bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant chemotherapy outcome in unselected single-center non-small cell lung cancer (NSCLC) population.
Authors: Florescu Marie , Blais Normand , Tehfe Mustapha Ali , Gravel Mathieu
Published: September 2018

e20089

Background: Adjuvant chemotherapy with Cisplatinum/Vinorelbine is an established regimen since a decade in selected resected NSCLC population in order to improve DFS and overall survival. However, the outcome of patients treated outside the research protocols is not as good as in clinical trials. Methods: We retrospectively reviewed 209pts resected stage I to III NSCLC patients using our SARDO database, treated in our University hospital between 2006 and 2015 with a median follow-up of 13mos. Any adjuvant chemotherapy was recorded. Results: Amongst 209 resected NSCLC patients, 185pts (89%) had negative margins and 24pts (11%) have positive margins resection. The observation group and the chemotherapy group in both settings were well-balanced in terms of demographic, co-morbidities and tumor characteristics. As expected, the median overall survival (mOS) in negative margins was significantly better than in positive margins patients (43mos vs 24mos p = 0.029). In negative margins patients, no survival benefit was seen in stage I (A and B) (57 mos for chemo group vs 77 mos for observation group p = 0,217) and stage III (A and B) (39mos mOS for chemo group vs 40mos for observation group, p = 0.37), but a trend for improved mOS was seen in stage II (52 mos for chemo group vs 38 mos for observation group, p = 0.114), also consistent with mPFS results for each group. However, for the small number of patients with positive margins, a significant improvement in survival was seen in chemotherapy arm (mOS 37mos) compared to observational arm (mOS 11mos p = 0,039). No significant difference in survival was seen between Carbo/Taxol regimen and Cisplatinum/Vinorelbine regimen (43 mos vs 38 mos p = 0,658). Conclusions: In our unselected population, adjuvant chemotherapy did not show the improvement in survival expected with margin negative resected NSCLC. In positive resected NSCLC, adjuvant chemotherapy benefit was statistically significant, emphasizing need to treatment to these patients.
Real-world data on treatment patterns and survival among ALK+ NSCLC patients in Japan.
Authors: Nosaki Kaname , Toyozawa Ryo , Taguchi Kenichi , Edagawa Makoto , Shimamatsu Shin-ichiro , Toyokawa Goji , Hirai Fumihiko , Yamaguchi Masafumi , Takeda Yoko , Seto Takashi , Takenoyama Mitsuhiro , Ichinose Yukito
Published: September 2018

e20505

Background: Three ALK inhibitors (ALKi) are approved in Japan for treatment of patients with ALK-positive (ALK+) advanced or metastatic non-small cell lung cancer (NSCLC). However, the optimal sequence of therapy with ALKi is unclear. The objective of this study was to provide real-world data on the treatment patterns and survival among ALK+ NSCLC patients. Methods: ALK+ patients treated with ALKi in our institute were included in this retrospective analysis. Data on the treatment patterns and outcomes were collected from medical records. Results: In total, 60 patients were included. The median age at the diagnosis was 52.5 years, with 60% female and 65% non-smokers. The first treatment was chemotherapy in 67% and ALKi in 33%. The median overall survival (OS) was 186 weeks. We found differences in the OS for Crizotinib use at any line (118 weeks; presence vs. NR; absence) and first-line use of an ALKi (127 weeks; Crizotinib vs. 416 weeks; Alecitinib or Ceritinib, p = 0.0048). Conclusions: The role of Crizotinib in the treatment of ALK+ NSCLC is decreasing. Alectinib followed by Ceritinib seems to be promising. Treatment decision-making based on a re-biopsy is immature at present. The development of sequential therapy with ALKi based on resistance mechanisms is urgently needed. [Table: see text]
Clinical significance of 22C3-PD-L1 IHC expression in surgically resected non-small cell lung cancer.
Authors: Lin Gen , Li Chao , Huang Cheng , Fang Rong Xi , Xu Peng Hai , Lin Dong xian , Wu Biao , Chen Xiaohui , Xu Chunwei , Mok Tony
Published: September 2018

e20507

Background: Multiple studies correlated PD-L1 expression with clinicopathologic and survival have reported conflicting results.Methods: We retrospectively collected 185 patients with NSCLC who underwent surgical resection to detect PD-L1 IHC using the clone 22C3 pharmDx kit and evaluated PD-L1 expression along with clinicalpathological characteristics and prognosis.Results: Most of tumors had TNM stage lower than stage III. Adenocarcinoma and squamous carcinoma was accounting for 56.8% and 43.2%, respectively. Heterogeneous distribution of PD-L1 staining was observed, PD-L1 strong-positive and weak-positive staining were detected in 11.4% and 24.3% of patients. In univariate analysis, smokers, squamous carcinoma, central type cancer, larger primary tumor size, metastatic lymphonode, neoadjuvant chemotherapy and TILs present was found associations with higher proportion of PD-L1 positive expression. In multivariate analysis, only primary tumor size, smoking status, TILs status and neoadjuvant chemotherapy were confirmed associations with PD-L1 positive expression. Especially, PD-L1 positive expression rate climbed gradually with the increase of tumor size, T≤3cm 21.0%, 3cm < T≤5cm 32.8%, 5cm < T 50.7%, respectively, p = 0.003. PD-L1 positive expression highly improved with patients with neoadjuvant chemotherapy versus without neoadjuvant chemotherapy, 88.9% vs 33.0%, respectively, p = 0.009. In survival analysis, neither PD-L1 expession/TILs status nor the interaction term between were confirmed as independent prognosis biomarkers . PD-L1 negative group had a tendency of longer OS than PD-L1 positive group, mOS 66.4 months (95%CI, 59.4-73.4) vs. 39.2 months (95%CI, 16.0-62.4), respectively, p = 0.096. Conclusions: PD-L1 expression showed heterogeneous distribution and was highly influenced by tumor size, smoking status, TILs and neoadjuvant chemotherapy.It indicated a strong spatial and temporal variability in the PD-L1 expression, which could be in part to explain the conflicting results in PD-L1 expression and correlation with clinicopathologic in multiple studies. The dynamics of PD-L1 expression may also limit its use as a prognosis biomarker.
Interlaboratory-concordance of PD-L1 IHC for NSCLC.
Authors: Scheel Andreas H. , Bänfer Gudrun , Baretton Gustavo Bruno , Dietel Manfred , Diezko Rolf , Henkel Thomas , Heukamp Lukas C. , Jasani Bharat , Jöhrens Korinna , Kirchner Thomas , Petersen Iver , Reu Simone , Schildhaus Hans-Ulrich , Schirmacher Peter , Tiemann Markus , Warth Arne , Weichert Wilko , Wolf Juergen , Rüschoff Josef , Buettner Reinhard
Published: September 2018

