bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of four dimensions CT simulation on planning target volume in radiotherapy for primary lung cancer.
Authors: Abuhijla Fawzi Jamil , Hammoudeh Lubna Abdelrahman , Abu-Hijlih Ramiz Ahmad , Khader Jamal
Published: September 2018

e20091

Background: 4D CT simulation has been evolved to estimate the internal body motion and considered as a useful tool for intra-thoracic tumor definition. This study aimed to evaluate the impact of using 4D simulation on the planning target volume (PTV) for primary lung tumor. Methods: Patients who underwent CT simulation for primary lung cancer radiotherapy between 2012-2016 using 3D- (free breathing) and 4D- (respiratory gated) institutional protocol were included in this retrospective review. For each patient, gross tumor volume (GTV) was contoured in free breathing scan (3D-GTV), exhale scan (e-GTV) and inhale scan (i-GTV). The corresponding CTVs (3D-CTV, e-CTV and i-CTV) were created by adding 1 cm in all directions. 3D-internal target volume (3D-ITV) was generated by 0.5 cm cranio-caudal expansion of 3D-CTV, while 4D-ITV was created by combination of e-CTV and i-CTV. Subsequently, a 0.5 cm margin was added to generate the 3D-PTV and 4D-PTV respectively. The volumes of 3D-PTV and 4D-PTV were compared to examine the impact of 4D CT simulation on changes in the volume of PTV. Univariable and multivariable analysis were performed to test the impact of volume and location of GTV on the changes of PTV volume by more than 10 % between free breathing and respiratory gated scans. Results: A total of 10 patients were identified. The median [range] GTV, i-GTV, e-GTV volumes were 13.55 [1.44-628.66], 13.17 [1.77-627.36], 12.85 [1.34-630.25] cc respectively. The 3D-CTV, i-CTV, e-CTV volumes were 86.37 [23.76-1209], 84.97 [25.5- 1220.4], 83.40 [23.36-1224.12] cc respectively. 3D-ITV and 4D-ITV median volume was 106.06 [3.99-1422.8], 88.02 [20.51-1338.18] cc respectively. 3D-PTV was significantly larger than the 4D-PTV; median [range] volumes were 182.79 [58.65- 1861.05] vs. 158.21 [52.76-1771.02] cc, p = 0.0068). On multivariable analysis, neither the volume of GTV (p = 0.4917), nor the location of the tumor (peripheral, p = 0.4914 or lower location, p = 0.9594) had an in impact on PTV differences between free breathing and respiratory gated scans. Conclusions: The use of 4D simulation reduces the PTV for primary lung cancer, and it should be routinely implemented in clinical practice regardless the tumor volume or location.
Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC) and brain metastases in the pivotal randomized phase 2 ALTA trial.
Authors: Ou Sai-Hong Ignatius , Tiseo Marcello , Camidge D. Ross , Ahn Myung-Ju , Huber Rudolf M. , Hochmair Maximilian J. , Kim Sang-We , West Howard Jack , Reckamp Karen L. , Molina Julian R. , Liu Geoffrey , Delmonte Angelo , Viteri Ramirez Santiago , Bearz Alessandra , Summers Yvonne J. , Reichmann William , Kerstein David , Gettinger Scott N. , Kim Dong-Wan
Published: September 2018

e20502

Background: The CNS is often a site of first disease progression in CRZ-treated ALK+ NSCLC. The ALTA trial is assessing BRG, an investigational next-generation ALK inhibitor, in pts with CRZ-refractory advanced ALK+ NSCLC, including pts with baseline brain metastases. Methods: In ALTA (NCT02094573), pts were stratified by presence of baseline brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Here, we show data for pts with baseline brain metastases. An independent review committee (IRC) assessed intracranial efficacy. Results: Of 222 pts (112 in arm A; 110 in arm B), 80 (71%)/74 (67%) in A/B had baseline brain metastases per investigators, with median age 49/55 y; 74%/76% had received chemotherapy. As of May 31, 2016, 51%/59% of these pts continued to receive BRG in A/B; median follow-up was 9.6/11.4 mo. Intracranial efficacy is shown in the table. Among these pts, most common treatment-emergent adverse events were: nausea 35%/46% (A/B), headache 30%/31%, vomiting 29%/31%, diarrhea 21%/38%, cough 25%/32%; grade ≥3: increased blood CPK 1%/12%, hypertension 4%/7%, increased lipase 4%/3%. Conclusions: BRG yielded substantial intracranial responses with robust iPFS and acceptable safety in ALK+ NSCLC pts with baseline brain metastases in ALTA. 180 mg (with lead-in) showed consistently improved intracranial efficacy compared with 90 mg. Clinical trial information: NCT02094573. [Table: see text]
Mutual transformation between adenocarcinoma and squamous carcinoma after EGFR tyrosine kinase inhibitors treatment in lung cancer.
Authors: Ying Zheng ming
Published: September 2018

e20510

Background: Knowledge on the epidermal growth factor receptor (EGFR) has improved survival of non-small cell lung cancer (NSCLC). Several mechanisms underlying have been discovered, here we would report a rare resistant mechanism of histology mutual transformations. Methods: From July 2013 to June 2015, we retrospectively collected 135 NSCLC patients who were in resistance with TKI treatments. Patients’ clinical data including pathologic result, gene status, demographic information, clinical staging, and treatment were recorded. [YL1] Results: Among the 135 NSCLC patients, we found two cases of lung cancer with histological transformation from adenocarcinoma to squamous cell carcinoma, one case from squamous cell carcinoma to adenocarcima after TKI treatment. These cases still harbored sensitive epidermal growth factor gene mutations and developed acquired resistance T790M mutation. Conclusions: Histologic evolution may be a mechanism associated with TKI resistance .
Fully automated and sensitive detection of EGFR exon 18, 19, 20 and 21 mutational status in <2.5 hrs from a single FFPE slice.
Authors: Sablon Erwin , Reijans Martin , Vandercruyssen Genevieve , Keuleers Inge , Helsens Kenny , Vandesteene Charlotte , Elsen Natasja , Peelman Natania , Vandenbroucke Ina , Maertens Geert G.
Published: September 2018

