bluuebunny/crossref_metadata_2025 huggingface dataset:
A feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation (H-RT) for malignant pleural mesothelioma (MPM): First all-Japan trial.
Authors: Tanaka Fumihiro , Hasegawa Seiki , Okada Morihito , Yamanaka Takeharu , Soejima Toshinori , Kamikonya Norihiko , Fukuoka Kazuya , Yokoi Kohei , Nakano Takashi
Published: March 2020

7583

Background: The first all Japan multi-institutional trial was conducted to evaluate the feasibility of tri-modality therapy for MPM with support by the Special Coordination Funds for Promoting Science and Technology from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the first analyses data including macroscopic complete resection (MCR) rate by EPP as well as treatment-related mortality were presented at the ESMO meeting 2011 after completion of planned patient enrollment, and all survival data collection has been completed in January 2013. Methods: Major eligibility criteria: a histologically confirmed diagnosis of MPM, including all subtypes clinical T0–3, N0–2, M0 disease considered to be completely resectable; no prior treatment for the disease; age between 20 and 75 years; ECOG performance status of 0 or 1; a predicted postoperative forced expiratory volume in 1 s of >1000 ml; and written informed consent. Treatment methods: Induction chemotherapy of pemetrexed 500 mg/m2 plus cisplatin 60 mg/m2 for 3 cycles, followed by EPP and postoperative H-RT (54 Gy). Primary endpoints: MCR rate by EPP and treatment-related mortality for tri-modality therapy. Results: A total of 17 institutions in Japan with certified specialists in oncology, surgery and radiation therapy participated in this trial. The study was initiated in May 2008 and patient enrollment was completed in November 2010 with 42 eligible patients. Median age 64.5 (range 43–74), M: F = 39:3, Clinical stage I:II:III = 14:13:15, Histological type epithelial: sarcomatous; biphasic; others = 28: 1: 9: 4. The trial met the primary endpoints with MCR rate of 71% and treatment-related mortality of 9.5%. All survival data to calculate disease-free survival and overall survival at 2 years after EPP have been collected, and results will be presented at the meeting. Conclusions: Results of the present trial will be the foundation of treatment strategy for resectable MPM. Clinical trial information: 000001154.
A clinical-based risk score for decision making for surgery after induction chemotherapy in malignant pleural mesothelioma patients.
Authors: Opitz Isabelle , Friess Martina , Stahel Rolf A. , Weder Walter
Published: March 2020

7587

Background: Scoring tools predicting the potential benefit from surgery after induction chemotherapy in mesothelioma patients may influence decision making. Our score is based on 4 clinical variables available before surgery. Methods: 128 patients were uniformly treated with cisplatin based induction chemotherapy followed by extrapleural pneumonectomy between 1999 and 2011. Based on clinical experience and survival influencing factors resulting from uni-and multivariate analysis, we designed a risk score. All 4 variables building up the score were available for 59 patients: pre chemotherapy volumetry above 500 ml, non-epithelioid histotype in the diagnostic biopsy, pre chemotherapy CRP value above 30 mg/l and progressive disease after chemotherapy according to modified RECIST criteria. The 5 resulting groups were analyzed for overall survival (OAS) and progression free survival (PFS) using Kaplan-Meier and Cox regression model. Results: The score strongly stratified patients into high and low risk groups for shorter OAS (Table) (p<0.0005). As to PFS, patients with Score 0 also had significantly longer median PFS (16 months; 95% CI: 12; 20) in comparison to patients with score 3 or higher (6 months; 95% CI: -; -) (p<0.0005). In Cox regression analysis the risk factor for shorter OAS and PFS increased correspondingly to our score. Conclusions: Our new score based on 4 clinical variables available before surgery identifies patients’ subgroups who may benefit from surgery after induction chemotherapy, which will be further assessed prospectively. [Table: see text]
Phase I/IIa study of the novel combination of bendamustine (B) with irinotecan (I) followed by etoposide (E) and carboplatin (C) in untreated patients (Pts) with extensive-stage small cell lung cancer (ESSCLC).
Authors: Allendorf Daniel Joseph , Bordani Rodolfo , Grant Stefan C. , Saleh Mansoor N. , Jerome Mary , Miley Debi , Cantor Alan , Reddy Vishnu , Robert Francisco
Published: March 2020

