bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of EGFR-TKI therapy in EGFR mutated metastatic lung adenocarcinoma in an inner city population.
Authors: Thekkekara Romy Jose , Kumar Rohit , Lad Thomas E. 
Published: September 2018

e20635 Background:Metastatic lung cancer with systemic chemotherapy has a median progression-free survival (PFS) of 5-6 months and median overall survival time (OS) of around 12 months. In Epidermal Growth Factor Receptor gene (EGFR) mutated metastatic lung cancer the use of EGFR Tyrosine Kinase Inhibitors (EGFR-TKIs) has increased the median PFS to12 months and the median OS to 30 months. The objective of this study is to evaluate the response to TKIs in EGFR mutated metastatic lung cancer in racially diverse inner city population with high smoking rates. Methods:Consecutive patients diagnosed with EGFR mutant metastatic lung adenocarcinoma and treated with TKIs in John H. Stroger Jr. Hospital of Cook County in Chicago, IL between January 2009 to June 2016 were retrospectively evaluated. Demographic data was collected and PFS and OS were analyzed. Results:35 patients with EGFR mutated metastatic lung cancer received EGFR-TKI during the study period. There was a female preponderance (63%). Hispanics formed the most common racial group (37%), followed by Asians (26%), African Americans (AA) (20%) and Caucasians (17%). Mean age of diagnosis of metastatic disease was 56.5± 11.5 years. 20% of the patients were ever smokers. Stage 4 disease at presentation was seen in 88.6 %. Sites of metastatic disease included lungs/pleura (60%), bone (60%), brain (22.9%) and liver (14.3%). 82.9% had TKI as first line treatment. Median PFS and OS were 9.89 (95% CI: 7.8-11.9) months and 19.3 (95% CI: 1.9-36.8) months respectively. The median PFS and OS were 12.88 and 17 months for Asians, 10.8 and 24.4 months for Caucasians and 9.2 and 33 months for Hispanics respectively. Among AA, PFS at 19 months and OS at 35 months was 0.58%, not reaching the median. Patients who continued to smoke had a median OS of 8.5 months vs 19.3 months in nonsmokers/ex-smokers. Conclusions: In an underserved population, patients treated with EGFR mutated metastatic lung adenocarcinoma with EGFR-TKI have similar survival compared previously known data. Race of the patient does not appear to alter response to EGFR-TKI therapy. Active smokers had a lower OS. Studies in minority populations with larger samples are required to further validate the above findings.
Early proliferation of PD-1+ CD8 T cells in peripheral blood as predictive of response to PD-1 inhibition for patients with advanced NSCLC.
Authors: Pillai Rathi Narayana , Kamphorst Alice O. , Yang Shu , Owonikoko Taofeek Kunle , Sica Gabriel , Nasti Tahseen , Akondy Rama , Wieland Andreas , Wu Hong , Patel Nikita , Yu Ke , Koenig Lydia , Behera Madhusmita , McCausland Megan , Khuri Fadlo Raja , Ahmed Rafi , Ramalingam Suresh S. 
Published: September 2018

e20648 Background: Anti PD-1 and PDL-1 antibodies are now established immune targeted therapies for a subset of patients with advanced non-small cell lung cancer (NSCLC). There is a need for predictive biomarkers to better guide patient selection. We profiled peripheral blood samples from patients receiving PD-1 pathway targeted antibodies for lymphocyte subsets and correlated temporal changes with clinical response. Methods: NSCLC patients treated at our institution with PD-1 or PDL-1 inhibitors (nivolumab, pembrolizumab, and atezolizumab) consented to an IRB-approved biomarker profiling protocol. We collected baseline peripheral blood samples before first treatment and subsequently prior to each new treatment cycle until progression of disease or for a maximum of six cycles. Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry for kinetics of proliferation of PD1+CD8+ T cells. Clinical response to anti PD-1 therapy was classified according to Response Evaluation Criteria in Solid Tumors (RECIST1.1) criteria and correlated with T cell proliferation kinetics. Results: We enrolled 27 patients with baseline characteristics: median age 66, male 70%, smokers 85%, adenocarcinoma 70%; 10 (37%) patients achieved partial response (PR), 7 (26%) had stable disease (SD) and 10 (10%) had disease progression (PD) as best response. There was a > 1.5-fold increase in Ki67+CD8+ T cells expressing PD-1 within 4 weeks of treatment initiation in 80% of patients with PR compared with 30% in patients with SD and 30% in those with PD. Conclusions: Early proliferation of PD1+CD8+ T cells in peripheral blood is a potential pharmacodynamic biomarker of anti PD-1 immunotherapy that could serve as a tool to identify the NSCLC patient subset most likely to respond to PD-1 and PDL-1 inhibitors.
Local consolidation therapy (LCT) after first line tyrosine kinase inhibitor (TKI) for patients with EGFR mutant metastatic non-small cell lung cancer (NSCLC).
Authors: Elamin Yasir , Gomez Daniel Richard , Papadimitrakopoulou Vassiliki , Tran Hai T. , Rinsurongkawong Waree , Lewis Jeff , Lacerda Lara , Roarty Emily , Lee J. Jack , Roth Jack A. , Swisher Stephen , Zhang Jianjun , Heymach John 
Published: September 2018