e20519

Background: Current molecular testing for mutations and indels in EGFRexons 18, 19, 20 and 21 is still laborious and often requires > 5 days in specialized labs. Multiple slices of FFPE tissue are often needed. Lack of experience, time or tissue for molecular testing are among the reasons why patients are often deprived of the proper targeted therapies. Therefore, a fast and fully automated assay with minimal hands-on time which can handle small samples should allow laboratories to quickly generate EGFR testing results as part of their precision medicine report. Methods: Idylla is a fully integrated MDx platform that combines speed and ease of use with high sensitivity and high multiplexing capabilities. For EGFR testing, it overcomes the current problem of lack of tissue and the time-consuming step of processing FFPE tissue samples. After insertion of a single 5 µm FFPE slice containing ≥10% neoplastic cells into the cartridge, the complete process of liquefication, extraction, rtPCR, data analysis and reporting is fully automated and takes < 2.5 hours. The Idylla EGFR Mutation Assay (RUO) allows the sensitive detection of 50+ mutations including indels in exons 18, 19, 20 and 21. Results: The Idylla EGFR Mutation Assay (RUO) was tested with single FFPE slices from 280 clinical NSCLC samples with known mutations as analyzed by NGS and digital droplet PCR. It demonstrated excellent specificity and sensitivity with an overall percentage agreement of > 96% and a positive and negative percentage agreement of > 97% and > 95%, respectively. Analytical sensitivity was assessed using cell line derived materials embedded in paraffin containing defined ratios of mutants and dilutions thereof in a WT background. Allelic frequencies ranging from 1 to 10% were tested in 6-fold and showed analytical sensitivities of 1% for all except one target which showed a sensitivity of 5%. Turnaround time of a run was < 2.5 hours and hands-on time was < 2 min. Conclusions:The new and fully automated Idylla EGFR Mutation Assay (RUO) demonstrates excellent specificity, high sensitivity, ease of use combined with a fast turnaround time for complete testing of more than 50 relevant EGFR mutations on FFPE samples from NSCLC patients.
Level of activated circulating endothelial cells to predict progression-free survival of Anlotinib treatment in patients with NSCLC: Analysis on ALTER-0303 study.
Authors: LI Kai , Wang Jing , Wang Xinyue , Liu Zhujun , Zhang Cuigui , Chen Peng , Meng Zhaoting , Chen Jinliang , Huang Chun , Jiang Xiangli , Liang Yan , Lin Li , Jiang Richeng , Wang Liuchun
Published: September 2018

e20530

Background: Activated circulating endothelial cells (aCECs) have been indicated as a potential biomarker of angiogenesis in a variety of cancers. Several studies have revealed that aCECs may reflect the extent of tumor angiogenesis, and the level of aCECs counts may has correlation with progression-free survival (PFS) in anti-angiogenesis therapy on NSCLC patients. Therefore, we investigated the association between aCECs and PFS of Anlotinib treatment in ALTER-0303 study. Methods: NSCLC patients with aCECs counts in ALTER-0303 study were observed. Samples were prospectively collected at six time points: before treatment (baseline), on the 7th, 15th, 21th, 42th, 63thday of Anlotinib treatment. aCECs was identified by Flow cytometry (FCM). The prognostic value of aCECs counts was analyzed and, the patients were stratified according to their ratio of the minimum aCECs counts in all time points and counts on baseline (aCECs min/baseline) as <1 and ≥1. Results: Forty-nine patients were included of which 35 and 14 had an aCECs min/baseline<1 and ≥1, respectively in Anlotinib arm. Median follow-up was 8.6 months. In univariate survival analysis, patients with min/baseline<1 had longer PFS [HR=0.439, 95% CI (0.211-0.912), P = 0.023], the median PFS for the patients with aCECs min/baseline <1 and ≥1 were 193 days and 124 days, respectively (shown in Table). However, there were no significant relation between PFS and such aCECs min/baseline ratio found in control arm of ALTER-0303 study. Conclusions: A decrease of aCECs counts from baseline during an initial period of Anlotinib therapy may predict longer PFS and good response in NSCLC patients. Information: NCT02029209, NCT02388919 Clinical trial information: NCT02029209. [Table: see text]
Cost-effectiveness analysis of afatinib vs gefitinib in EGFR-mutated population with advanced non-small-cell lung cancer.
Authors: Chouaid Christos , Luciani Laura , Le Lay Katell , De Pouvourville Gerard
Published: September 2018

