bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact on OS of 2nd and 3rd generation TKI in EGFR mt+ and ALK+ patients: Results of the NOWEL network.
Authors: Roeper Julia , Netchaeva Maria , Lueers Anne Christina , Stropiep Ursula , Hallas Cora , Tiemann Markus , Neemann Nicole , Heukamp Lukas C. , Falk Markus , Wiest Gunther , Wesseler Claas , Ukena Dieter , Sackmann Sandra , Griesinger Frank
Published: September 2018

e20560

Background: Available clinical research data shows that early mutation testing for patients with NSCLC stage IV could lead to an effective choice of therapy for patients with proven mutations. Targeted therapies achieve a higher ORR, PFS, OS and a better quality of life than chemotherapy in mt+ patients. With the advent of 2nd and 3rd generation TKI´s effective in 1st generation TKI resistant tumors, we wanted to study the impact of these drugs on the outcome of patients in a real life setting in 3 lung cancer centers. Methods: 1383 patients from the three cancer centers diagnosed with NSCLC stage IV (UICC 7) were examined. Methods for the detection of mutations included Sanger Sequencing, hybridization based COBAS testing as well as hybrid cage next generation sequencing. Results: 880/1383 (64%) consecutive patients with non-squamous cell NSCLC from the cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The EGFR mutation rate was 16.6% (141/880), and the ALK-translocation rate 3.8% (24/635). Median OS in EGFR mt+ patients was 31 (n = 78) vs. 32 (n = 38) vs. 16 (n = 14) months respectively (center 1 vs. center 2 vs. center 3). Median OS in ALK mt+ patients was 25 (n = 17) months in center 1 and 11 (n = 5) months in center 2 (p < 0.05). Use of 3rd generation TKI Osimertinib (n = 17) lead to a significantly higher OS (n = 17, median OS 67 mo) than the use of only 1st and 2nd generation TKI (n = 113, median OS 24 mo, p < 0.000). Similarly, use of 2nd and 3rd generation ALKi impacted significantly on median OS: Crizotinib alone n = 7, 17 months, Crizotinib followed by Ceritinib and/or Brigatinib (n = 9) median OS not reached, p < 0.001. Conclusions: Smalldifferences in OS were observed, depending on the treatment centers, but the use of multiple EGFR and ALK-I impacted highly significantly on the outcome of patients with EGFR and ALK-alterations in a real life setting.
The efficacy and safety of nivolumab in advanced non-small cell lung cancer in clinical practice in Japan: A multicenter analysis.
Authors: Kobayashi Keigo , Naoki Katsuhiko , Nakachi Ichiro , Oyamada Yoshitaka , Nakamura Morio , Inoue Takashi , Tateno Hiroki , Sakamaki Fumio , Sayama Koichi , Terashima Tsuyoshi , Ko Hidefumi , Nishino Makoto , Masuzawa Keita , Hasegawa Hanako , Manabe Tadashi , Arai Daisuke , Yasuda Hiroyuki , Kawada Ichiro , Soejima Kenzo , Betsuyaku Tomoko ,   Keio Lung Oncology Group
Published: September 2018