e20508

Background: Immunohistochemistry (IHC) of the PD-L1 protein has become a mandatory diagnostic test for NSCLC. We conducted a two-step round robin test to analyze interobserver- and interlaboratory-concordance of PD-L1 IHC and to compare four clinical trial assays (CTAs; 28-8, 22C3, SP264, SP142) and laboratory-developed tests (LDTs). Results of step-one showed that reproducible PD-L1 IHC scoring is feasible; here we present the data on interlaboratory concordance Methods: Interlaboratory-concordance was tested by a centrally prepared tissue-microarray containing 21 NSCLC specimens that was stained at ten sites using CTAs and LDTs. Assay-performance was assessed with a second tissue-microarray containing eleven cell-lines with defined PD-L1 expression. Slides were evaluated by central quality-control and image-analysis. Results: The four CTAs yielded reproducible IHC-stainings at all sites while the results of the LDTs were mixed: Six protocols showed appropriate IHC quality with staining patterns similar to 22C3 and 28-8 CTAs, five protocols yielded less DAB-deposits and reduced staining intensity. Interlaboratory-concordance of carcinoma cell scoring using the 6-step system was moderate (κ = 0.43-0.69) while the included cut-offs ≥1% and ≥50% showed substantial concordance for the CTAs (κ = 0.73-0.89) and moderate concordance for the LDTs (κ = 0.50). No significant differences in interlaboratory-concordance were found among the CTAs. However, differences in the resulting staining patterns were noticed: While 22C3 and 28-8 showed similar staining patterns, SP263 showed minor differences in some cases and SP142 showed distinct patterns. Conclusions: The data show that the PD-L1 CTAs can be reproducibly employed and scored at different sites. LDTs with staining patterns similar to the CTAs are possible yet have to be carefully calibrated to match the appropriate intensity-range. The choice of assay and the set-up of the IHC-protocol may strongly influence the resulting staining.
Detecting KRAS and NRAS resistance mutations in plasma of lung cancer patients.
Authors: Potikyan Gary , Falat Magdalena , Duchoud Fabienne , Maland Matthew , Adhikari Sanjay
Published: September 2018

e20511

Background: Mutations in KRAS and NRAS have been found in a number of malignancies, particularly metastatic colorectal cancer, lung adenocarcinoma, and thyroid cancer. Several studies have shown that specific mutations in KRAS and NRAS are less likely to respond to anti-EGFR therapies. Several diagnostics have been developed to identify such mutations. However, in a large number of cancer patients, tumor biopsy poses a significant health risk thereby limiting the tissue available for current molecular diagnostics. Non-invasive liquid biopsy diagnostics are revolutionizing cancer treatment selection, patient prognosis, and monitoring. Low abundance circulating tumor DNA (ctDNA) is purified from patient plasma and used as an alternative source of genomic material for detecting tumor mutations. Currently available qPCR kits for detecting RAS mutations have a limited sensitivity and coverage since they are not optimized for liquid biopsy purposes. Methods: We have developed a two-step PCR to qPCR method to identify down to single mutant copies of KRAS or NRAS in ctDNA isolated from plasma. The mutant copies are first enriched by a novel multiplexed formula of primers and wildtype (WT) allele blockers. The mutations are then identified by EntroGen’s RAS Mutation Screening Panel or next generation sequencing (NGS). Synthetic mutant DNA was spiked in a background of WT DNA purified from plasma to yield a range of mutant allelic burden over WT background. The dilutions were analyzed to determine the method’s sensitivity. We subsequently used the method to screen 53 non-small cell lung cancer (NSCLC) patient samples. Results: Our two-step method detects single digit mutant copies of 35 clinically significant KRAS and NRAS mutations. Furthermore, NGS experiments demonstrated the two-step method can enrich mutations more than 52-fold. KRAS 12/13 mutations were identified in 6 out of 53 (11%) NSCLC patients. Conclusions: ctDNA-based liquid biopsy tests have been employed by few laboratories but are generally available only as a service. EntroGen’s platform agnostic liquid biopsy RAS assay provides clinicians the tools necessary to determine cancer treatment and monitor patients using most PCR and qPCR instruments.
The value of Fn14, CD44v, and EGFR expression in lung adenocarcinoma patients with and without activating EGFR gene mutation.
Authors: Bryl Maciej , Bednarek-Rajewska Katarzyna , Zalewski Przemysław , Janicka-Jedyńska Małgorzata , Ramlau Rodryg , Barinow Wojewódzki Aleksander , Woźniak Aldona
Published: September 2018