e20548

Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial (LL7) for first-line treatment of advanced EGFR mutation-positive non-small-cell lung cancer (EGFRm+ NSCLC). We aimed to assess the cost and health outcomes of afatinib and gefitinib in this setting. Methods: A partitioned survival model was designed to assess the cost-effectiveness of afatinib versus geftinib in the French context for EGFRm+ NSCLC.Outcomes and safety are taken primarily from the head-to-head LL7 trial. Only direct medical costs were considered. Resources use and utilities were derived from the trial, expert panel and published literature. Incremental cost-effectiveness ratios (ICER) were calculated in the common EGFR population and also, in the sub-groups with EGFR Exon 19 deletion (del 19) and EGFR Exon 21 L858R (L858R) mutation over a 10 year-time horizon. Deterministic and probabilistic sensitivity analyses were performed. Results: For common EGFR+ NSCLC, the ICER of afatinib versus gefitinib was €45,211 per QALY (with a gain of 0.170 QALYs, and an incremental cost of €7,697). The ICERs for del 19 and L858R populations were €38,970 and €52,518 respectively. Afatinib had a probability of 100% to be cost-effective at a willingness-to-pay threshold of €70,000 for patients with common EGFR mutation, and also in the del 19 and L858R subgroups. Conclusions: Afatinib is a cost-effective treatment compared to geftinib in patients with EGFRm+ NSCLC with an ICER varying between €38,970/QALYs and €52,518/QALYs.
De novo EGFR T790M, KRAS and PIK3CA somatic mutations in cell free DNA in non-small cell lung cancer patients and clinical characteristics.
Authors: Chang Won Jin , Kim Yeul Hong
Published: September 2018

e20561

Background: Several mechanisms for acquired drug resistance EGFR-TKIs in NSCLC have been suggested. These include EGFR T790M mutation and mutations in KRAS, and PIK3CA. Rarely, a de novoT790M mutation has been reported. However, the clinical significance of these mutations remains controversial. Here, we used highly sensitive methods to detect T790M, KRAS and PIK3CA mutations in cell free DNA (cfDNA) and evaluate the clinical significance of those mutations. Methods: The blood samples were collected from 125 patients with NSCLC. Ion AmpliSeq Cancer Hotspot Panel (ICP) using a targeted ultra-deep sequencing (mean depth 22,868x) was performed in cfDNA, which were validated with droplet digital PCR (ddPCR). Results: ICP detected EGFR T790M mutation in 30 of 125 cfDNA (24%), KRAS mutations in 18 (14.4%) and PIK3CA in 33 (26.4%). ddPCR confirmed concordant T790M results in 22 (73.3%) and KRAS in 13 (72.2%). The 8 of 22 (36.4%) in T790M and 2 of 13 (15.4%) in KRAS had simultaneous activating EGFR mutations in cfDNA or tumor tissue. The most single KRAS mutations appeared in codon 12 (n = 7, 63.6%) (3 in G12C, 2 in G12S, 1 in G12V and 1 in G12D) with three mutations in codon 13 (27.3%) and one mutation in codon 61 (9.1%). About 20% to 50% had bone or brain metastases at diagnosis in patients with these mutations. The 5 (62.5%) (4 PR and 1 SD) of 8 patients in T790M and 8 (61.5%) (All PR) of 13 in PIK3CA showed response or stabilization. The median time to disease progression after EGFR-TKIs treatment was 13.5 months in PIK3CA and not reached in T790M. Conclusions: The de novo T790M, KRAS and PIK3CA mutation was detected in 24%, 14.4% and 26.4% using ICP in cfDNA. In our study, the KRAS and EGFR mutation may not be mutually exclusive and PIK3CA mutations may be a factor associated with metastatic sites rather than predictive factor for EGFR-TKIs. In addition, we suggested that although the clinical presentation is more aggressive in patients with de novo T790M and PIK3CA mutation, the EGFR-TKIs could be used in patients who present with both activating EGFR mutations and those mutations.
A retrospective analysis of apatinib in advanced non-small cell lung cancer patients refractory to chemotherapy.
Authors: Xu Jianping , Liu Xiaoyan , Yang Sheng , Zhang Xiangru , Shi Yuankai
Published: September 2018

e20562

Background: Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2. A phase II clinical study proved that 750 mg qd apatinib showed clinical benefit in patients with advanced non-squamous NSCLC refractory to two or more lines of chemotherapy (Zhang et al. 2012 ASCO, 7548). In this retrospective study, we assessed the efficacy of apatinib at a more frequently used dose of 500 mg qd in advanced chemo-refractory NSCLC. The preliminary clinical outcome of apatinib in patients with brain metastases was also reported. Methods: Clinical data of 25 advanced NSCLC patients who received oral apatinib 500 mg once daily as second-line and beyond therapy between August 2015 and May 2016 were reviewed. Results: The median progression-free survival (PFS) was 5.17 months (95% CI: 0.76–9.57 months). The response rate (RR) and disease control rate (DCR) were 8.0% and 68.0%, respectively. In the second-line setting (n=13), the mPFS was 7.37 months (95% CI: 0.01–14.72 months), and the RR and DCR were 0.0% and 61.5%, respectively. In the third-line and beyond setting (n=12), the mPFS was 5.17 months (95% CI: 1.78–8.55 months), and the PR and DCR were 16.7% and 75.0%, respectively. The DCR was 57.1% for 7 patients with brain metastases following apatinib administration. All patients were well tolerant to apatinib without any Grade 3 or 4 adverse events. The most common Grade 1 or 2 adverse events included hypertension (72.0%), hand-foot syndrome (24.0%), fatigue (24.0%), abnormal liver function (20.0%), nausea (12.0%) and palpitation (8.0%). Conclusions: Apatinib is effective and well tolerated in patients with advanced NSCLC, even at a dose of 500 mg qd, and might offer a new option for the treatment of such patients with brain metastases.
Liquid biopsy analysis of ALK alterations from advanced NSCLC patients: The value of exosomal RNA cargo (ExoALK).
Authors: Rolfo Christian Diego , Laes Jean-Francois , Reclusa Pablo , Lienard Maxime , Gil-Bazo Ignacio , Malapelle Umberto , Rocco Danilo , Van Meerbeeck Jan , Pauwels Patrick , Peeters Marc , Giallombardo Marco
Published: September 2018