e20577

Background: Nivolumab, an immune checkpoint inhibitor, is now approved as standard treatment for pre-treated advanced non-small cell lung cancer (NSCLC) based on the results from mega clinical trials with carefully selected patients. We sought to clarify the real-world efficacy and safety of nivolumab and to identify the clinical factors influencing the efficacy. Methods: This study enrolled 142 patients with pre-treated advanced NSCLC who had been administered nivolumab (3mg/kg, Q2W) from January to July 2016 at Keio University and affiliated hospitals in Japan. We retrospectively evaluated objective responses, adverse events (AEs), and analysed clinical factors associated with the response. Results: The overall response rate and disease control rate were 17% and 62%, respectively. The rate of any grade AEs was 45%, while the rate of grade 3-4 AEs was 13%. Among patient’s clinical factors such as age, gender, ECOG performance status, types of carcinoma, epidermal growth factor receptor ( EGFR)/ anaplastic lymphoma receptor tyrosine kinase (ALK) mutation status, smoking status, number of previous treatment lines, presence of central nervous system (CNS) metastasis and presence of prior radiotherapy, “ EGFR/ALK mutation negative” and “administration of prior radiotherapy” were independently associated with the good response to nivolumab treatment by multivariate logistic regression analysis (OR NA/ p < 0.01, OR 5.4/ p < 0.01, respectively). None of the 19 EGFR/ALK mutation positive patients showed response. Although a significant difference was not recognized between “current, former smokers” and “never smokers” (chi-square test, p = 0.1), a subsequent analysis showed smoking pack years (PY) was significantly higher in responders than in non-responders ( t-test, p = 0.035). Conclusions: The objective responses and the profiles of AEs confirmed in our study were similar to those observed in Checkmate 057/017 trials. We can use nivolumab safely regardless of age or number of treatment lines. EGFR/ALK mutation and presence of prior radiotherapy were key clinical factors statistically associated with the nivolumab efficacy.
Comparative study of two PD-L1 expression assays in patients with non-small cell lung cancer (NSCLC).
Authors: Feng Zheng , Schlichting Michael , Helwig Christoph , Chand Vikram K. , Gelb Arnold , Jin Hulin , Grote Hans Juergen
Published: September 2018

e20581

Background: Response to anti–PD-L1/PD-1 therapy in patients with NSCLC has been associated with tumor PD-L1 expression. Avelumab is a fully human anti‒PD-L1 IgG1 antibody that has shown antitumor activity in advanced NSCLC, with a trend for greater efficacy in patients with PD-L1+ vs PD-L1– NSCLC tumors, as assessed using a proprietary PD-L1 assay in development (Dako, Carpinteria, CA; based on antibody clone 73-10, Merck KGaA, Darmstadt, Germany). This study compares the analytical performance of the 73-10 assay with the FDA-approved PD-L1 IHC 22C3 pharmDx diagnostic assay (Dako) in NSCLC tumors. Methods: Formalin-fixed paraffin-embedded NSCLC tumor samples were obtained from a commercial source and from a study of first-line (1L) avelumab in patients with advanced NSCLC (NCT01772004). Tumor membrane PD-L1 expression was assessed with the 73-10 and 22C3 assays by immunohistochemistry. Correlation between assays was determined at different PD-L1 cut-off levels. Results: In initial staining of commercial NSCLC samples, the 73-10 assay showed a broad dynamic range. Of 148 commercial samples, the 73-10 assay with ≥1%, ≥50% and ≥80% cut-offs classified 64.2%, 36.5% and 23.6% of samples as PD-L1+, respectively, whereas 20.3% were PD-L1+ with the 22C3 assay at a pre-specified ≥50% cut-off. The overall percentage agreement between assays was 83.8% using the ≥50% cut-off for both assays, and 93.9% using the ≥80% cut-off for 73-10 and ≥50% for 22C3. In follow-up studies, 83 study samples from the 1L NSCLC cohort were evaluable with both assays. With the 73-10 assay at ≥1%, ≥50%, and ≥80% cut-offs, 79.5%, 45.8%, and 31.3% of study tumors, respectively, were PD-L1+; with the 22C3 assay at ≥1% and ≥50% cut-offs, 59.0% and 21.7% were PD-L1+. Conclusions: Using a high tumor cell PD-L1 staining cut-off, the 73-10 and 22C3 assays showed highly concordant staining of NSCLC samples, with similar sensitivity observed with an ≥80% cut-off for 73-10 and ≥50% for 22C3. Using a low frequency of tumor PD-L1 expression, data suggested that the 73-10 assay had greater sensitivity than the 22C3 assay. These results provide a rationale for additional studies using the 73-10 assay at various cut-offs within the avelumab trial program. Clinical trial information: NCT01772004.
In silico analysis of DNA damage repair variants in advanced NSCLC patients (pts) to predict response to platinum-based chemotherapy (PBC).
Authors: Karri Saradasri , Stein Matthew K , Patel Kruti , Crawley Melissa , Vontela Namratha Reddy , Alloway Taylor , Morris Lindsay Kaye , Mays John , Hare Felicia , Prouet Philippe , Byrd Kenneth P , Wiedower Eric , Chandler Jason Claud , Fenton Moon Jung , Weksler Benny , Schwartzberg Lee Steven , Martin Michael Gary
Published: September 2018