e20514

Background: Lung cancer is considered the most common cause of death in the world. The prognosis for patients is poor and depends on the clinical stage and the histological type of cancer. There is a need to identify and develop new therapeutic targets that could improve the prognosis of NSCLC patients and may be responsible for development of resistance to TKI therapy. Increased expression of Fn14 or CD44v and EGFR was observed in many tumors and also correlated with the overall survival of NSCLC patients Methods: We analyzed the clinical data and the immunohistochemical expression of Fn14, CD44v and EGFR in tumor tissues from 61 patients with NSCLC divided in two groups according to the presence of activating EGFR gene mutation. The aim of the study was to evaluate the correlation between the expression of the studied molecules and the neoplastic disease course of NSCLC patients. Results: Increased expression of Fn14 was observed in study group (B) compared to expression of this molecule in the control group (K). There were no differences in the intensity of the reaction with anti CD44v and EGFR antibodies in both groups. OS was significantly longer in the study group. Histological grade of tumor correlated with the intensity of CD44v expression in both groups. There was no correlation between the OS and Fn14 expression in any group. Negative correlation was noted between the expression of CD44v and the OS in the study group and between EGFR expression and the OS in both groups. Conclusions: Our observations suggest that the expression of CD44v and EGFR may be useful clinical markers of prognostic value in lung adenocarcinoma patients regardless of the presence of activating mutation in EGFR gene. Simultaneous assessment of Cd44v and EGFR expression may grant a greater prognostic value than the assessment of each receptor separately. Increased expression of Fn14 receptor in patients with EGFR gene mutation may become a new target in therapy allowing to eliminate the problem of secondary resistance to treatment with TKI’s
Prognostic factors for oligometastasis after 1st line first or second generation TKI for EGFR-mutated metastatic NSCLC.
Authors: Lee Victor HF , Choi Cheuk-Wai , Yau Tsz-Yui , Or Dicky , Choy Tim-Shing , Leung Dennis KC , Lau Kin-Sang , Lam Ka-On , Leung To-Wai
Published: September 2018

e20521

Background: First and second generation TKI (gefitinib, erlotinib, afatinib) is the standard 1st line therapy for EGFR-mutated metastatic NSCLC. Resistance ultimately develops despite initial durable response. Oligometastasis (OM) (defined as ≤5 newly developed metastatic lesions after TKI therapy) can be effectively treated with local ablative therapy so that the original TKI can be continued until further disseminated progressive disease. Methods: 151 patients treated with 1st line TKI for their EGFR-mutated metastatic NSCLC recruited between 2009 and 2013 in our previous study (Lee et al, Journal of Thoracic Oncology 2013) were now included in the training set. Another 263 prospectively recruited patients treated in the same setting between 2013 and 2016 were in the validation set. The factors prognostic of OM-free survival in the training set were re-tested again in the validation set. Results: The OM-free survival for the training set did not differ from that for the validation set (mean 68.4 months vs. 56.1 months; p = 0.961, median OM-free survival were not reached for both sets). 37 (24.5%) and 56 (21.2%) patients in the training set and validation set respectively developed OM. Sex (hazard ratio 0.490, 95% confidence interval 0.257–0.936; p = 0.031) was the only significant prognostic factor of OM-free survival in the training set while it was just borderline significant in the validation set (hazard ratio 0.631, 95% confidence interval 0.366–1.088; p = 0.098). Conclusions: Male patients were more likely to develop OM after 1st line first or second generation TKI. A more closer vigilance should be adopted for them so that effective local ablative therapy can be duly performed to procrastinate the use of 2nd line treatment.
The advantage of pemetrexed combined with platium chemotherapy treatement for advanced nonsquamous non-small-cell lung cancer (NSCLC) patients without drive oncogene.
Authors: Xu Haiyan , Wang Yan
Published: September 2018

e20527

Background:Platinum-based chemotherapy is the standard first-line treatment for non-squamous NSCLC patients without driver oncogene (EGFR, KRAS, and ALK mutations). However, it remains unknown that from which chemotherapy regimens can those patients get more benefit. Therefore, the study explore whether pemetrexed combined with platinum chemotherapy is superior to the other platinum-based chemotherapy regimens.Methods:We performed a retrospective study on 114 histologically or cytologically advanced IIIB-IV NSCLC patients admitted to Cancer Hospital from 1 Jan 2013 to 30 Dec 2015. The primary endpoint was the median progression free survival (PFS) and the disease control rate (DCR). And objective response was evaluated every two cycles by imaging according to the Response Evaluation Criteria In Solid Tumors (RECIST version 1.0). The multivariate logistic analyses were carried out by SPSS version 16.0. Results:114 patients received platinum-base doublet as first-line treatment. Among them, 59 patients underwent pemetrexed-containing regimens, and 55 patients received non-pemetrexed-containing regimens (38 patients for paclitaxel-containing regimens, 13 patients for gemcitabine-containing regimens, and 4 patients for other regimens.). The baseline characteristics between two groups were comparable ( p>0.05). The median PFS of pemetrexed-containing regimens was significantly longer compared with that of non-pemetrexed-containing regimens (7.2 months [95% CI: 5.3–9.1] vs. 4.9 months [95% CI: 3.2–6.6], p%0.05). DCR of pemetrexed-containing regimens was better than that of non-pemetrexed-containing regimens in the multivariate logistic analysis (89.8% vs.74.5%, p%0.05).Conclusions:Pemetrexed-containing regimens displayed more benefit than the other chemotherapy regimens for non-squamous NSCLC patients without driver oncogene. However, large scale perspective study is warranted in the future.
EGFR-TKI rechallenged treatment combined with apatinib in non-small cell lung cancer with EGFR-TKI resistance.
Authors: Liang Li , Li Fang , Cao Baoshan , Zhang Zhaohui , Zhu Xiang , Wang Jiadong
Published: September 2018