7591

Background: Standard therapy for ESSCLC consisting of E and a platin drug (Plat) yields a median time to progression (TTP) of 4 months (m) and overall survival (OS) of 9 m. DNA damage from B is repaired by excision repair, akin to Plat. The activity of I, a topoisomerase (Top)-1 inhibitor, leads to increases in Top-2, the target of E. The sequence B+I → E+C was hypothesized to increase TTP by exploiting mitotic catastrophe. Methods: This is an open label trial enrolling pts with ESSCLC and evaluable disease. The phase I primary endpoint was to determine the maximum tolerated dose (MTD) of B+I; the phase IIa primary endpoint was TTP after B+I→E+C. Secondary endpoints were objective response rate (ORR) and OS. In the phase I (N=15), cohorts received I (150 mg/m2, d 1) with B at 80, 100, or 120 mg/m2/day (d 1,2) every 3 weeks for 3 cycles. Phase IIa Pts were treated at the recommended dose of B+I for 3 cycles followed by E (100 mg/m2, d 1-3) + C (AUC 6, d 1) for 3 cycles. Restaging was performed after 3 cycles of each regimen. The phase IIa was powered to detect a 30% increase in TTP from 4 to 5.2 m with a of 0.1. The Kaplan-Meier method was used to calculate TTP and OS. Toxicities were evaluated using the NCI CTCAE. Results: The MTD of B was not reached. The recommended phase IIa dose of B was 100 mg/m2; dose-escalation was allowed in subsequent cycles of therapy. Dose limiting toxicities were diarrhea, nausea, and vomiting. One treatment-related death from metabolic encephalopathy occurred in the phase IIa. The commonest grade 3/4 hematologic toxicity was neutropenia. Fatigue, nausea, vomiting, and diarrhea were common non-hematologic toxicities. Conclusions: B+I is an active regimen in ESSCLC and the treatment sequence B+I→E+C seems to improve the TTP and OS in ESSCLC compared to historic values for E+C. Toxicities were increased compared to historic values for E+C, but were manageable. Correlative studies with pre-treatment assessment of tumor ERCC-1, Top-1, and Top-2 as predictors of response are ongoing. Clinical trial information: NCT00856830. [Table: see text]
Small cell lung cancer (SCLC) among patients who are never smokers.
Authors: Varghese Anna M. , Yu Helena Alexandra , Won Helen H. , Sima Camelia S. , Riely Gregory J. , Krug Lee M. , Rekhtman Natasha , Kris Mark G. , Berger Michael F. , Zakowski Maureen Frances , Pietanza Maria Catherine
Published: March 2020

7593

Background: Although most patients (pts) with SCLC are current or former smokers, SCLC has been reported in pts who are never smokers, most recently in pts with EGFR-mutant lung cancers who develop acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs). We describe clinical, pathologic, and molecular characteristics of never-smoking pts with SCLC at diagnosis and in the AR setting. Methods: We identified cases through systematic review of pts seen at MSKCC from 2005 – 2012. Smoking history was obtained prospectively. SCLC diagnosis was confirmed by expert pathology review. We collected age, sex, stage, treatment, and survival data. EGFR, KRAS, PIK3CA, and ALK testing and next generation sequencing of 279 cancer genes was performed on available samples. Results: 2.2% (23/1040, 95% CI 1.5 to 3.3%) of pts with SCLC seen at MSKCC were never smokers: 61% women, median 64 years, 74% extensive stage, and 22% with brain metastases at diagnosis. 83% (19/23) had de novo SCLC, whereas only 17% had SCLC as AR to EGFR TKI after treatment for EGFR-mutant lung cancers, all of whom had persistent EGFR mutation confirmed at resistance. Median survival from SCLC diagnosis is 23 months (95%CI: 11-26) for all pts and 23 months (95% CI: 8–27) for the 19 pts with de novo SCLC. Pathologic review demonstrated 19 cases of pure SCLC and 4 mixed histology cases with SCLC and other histologies. Treatment history was available for 15/19 pts with de novo SCLC: 53% etoposide-platinum sensitive. ALK rearrangement and KRAS mutations were identified in 0/5 and 0/10, respectively. One pt with de novo mixed SCLC and adenocarcinoma had an EGFR mutation and another pt with de novo pure SCLC had EGFR and PIK3CA mutations. Mutations were identified in p53 and Rb1 with amplification in TERT in 1 sample to date tested with next generation sequencing. Conclusions: 2% of pts with SCLC are never smokers. While transformation to SCLC can occur in the setting of AR to EGFR TKI, de novo SCLC occurs in the majority of our never smokers with this disease. EGFR mutations uniformly exist in SCLC in the AR setting. EGFR mutations were rare, and we found no KRAS mutations or ALK rearrangements. Comprehensive, multiplexed genotyping can aid in providing optimal care and facilitate research in this unique population.
Can hippocampus be spared in patients with small cell lung carcinoma (SCLC) during cranial radiation therapy (CRT)?
Authors: Kundapur Vijayananda , Ellchuk Tasha , Ahmed Shahid
Published: March 2020