e20582

Background: There are no biomarkers that reliably predict benefit from PBC in NSCLC. We hypothesize cancers with DNA damage repair pathway nsSNPs may be more sensitive to PBC. Methods: Pts with advanced NSCLC that received first-line PBC and next-generation sequencing (NGS) with Caris (2013-2015) were retrospectively identified. The total pathogenic burden (SUM) was defined as test-determined pathogenic mutations (Pmut) plus nsSNPs predicted-damaging (pnsSNPs) by in silico analysis with PolyPhen-2 (Harvard). 13 DNA damage repair genes were also selectively analyzed. All p-values were two-tailed. Results: 84 pts were found; 35% female; 58% white, 37% black; median age was 64 (range 26-81); 82% had ≥20 pack-years (py), 12% with < 20 and 6% never-smokers; 27% received immunotherapy (IT) and 5% tyrosine kinase inhibitors (TKI) subsequently. 49 pts had primary progressive disease (58%), 9 stable disease (11%), 16 partial response (19%) and 10 complete response (12%). Median overall survival (OS) was 11 months (1-18). Median SUM was 5 (0-14) with median pnsSNPs 3 (0-11) and Pmut 1 (0-4). For all genes, no link was found between SUM and response (p = 0.95, ANOVA) or OS (p = 0.48, log-rank test). 26 pts (31%) had DNA damage repair lesions (range 1-3) with 33 nsSNPs (23/33 pnsSNPs) and 4 Pmut; genes commonly-mutated were ATM (16), BRCA2 (10) and BRCA1 (5). Race and smoking status did not predict mutation frequency. A trend towards better OS was seen for pts more heavily-mutated in DNA damage repair ( p= 0.01, log-rank test for trend) as > 60% pts with 1-3 nsSNPs survived > 300 days versus < 50% pts with 0. OS was longer for pts with 1+ DNA damage repair lesions (455 days) versus 0 (252 days) [HR 1.81; CI 1.19-3.89; p = 0.01]; no difference in response rate ( p= 0.59, Fisher’s exact) was found. Similar proportions of pts without (16/58; 28%) and with (7/26; 27%) DNA damage repair variants received IT; 4/4 pts TKI-treated had no such lesions. Conclusions: Advanced NSCLC tumors with ≥1 DNA damage repair nsSNP had a superior OS of > 200 days; however, no link with response was found. Further studies are indicated to determine the extent to which DNA damage repair burden can predict benefit in platinum-treated NSCLC pts.
The feasibility of using small biopsy samples from lung cancer for targeted next-generation sequencing.
Authors: Kim Hee Kyung , Ku Bo Mi , Lee Hansang , Heo Mi Hwa , Hong Joo Hyun , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju
Published: September 2018