e20654 Background: Although most NSCLC patients with sensitizing EGFR mutations (L858R, Exon 19 deletion) have an impressive initial response, the vast majority develop acquired resistance after 9-14 months of EGFR TKI therapy. Clearly, more effective strategies to prevent resistance emergence are needed. We recently reported a randomized phase 2 trial that showed that LCT with surgery or radiation, for molecularly unselected patients with oligometastatic NSCLC who did not progress after initial systemic therapy, improved progression-free survival (PFS) compared to maintenance therapy alone (Gomez, et al., 2016). Herein, we aim to determine the outcomes of LCT after first line TKI in patients with metastatic EGFR mutant NSCLC. Methods: This is a post-hoc analysis of our recently published phase 2 clinical trial and a retrospective review of MD Anderson Cancer Center GEMINI database. Eligible patients had metastatic EGFR mutant NSCLC, had first line TKI without progression followed by LCT with surgery or radiation. Results:In GEMINI database, 129 EGFR (L858R/Exon 19 deletion) mutant NSCLC patients were treated with first line TKI (erlotinib, gefitinib or afatinib) and 12 were treated with TKI followed by LCT (3 treated within our published clinical trial and 9 at the discretion of their physician). Among the 12 patients treated with TKI plus LCT, 8 patients had oligometastatic disease (defined as ≤3 metastases) and 4 patients had > 3 metastases. LCT regimens were hypofractionated radiotherapy or stereotactic ablative body radiotherapy for 11 patients and surgery for one patient. Patients treated with TKI followed by LCT had a significantly longer PFS (36 months) compared to patients treated with first line TKI alone (PFS 14 months, p = 0.0024, log-rank). Conclusions:Our retrospective data suggests that first line TKI plus LCT is a promising therapeutic strategy that led to a significant outcome improvement for patients with EGFR mutant NSCLC. A multicenter phase 2 clinical trial comparing TKI plus LCT to TKI alone is planned.
Contribution to the development of precision medicine and clinical utility of nationwide lung cancer genomic screening in Japan (LC-SCRUM-Japan).
Authors: Ohashi Kadoaki , Matsumoto Shingo , Yoh Kiyotaka , Ohe Yuichiro , Shimokawaji Tadasuke , Kataoka Yuki , Kodani Masahiro , Sekine Akimasa , Saeki Sho , Furuya Naoki , Seto Takashi , Yokoyama Takuma , Shingyoji Masato , Hattori Yoshihiro , Kim Young Hak , Tsuchihara Katsuya , Goto Koichi 
Published: September 2018