7596

Background: Although CRT is a standard therapy for prevention and treatment of brain metastases (BM) in patients with SCLC, neurocognitive impairment (NI) following therapeutic whole brain radiation treatment (WBRT) or prophylactic cranial irradiation (PCI) is a major problem and can cause impairment in quality of life. A RTOG study is assessing various outcomes by avoiding the hippocampus (AH) during WBRT in different malignancies. The estimated risk of hippocampal avoidance region metastases (HM) in patients with SCLC before & after WBRT/PCI is not known. AH during CRT may delay the onset of NI in such patients. Our study aims to determine risk of HM in patients with SCLC and to assess clinical factors correlate with it. Methods: A patients cohort of SCLC diagnosed and treated at the Saskatoon Cancer Center between 2005 and 2012 were followed. All MRI and/or CT scans were independently reviewed by a neuroradiologist. HM was defined as BM within 5 mm of hippocampus. Binary Logistic regression analysis was done to assess correlation between various clinical variables and HM using SPSS. Results: 162 patients with SCLC were identified, 60 (37%) have developed BM. The preliminary data of 39/60 patients is presented here. All 39 patients received CRT and 17 patients received upfront chemotherapy. Their median age was 63 yrs (range: 41-82) & M:F was 22:17. 30 (77%) had extensive stage SCLC and 30 (77%) had de novo BM before CRT. A total 198 (range: 1-33) BM were identified among these patients with a mean BM of 6.6 per patient. 4 (13.3%) of 30 patients had HM involvement with mean BM of 1.3 per patient. Median follow up was 13.5 months (range: 1-69). Post-CRT 13 (33%) of 39 patients (4 PCI, 9 WBRT) developed central nervous system (CNS) progression. None of 13 patients with CNS failure following CRT developed HM. Overall 4 (10.2%) of 39 patients developed HM. No clinical factors significantly correlated with HM. Conclusions: The preliminary result revealed that overall incidence of HM before and after WBRT/PCI is low. AH in such patients may consider during CRT to avoid NI. The study is ongoing and final analysis will be presented.
Development of a SOMAmer (slow off-rate modified aptamer)-based assay to detect NSCLC.
Authors: Park Noh Jin , Root Dana , Wang Xiuqiang , Diaz Angelica , Esmailpour Taraneh , Birse Charlies e , Lagier Robert , Sun Weimin , Morrone Robert J. , Waldman Frederic , Strom Charles m
Published: March 2020

7601

Background: Support for low-dose helical computed tomography (CT) screening for lung cancer in a high risk population has emerged from the National Lung Screening Trial (NLST). However, the low specificity of CT raises concerns regarding the cost and potential morbidity associated with resection of benign nodules. Non-invasive lung cancer biomarkers may serve as a useful complement to imaging, providing a simple means to further clarify the diagnosis of suspicious pulmonary nodules. SOMAmer-based chip technology was previously used to identify a panel of serological biomarkers capable of accurately classifying NSCLC. Here we assess the analytical and clinical performance of an automated assay that uses SOMAmer reagents and qPCR to simultaneously quantify a subset of these markers (n=12). Methods: Biomarker levels were measured in sera from 43 subjects with stage I-III NSCLC and 63 long-term smoker controls. qPCR results were analyzed by relative (ΔΔCT) quantitation, which uses calibrator serum and a set of normalizers. Linear mixed-effects models were fit to identify key sources of analytical variability (variance components), including plate-to-plate, within-sample, and between sample effects. Clinical performance for distinguishing NSCLC from control sera was established by a random forest predictive model. Results: Median within-sample %CV for the 12 markers was 6.7%. Variance components analyses suggest that, on average, 5.7% of the variance for a given biomarker was due to within-sample effects, 5.2% to plate-to-plate effects, and 86.2% to between-sample effects. A 10-marker random forest model exhibited an AUC [95% CI] of 0.915 [0.905, 0.924], classifying NSCLC from control sera with 79% sensitivity and 90% specificity. Conclusions: We have developed a highly reproducible automated assay designed for the clinical laboratory. Combining SOMAmer-based protein capture and qPCR-based quantification, the assay monitors the levels of 12 potential lung cancer markers. An algorithm-based model incorporating 10 of these markers showed good accuracy for distinguishing NSCLC from control sera. Further studies are warranted to evaluate the performance of the test in classifying pulmonary nodules.
Randomized phase III trial of erlotinib (E) versus docetaxel (D) as second- or third-line therapy in patients with advanced non-small cell lung cancer (NSCLC) who have wild-type or mutant epidermal growth factor receptor (EGFR): Docetaxel and Erlotinib Lung Cancer Trial (DELTA).
Authors: Okano Yoshio , Ando Masahiko , Asami Kazuhiro , Fukuda Masaaki , Nakagawa Hideyuki , Ibata Hidenori , Kozuki Toshiyuki , Endo Tateo , Tamura Atsuhisa , Kamimura Mitsuhiro , Sakamoto Kazuhiro , Yoshimi Michihiro , Soejima Yoshifumi , Tomizawa Yoshio , Isa Shunichi , Takada Minoru , Saka Hideo , Kubo Akihito , Kawaguchi Tomoya
Published: March 2020

