayanankutty
Published: May 2020

e21615

Background: Epidermal growth factor receptor (EGFR) mutations on circulating tumour free DNA (ctDNA) by liquid biopsy is suitable option in those with difficulty in obtaining tissue samples. Correlation in tissue and plasma results of EFGRm has not been established in the Indian population. 1,2,3 This study was done to investigate the utility of ctDNA for EGFRm testing with Next-Generation Sequencing (NGS) in a real-world diagnostic setting. Methods: This is a multicentre, prospective, diagnostic observational study in 245 newly diagnosed treatment naïve, histologically confirmed, advanced lung adenocarcinoma patients. This was a single visit study. The primary objective of the study was to determine the level of concordance between EGFR mutation status obtained by tissue and ctDNA from blood (plasma) based testing in terms of overall concordance, sensitivity & specificity. Study was registered at Clinicaltrials.gov NCT03562819 & CTRI/2018/08/015290. Results: Seventy-five (30.6%) and eighty-four (34.3%) subjects showed positive mutation status by plasma & tissue testing respectively. The overall concordance of 82.9% was observed between tissue and ctDNA (Plasma) based testing. Sensitivity of EGFR mutation status between ctDNA and tissue was observed for EGFR mutation subtypes was observed to be 100% while specificity was observed to be 90.1%. Plasma and tissue sample testing detected 1.2% (n = 3) and 2.4% (n = 6) positive in exon 20 T790M EGFR mutation, respectively. In terms of secondary outcomes, plasma sample testing detected 16.7% (n = 41) positive for Exon 19 deletions type EGFR mutation followed Exon 21 L858R [11.4% (n = 28)]. Conclusions: CONCORDANCE, a real-world study in Indian patients suggest that ctDNA testing for EGFR mutation analysis is a diagnostic option in newly diagnosed lung adenocarcinoma patients. EGFR Mutation testing in ctDNA, being non-invasive and especially in patients without available/evaluable tumor sample may enable more patients to receive appropriate targeted therapies. [Table: see text]
The impact of prior chemotherapy (PrC) on immunotherapy outcomes in non-small cell lung cancer (NSCLC) patients: Real data from a mono-institutional study.
Authors: Macerelli Marianna , Rizzato Simona , Giavarra Marco , Valent Francesca , Cattaneo Monica , Cortiula Francesco , Targato Giada , Rossetto Ciro , Bozza Claudia , Corvaja Carla , Fioraso Roberto , Fasola Gianpiero
Published: May 2020

e21639

Background: Immunotherapy has changed the paradigm on NSCLC treatment. No widespread and reproducible predictive biomarkers have been established. We analyzed how PrC could affect ICI outcomes. Methods: We conducted a retrospective observational study and analyzed all NSCLC patients (pts) treated with ICI (nivolumab or atezolizumab or pembrolizumab) in our institution from 2015 to 2018 and followed until January 2020. All pts had received at least one PrC. We recorded clinical features of pts both before and after ICI treatment. Results: A total of 83 pts were included, with a median age of 69 (range, 47-82). Sixty pts (73%) were male, 74 (89%) were smokers and 81 (97%) had ECOG PS 0-1. Thirteen (15.7%) pts had a immune-related toxicity (iRT, G1-G2 76.9% and G3-G4 23.1%) and 21 (25.3%) continued ICI therapy beyond progression disease (PD). Patients with a PD as best response to PrC had more probability to reach a PD with ICI (p = 0.06). Median Progression-Free Survival (PFS) on ICI was 2.9 months (interquartile range, 1.9-9.4) with no statistical difference between pts with oligo- or diffuse progression (≤ or > 5 metastasis) during PrC (p = 0.42). Corticosteroids use was associated with worse PFS (p < 0.01). Median Overall Survival (OS) was 9.1 months (interquartile range, 3.3-26.5), with a benefit for pts with a stable disease (SD) or partial response (PR) to PrC (p = 0.02), for pts who experimented iRT (p = 0.04) and who didn’t receive corticosteroids (p < 0.01). In multivariate analysis liver or brain metastases (HR 8.8, 95% CI 2.9-26.8 and HR 2.2, 95% CI 0.6-8.1), coticosteroids use (HR 3.7, 95% CI 1.3-10.5) or previous cisplatin-based chemotherapy (HR 8.4, 95% CI 2.3-30.1) were associated with worse OS. Instead, pts whit iRT (HR 0.4, 95% CI 0.1-1.3) and PR as best response to PrC (HR 0.8, 95% CI 0.3-2.0) had a better OS. Conclusions: Our study confirms literature data and suggests that PrC could affect ICI outcomes. Tumor burden seems not to influence ICI outcomes, unlike response rate to PrC. Systemic corticosteroids use and iRT predicts ICI outcomes.
Lungful: An observational prospective study to assess the molecular epidemiology of EGFR mutations upon progression on or after first line EGFR-TKI therapy, in real-life clinical settings in Greece.
Authors: Mountzios Giannis Socrates , Mavroudis Dimitrios , Samantas Epaminondas , Koumarianou Anna , Fergadis Evangelos Georgios Konstantinos , Katsaounis Panagiotis , Athanasiadis Ilias , Karamouzis Michalis , Boukovinas Ioannis , Lampaki Sofia , Rapti Aggeliki , Froudarakis Marios E , Kalampaliki Stamatia-Eleni , Anastasopoulou Eleftheria , Somarakis Alvertos , Syrigos Konstantinos N.
Published: May 2020