e20529

Background: Acquired resistance to EGFR-TKIs frequently occurs in non-small cell lung cancer (NSCLC) patients (pts) with sensitizing EGFR mutations. EGFR-TKIs rechallenged therapy is one of the recommended strategies. This study aimed to explore the efficacy and safety of EGFR-TKI combined with apatinib (a TKI against VEGFR-2) in EGFR-TKIs resistant pts. Methods: From Aug 2015 to Nov 2016, we retrospectively screened 16 NSCLC pts who acquired resistance to the EGFR-TKI therapy and chose apatinib plus EGFR-TKI as the second-line treatment in our hospital. All pts signed informed consent before treatment. Results: Pts characteristics and efficacy are shown in the table below. Two pts discontinued on the 4th and 10th day due to side effects, respectively, and thus were excluded from short efficacy analysis. No CR, 4 PR and 10 SD were confirmed, resulting in an objective response rate of 28.6% and a disease control rate of 100%, respectively. At the cut-off date on Feb 7, 2017, 6 pts were still being treated. The median progression-free survival was 4.60 months (95%CI, 2.23–12.52 months). The main adverse events were hypertension, hand-foot skin reaction (HFSR) and diarrhea. Five (31.3%) grade 3 hypertension, 1 (6.3%) grade 3 HFSR and 1 (6.3%) grade 3 diarrhea were observed. Conclusions: EGFR-TKI combined with apatinib may stand for a new option for NSCLC pts with acquired EGFR-TKIs resistance. [Table: see text]
Effect of liquid withdraw technique on the incidence of pneumothorax and tumor tissue amount of CT-guided cutting needle lung biopsy: An expanded retrospective study.
Authors: Li Rutian
Published: September 2018

e20535

Background: CT-guided cutting needle lung biopsy is important for the diagnosis of lung cancer especially in the area of precision medicine. In ASCO 2015, we reported that “Liquid withdraw” technique (to inject small amount of liquid while withdraw of the needle) can prominently reduce incidence of pneumothorax when combined with co-axial technique in 38 cases. In this reported, we retrospectively studied 90 patients undergoing CT-guided cutting needle lung biopsy to investigate the role of this technique in reducing complications and promoting biopsy effectiveness. Methods: From Jan 1st, 2014 to Nov 30th, 2016, we retrospectively studied 92 CT-guided percutaneous lung biopsies using co-axial and liquid withdraw techniques in 90 patients. The pathologies and complications secondary to biopsy procedure were noted. Pneumothorax and bleeding was graded as mild (mild and very mild), moderate, and severe. Results: 88 cases were diagnosed out of 92 biopsies (95.7%), of which 60 cases were adenocarcinoma. Liquid withdraw technique assured adequate tissue for diagnosis and treatment planning of lung cancer. Among 71cases diagnosed as NSCLC, only 5 (7.0%) were diagnosed as NOS. Among 52 cases of adenocarcinoma who consented EGFR mutation test, only 1 case (1.9%) failed due to insufficient tissue. Among all the biopsies, when acquiring specimens 4-6 times per procedure, the incidence of pneumothorax was in 18 cases (19.6%), among which 13 cases (14.1%) were very mild pneumothorax (lung surface retraction of≤1 cm), mild and moderate pneumothorax accounted for just 4.3%. No severe pneumothorax occurred. 19 cases (20.7%) happened bleeding (18 cases were mild bleeding). No infection, tumor implantation or aeroembolism happened. Conclusions: Compared to lung biopsy without liquid withdraw, the incidence of pneumothorax was reduced from approximately 35% to 19.6%. The liquid withdraw technique also resulted in low rate of other complications and adequate tissue for diagnosis. Next, we are planning to conduct a prospective study to further evaluate the role of this technique in the precision diagnosis and treatment of lung cancer.
The reasons why re-biopsies were not performed after failure with EGFR-TKI.
Authors: Oguri Tomoyo , Horiike Atsushi , Ariyasu Ryo , Koyama Junji , Saiki Masafumi , Sonoda Tomoaki , Takano Natsuki , Nishikawa Shingo , Kitazono Satoru , Yanagitani Noriko , Ohyanagi Fumiyoshi , Nishio Makoto
Published: September 2018

e20540

Background: Repeat biopsy becomes important to determine subsequent treatment after failure of EGFR-TKI. However, some patients did not receive re-biopsy in real world. Here we retrospectively analyzed the reasons why the patients did not receive re-biopsy. Methods: We reviewed medical records of 235 patients treated with EGFR-TKI at our institution between January 2014 and September 2016 and analyzed the treatment, the progression site after failure of EGFR-TKI and the reasons why they did not receive re-biopsy. Results: 127 of 235 (54%) patients had tumor progression after treatment with EGFR-TKI and 93 (73.2%) of 127 patients received re-biopsy and 34 (26.8%) patients didn’t. The characteristics of 34 patients who did not received re-biopsy were; the median age, 67 years (29-83), male/ female: 12/22, PS0-1/2 ≥:27/7, stage IV/recurrence/other:20/10/4, smoking history never/ex/current: 15/17/2, histology : adeno/other 34/0, EGFR mutation type; 19del/L858R/Other = 13/15/6, prior EGFR-TKI; Gefitinib/Erlotinib/Afatinib/other: 22/9/2/1. The commonest reason why they did not receive re-biopsy was no target lesion to get biopsy (n = 13,38%). CT scans of these patients were retrospectively evaluated and it was confirmed that there were no lesions that could be accessed safely at that time. Central nervous system lesions, multiple small pulmonary lesions and bone metastasis were unaccessible lesions. Although 21 patients had accessible lesions including lung, superficial lymph nodes, pleural effusion, liver, they did not receive re-biopsy because of patient refusal (n = 9), worsening of general condition (n = 3), need for other therapy immediately (ex: chemotherapy, radiotherapy) (n = 3), old age (n = 2), existence of de novo T790M (n = 2), complications (n = 1) and physician’s choice (n = 1). Conclusions: Some patients who did not recieve re-biopsy had some target lesions and it could be increase the re-biopsy rate.
Phase II trial of the c-Met inhibitor tepotinib in advanced lung adenocarcinoma with MET exon 14 skipping mutations.
Authors: Paik Paul K. , Felip Enriqueta , Veillon Remi , Scheele Jürgen , Bruns Rolf
Published: September 2018