e20569

Background: About 5% of NSCLCs present alterations in the ALK gene. Among them the most common is EML4-ALK translocation. The gold standard detection method to treat the patient with ALKi is the tissue, thus, it is mandatory to develop new techniques that allow to detect ALK alterations in liquid biopsy. The purpose of this study is, analyze the feasibility to detect ALK alterations in exosomes (Exo-ALK) derived from NSCLC patients. Methods: We recruit 18 NSCLC patients including EML4-ALK and wild-type patients stage- and time-independent. ALK-positive status is identified by IHQ. The isolation of RNA with the exoRNeasy Kit Serum/Plasma (Qiagen) in UZA and the retrotranscription with ProtoScript II First Strand cDNA Synthesis kit. The ALK alteration present in the exosomes is determined by NGS and bio-informatic analysis in OncoDNA. Samples were provided by the Biobank of the University of Navarra, the UZA Biobank and the University of Naples Federico II. Samples and data were processed following the processes approved by the local Ethical and Scientific Committees. Results: Among analyzed patients, 15 patients were EML4-ALK tissue positive, and 3 were EML4-ALK tissue negative. With our analysis, 9 patients were positive, 7 negative and 2 sample were degraded at the time of analysis. Comparing the results, the 9 positive patients in the exosomes were also positive in the tissue. Moreover, the 2 negative patients were also negative for the translocation in the tissue. However, we were unable to detect 4 positive EML4-ALK patients in the exosomes. Nonetheless, these data show a sensitivity of 69% and a specificity of 100%. No correlation was found comparing treatment-naïve and pretreated patients. Conclusions: Exosomes are raising as a very promising tool to determine the tumor profile due to their stability and their cargo. With further study and a larger number of patients, we demonstrate that exosomes isolation and analysis will be feasible tool, and thus we will reduce the tumor biopsy risks and costs in the clinical practice. Our preliminary results show a good specificity for a proof of concept analysis. These results will be cross-validated and amplified with more patients in the following months.
Does blood sugar impact on metastatic non-small cell lung cancer (NSCLC) outcome?
Authors: Gravel Mathieu , Blais Normand , Tehfe Mustapha Ali , Florescu Marie
Published: September 2018

e20579

Background: Diabetes is a frequent diagnostic (9.3%) in general Western population, and because of its complications, becomes a comorbidity in NSCLC patients that could impact on prognostic. Impact of diabetes on NSCLC prognosis is unknown but the majority of patients fear eating desserts because feeding mostly the NSCLC tumor cells. Methods: Using our SARDO database and hospital files, we retrospectively reviewed 548 patients with metastatic NSCLC diagnosed and treated in our University hospital between 2006 and 2015. Uncontrolled diabetes was established when Hb1Ac > 7% or with more than 2 hospital glycemia over 11 mmol/L. Results: Amongst 418 metastatic NSCLC patients, 294pts (70%) had synchronous metastasis at diagnostic and 117pts (30%) have metachronous metastasis. As expected metachronous metastasis patients had a better survival (mOS 25mo) than synchronous metastasis (mOS 6mo). Then, we divided our patients in 4 subgroups: 1) Patients with diagnosed and uncontrolled diabetes (n = 78); 2) Patients with high glycemia but not previously diabetes diagnostic (n = 19); 3) Patients with controlled diagnosed diabetes (n = 59); 4) Control patients with normal glycemias or HBA1c (n = 262). Some tumor stage and demographic disparities were seen between the 4 groups but we controlled for them. In upfront metastatic NSCLC patients, mOS was 4.0 months for group 1, 4.0 months for group 2, 4.0 months for group 3 and 7.0 months for our control group, not statistically different, which is lower than literature but expected for this unselected population treated before 2015. In metachronous patients, group 1 mOS was 21mo, group 2 was 58mo, group 3 was 30mo and mOS was 23mo for control patients, with no statistically difference between groups. Women had a better mOS 8 mo compared to 4 mo in men (p = 0,003) independently of diabetes or sugar status. Conclusions: This retrospective data is reassuring regarding patients blood glycemia during the metastatic lung cancer treatment. Even in a long term metachronous disease perspective, blood sugar or diabetes diagnostic did not seem to influence the outcome. However, these data should be validated in a prospective study that could acknowledge if blood sugar control could improve lung cancer outcome.
Understanding real-world outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs.
Authors: Fernandes Ancilla , Skinner Karen E , Walker Mark Stephen , Pavilack Melissa , Vanderwalde Ari M.
Published: September 2018

e20589

Background: Epidermal growth factor receptor (EGFR)tyrosine kinase inhibitors (TKIs) are recommended for patients (pts) with EGFR mutation ( EGFRm) positive non-small cell lung cancer (NSCLC). Limited data are available for real-world outcomes in pts who experience progression on 1st-/2nd-generation EGFR TKIs, which was the focus of this study. Methods: A retrospective chart review of pts with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed 1/1/2008—1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Pts were classified into cohorts based on TKI initiation (1L or 2L) and EGFRm status. Progression-free survival (PFS) and overall survival (OS) were evaluated for the TKI treatment period and the post-progression period. Results: The study included 364 pts: 77.7% white, 17.3% African American; mean (SD) age 66.3 (11.3) years. PFS and OS were longer for 1L and EGFRm+ pt cohorts during the TKI treatment period. After progression, 25.3% (80/316) pts continued TKI, while around half received chemotherapy (56.3%; 178/316). The effects of other variables evaluated as predictors of PFS and OS were largely nonsignificant. Conclusions: Outcomes were worse after progression irrespective of EGFRm status and whether TKI was initiated 1L or 2L. This finding highlights the need for therapeutic options that improve outcomes in pts after progression on a 1st-/2nd-generation EGFR TKI. [Table: see text]
Correlation between re-biopsy site and detection of T790M mutation in NSCLC patients treated with EGFR TKI.
Authors: Shigematsu Fumie , Kogure Yoshihito , Saka Hideo , Yamada Arisa , Ishida Akane , Ise Yuko , Hori Kazumi , Oka Saori , Nakahata Masashi , Kitagawa Chiyoe , Oki Masahide
Published: September 2018