e20584

Background: As the genomic based personalized medicine has been advanced, biomarker analysis using targeted next-generation sequencing (NGS) becomes crucial diagnostic approach for treatment of lung cancer. Most patients of lung cancer are diagnosed on small biopsy specimen, but the feasibility of the small tissue samples for targeted NGS has not been evaluated. We aimed to investigate the feasibility of using small tissue samples of lung cancer for targeted NGS. Methods: The medical records of the patients who underwent biopsy and targeted NGS were reviewed. Two types of panel for targeted NGS were used which were AmpliSeq Cancer Hotspot panel v2 and Oncomine Focus Assay. Results: A total of 603 biopsy specimens of lung cancer were analyzed from April 2014 to October 2016. The sites of biopsy were lung or bronchus (51.2%), lymph node (26.2%), Pleura (2.3%), liver (2.5%), Brain (1.7%) and the others (adrenal gland, bone, muscle, spleen, stomach, thymus). Percutaneous transthoracic core needle biopsy (PTCNB) was most frequently used method for acquisition of tissue (24.9%). The other methods of biopsy were bronchoscopy (14.4%), endobronchial ultrasound (EBUS, 23.8%), Video-assisted transthoracic surgery (VATS, 9.9%) and so on. The types of tissue samples were formalin-fixed, paraffin-embedded (FFPE, 80.6%) and fresh tissue (19.4%). All of these samples, 398 cases (66.0%) were successfully analyzed using targeted, NGS. In 34% of analysis failure cases, 23.5% were not adequate for DNA or RNA extraction and 10.5% had amount not to be enough. On multivariate analysis, PTCNB was more likely to fail than other methods of biopsy such as bronchoscopy, EBUS (HR 2.31, 95% CI 1.4-3.8, p = 0.001). Conclusions: The biopsy of lung cancer for targeted NGS was taken from a variety of sites via different methods, and the type of tissue samples was mostly FFPE. Considering the yield of our study, small biopsy specimens could be used to investigate genomic characteristics of lung cancer via targeted NGS.
Activity of an oral hyroxysterol.
Authors: Habib Nabil , Daaboul Hamid Elia , Hage George , Jabbour Abdo , Zeitouni Hind , Khalife Ryiad
Published: September 2018

e20587

Background: Hydroxysterols are oxygenated derivatives of cholesterol. They have been shown to interfere with proliferation and cause the death of many cancer cell types, such as leukaemia, glioblastoma, colon, breast and prostate cancer cells. They control the transcription and the turnover of the key enzyme in cholesterol synthesis. Hydroxysterols interfere with PI3K/AKT, MAPK/ERK, hedgehog and Wnt pathways of proliferation and differentiation. When administered in vitro to cancer cell lines, hydroxysterols invariably both slow down proliferation and provoke cell death. Many of these compounds show antitumor activity in experimental models and most of them are very toxic. (24-ethyl-cholestane- 3β,5α,6α-triol) is the first oxysterol being tested in the clinic. It is also one of the safest in this class of compounds. Methods: We have treated with this new drug 18 patients suffering from Non-small cell lung cancer (NSCLC); sixteen males and two females. Thirteen had adenocarcinomas and five had squamous-cell carcinoma. The median age was 65. Sixteen patients had a stage IV disease and two had a stage III disease. Seven had a PS: 1, seven had a PS: 2 and four had a PS:3. Seventy-five percent were symptomatic and fifty percent were taking pain killers. Six patients only did not receive previous chemotherapy and five received radiotherapy. Patients received daily 10 mg/Kg of oral (24-ethyl-cholestane- 3β,5α,6α-triol) divided in 3 equal doses, until disease progression. Results: Twelve patients had a partial response (PR), three patients had a stable disease (NC) and three patients had a disease progression (PD). The median duration of response was 8 months but 2 patients are still under treatment. No toxicity was observed so ever. Seventy-five percent of symptomatic patients had a remarkable symptom control. Conclusions: These encouraging results make this new and safe drug a good candidate for further clinical trials either alone or in association with other drugs for the treatment of NSCLC.
MET exon 14 splice site mutation, protein expression, and amplification in pulmonary sarcomatoid carcinoma: A multi-center study from China.
Authors: Chen Xinru , Wang Fang , Xu Chunwei , Sun Wen yong , Gao Fang san , Zhang Yu , Liu Wen xue , Chen Likun
Published: September 2018