e20541

Background: Approximately 3-4% of lung adenocarcinomas express a truncated form of c-Met (c-Metex14) due to mutation-induced exon 14 skipping. c-Metex14 accumulates on the cell surface and is constitutively active with the ability to drive NSCLC. Data suggest that lung adenocarcinomas harboring c-METex14 are sensitive to c-Met kinase inhibitors. The highly selective c-Met inhibitor tepotinib is well tolerated and active at an oral dose of 500 mg QD. This single-arm phase II trial (NCT02864992) is investigating the efficacy and safety of tepotinib in patients (pts) with advanced lung adenocarcinoma harboring METex14. Methods: Adults with stage IIIB/IV lung adenocarcinoma who have failed 1 or 2 lines of systemic therapy, including a platinum doublet-containing regimen, are eligible. Tumors must harbor mutations that are known to cause exon 14 skipping, confirmed by a central laboratory, but not activating EGFR mutations or ALK rearrangements. Pts receive tepotinib 500 mg QD until disease progression, intolerable toxicity, or withdrawal from treatment for other reasons. The primary endpoint is objective response rate. Secondary endpoints include progression-free and overall survival, safety, pharmacokinetics, and quality of life. Recruitment of 60 patients in Europe, USA, and Japan is planned. Results: Four pts (age 64–77 years; 3 stage IV, 1 stage IIIB, all Caucasian males) have been enrolled. All had received two prior chemotherapy regimens including a platinum doublet. Pts have currently completed 1–5 cycles of tepotinib therapy. The majority of adverse events observed to date have been grade 1/2 in severity; grade 3 disease-related dyspnea, pulmonary embolism, and pleural effusion were observed in one patient and grade 3 tepotinib-related elevated serum amylase in another. Of the 3 pts with post-baseline tumor evaluations, two have had an unconfirmed partial response and the third (with only one post-baseline assessment) stable disease. Conclusions: These initial data suggest that the efficacy of tepotinib 500 mg QD is comparable to that of less selective c-Met inhibitors in pts with c-METex14 NSCLC (ORR > 40%). Tepotinib is also well tolerated. Recruitment to the trial is ongoing. Clinical trial information: NCT02864992.
A comparison of gefitinib for advanced non-small cell lung cancer patients with different EGFR mutation types.
Authors: Zhang Haijun , Patel Nishant , Wu Pingping
Published: September 2018

e20544

Background: The aim of this study was to compare the efficacy and toxicity of gefitinib as first or second line therapy for advanced non-small cell lung cancer (NSCLC) patients with positive exon 21 (L858R) or exon 19 deletion mutation. Methods: We retrospectively analyzed the clinical data of 60 endothelial growth factor receptor ( EGFR) mutated advanced lung adenocarcinoma patients from July 2011 to November 2015, who have received oral gefitinib 250 mg once daily. Gefitinib was taken until disease progression, intolerable toxicity or death. Results: At the time of last follow-up visit, 1 death had occurred. Among the 59 patients who remained survival, 17 patients progressed. Overall, the median progression-free survival (mPFS) was 10 months (95% confidence interval (CI): 7.53–12.46 months, p < 0.05). The response rate (RR) and disease control rate (DCR) were 33.33% and 71.66%, respectively. However, there was longer mPFS in first line therapy than that in second line therapy: in first-line gefitinib therapy, mPFS was 12 months among 41 patients (95% CI: 9.58–14.41 months, p < 0.05); in the second line therapy, mPFS was 7 months among 19 patients (95% CI: 1.31–12.68 months, p < 0.05). Furthermore, in subgroup analyses examining different EGFR mutation types, we noted mPFS was significantly longer for patient with exon 19 deletion than that with positive exon 21in both first line therapy and second line therapy. The most common Grade 1 or 2 adverse events included rash (76.6%), abnormal liver function (60%), dry skin (48.3%), diarrhoea (46.6%), fatigue (40%) and paronychia (33.3%) etcetera in non-haematological toxicity, whereas anemia(33.3%), leukocytopenia (20%) etcetera were included in haematological toxicity. Conclusions: Patients with NSCLC who were selected by positive exon 21 or 19 deletion mutations had significantly longer mPFS in first line therapy than that in second line therapy when treated with gefitinib. And EGFR mutation types may influence the response to gefitinib therapy.
Smad4 expression and chemosensitivity in non-small cell lung cancer.
Authors: Ziemke Michael , Patil Tejas , Nolan Kyle , Malkoski Stephen
Published: September 2018