e20620

Background: Re-biopsy is important to decide the treatment after EGFR-tyrosine kinase inhibitor (TKI) failure in non-small cell lung cancer (NSCLC) patients. We hypothesized that the T790M mutation in EGFR might show heterogeneity depending on the re-biopsy site. Methods: NSCLC patients who had received initial EGFR-TKI since January 2009 to December 2016, at any stage and recurrence after surgery and at any line of treatment, were included. Results: In total, 128 patients were included. Median age at EGFR-TKI therapy initiation was 73 (range, 38–97) years; 67% patients were female, all were Asian, 56% had never smoked, and 99% had adenocarcinoma. Of total 128 patients, 109 showed progressive disease. Median progression-free survival (PFS) was 10 (0.56–57) months. Median period since EGFR-TKI failure until the first re-biopsy was 197 (0–1322) days. Re-biopsy was performed 50 times in 42 patients; the number of T790M positive, negative, and pathologically negative patients was 20, 17, and 5, respectively, and the number of re-biopsies in these patients was 20, 22, and 8, respectively. Median PFS was longer in T790M positive patients than in negative patients significantly (17 [11–24] vs. 7.6 [4.3–11] months, P = 0.007). Characteristics such as gender, smoking status, proportion of stage IV, time between EGFR-TKI failure and first re-biopsy, and number of biopsies did not affect the T790M status in the biopsies. T790M positive group had more exon 19 deletions than negative group significantly (75% vs. 23%, P = 0.012). Biopsies at primary lesion, distant, and pleural effusion (PE) were 25% vs. 50%, 60% vs. 36%, and 15% vs. 14%, respectively, in the T790M positive vs. negative groups. Compared with the biopsy-site at diagnosis, the site was same as before in 35% vs. 50% cases (primary lesion [20% vs. 45%], distant [10% vs. 4.5%], and PE [5% vs. 0%]) and was new in 55% vs. 41% cases (distant lesions [45% vs. 27%] and PE [10% vs. 14%]) in the T790M positive vs. negative groups, respectively. Conclusions: In NSCLC patients treated with EGFR-TKI, re-biopsy was performed in distant lesions more frequently in the T790M positive cases than in negative cases. However, the T790M status was not correlated with the re-biopsy site.
Association of early specialist-delivered palliative care with less aggressive chemotherapy in patients with advanced lung cancr.
Authors: Lammers Austin J. , Sullivan Donald Richard
Published: September 2018

e20621

Background:Advanced stage lung cancer has a poor prognosis with high symptom burden. Early specialist-delivered palliative care (ESDPC) has been shown to improve quality of life (QOL) and may even improve survival, but a minority of patients receive this care. Previous studies have found that > 1 regimen of chemotherapy is associated with reduced QOL near death, but it is unknown how palliative care affects aggressive chemotherapy use. We sought to determine if ESDPC impacted aggressive chemotherapy receipt in patients with advanced lung cancer. Methods: A cohort of Veterans with advanced stage IIIB/IV lung cancer in the national Veterans Health Administration network diagnosed between 2007-2013 were included. Demographic data, cancer characteristics, chemotherapy characteristics and early palliative care consultation (within 90 days of diagnosis) were recorded. Aggressive chemotherapy was defined as receipt of a Bevacizumab/Cetuximab triplet, > / = 2 lines of chemotherapy, and more than 4 cycles of a platinum doublet. Descriptive statistics were used to compare demographic data. Unadjusted p-valves were calculated using two-sample t-test. Results: Among 23,660 patients, mean age 68, 98% male, 71% white, 56% current tobacco users. In total, 45% received chemotherapy and 37% received ESDPC. Mean Charlson comorbidity index (CCI) was 4.5 and functional comorbidity index (FCI) was 3. 89% were stage IV, 82% NSCLC. Patients with ESDPC were notably different in CCI (5.4 vs 4) and stage IV (93 vs 86). Of those receiving ESDPC, patients were less likely to receive triple drug therapy (Bevacizumab or Cetuximab combo), less likely to receive > / = 2 lines of chemotherapy and less likely to receive > / = 4 cycles of platinum doublet (all with p-values < 0.001). Conclusions: Our study found that patients who received ESDPC were less likely to receive aggressive chemotherapy. However, comorbidities, cancer stage, and age may have contributed to this difference. We plan to further analyze this data in an adjusted analysis to determine the association between ESDPC and chemotherapy receipt. Future research should focus on identifying patients that will most benefit from aggressive chemotherapy.
Phase II study of stereotactic radiosurgery or other local ablation followed by erlotinib for patients with EGFR mutation who have previously progressed on an EGFR tyrosine kinase inhibitor (TKI).
Authors: Weiss Jared , Kavanagh Brian D. , Deal Allison Mary , Zagar Timothy , Marks Lawrence Bruce , Stinchcombe Tom , Borghaei Hossein , West Howard Jack , Morris David E. , Villaruz Liza Cosca , Pennell Nathan A.
Published: September 2018