8006

Background: E and D are standard cares for previously treated patients with advanced NSCLC. Although E shows significant clinical benefits over best supportive care in the EGFR wild type tumors, it remains unknown whether E or D is more active against the disease. Methods: This is an open-label, multi-center phase III study, sponsored by the Japanese National Hospital Organization. Patients were randomized to E (150 mg, daily), or D (60 mg/m2, q3w) by the minimization method according to gender, performance status, histology, and institution. The primary endpoint was progression free survival (PFS), and secondary endpoints included overall survival (OS), response rate, safety, and analyses on EGFR wild type tumors. Eligible patients were those with pathologically proven NSCLC with stage IIIB or IV (AJCC version 6) previously treated with one or two chemotherapy regimens including at least one platinum agent, evaluable or measurable disease, and ECOG PS 0-2. Target sample size was calculated to be 280 based on the assumption that E was superior to D in PFS (3.5 months [m] v 2.5 m, α =0.05 [two sided], β =0.80). Results: From August 2009 to July 2012, 301 patients were accrued from 41 institutions. In the ITT population, 150 and 151 patients were randomly assigned to E and D, respectively, including respective 109 (73%, E) and 89 (59%, D) with EGFR wild type tumors. Median PFS and OS for E v D were 2.0 m (95% CI: 1.3-2.8) v 3.2 m (2.8-4.0, log-rank p=0.092; HR=1.22, 95% CI: 0.97-1.55), and 14.8 m (9.0-19.4) v 12.2 m (9.0-15.5, p=0.527; HR=0.91, 95% CI: 0.68-1.22), respectively. In the EGFR wild type tumors, PFS and OS for E v D were 1.3 m v 2.9 m (p=0.013; HR =1.44, 95% CI: 1.08-1.92), and 9.0 m v 9.2 m (p=0.914; HR =0.98, 95% CI: 0.69-1.39), respectively. Main grade 3/4 toxicities were rash (13.3% [E] v 0.7% [D]) and leukopenia (5.4% [E] v 62.9% [D]). Conclusions: E failed to show better PFS over D. While PFS was significantly longer in D than E in EGFR wild type tumors, the difference did not translate into OS in this pragmatic trial. Clinical trial information: 000002314.
Effect of maintenance bevacizumab (Bev) plus pemetrexed (Pem) after first-line cisplatin/Pem/Bev in advanced nonsquamous non-small cell lung cancer (nsNSCLC) on overall survival (OS) of patients (pts) on the AVAPERL (MO22089) phase III randomized trial.
Authors: Rittmeyer Achim , Scherpereel Arnaud , Gorbunova Vera A. , Gervais Radj , Vikström Anders , Chouaid Christos , Chella Antonio , Kim Joo-Hang , Ahn Myung-Ju , Reck Martin , Pazzola Antonio , Kim Heung Tae , Aerts Joachim , Groen Harry J.M. , Morando Claire , Loundou Anderson , Barlesi Fabrice
Published: March 2020