e20595

Background: MET exon 14 splice site mutation (MET exon 14Δ) was identified as a potential driver mutation in non-small cell lung cancer (NSCLC). Previously, several small sample size studies have revealed a higher frequency in pulmonary sarcomatoid carcinoma (PSC) than other types of NSCLC. In order to reveal the accurate frequency of MET gene alterations in Chinese PSCs, we comprehensively studied the frequency and the relationship among MET exon 14Δ, protein expression and amplification in a large cohort of PSCs. Methods: MET exon 14Δ, protein expression and amplification were detected in 148 surgically resected PSC samples from multiple medical centers by using Sanger sequencing, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Results: MET exon 14Δ was identified in 9 (6.1%) of 148 cases. Six were pleomorphic carcinoma, two were spindle cell carcinoma and one was carcinosarcoma. MET exon 14Δ was more common in pleomorphic carcinoma compared with other subtypes of PSCs (p = 0.01, X2 test) and have an obvious tendency to occur in elder patients. MET protein overexpression was detected in 16.2% (24/148) of PSCs, and was found significantly associated with MET exon 14Δ (p = 0.045). MET FISH positive was detected in 15.5% (23/148), and 6 (4.1%) of them were confirmed as gene amplifications. MET FISH positivity (P < 0.001, X2 test) and amplification (P < 0.001, X2 test) were significantly associated with the IHC positive. No significant relationship between MET exon 14Δ and amplification was found. Conclusions: Chinese PSC has high incidence of METexon 14Δ and amplication. MET inhibition may benefit this specific subgroup of patients.
Prognostic prediction of pemetrexed-platinum chemotherapeutic regimen for NSCLC by serum metabolomics.
Authors: Wang Jie , Tian Yanhua , Wang Zhijie , Bai Hua , Duan Jianchun
Published: September 2018

e20603

Background: Pemetrexed-platinum chemotherapeutic doublet has become a standard schedule as the first-line treatment for advanced non-squamous NSCLC due to its promising efficacy and a favorable toxicity profile. However, chemotherapy resistance inevitably limits the therapeutic effect of this preferred chemotherapeutic regimen, especially for these intrinsically resistant patients. Development of predictive biomarkers to identify those patients who can benefit from this pemetrexed-based regimen has great significance for personalized chemotherapy. Methods: Total 354 patients who were diagnosed with inoperable stage IIIB or IV lung adenocarcinoma (LADC), assigned to receive pemetrexed-platinum doublet chemotherapy as the first-line treatment were enrolled into this prospective study, including 251 cases diagnosed ahead as training set for predictive model establishment and the subsequently diagnosed 103 cases into validation set. Ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS) analytical platform were applied to perform the metabolic profiling studies of pre-treatment serum samples. Results: In the training set, eight potential biomarkers, comprising of hypotaurine, taurine, choline, betaine, dimethylglycine, uridine, dodecanoylcarnitine and L-palmitoylcarnitine, were discovered to be differentially expressed between the patients in disease progressive group (PD, n = 53) and disease control group (including CR, PR and SD, n = 198). In the validation set (PD vs non-PD: 23 vs 80), targeted quantitative analysis of these metabolic biomarkers revealed similar levels as that observed in the training set. Logistic regression model was accordingly established based on this eight-metabolic biomarker panel, to discriminate patients who might benefit from this chemotherapy regimen with over 90% accuracy. Conclusions: This prospective study identified blood-based biomarker panel by metabonomics analysis could predict the clinical outcome of pemetrexed-platinum chemotherapy prior to treatment for LADC patients, which needed to be validated by clinical trials of large samples.
A phase I/II study of pembrolizumab (P) with gemcitabine (G) in patients (Pts) with previously-treated advanced non-small cell lung cancer (NSCLC): Phase I safety results.
Authors: Sanborn Rachel E. , Duffy Regan M. , Fisher Brenda K , Perlewitz Kelly Shea , Redmond William L , Koguchi Yoshinobu , Fox Bernard A.
Published: September 2018