e20623

Background: For patients with metastatic EGFR mutated NSCLC, 1stline treatment with EGFR TKIs such as erlotinib result in a median PFS of about 10 months. In patients with a limited number of progressing lesions, local ablation therapy (LAT) of progressive lesions followed by re-initiation of TKI has shown promise in retrospective studies but to date this strategy has not been testing in prospective fashion. Methods: As part of an IRB approved open label prospective phase II trial (NCT01573702), patients with EGFR mutated NSCLC and immediate progression on a TKI in < 5 locations were treated with stereotactic radiosurgery (SRS) to progressing lesions followed by re-initiation of erlotinib. Our primary endpoint is PFS, and we hypothesize that it will be at least 3 months. Results: 25/40 planned patients have been enrolled and data is available on 23. By local reporting, 14 had exon 19, 5 had exon 21, 1 had compound exon 18 and exon 20, 1 had compound exon 19 and EML4/ALK and 2 were unknown. 65% were female, all were non-Hispanic white, median age 62.5 (range 43-85), PS0 65.2%/PS1 34.8%, median Charlson Comorbidity Index 6, and 71.4% were never smokers. Median number of lesions treated was 1 (range 1-3). Treated lesions included lung (14), bone (6), liver (3) and brain (2). There were no G3-4 AEs to SRS. Two subjects had grade 3 rash on erlotinib. Median PFS post treatment was 5.8 months (95% CI, 2.5 to 11.3) and median OS was 2.9 years (95% CI 1.1 to 2.9). Conclusions: LAT resulted in a modest extension in the duration of targeted therapy, supporting retrospective data in this population. Accrual to this study has been challenging due to the availability of 3rd generation EGFR TKIs and because LAT is often done outside of a clinical trial. Clinical trial information: NCT01573702.
Co-existance of KRAS and LKB1 mutation as predictor of resistance to Erlotinib: Customized next-generation sequencing (NGS) of TAILOR trial.
Authors: Rulli Eliana , Serafini Mara Serena , Marabese Mirko , Caiola Elisa , Sozzi Gabriella , Moro Massimo , Bria Emilio , Simbolo Michele , Busico Adele , Tamborini Elena , Corrao Giulia , Farina Gabriella , Broggini Massimo , Ganzinelli Monica , Garassino Marina Chiara
Published: September 2018

e20631

Background: The prognostic and predictive value of KRAS mutation in advanced NSCLC is still debatable. In TAILOR (NCT00637910) trial EGFR wild-type patients were randomized to receive 2nd line erlotinib versus docetaxel, and no interaction was detected according to KRAS mutational status. Recent evidences indicate that the concurrent mutation of KRAS and LKB1 (key factor for cell metabolism) may be associated with worse prognosis. Methods: Availableformalin-fixed embeddedtissue samples with annotated clinical data from TAILOR were gathered. Customized deep sequencing (Ion proton Technology) of 111 genes most frequently associated with cancer, was performed; 5% of frequency was used to identify mutations. Association between genes and clinical features was performed with non-parametric tests; Cox regression analysis was used to assess the prognostic and predictive value of LKB1. Results: 123 out of 222 (55%) randomized patients had available tissue and were successfully sequenced. 42/123 (34%) patients had a KRAS mutation. KRAS and LKB1 mutations were found in 11/42 (26%) KRAS patients, while only 6 patients had a LKB1 mutation without KRAS. The presence of a concurrent KRAS-LKB1 mutation did not adversely influence progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS 1.08, 95% confidence interval (CI) 0.57-2.05, P = 0.81; OS 1.09, 95% CI 0.56-2.14, P = 0.78]. Patients receiving docetaxel experienced longer survival regardless of the KRAS-LKB1 mutational status (mutated KRAS-LKB1 HR 0.42, 95% CI 0.08-2.29; wild-type KRAS-LKB1 HR 1.16, 95% CI 0.72-1.87, P = 0.55; interaction P = 0.10). Conclusions: Although the significant attrition and the limited number, these data generate the hypothesis that the concurrent mutation of KRAS and LKB1 may potentially be associated with resistance to erlotinib. Overall, the coexistence of mutation in KRAS and LKB1 is not associated with worse prognosis in NSCLC. For these patients refractory to EGFR targeting, metabolic strategies represent a future research opportunity.
Understanding treatment patterns and outcomes in patients with metastatic NSCLC treated in a US community oncology network.
Authors: Nadler Eric S. , Espirito Janet L. , Pavilack Melissa , Boyd Marley , Vergara-Silva Andrea Leninka , Fernandes Ancilla
Published: September 2018

e20643

Background: Multiple therapeutic options exist for metastatic non-small cell lung cancer (mNSCLC), including chemotherapy (CH), targeted therapy (T), and immunotherapy (IT). The first IT for mNSCLC was FDA approved in 2015 for use after progression on platinum-based CH and T in patients (pts) with EGFR or ALK mutations. The current study evaluates treatment (tx) patterns and outcomes in mNSCLC pts receiving first- (1L), 2nd- (2L), and 3rd-line (3L) therapy. Methods: This is a retrospective, observational cohort study of mNSCLC pts receiving initial tx from 1/2012–4/2016, with follow-up to 6/2016. Data were obtained from The US Oncology Network/McKesson Specialty Health electronic health records database. Demographics, clinical characteristics, and tx patterns were characterized. Overall survival (OS) was assessed using the Kaplan-Meier method. Results: 10,689 1L pts were identified during the study period. Median age was 68 y, and 54% were male. Most pts (59%) had an ECOG performance status of 1, 77% had nonsquamous histology, and 85% were former or current smokers. Initial tx was CH in 93% of pts. Among pts receiving initial T therapy, most were never smokers (48%) vs initial CH pts (12%; P< 0.0001). Median OS (mOS) for all pts at 1L was 12.3 mo (95% CI, 11.9–12.7), and mOS was significantly longer in pts who received T (24.3 vs 11.7 mo for T vs CH, p< 0.0001). Among pts who received 2L therapy in the study period (n = 4235), 66%, 17%, and 17% received CH, T, and IT respectively. Pemetrexed or docetaxel monotherapy was most commonly used for 2L CH, erlotinib was most used as 2L T, and nivolumab for 2L IT. mOS from start of 2L for CH, T, and IT was 9.2, 11.2, and 9.7 mo, respectively (log rank P= 0.01). In 3L pts (n = 1580), nivolumab was most frequently used (17%), and mOS from 3L for CH, T, and IT was 8.0, 7.4, and 11.3 mo, respectively ( P= 0.0187). Conclusions: These data demonstrate integration of novel therapies for mNSCLC in the community. Longer survival was observed in 2L and 3L patients treated with T and IT as compared with CH. This warrants additional randomized studies to investigate optimal sequencing of these agents.
Efficacy of PD-1/PD-L1 inhibitors in the front-line setting as compared to previously treated patients.
Authors: Jain Prantesh , Khunger Monica , Pasupuleti Vinay , Hernandez Adrian V , Velcheti Vamsidhar
Published: September 2018