8014

Background: Maintenance monotherapy has been associated with improved survival for NSCLC pts. AVAPERL was designed to evaluate the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment and demonstrated improved progression-free survival (PFS) (Barlesi, JCO in press). Methods: Pts with advanced nsNSCLC received first-line Bev (7.5 mg/kg), cisplatin (75 mg/m2), and Pem (500 mg/m2) every 3 weeks (q3w) for 4 cycles. Those non progressing were randomized to maintenance Bev (7.5 mg/kg) +/-Pem (500 mg/m2) q3w until progressive disease or unacceptable toxicity. The primary end point (PFS) was met. An independent update analysis has been conducted to assess OS. Results: A total of 376 pts receive induction treatment; 125 and 128 were randomized to the Bev-alone and Bev+Pem arms, respectively. Induction therapy resulted in confirmed disease control in 71.9% of pts. After a median follow-up of 14.8 months, PFS for the Bev+Pem arm was significantly improved both from induction (10.2 v 6.6 m, HR 0.58 [0.45-0.76], p<.0001) and randomization (7.4 v 3.7 m, HR 0.57 [0.44-0.75], p<.0001). With 58% of events, OS for the Bev+Pem arm was also improved both from induction (19.8 v 15.9 m, HR 0.88 [0.64-1.22], p=.32) and randomization (17.1 v 13.2 m, HR 0.87 [0.63-1.21], p=.29). The PFS and OS improvements were comparable across age, PS, smoking status, and response to induction (SD vPR/CR) subgroups. No new safety signal was observed during this updated analysis. Conclusions: Continuation maintenance with Bev+Pem in an unselected population of nsNSCLC pts who had achieved disease control after induction was associated with an increase by almost 4 months in OS benefit over standard Bev alone. Clinical trial information: NCT00961415.
LUX-Lung 6: A randomized, open-label, phase III study of afatinib (A) versus gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung.
Authors: Wu Yi Long , Zhou Caicun , Hu Cheng-Ping , Feng Ji Feng , Lu Shun , Huang Yunchao , Li Wei , Hou Mei , Shi Jian Hua , Lee Kye Young , Massey Dan , Shi Yang , Chen Jiongjie , Zazulina Victoria , Geater Sarayut Lucien
Published: March 2020

8016

Background: A is an oral, irreversible, ErbB Family Blocker, blocking signaling from EGFR (ErbB1), HER2 (ErbB2) and ErbB4. A was superior to first-line pemetrexed/cisplatin in a global phase III trial (LUX-Lung 3) in EGFR M+ NSCLC. This study compared the safety and efficacy of first-line A with GC in EGFR M+ Asian pts. Methods: The trial was conducted in Asian countries. Following central testing for EGFR mutations (TheraScreen EGFR RGQ PCR kit), 364 pts (stage IIIB/IV, PS 0–1, chemo-naïve) were randomized 2:1 (A: 242; GC: 122) to daily A 40 mg or IV GC (1,000 mg/m2 D1, 8 + 75 mg/m2q21 days up to 6 cycles). Primary endpoint was PFS by central independent review. Results: Baseline characteristics were balanced in both arms: Female (64.0 vs 68.0%), non-smoker (74.8 vs 81.1%), exon 19 deletion (51.2 vs 50.8%), L858R (38.0 vs 37.7%) in A and GC arms, respectively. PFS was significantly prolonged with A compared with GC by independent review (median PFS 11.0 vs 5.6 months, HR=0.28, p<0.0001); this finding was consistent across all subgroups. Results from the investigator review were similar: HR=0.26, p<0.0001, median 13.7 (A) vs 5.6 months (GC). Objective response (66.9% vs 23.0%, p<0.0001) and disease control (92.6% vs 76.2%, p<0.0001) rates (ORR/DCR) were significantly higher with A. OS, based on 43% of events shows HR=0.95, p=0.7593. Drug-related AEs of ≥G3 were reported in 36.0% (A) and 60.2% (GC) of pts, the most common of which were rash/acne (14.6%), diarrhea (5.4%) and stomatitis/mucositis (5.4%) with A and neutropenia (17.7%), vomiting (15.9%) and leukopenia (13.3%) with GC. Related AEs led to discontinuation in 5.9% (A) and 39.8% (GC) of pts. Patient reported-outcomes (PROs) showed significantly better control of cancer-related dyspnea, cough and pain with A. Conclusions: In EGFR M+ Asian pts, A significantly prolonged PFS with significant improvements in ORR, DCR, PROs. AEs in both arms were as expected, with a more favorable safety profile with A. LUX-Lung 6 is the largest prospective trial in EGFR M+ lung cancer, providing further evidence of superiority of A over standard chemotherapy in this setting. Clinical trial information: NCT01121393.
Explicit and implicit attitudes toward lung cancer (LC) relative to breast cancer (BC).
Authors: Schiller Joan H. , Bowden Chris J. , Mills Jennifer , Lang Edward , Dickson Holli , Hamann Heidi A , Sriram N.
Published: March 2020