e20550

Background: Smad4 is a tumor suppressor that transduces transforming growth factor beta signaling and regulates genomic stability. We previously found that reduced Smad4 expression was associated with increased DNA damage in both human NSCLC and murine NSCLC models and that reduced Smad4 expression inhibits DNA repair and increases sensitivity to DNA topoisomerase inhibitors. In this study, we assessed the association between reduced Smad4 expression and DNA topoisomerase inhibitor sensitivity in human NSCLC as well as the relationship between Smad4 mutation and homozygous deletion and molecular alterations in other DNA repair molecules. Methods: After IRB approval, we retrospectively identified NSCLC patients who received etoposide or gemcitabine and had an evaluable tumor on CT scan at the University of Colorado Hospital between 2004 to 2014. Chemotherapeutic response was quantified by RECIST criteria, while Smad4 expression was assessed by immunohistochemistry (IHC) and quantified on a 0-300 scale. The relationship between Smad4 mutation and other DNA repair molecule alterations was assessed using TCGA data via cBioPortal. Results: Of the 21 evaluable patients, 19/21 received gemcitabine or etoposide for advanced (stage 3 or 4) disease and 10/21 received these agents with concurrent radiation therapy. Reduced Smad4 expression (IHC score < 100) occurred in 8/21 patients and was associated with non-significant trend (p = 0.18, fisher exact test) toward responsiveness to gemcitabine or etoposide. TCGA data analysis revealed that while Smad4 mutation or homozygous loss was not associated with reduced survival, Smad4 alterations were mutually exclusive to defects in DNA repair molecules. Conclusions: Reduced Smad4 expression may be a biomarker for responsiveness to treatment with chemotherapeutic drugs that inhibit DNA topoisomerase, though this study was underpowered to detect this. That Smad4 signaling alterations are mutually exclusive with alterations in other DNA repair machinery is consistent with a role of Smad4 in regulating DNA repair.
Outcome of EGFR mutant patirnts included in a clinical trial after progression on EGFR TKI.
Authors: Pardo Aranda Nuria , Remon Jordi , Martinez Marti Alex , Martinez de Castro Ana Maria , Cedres Perez Susana , Navarro Alejandro , Scheenaard Eulalia , Piera Adelaida , Carbonell LLuisa , Vivancos Ana , Felip Enriqueta , Gámez Córdoba Esther
Published: September 2018

e20555

Background: EGFR mutant(EGFRm) NSCLC patients develop adquired resistance after 12 months on EGFR TKI. Acquired T790mutation(T790M) is the most common mechanism of resistance in around 60% of patients, followed by MET amplification in 20% of cases. Inclusion in a clinical trials at progression may have an impact in patients’ outcome. Methods: We retrospectively assessed the overall survival in EGFRm patients according to post-progression treatment on 1st/2nd generation EGFR TKI: standard vs. experimental (clinical trial). Also, we assessed the survival in the cohort of acquired T790M NSCLC patients(p). X2 test and long rank test P values are described. OS was defined since progression 1st/2nd generation EGFR TKI to death or last follow up Results: 42p EGFRm were enrolled. According to EGFRm subtype (24 p EGFR del19, 14p EGFR L858R, 1p EGFR exon18, 1 EGFR exon20 ,2p unknown). Median age was 58 (33-83) and 27 (64%) females. First-line EGFR TKI was 30% gefitinib / 58 % erlotinib /10 % afatinib/2% dacotinib At PD, in 51 biopsies (b) were performed,11p were biopsy twice.Tumor tissue for molecular determinations was available in in 86% of cases. Druggable molecular alterations were detected in 57% of cases: 20 acquired T790M and 4 MET amplification. According to these results all 24 p were enrolled in a clinical trial (NCT02108964,NCT01802632,NCT02147990,NCT02335944, NCT02151981), and 18p were screening failure; 8p (45%) of them due to abscense of adquired resistance mechanisms. 10 received platinum-based chemotherapy and 6 only received best supportive care. OS metastatic disease was 51 months for patients included in a clinical trial vs 22 months for those on standard treatment (p < 0.001; 95%CI: 14.4-47). OS was: 34 months vs 10 months for those included in a clinical trial vs standard, respectively (p < 0.001; 95%CI: 8.88-25). For T790M tumours, OS post-progression was 25 months Conclusions: Enrolling patients in clinical trials may allow personalised treatment according to mechanisms of resistance improving survival after 1st/2nd generation EGFR TK progression disease.
Response to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with de novo epidermal growth factor receptor (EGFR) T790M and S768I resistance mutations.
Authors: Kelly Deirdre , Prior Lisa Mary , Gleeson Jack Patrick , McSorley Lynda M. , Kearns Rachel , Brady Claire , Sui Jane Sze Yin , Dawod Mohammed Adam Ibrahim , Burke Louise , McCarthy Julie , McDermott Ray , McCaffrey John , Power Derek Gerard , O'Reilly Seamus , O'Mahony Deirdre , Finn Stephen P. , O'Brien Cathal , Bambury Richard M.
Published: September 2018

e20557

Background: Patients with synchronous de novo EGFR sensitising and resistance mutations are rare. Little is known about the response of these patients to EGFR TKIs, especially in a Caucasian population. Methods: We identified NSCLC patients found to have EGFR mutations using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing using a large multi-institutional database. Baseline clinical characteristics, response rate, progression free survival (PFS) and overall survival (OS) were calculated. Results: From 2008-2015, we observed de novo synchronous EGFR sensitising and resistance mutations in 12 patients representing an overall incidence of 3.6% of EGFR mutants and 0.4% of all NSCLC patients tested. Seven patients were treated using EGFR TKI therapy with erlotinib. In all cases, T790M (n = 4,50%) or S768I (n = 4, 50%) occurred concurrently with another sensitising EGFR mutation, either L858R (n = 4, 34%) or exon 19 deletion (n = 8, 66%). Objective responses were seen in two patients (29%). Three further patients had stable disease lasting 6, 23 and 54 months respectively. The median progression-free survival was 24 months and the median overall survival was 34 months. All patients with baseline EGFR S768I mutations (n = 3) had an objective response or stable disease on erlotinib while two of four patients with T790M demonstrated de novo resistance. Conclusions: This is the largest Irish review of synchronous de novo EGFR mutations. The incidence of co-occurring EGFR mutations was 0.4% and erlotinib demonstrated activity in this cohort of patients. Ongoing trials will determine whether next-generation EGFR TKIs such as osimertinib are preferable as first-line therapy in these patients.
Association of the bevacizumab pharmacokinetics with efficacy and toxicity in advanced non-squamous non-small cell lung cancer: Kumamoto Thoracic Oncology Study Group (KTOSG) 1003 study.
Authors: Saeki Sho , Sasaki Jiichiro , Sakata Shinya , Sato Ryo , Saruwatari Koichi , Sakamoto Yasumiko , Inaba Megumi , Kishi Hiroto , Fujii Shinji , Tsumura Shinsuke , Ouchi Mayu , Saito Hideyuki , Hamada Akinobu , Kohrogi Hirotsugu
Published: September 2018