e20646

Background: Drugs targeting the PD-1/PD-L1 pathway show significant clinical activity in non-small cell lung carcinoma (NSCLC). Nivolumab, pembrolizumab and atezolizumab are currently approved for NSCLC patients who have progressed while on platinum-based chemotherapy. Recently, pembrolizumab received FDA approval for treatment naive NSCLC patients with tumor PD-L1 expression of ≥50%. However, there is relative lack of data on comparative efficacy of these drugs in the chemotherapy naive versus post-chemotherapy setting. In the current meta-analysis we compare the efficacy and toxicity of these drugs in chemotherapy naïve patients with those who receive them as subsequent therapy (after previous chemotherapy). Methods: A systematic search of electronic databases (PubMed-Medline, EMBASE, Scopus) and major conference proceedings was done for all clinical trials using PD1/PD-L1 inhibitors. Objective response rates (ORR) for patients determined to have positive tumor PD-L1 expression (Tumor Proportion Score ≥1%) from all phase I-III trials investigating nivolumab, pembrolizumab, atezolimumab, durvalumab and avelumab for NSCLC were collected. Only single agent PD-1/PDL-1 inhibitor trials were included. The ORR across trials was combined using DerSimonian-Laird random effects models. Higgins’ I2 statistic was used to assess heterogeneity. Results: 19 trials (7 with treatment naïve patients [n = 651]; 14 with chemotherapy treated patients [n = 2205]; 2 with separate treatment naïve and previously treated arms) were included. Treatment naïve patients were found to have statistically significant higher efficacy [ORR 28.27%(95% CI 20.70-36.52)] than those who received these drugs as subsequent therapy [ORR 20.13% (95%CI 17.53-22.85) (p = 0.02). Treatment naive patients had statistically significant higher rates of all grade pneumonitis as comapred to previously treated patients (4.9, 95%CI 3.4-6.7 vs 3.0 95% CI 2.0-4.1). Conclusions: PD1/PDL1 therapy for advanced NSCLC has a significantly improved efficacy (based on ORR) when used in treatment naïve patients as compared to its use in patients who have been previously treated with chemotherapy.
Impact of different timing of radiation therapy in patients with brain metastases from epidermal growth factor receptor-mutant non-small cell lung cancer.
Authors: Ying Xiaozhen , Han Shuiyun , Jiang Chenxue , Sun Xiaojiang , Xu Yaping , Mao Weimin
Published: September 2018

e20667

Background: To perform a retrospective analysis of patients with brain metastases (BM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to evaluate the preferred treatment timing of EGFR-tyrosine kinase inhibitors (TKIs) in this population. Methods: Of 94 initial or recurrent patients diagnosed BM from EGFR-mutant NSCLC between Jan 1, 2012, and Jun 31, 2016, 30 received upfront brain RT followed by EGFR-TKI, 39 EGFR-TKI combined with concurrent brain RT, and 25 upfront EGFR-TKI then brain RT. Disease-specific-graded prognostic assessment was similar among all 3 groups. The primary endpoint was overall survival (OS), and the second endpoint was intracranial progression-free survival. Results: Although the median OS was not significantly different among the upfront RT, concurrent treatment, and upfront EGFR-TKI groups (29.0 vs 24.0 vs 17.0 months; P = 0.186), however, it was longer in the upfront RT group compared with the upfront EGFR-TKI group (P = 0.035). On subgroup analysis, the exon 19 deletions patients had longer OS than the exon 21 mutations patients in upfront EGFR-TKI group (23.0 vs 15.0 months; P = 0.048), but the upfront RT (34.0 vs 23.0 months; P = 0.186) and the concurrent treatment groups (24.0 vs 13.0 months; P = 0.827) did not. According to multivariate COX analysis, KPS (≥ 70) and intracranial metastasis alone was associated with a longer OS. The median intracranial progression-free survival was significantly improved in patients receiving upfront RT compared with those receiving concurrent treatment or upfront EGFR-TKI (not reached vs 40.0 vs 9.0 months; P = 0.003). Conclusions: The present study suggests that the use of upfront brain radiotherapy, and the deferral of EGFR-TKI may result in superior OS in patients with brain metastases from EGFR-mutant NSCLC. Also, upfront brain radiotherapy management could significantly reduce the risk of intracranial progression. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI then RT versus upfront RT followed by EGFR-TKI is urgently needed, especially based on different subgroup population.
Retrospective analysis of patients (pts) with metastatic melanoma (MM) showing long-term response (LTR) to vemurafenib (Vb).
Authors: Galli Giulia , Di Guardo Lorenza , Cimminiello Carolina , Cavalieri Stefano , Rodolfo Monica , Rivoltini Licia , Valeri Barbara , Bono Aldo , Tolomio Elena , Del Vecchio Michele
Published: September 2018