e20659 Background: A nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) was established in 2013. The objective of this project is to contribute to the development of precision medicine through the genomic biomarker screening, leading to improvement of patient prognoses. Methods: Advanced non-squamous non-small cell lung cancer (non-sq NSCLC) without EGFR mutations were eligible for inclusion. The tumors were analyzed for ALK/ROS1/RET fusions using RT-PCR and FISH. Since March 2015, the samples were further subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. Since April 2016, MET exon 14 skipping ( MET skip) was also analyzed by RT-PCR. The clinical course and prognosis of patients were monitored every 6 month. Results:As of December, 2016, 3206 patients from 242 institutions across Japan had been enrolled. The success rates for RT-PCR and NGS were 94% (3020/3206) and 91% (1523/1666), respectively. ALK/ROS1/RET fusions were detected in 65 (2%)/116 (4%)/84 (3%), respectively. The NGS assay showed that 753 tumors (49%) had actionable gene alterations, including 184 KRAS (12%), 92 ERBB2 (6%), 73 BRAF (5%), 42 PIK3CA (3%), 11 NRAS (0.7%), 7 MAP2K1 mutations (0.5%) and 5 FGFR2/3 fusions (0.3%). ERBB2/MET/FGFR1 amplifications were also detected in 36 (3%)/28 (2%)/11 (1%) cases, respectively. The frequency of MET skip was 4% (26/597). Through this screening, a total of 576 genotype-matched patients to clinical trials of targeted agents were identified, and 111 of them (19%) were enrolled into the trials. Of the 1523 patients analyzed by NGS, the monitoring data were available in 870 (57%). The patients with actionable gene alterations who received targeted agents (n = 100) showed significantly longer survivals than those who did not receive targeted agents (n = 358) or the patients without actionable gene alterations (n = 412) (median survival [95%CI], 5.1 [3.0-N.R.] vs. 3.3 [2.1-5.9] vs. 2.3 [1.9-2.9] years, respectively; p < 0.01). Conclusions: Our nationwide screening contributes to the development of precision medicine for non-sq NSCLC and could improve patient prognoses.
Response to osimertinib following treatment with EGF816 in patients with T790M EGFR mutant NSLCLC.
Authors: Arbour Kathryn Cecilia , Sequist Lecia V. , Piotrowska Zofia , Kris Mark G. , Paik Paul K. , Ni Ai , Plodkowski Andrew , Riely Gregory J. , Yu Helena Alexandra 
Published: September 2018

e20673 Background: Third generation (3rd gen) epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat EGFR T790M-mediated resistance to EGFR TKIs by inhibiting EGFR T790M, as well as EGFR L858R and EGFR exon 19 deletions. The mechanisms of resistance to third-generation EGFR TKIs are largely unknown and clinical cross-resistance among 3rd gen EGFR TKIs has not been routinely evaluated. Osimertinib is an FDA-approved irreversible 3rd gen EGFR TKI. In patients with EGFR T790M mutant NSCLC, the response rate (ORR) to osimertinib is 61%. EGF816 is a covalent, irreversible, 3rd gen EGFR TKI in clinical development. In early phase data of EGF816, the ORR was 47% and disease control rate was 87% in patients with EGFR T790M mutant NSCLC. To assess clinical cross-resistance between EGF816 and osimertinib, we evaluated the clinical outcomes of patients treated with osimertinib in patients previously treated with EGF816 during the phase I/II trial. Methods: Patients with metastatic EGFR mutant lung adenocarcinoma were identified who were previously treated with EGF816 and received osimertinib after progression of disease on EGF816 (NCT02108964). All patients had documented T790M mutation prior to treatment with EGF816. The best overall response to osimertinib was determined by RECIST 1.1 criteria. Duration of clinical benefit was defined as duration of osimertinib therapy. Results: Fourteen (3 men, 11 women, median age 58 [range 33-77]) patients met eligibility criteria at our centers. The ORR to subsequent osimertinib therapy was 14% (1 CR, 1 PR, 8 SD, 4 POD). Patients continued treatment with osimertinib for a median of 9 months (95% CI 3.8-10.1, [median follow up 11 months, range 1-13 months]). 5 patients are still on osimertinib to date (one patient each 3+, 6+, 8+, 11+, and 12+ months). Conclusions: This series suggests a potentially meaningful clinical benefit for patients with sequential therapy with two different third-generation EGFR inhibitors, emphasizing the importance of understanding resistance mechanisms (genetic alteration of target, bypass signaling, pharmacology, etc.) and raising the possibility of the need for multiple third generation EGFR TKIs in clinical practice.
Patients with metastatic melanoma treated with vemurafenib as monotherapy or in combination with cobimetinib.
Authors: Ocvirk Janja , Rebersek Martina , Boc Marko , Mesti Tanja 
Published: September 2018