e21641

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the gold standard 1st line strategy for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations (EGFRm), associated with improved survival outcomes and quality of life compared to chemotherapy. Despite the high response rate with first- and second- generation TKIs, most patients develop resistance to treatment and progress. The acquisition of T790M mutation in exon 20 is considered the most common resistance mechanism. This study aims to investigate the molecular epidemiology of EGFR resistance mutations, focusing on T790M in EGFRm NSCLC patients treated with TKIs. Methods: The study included patients with locally advanced/metastatic EGFRm NSCLC who have progressed on or after 1st line treatment with first- or second- generation TKI. Samples either from plasma-based liquid biopsy and/or tissue re-biopsy were analysed using the Cobas EGFR Mutation Test v2. All patients signed informed consent and were enrolled between July 2017 and September 2019. Statistical analyses were performed using SAS software, Version 9.4. Results: Ninety-six eligible patients were enrolled. At the time of progression, T790M mutation was detected in 16.7%of the patients using plasma-based liquid biopsies. Among patients with negative T790M result, in plasma, tissue re-biopsy was performed in 22,7% with evaluable/valid results in 72.2% of them. T790M mutation was identified in 38.5% of re-biopsy samples. According to Cobas EGFR Mutation test results (combined plasma and tissue), T790M mutation was identified in 21.9% of the patients. Of T790M-positive patients 42.9% had previously received first and 57.1% second generation EGFR-TKI. Conclusions: Results from this study in real world clinical setting in Greece, show that EGFR-T790M acquired resistance positivity rate in plasma is lower compared to previous reports. Moreover, these data underline the challenges of implementing precision medicine using tissue re-biopsy in advanced/metastatic NSCLC. Clinical trial information: D133FR00126. [Table: see text]
Molecular characterization and prognostic analysis of non-small cell lung cancer: A single centric real-world study.
Authors: Zhang Hongbin , Wang Yuan , Ji Qiaoxia , Cai Hongmei , Liang Xiangcun , Xie Jiong , Li Hua , Wang Jun , Zhu Guiyun , Tian Erpeng , Zhu Lingling , Yuan Mingming , Wang Kai , Chen Rongrong , Zhao Min
Published: May 2020