e20605

Background: P, an anti-PD1 antibody active in advanced NSCLC, has optimal benefit in tumors with high PD-L1 expression. G may increase antigen cross-presentation and prime CD8 T cell responses via increased tumor cell apoptosis. The combination of antigen cross-presentation and T cell activation may have a synergistic effect with concurrent anti-PD1 immunotherapy. This study is evaluating P + G in pts with previously-treated advanced NSCLC with goal to establish feasible dosing prior to phase II evaluation. Methods: The phase I portion enrolled sequential cohorts of 2 pts each with advanced NSCLC (1-3 prior lines of therapy), regardless of PD-L1 status. Treatment consisted of G, 1250 mg/m2, Days (D) 1 & 8 + P 200 mg D 1; 21-day cycles. Pts received G to max 6 cycles, P to max 2 years. Each cohort closed until pts completed 6 weeks therapy (2 cycles). Dose limiting toxicity (DLT) was defined as Gr 4 hematologic or Gr 3/4 non-hematologic toxicity at least possibly treatment-related within the first 6 weeks. Dose de-escalation would occur if ≥ 2 related DLTs occurred in the first 6 pts (accrual 6-36 pts); de-escalation was allowed for each drug independently based on toxicity attribution. Tumor tissue was collected for central PD-L1 testing and immune score analysis. Exploratory analysis of immune response via protein array and whole blood immunophenotyping is pending. Results: 6 pts were enrolled. Male/Female: 2/4; Age 53-73 (Median 67.5); ECOG 0/1: 1/5 pts, respectively. Median prior lines of therapy: 1 (Range 1-3). DLT: Gr 4 pulmonary hemorrhage with respiratory failure (1 pt, related to G). Other toxicities in DLT period: Gr 3 neutropenia (1), anemia (2 events in 1 pt). Other toxicities were Gr 1/2. 1 pt developed Gr 3 pneumonitis after DLT period ended (after cycle 3) and was removed from study treatment. Median cycles: 4 (Range 2-8). Primary reason for discontinuation was progression (4 pts). PD-L1 results by central analysis are pending. Conclusions: 1 DLT was observed in phase I; de-escalation was not triggered and the combination is considered feasible for phase II evaluation with G 1250 mg/m2 and P 200 mg (enrolling). Clinical trial information: NCT02422381.
A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small cell lung cancer with wild type EGFR (OLCSG1202).
Authors: Bessho Akihiro , Ochi Nobuaki , Kuyama Shoichi , Fujimoto Nobukazu , Umeno Takahiro , Ninomiya Kiichiro , Ikeda Genyo , Harada Daijiro , Kishino Daizo , Hosokawa Shinobu , Chikamori Kenichi , Nogami Naoyuki , Harita Shingo , Ueoka Hiroshi , Hotta Katsuyuki , Takigawa Nagio , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: September 2018

e20614

Background: S-1 is an oral fluoropyrimidine anticancer agent that combines tegafur, gimeracil, and oteracil potassium. Two phase III trials in advanced non-small cell lung cancer (NSCLC) showed the non-inferiority of combination of S-1 with carboplatin or cisplatin compared with standard platinum doublet chemotherapy. Although the S-1/platinum is one of the first line combinations for advanced NSCLC, efficacy and safety of the regimen in the elderly remain unknown. Methods: Patients were required to be previously untreated advanced NSCLC with wild-type EGFR, aged 70 or more, PS of 0-2. They received oral S-1 (40 mg/m2, twice daily) for 2 weeks and carboplatin (AUC 5 on day 1) every 4 weeks as an induction treatment. After 4 cycles of the induction, S-1 alone (40 mg/m2, twice daily for 2 weeks) was administrated every 4 weeks as a maintenance therapy until PD. Primary endpoint was overall response rate (ORR), which was expected more than 20%, and secondary endpoints included disease control rate (DCR), PFS, OS, and toxicity profile. The association between clinical outcomes and gene expressions including thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, orotate phosphoribosyl transferase, VEGF and ERCC1 in tumors was evaluated. Results: Thirty-three patients were enrolled between March 2013 and June 2015. Median age was 78 years old (range: 70 – 89), and 51.5% had a PS of 0. ORR was 30.3% (95% CI: 14.6 – 46.0%) and DCR was 57.6% (95% CI: 40.7 – 74.4%). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%) and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. Median PFS and OS times were 134 days (95% CI: 79 – 173) and 479 days (95% CI: 250 – 571), respectively. Low thymidine phosphorylase expression was associated with DCR (P < 0.01). Conclusions: Carboplatin plus S-1 showed preferable efficacy and tolerable toxicity for elderly with NSCLC. (Clinical trial number: UMIN000009345) Clinical trial information: 9345.
Metabolic activity by 18F-FDG-PET/CT to predict for early response after nivolumab in previously treated NSCLC.
Authors: Kaira Kyoichi , Naruse Ichiro , Higuchi Tetsuya , Alltan Bolag , Mogi Akira , Shimizu Kimihiro , Sunaga Noriaki , Hisada Takeshi , Asao Takayuki
Published: September 2018