e21016 Background: This is a retrospective analysis of patients (pts) with metastatic melanoma (mM) designed to evaluate the efficacy and safety of vemurafenib as monotherapy (V) in comparison with vemurafenib in combination with cobimetinib (V+C) in routine clinical practice. Methods: Baseline characteristics, treatment-related adverse events, and efficacy data were collected from 58 mm pts who were treated with V and 32 mm pts treated with V+C. Cobimetinib was given within approved pre-approval access program. Results: In 39-month period, 241 pts were diagnosed with unresectable or mm and in 137 pts (57%) tumor tissue was positive for BRAF V600E/K mutation (89% BRAF V600E and 11% BRAF V600K). 58 BRAF-positive pts were treated with V (median age 55.1, 66% males, 62% pts with elevated LDH level, 74% M1c) and 32 BRAF-positive pts with V+C (median age 54.5, 69% males, 31% pts with elevated LDH level, 81% M1c). V was given as first, second or third line treatment to 49 (85%), 6 (10%) and 3 (5%) pts respectively, while V+C was given only as first line treatment. In pts with assessable disease (88% in V and 100% in V+C group) the overall response rate (ORR) was 41% in V group and 56% in V+C group. Disease control rate (DCR) was 69% in V group and 91% in V+C group. Complete responses (CR) were reported in 4 pts (7%) in V group and in 1 pts (3%) in V+C group. Partial responses (PR) were more frequent in V+C group (53%) than in V group (29%). Median progression-free survival (PFS) was 5.0 months (95% CI, 2.8-7.2) in V group and 7.9 months (95% CI, 6.1-9.7) in V+C group. Median overall survival (OS) was 6.7 months (95% CI, 4.0-9.4) in V group and 9.7 months (95% CI, 7.6-11.8) in V+C group. At the time of analysis 16% of pts are alive in V group and 41% in V+C group. The best outcomes had subgroup of pts with normal LDH level in V+C group (DCR = 95%), with 50% pts alive at the time of data analysis. Adverse events (AEs) were reported in 83% of pts in V group and 63% in V+C group and 83% and 94% of reported AEs were grade 1-2 respectively. Dose reduction was required in 50% of pts in V group and in 28% of pts in V+C group. Conclusions: Vemurafenib in combination with cobimetinib has shown meaningful efficacy and managable safety profile in real-world setting.
A pilot study of individualised monitoring of patients with metastatic melanoma using plasma and urine DNA.
Authors: Wan Jonathan , Murphy Suzanne , Gale Davina Gillian , Morris James Anthony , Mouliere Florent , Gill Andrew , Marass Francesco , Heider Katrin , Parkinson Christine , Gallagher Ferdia Aidan , Durrani Amer J , McDermott Ultan , Massie Charles , Corrie Philippa , Rosenfeld Nitzan 
Published: September 2018

e21032 Background: Circulating tumour DNA (ctDNA) is released by cancer cells into the bloodstream and can be analysed via liquid biopsy, providing a real-time snapshot of tumour burden. After treatment, ctDNA concentrations may be low, making detection challenging, and collecting larger sample volumes may be impractical. Our study aims to achieve high-sensitivity monitoring of melanoma patients melanoma on therapy, maximising the number of mutations targeted per patient by individualised sequencing. Methods: 72 patients with stage 3 or 4 melanoma have so far been recruited to MelResist, a translational research study. 235 plasma, urine, tumour and buffy coat samples have been analysed for 10 BRAF mutant metastatic melanoma patients receiving systemic therapies, and 30 matched CT scans were analysed for RECIST response. Exome or targeted sequencing were carried out on tumour samples and plasma at baseline and progression and mutations identified were used to design individualised amplicon and hybrid-capture sequencing panels targeting hundreds to thousands of mutations per patient. Results: Baseline ctDNA allele fraction predicted for overall survival ( r = -0.56, p < 0.05). Longitudinal analysis of ctDNA showed that mutant allele fractions significantly correlated with tumour burden from CT imaging ( r = 0.79, p < 0.0001) and ctDNA changes were concordant with 20/22 (90%) of RECIST response events. ctDNA allele fractions increased with a lead time of 70 days relative to serum lactate dehydrogenase, a standard measure of disease burden (IQR = 42-142 days). Targeting multiple mutations per patient enabled detection of less than one mutant genome copy per sample and allowed comprehensive monitoring of clonal evolution on therapy, even using limited sample volumes. Conclusions: Analysis of an initial cohort of BRAF mutant metastatic melanoma patients has confirmed feasibility to apply an individualised targeted sequencing panel on both plasma and urine DNA. For a given sample volume, monitoring multiple mutations improves detection sensitivity compared to targeting individual loci, has predictive value and can be applied to all melanoma patients, irrespective of BRAF mutation status.
Clinical characteristics of melanoma in an ethnically diverse population of adolescents and young adults.
Authors: Miller Kimberly Ann , Pham Anthony , Thomas Jacob Stephen , Cockburn Myles G , Freyer David Robert , Hu James , Milam Joel , Wojcik Katherine , In Gino Kim 
Published: September 2018