e20559

Background: Biomarkers predicting the efficacy and toxicity of bevacizumab (Bev) have not yet been established. Therefore we conducted this pharmacokinetic study to elucidate the role of plasma concentration of Bev as a biomarker to predict outcome in the treatment of patients with lung cancer. Methods: This multicenter prospective pharmacokinetic study was conducted among nine centers in Kumamoto Prefecture, Japan. Patients with non-squamous non-small cell lung cancer who were treated using tri-weekly Bev (15mg/kg) with platinum-doublet chemotherapy were enrolled. Plasma samples were collected from all patients before the administration of every dose of Bev until disease progression or treatment discontinuation owing to toxicity. Plasma concentrations of Bev were analyzed via nano-surface and molecular-orientation limited proteolysis coupled with liquid chromatography-mass spectrometry. Results: Between July 2010 and May 2014, 30 patients were enrolled in this study. Majority of the patients received pemetrexed with cisplatin or carboplatin (24 patients, 80%) and others received paclitaxel with carboplatin. The trough concentrations of Bev after first administration (day 22) were 63.19 ± 19.57 μg/mL. Trough concentrations gradually increased until the six cycle of Bev and reached a steady state. Plasma concentrations of Bev did not decrease until disease progression in patients with a long treatment period. Higher mean plasma concentrations of Bev correlated with female sex (p = 0.034) and high serum albumin levels (p = 0.034). Patients who received pemetrexed had higher mean concentrations of Bev (p = 0.038) than those who received paclitaxel. The response rate and progression-free survival did not correlate with the plasma concentration of Bev. Proteinuria (≥Grade 2) correlated with higher concentrations of Bev. Conclusions: Our study demonstrated that various types of chemotherapy influenced the concentrations of Bev, and a higher concentration of Bev may predict the incidence of proteinuria. In addition, clearance of Bev did not change after long treatment period until disease progression. Clinical trial information: 000007630.
Clinical outcomes after whole genome sequencing in patients with metastatic non-small cell lung cancer.
Authors: Tsang Erica S , Shen Yaoqing , Chooback Negar , Ho Cheryl , Jones Martin , Renouf Daniel John , Lim Howard John , Sun Sophie , Yip Stephen , Pleasance Erin , Ma Yussanne , Zhao Yongjun , Mungall Andrew J. , Moore Richard , Jones Steven , Marra Marco , Laskin Janessa J.
Published: September 2018

e20563

Background: The Personalized OncoGenomics (POG) program at the BC Cancer Agency integrates whole genome (DNA) and RNA sequencing into practice for metastatic malignancies. We examine patients with metastatic NSCLC and report the prevalence of actionable targets, treatments, and outcomes. Methods: Between 2012-2016, 217 patients had a tumor biopsy and blood sample with comprehensive DNA (80X; 40X normal) and RNA sequencing followed by in-depth bioinformatics to identify potential cancer “drivers” and/or actionable/treatable targets. In NSCLC cases, we compared the progression-free survival (PFS) of “POG-informed therapies” with the PFS of the last regimen prior to POG (PFS ratio). Results: In 29 NSCLC cases, median age was 60.2 years (range 39.4-72.6), 11 were male (38%), and histologies were: adenocarcinoma (93%); squamous cell carcinoma (7%). Potential molecular targets (i.e. cancer “drivers”) were identified in 26 (90%), and 21 (72%) had actionable targets. 13 received POG-informed therapies, of which 3 had no therapy before POG. Of 10 patients with POG-informed therapy, median PFS ratio was 0.94 (IQR 0.2-3.4). 3 (30%) had a PFS ratio ≥1.3, and 3 (30%) had a PFS ratio ≥0.8 and <1.3. Conclusions: In this NSCLC cohort, 30% demonstrated longer PFS with POG-informed therapies. Larger studies will help clarify the role of whole genome analysis in clinical practice. [Table: see text]
Outcomes after the diagnosis of brain metastases in Brazilian NSCLC patients.
Authors: Ce Coelho Juliano , Weis Luiza , Marks Patricia , Geib Guilherme , Liedke Pedro Emanuel Rubini , Pereira Rodrigo Perez , Rebelato Taiane , Franzoi Maria Alice B , Branco Mariane , Schwartsmann Gilberto , Azevedo Sergio J
Published: September 2018