e21646

Background: Identifying targetable genetic variants may help maximize clinical benefit of non-small cell lung cancer (NSCLC). Here, we retrospectively analyzed the benefit of next-generation sequencing (NGS) for NSCLC in routine clinical practice. Methods: A total of 59 NSCLC patients were enrolled in the study from Jun. 2018 to Dec. 2019. Formalin-fixed paraffin-embedded tissues samples were collected and sequenced by NGS, which detects single-nucleotide variants, small insertions/deletions, rearrangements, and copy-number alterations of either 59 or 1021 tumor related genes. The tumor response was evaluated using RECIST v1.1. Results: The detection rate of targetable variants was 59.32% (35/59), including EGFR mutation 49.15% (29/59), ALK rearrangement 5.08% (3/59), ROS1 rearrangement 1.69% (1/59), BRAF V600E mutation 1.69% (1/59), and ERBB2 mutation 1.69% (1/59). Of 29 patients with EGFR mutations, 5 patients (17.24%) had multiple EGFR mutations, including 2 patients (6.89%) with uncommon mutations. 25patients (86.21%) harbored concurrent mutations that may limit the efficacy of EGFR-TKIs, including EGFR amplification, activation of bypass signaling pathways, TP53 exon8 mutation, BCL2L11 deletion polymorphism, and PI3K-AKT-mTOR and cell cycle gene alterations. Among 25 patients received EGFR-TKIs, TKI effectiveness was evaluated in 18 patients. The disease control rate was 100% and overall response rate was 27.78%. The proportion of patients with TMB-H and/or PD-L1≥1, and targetable variants negative was 33.89% (20/59). Only one patient of this group received immunotherapy with pembrolizumab and achieved SD at the 2nd month. The proportion of patients with targetable variants negative, TMB-L, and PD-L1 < 1 or unknow patients was 6.78% (4/59), two patients of them left hospital without additional treatment, two patients received chemotherapy and the KRAS mutation present in one of them suggested that he might be resistant to EGFR-TKIs. Conclusions: More than half of NSCLC patients have targetable genetic variants and more than 30% patients have a molecular signature that can be treated with immunotherapy. Compared with immunotherapy, targeted therapy has higher acceptability in real-world. NGS-based genetic testing may have clinical value to predict the effectiveness of targeted therapy and immunotherapy. It can be widely implemented and standardized into clinical use.
The genomic characterization of different progression patterns in advanced lung cancer (LC) patients upon immune checkpoint inhibitor (ICI) treatment.
Authors: Zhong Hua , Li Jingwen , Xiang Chan , Wang Yue , Zhou Yan , Cao Shuhui , Ling Xuxinyi , Ye Junyi , Zheng Jingjing , Shao Lin , Han Yuchen
Published: May 2020

e21653

Background: Hyperprogressive disease (HPD), characterized by a rapid increase in tumor growth rate (TGR), has been reported in 13.8% NSCLC patients (pts) treated with ICI. Besides, 10.4% of NSCLC pts experience FP (fast progression) and/or early dearth (ED) upon atezolizumab. Although defined differentially, it has been shown that these progression patterns have overlapped portions. The molecular characteristics in different progression patterns have not been well elucidated and compared. Methods: 117 advanced LC pts treated with ICI were recruited, whose progression pattern was assessed according to the following criteria: FP was defined as ≥ 50% increase in the sum of long diameters within 6 weeks (wks) of ICI start; ED was defined as deaths within 12 wks. HPD was defined as the change in TGR greater than 50% compared with that prior to the initiation of ICI (TGR2/TGR1 > 1.5). There were 14, 8 and 9 ED, FP and HPD patients respectively. 5 patients were qualified for than one definition and 1 patient qualified for all 3 definitions. Tissue samples from 36 pts (18 FP/ED/HPD patients) were subjected to genomic profiling using a panel of 520 cancer-related genes. For genomic comparison, additional 693 non-HPD, non-ED and non-FP LC samples with matched TMB and histology were retrieved from our internal database. Results: The FP, HPD and ED occurred in 7.21%, 9.38% and 11.97% pts, respectively. The PFS was comparable among the 3 groups (P = 0.541). The median OS for FP, HPD and ED was 3.19, 11.2 and 1.84 months, respectively (P < 0.001). The genomic landscape of 18 FP/ED/HPD pts revealed 1 EGFR amp, 1 ALK fusion, 6 KRAS mutations, 1 ERBB2 amp, 1 MET amp and 1 RET fusion. Two ED pts harbored concomitant STK11 and KRAS mutations. MDM2 and MDM4 mutations co-occurred in 1 ED patient. 1 patient with ED and HPD had MDM4 mutation. Genomic comparison analysis revealed that ED pts had higher mutation frequency in KRAS (P < 0.01) and CDKN1B (P < 0.01) comparing with the 693 controls. Furthermore, FP pts were more likely to have RAD54L (p = 0.018) an MYC (p = 0.04) mutations. HPD pts showed higher rate of RAD54L (P < 0.001) and ARID1A (p = 0.04) than controls. Conclusions: We revealed FP, HPD and ED have comparable PFS but significant difference is OS. We also demonstrated different genomic characteristics associated with different progression patterns upon ICI treatment, which might further facilitate clinicians to stratify pts for ICI therapy.