e20615

Background: Nivolumab, an immune checkpoint inhibitor and approved as an anti PD-1 drug, is administered to patients with previously treated non-small cell lung cancer (NSCLC). However, there are no established biomarkers to predict the efficacy of nivolumab. Here, we report a prospective study to investigate whether 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can predict therapeutic response after early-phase nivolumab treatment. Methods: Twenty-four patients who received nivolumab were enrolled from January to September 2016. 18F-FDG-PET/CT was performed before and 1-month after nivolumab therapy. SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated in comparison with CT scan. We also analyzed the protein expression of PD-L1 and identified tumor infiltratrating lymphocytes (TILs) such as CD4-, CD8-, and Foxp3-positive cells within tumor specimens by immunohistochemistry. Correlation of response and nivolumab plasma concentration 1-month post therapy was analyzed. Results: Among the 24 patients, an early metabolic response to nivolumab was observed in 7 patients (29%) on SUVmax, 6 patients (25%) on MTV, and 8 patients (33%) on TLG, whereas 7 (29%) patients achieved a partial response (PR) by RECIST. Out of the 7 patients with confirmed PR, early metabolic response by SUVmax, SUVmean, MTV, and TLG were observed in 6 (85.7%), 5 (71.4%), 5 (71.4%) and 7 (100%) patients, respectively. However, only one patient (14.2%) yielded a PR by CT scan 1-month after nivolumab. All 9 (100%) patients with progressive metabolic disease by TLG had confirmed progressive disease (PD). Progression-free survival of more than 5 months was observed in all patients with early metabolic response by TLG. The morphological change by CT scan was not clearly identified as an early response. No significant correlation was found between metabolic response and nivolumab plasma concentration and expression of PD-L1 and TILs. Conclusions: Metabolic response calculation by TLG could be a better early-phase predictor of efficacy and survival after nivolumab in comparison with immune biomarkers such as PD-L1. Clinical trial information: UMIN000020814.
Feasibility and outcome of repeat biopsy upon progression on tyrosine kinase inhibitors in patients with EGFR mutation positive adenocarcinoma of lung-an Indian tertiary cancer centre experience.
Authors: Zanwar Saurabh , Noronha Vanita , Joshi Amit , Patil Vijay Maruti , Chougule Anuradha , Janu Amit , Kumar Rajiv , Prabhash Kumar
Published: September 2018