e21001

Background: Efficacy of Vb in the treatment of mm has been established. We aimed to analyze characteristics of pts achieving LTR to Vb in order to identify potential predictive factors of prolonged benefit. Methods: We collected information about pts affected by BRAF V600 mutated mm treated with Vb at Medical Oncology Unit of Istituto Nazionale dei Tumori, Milan, Italy, from 09/2010 to 08/2014. LTR was defined as clinical or radiological benefit longer than 14 months (mos). Biological data about circulating lymphocyte subpopulations and CCL2 levels were also determined. Results: 46 pts (26 men, 20 women) were identified. Median age was 58 years. ECOG performance status was 0 in 44 pts. Disease stage was M1a in 14 pts, M1c in 20 pts. 8 pts had high serum LDH levels and 5 brain metastases at baseline. 41 pts harbored BRAF V600E mutation, 5 V600K. Median follow up was 47 mos. 5 pts had received adjuvant interferon; 9 pts had been treated with up to 3 lines for metastatic disease (either chemotx or ipilimumab). According to RECIST 1.1, 22% of pts showed complete response (CR), 50% partial response and 22% stable disease. Notably, all CRs were maintained for more than 2 years. 26 pts progressed, mostly (38%) with brain metastases; 16 of them continued tx beyond progression. Median duration of response was 33 mos, being significantly longer in M1a than in M1c (44 versus 28 mos). Median PFS was 32.5 mos; median OS was not reached. All pts experienced at least 1 adverse event (AE); the AEs were moderate or severe in 22% of cases. 19 pts underwent dose reduction, but no discontinuation due to AEs was observed. After 6 mos of tx, pts with LTRs had less myeloid derived suppressor cells (CD11b+ CD14+) and more memory Th1 cells (CD8+ CXCR3+) if compared with pts not bearing LTRs. The same pts after 1 mo of tx showed lower plasma levels of CCL2, a marker of acquired resistance to Vb. Conclusions: Vb can induce LTRs in a subset of pts with mm also in presence of unfavorable prognostic factors, though M1a pts are more likely to obtain prolonged benefit. Toxicity is frequent, but manageable with limited dose reductions. Exploratory biological analyses suggest an immunomodulatory effect of Vb and the existence of circulating biomarkers of LTR.
Efficacy of combined hypofractionated radiotherapy and anti-PD-1 monotherapy in patients with melanoma.
Authors: Roger Anissa , Finet Adeline , Boru Blandine , Mazeron Jean-Jacques , Otmezguine Yves , Blom Astrid , Longvert Christine , De Maleissye Marie-Florence , Beauchet Alain , Saiag Philippe
Published: September 2018

e21008

Background: Information on the role and type of radiotherapy in melanoma pts treated with anti-PD1 is limited. We report a cohort of advanced melanoma pts having received simultaneous hypofractionated radiotherapy and anti-PD-1 monotherapy. Methods: Database search in the prospective database of a referral center with standardized radiotherapy procedures for all pts having received both treatments between 1/1/15-30/6/16. Radiologists performed independent tumor evaluations (RECIST 1.1) every 3 m, both on radiated and non-radiated lesions. Results: 25 pts with inoperable AJCC stage 3-4 melanoma, mean age 60.5 Y. Anti-PD-1 monotherapy was first systemic treatment in only 40% of pts. Median follow-up after onset of anti-PD-1 therapy (83% nivolumab, 17% pembrolizumab) was 13.3 m, with 48% of pts still alive at last follow-up. Radiotherapy was performed either early (within first 3 m of PD-1 blockade) in pts with rapidly progressing symptomatic lesion(s) (60% of pts) or late ( > 3 m) in pts with slow progression or dissociated response (40% of pts). It consisted of 1 weekly radiation during 4-5 w (84% of pts), or 1 gammaknife radiation for cerebral mets (16% of pts). Median delay between onset of PD-1 blockade and radiotherapy was 1.8 m (range 0.5-11 m). For radiated lesions, rates of complete (CR), partial (PR) responses, stabilization (S) or progression (P) were 24%, 8%, 44%, and 28%, respectively. For non-radiated lesions (84% of pts), rates of CR, PR, S, and P were 29%, 19%, 19%, and 33%, respectively. Among pts radiated late for insufficient response to anti-PD-1 monotherapy, CR or PR in non-radiated lesions (i.e. abscopal response) was observed in 56% of pts. Anti-PD-1 therapy could be discontinued in 4 pts with CR, without relapse to date. No unusual adverse event was recorded. Conclusions: Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in difficult-to-treat pts. Controlled studies are needed.
Association of loss of nuclear BAP1 expression with prognosis in oral mucosal melanoma.
Authors: Guo Wei
Published: September 2018

e21021

Background: The prognostic factors of oral mucosal melanoma (OMM),a rare and aggressive neoplasm, remain to be determined. BAP1 is a tumor suppressor that has been associated with the outcome of melanomas and other malignancies. In this study, we investigated the genetic alterations in BAP1 and the prognostic potential of BAP1 protein expression in oral mucosal melanoma. Methods: DNA sequence analysis of BAP1 from 12 OMM patient samples revealed missense mutations in the tissues from four patients. Results: Based on immunohistochemical staining, loss of nuclear BAP1 expression was associated with poor overall survival (P < 0.001, Log-rank = 21.308) and distant metastasis (P = 0.034, OR = 0.320). Multivariate analysis showed BAP1 to be an independent prognostic factor (P = 0.027, HR = 0.479). Conclusions: It thus appears that loss of nuclear BAP1 expression is an independent prognostic factor of poor overall survival and associated with distant metastasis in OMM.