e21043 Background: Melanoma is the third most common cancer among adolescents and young adults (AYAs; aged 15-39). Disease characteristics have not been well-described in this age group, particularly among diverse populations. We describe clinical features of AYAs diagnosed with melanoma at a large public hospital serving an ethnically diverse population. Methods: We reviewed medical chart data from patients diagnosed with melanoma between 2001-2016 at Los Angeles County + USC Medical Center. We describe clinical characteristics of AYA patients and compare to non-AYAs (aged ≥40) using Fisher’s exact test. A p-value < 0.05 was considered statistically significant. Results: Of the 273 melanoma patients identified, 47 (17.3%) were AYAs (mean age 32.3; SD±4.45; lower age range 18). The majority of patients were Hispanic (AYA, 53.2%; non-AYA, 51.1%), followed by non-Hispanic whites (AYA, 38.3%; non-AYA, 38.7%). A greater proportion of AYA patients were female (59.6%) compared to non-AYAs (38.2%) (p < 0.01). No AYA patients reported prior skin cancer compared to 19.9% of non-AYAs; 8.5% of AYAs reported family history of melanoma compared to 6.3% of non-AYAs. For all patients, superficial spreading melanoma was the most common histological subtype (AYA, 21.3%; non-AYA, 20.9%). Nodular melanoma was the second most common subtype in AYAs (17.02%) in contrast to acral lentiginous melanoma among non-AYAs (20.9%). Median Breslow depth was 3.0 mm for AYAs and 2.55 mm among non-AYAs. A slightly higher percentage of AYAs were diagnosed with regional disease (31.9%) than non-AYAs (24.4%), and a greater proportion of non-AYAs presented with distant metastases (AYA, 6.4%; non-AYA, 18.7%). The most common site of diagnosis were the extremities for all patients (AYA, 45.0%; non-AYA, 29.3%). Conclusions: We found similar clinical characteristics between AYA and non-AYA melanoma patients. However, we found a statistically significant difference for gender. The increased incidence of melanoma in female AYAs may be driven by biological factors such as sex hormones or genotype, or tanning behaviors. Further research is warranted to identify predictive and prognostic factors of melanoma among diverse AYAs, particularly females.
Non-progression during avelumab treatment is associated with clinically relevant improvements in health-related quality of life in patients with Merkel cell carcinoma.
Authors: Bharmal Murtuza , Fofana Fatoumata , Mahnke Lisa , Schlichting Michael , Kaufman Howard 
Published: September 2018

e21070 Background: There is little data on quality of life (QoL) for patients (pts) with Merkel cell carcinoma (MCC). To better understand how new treatments might impact QoL in MCC, pts with stage IV chemotherapy-treated MCC from a single-arm, open-label, multicenter, international phase 2 trial (NCT02155647) of a novel immunotherapy were followed for QoL and clinical outcomes. Methods: Because there is no MCC-specific QoL instrument, the FACT-Melanoma (FACT-M), a validated QoL questionnaire including multiple subscales and summary scores (Trial Outcome Index [TOI], FACT-G total and FACT-M total) was used. Pts completed the FACT-M at baseline (BL), week 7, every 6 weeks until disease progression (PD) and at end of treatment (EOT). Linear mixed models (LMM) were fitted for change from BL for each scale including the time-varying covariate PD vs non-PD. Established minimal important differences (MID) were used to interpret meaningfulness of changes. Sensitivity analyses explored the effects of missing data. Results: 70 pts were analyzed. Overall, no meaningful changes from BL were observed for each scale during treatment. Moderate correlations between reduction in tumor size and improvements in FACT-M were observed at week 7 for Functional Well-being (-0.47), TOI (-0.36), FACT-M total (-0.36), and FACT-G total (-0.34), suggesting improvements in QoL with tumor shrinkage. LMM showed differences between PD vs non-PD groups in the range of MIDs for Functional Well-being (2.23, p = 0.018), Melanoma (3.19, p = 0.012), Surgery (1.95, p = 0.109), TOI (6.36, p = 0.012) and FACT-G total (3.89, p = 0.105). These models showed improvement for the non-PD group in Emotional Well-being (1.55, p = 0.004) and worsening for the PD group in Physical Well-being (-1.63, p = 0.041), Surgery (-2.09, p = 0.044) and TOI (-4.56, p = 0.036). As expected, all scales worsened in the range of MIDs at EOT, mostly due to PD. Sensitivity analyses were consistent, with modest increases in estimated differences. Conclusions: In pts with metastatic MCC, non-progression during avelumab treatment contributed to statistically and clinically meaningful improvements in health-related QoL. Clinical trial information: NCT02155647.