e20628

Background: A repeat biopsy at the time of progression is important to evaluate the mechanism of resistance to tyrosine kinase inhibitors (TKIs) in EGFR mutation positive adenocarcinoma (ADC) of lung and dictates decisions for further therapy. Being an invasive procedure, a rebiopsy is not always possible and presents various hindrances. Methods: Between January 2012 and November 2016, EGFR mutation positive ADC of Lung treated with TKIs were evaluated for and offered a repeat biopsy at the time of progression on TKI. Feasibility of rebiopsy was done by a team of experienced interventional radiologists. Proportion of patients undergoing a rebiopsy, reason for inability to undergo a rebiopsy, histopathology findings including any small cell transformation and adequacy of tissue for further molecular testing were assessed. Results:154 patients were offered a repeat biopsy out of which 119 patients (77.3%) underwent a repeat biopsy. There was no evidence of malignancy in 17.6% (21/119) patients on the rebiopsy specimen and tumor was inadequate for molecular testing in 9 out of 98 patients (9.2%) in whom malignancy was detected on the repeat biopsy specimen. Small cell transformation was seen in 3.3% (4/119) patients who underwent a repeat biopsy. Amongst the 34 patients who could not undergo rebiopsy, patient unwillingness for the procedure was the most common reason, accounting for 47% cases (16/34) followed by a technically difficult biopsy as per judgement of the interventional radiology team in 32.3% (11/34). 5 out of 34 patients were not subjected to a rebiopsy a poor performance status and 3 patients were not subjected to rebiopsy as per treating clinician’s discretion. Thus, out of 154 patients, adequate tissue was not available for molecular testing in 41.5% patients who progressed on TKI due to various reason as elaborated above. Molecular testing is planned on the remaining biopsy specimens. Conclusions: Conventional invasive rebiopsy upon progression on TKIs fails to collect adequate tissue for molecular testing in almost 40% cases due to various reasons making liquid biopsy a very important tool in this setting.
Neutrophil lymphocyte ratio (NLR) as a predictive biomarker for PD-1/PD-L1 directed therapy in metastatic non-small cell lung cancer (NSCLC).
Authors: Bumma Naresh , Jeyakumar Ghayathri , Kim Seongho , Galasso Cathy , Thakur Manish K. , Gadgeel Shirish M. , Vaishampayan Ulka N. , Wozniak Antoinette J.
Published: September 2018

e20633

Background: PD-1/PD-L1 directed therapy is approved in the second and first-line treatment of metastatic NSCLC. While PD-L1 expression can be predictive of outcomes with such therapy, there remains a need for additional biomarkers to guide patient (pt) selection. NLR is an easy to use biomarker that was predictive for clinical outcomes in the treatment of kidney cancer and melanoma. This study evaluated NLR as a predictor of response rate (RR), PFS and OS in metastatic NSCLC pts treated with PD-1/PD-L1 inhibitors as second line therapy. Methods: A retrospective chart review of NSCLC pts treated with PD-1/PD-L1 inhibitors was conducted. Data were collected on pt demographics, smoking status [<10 pack years (PY) and ≥10 PY], histology, NLR pre-therapy and NLR post 3 doses. Correlation with RR, PFS and OS was evaluated by univariate and multivariate analyses. Results: 58 pts with NSCLC were included in the analyses. Median age was 62.5 yrs (39-85) and 34(59%) were male. 36 (62%) were Caucasian, 16(28%) African American and 6(10%) Asian. 39 (63%) had adenocarcinoma histology, 23 (40%) patients smoked <10 PY and 35(60%) ≥10 PY. On Day 1, 33 (57 %) had NLR <4 and 28 (48%) had NLR <4 after cycle 3. 43 (74%) pts had disease control with 2 (3%) complete remissions, 22 (38%) partial responses. Pre-therapy NLR ≥4 was associated with shorter PFS (HR = 1.79 p=0.10) and shorter OS (HR =2.57; p=0.04). NLR≥4 post 3doses was associated with shorter PFS (HR= 2.14,p=0.04) and shorter OS (HR= 3.11; p=0.04). In multivariate analysis, heavy smoking (≥10 PPY) was associated with longer PFS; HR=0.50 (95% CI 0.25-1.01; p=0.05); but had no effect on OS with a HR 0.58(95%CI 0.21-1.56; p=0.28). Squamous histology appeared to have longer PFS HR=0.62 (95% CI 0.61-2.35: p =0.61), though not statistically significant. Conclusions: Pretherapy NLR ≥4 was found to be associated with shorter OS in NSCLC pts treated with PD-1/PD-L1 therapy. This suggests that NLR may be a predictive factor for benefit with PD1/PDL1 therapy. A larger sample study is warranted to validate this observation. [Table: see text]
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.