e20568

Background: Brain metastases (BM) are common and affects near half of patients with non-small-cell lung cancer (NSCLC), with poor prognosis. Few data is available about this group of patients and Brazilian are underrepresented. Methods: Patients with NSCLC that developed BM between January 05 and December 15 at Hospital de Clinicas de Porto Alegre were identified and medical records were reviewed. OS and PFS were estimated by Kaplan-Meier curves. Multivariate analysis was performed to identify factors associated with survival. Statistical analysis was performed with SPSS 22.0. Results: 113 patients were identified. Mean age was 60.1 ± 8.7 years, 50% were female, 84% were Caucasian, 87% had a positive smoking history, 71% had adenocarcinoma histology and 72% had stage IV disease at presentation. BM was present at initial diagnosis in 38% of patients. At diagnosis of BM, 39% of patients had a Karnofsky performance status < 70, 20% had systemic disease under control, 31% had more than 3 brain lesions and 81% had a GPA score ≤2. 35 patients (31%) were submitted to either surgery or stereotaxic radiotherapy (SRDT), 52 (46%) to whole brain radiation (WBRT) and 26 (23%) to best supportive care (BSC). With a median follow-up of 11.2 months, 96% of patients have died. The OS was 11.2 months (95% IC, 9.4 to 13.1). The median survival time following diagnosis of BM was 4.9 months and survival according to treatment was 16.3 months for resection, 8.9 months for SRDT, 3.8 months for WBRT and 0.7 months for BSC. A Karnofsky performance status < 70 at diagnosis of BM and palliative treatment to BM (WBRT or BSC) were associated with worse outcome in multivariate analysis. The GPA score wasn't statically associated with prognosis. A longer survival of patients submitted to WBRT was seen when compare to BSC, HR of 0.38. There is a trend for longer survival in patients submitted to BM resection when compared to SRDT, but without statically significance. Conclusions: To our knowledge this is the largest report of NSCLC patients with BM from Latin America. Our data is in line with previous reports. A poor Karnofsky performance status and palliative treatment to BM are associated with poor survival. WBRT is associated with longer survival when compared to BSC in all the GPA score stratus.
IGFBP-7 to confer resistance to the epidermal growth factor receptor tyrosine kinase inhibitor.
Authors: Wu Shang-Gin , Chang Tzu-Hua , Chang Yih-Leong , Tsai Meng-Feng , Yu Chong-Jen , Shih Jin-Yuan
Published: September 2018

e20572

Background: Lung cancer is a leading cause of cancer death worldwide. The EGFR mutation-positive patients of lung adenocarcinoma had dramatic response to EGFR tyrosine kinase inhibitors (TKIs). However, acquired drug resistance developed invariably after one year treatment course of EGFR TKI. IGFBP-7, a secreted 31 kDa protein, exhibits low affinity for IGF but binds strongly to insulin. No previous studies had been mentioned the correlation between the protein and acquired EGFR TKI resistance. Methods: cDNA microarray was used to screen differentially expressed genes between EGFR TKI-sensitive (PC9 and HCC827) and acquired EGFR TKIs-resistance cell lines (PC9/gef and HCC827/gef). The expression levels of the screened genes were validated by RT -PCR and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of IGFBP-7 on gefitinib resistance in vitro. In addition, clinical specimens were collected to validate the imact of IGFBP-7 on the efficacy of EGFR TKI treatment . Results: IGFBP-7 is over-expressed in gefitinib-resistant cells. The IGFBP-7 mRNA expression in the malignant pleural effusion of patients with acquired resistance to EGFR TKI was significant higher than that in the treatment-naïve patients. Knockdown IGFBP-7 reverses gefitinib resistance in PC9/gef cells. Knockdown IGFBP-7 could increase gefetinib induced-apoptosis through the regulation of BIM. IGFBP-7 affected the mechanism of EGFR TKI resistance resulted from inhibition of IGF-IR.. In clinical practice, low IGFBP-7 serum level is associated with longer progression free survival (PFS) of EGFR TKI as the first line treatment. Furthermore, lower IGFBP-7 level of resected tumor predicts a longer 5-year tumor relapse-free survival. Positive IGFBP-7 immunoihistochemical stain could predict a shorter PFS of the first-line EGFR TKI treatment. Conclusions: IGFBP-7 confers resistance to the EGFR TKI and may be a target for future treatment investigation.
ΔCT value of amplified refractory mutation system (ARMS) to predict efficacy of EGFR-TKIs in non-small cell lung cancer: A multicenter retrospective study.
Authors: Liu Laiyu , Chen Min , Li Gong , Yang Dongyong , Xiao Nanjie , Zhang Weijian , Guo Libin , Guan Jian
Published: September 2018

e20573

Background: This multi-center retrospective study was to determine whether the ΔCt value of Amplified Refractory Mutation System (ARMS) in EGFR mutated detection in tumors predicts the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC). Methods: A total of 108 NSCLC patients harbored an exon 19 deletion (19Del) or exon 21 L858R mutation detected by ARMS were enrolled. We identified patients with ΔCt<1(Group L) harbored a high proportion of EGFR mutation but the patients with ΔCt≥1 (Group H) harbored a low proportion of EGFR mutation in the tumor sample. The progression-free survival (PFS), objective response rates (ORRs) and overall survival (OS) between the groups were analyzed. Results: In the 108 patients we enrolled, 63 were in group L and 45 were in group H. Patients’ demographics and clinical characteristics including age, sex, smoking history, pathology, mutation sites, TNM stage, line of TKIs therapy were not significantly difference between group L and group H. The Median PFS was 331 days (95%CI: 311.8 to 350.2) in group L and 206 days (95%CI, 157.2 to 254.8) in group H and the difference showed statistically significant (P < 0.001). Moreover, the ORRs in group L was significant higher than the group H (60.0% vs 34.9%, P = 0.011). The median OS was 744 days (95%CI, 635.5 to 852.5) in group L and 596 days in group H (95%CI, 491.7 to 700.0) but showed not statistically significant ( P = 0.098). Conclusions: ΔCt value of ARMS in EGFR mutated detection could be an efficacy predictor for EGFR-TKIs treatment in advanced EGFR-mutant NSCLC.