8017

Background: Emerging research suggests that LC may be associated with greater levels of stigma, shame and hopelessness compared to other cancers. This study measured explicit, conscious attitudes (EAs) and used the Implicit Association Test (IAT) to assess implicit, unconscious attitudes (IAs) of LC relative to BC. Methods: To assess EAs, participants (Ps), [people with cancer (n=243), caregivers (n=677), healthcare providers (HCPs, n=142), and the general public (n=864)] were asked to rate their agreement, on a six-point scale, with statements about how people with LC and BC “do feel” (descriptive attitudes) or “ought to feel” (normative attitudes) about their disease. IAs were measured with three IATs that used LC or BC images with words representing good/bad; hope/despair; or suitable/shameful. An IAT D score indicated the strength of bias against LC relative to BC: >0.65 = strong bias; 0.35-0.65 = moderate bias; 0.15-0.35 = slight bias; -0.15 -+0.15 = no bias, and < -0.15 indicated bias against BC. Results: EAs and IAs were substantially more negative towards LC. Most Ps provided more negative ratings for LC than BC for both descriptive (70%vs.8%) and normative statements (56% vs. 3%). Ps had strong negative IAs towards LC compared to BC (bad: 74% vs. 10%; despair: 75% vs. 9%; shame: 67% vs. 17%). These trends were consistent across caregivers, patients, HCPs, and the public. EAs and IAs were uncorrelated. Conclusions: Ps had greater explicit and implicit negative bias against LC compared to BC. [Table: see text]
RET rearrangements detected by FISH in “pan-negative” lung adenocarcinoma.
Authors: Varella-Garcia Marileila , Xu Liang Guo , Mahale Sakshi , Berge Eamon M , Bennati Chiara , Le Anh T. , Aisner Dara , Crinò Lucio , Bunn Paul A. , Camidge D. Ross , Doebele Robert Charles
Published: March 2020

8024

Background: RET rearrangements have recently been reported in NSCLC and there is pre-clinical evidence that RET tyrosine kinase inhibitors (TKIs) block activated RET kinase. Efficient and accurate detection of RET rearrangements are crucial for the success of RET TKIs in clinical trials. RET rearrangements have been detected by specialized sequencing techniques with limited applicability to clinical practice. Methods: A 3-target FISH probe set was developed to detect KIF5B-RET fusions and identify patterns suggestive of RET rearrangements with non-KIF5B partners. 51 lung adenocarcinomas negative for EGFR, KRAS, ALK and ROS1 (36 were also negative for 7 other molecular markers) were investigated. Clinical and demographic characteristics were collected. Results: Eight patients (15%) had rearrangements in the RET gene: 5 with KIF5B-RET fusions, 2 with patterns consistent with the CCDC6-RET fusion, and 1 with extra copies of single 3’RET (loss of 5’RET). Atypical FISH patterns were detected both in RET + and negative specimens suggesting high genomic instability in the KIF5B – RET region. RT-PCR assay determined the exon/fusion variant in 4 cases including 2 patients with K15:R12, 1 with K16:R12 and 1 with C1:R12. Median age at diagnosis was 58.5 in the mutation negative and 63 in the RET+ patients. Both cohorts were predominantly male (66% and 56%, respectively), with a majority of never smokers (59 and 89%, respectively), and stage IV disease at diagnosis (72 and 89%, respectively). Two heavily pretreated RET+ patients had stable disease at their initial restaging scans following treatment with the RET inhibitor vandetanib (radiographic assessment per RECIST 1.1); two others had early radiographic progression with sunitinib. Conclusions: The FISH probe proved efficient to detect RET rearrangements in lung adenocarcinomas, involving KIF5B and non-KIF5B partners. Frequency of RET rearrangements in this enriched lung adenocarcinoma cohort was considerably higher than reported in unselected cohorts. Further molecular analyses are being performed to increase understanding of the natural history of this new molecular subtype of NSCLC. Support: B J Addario Foundation, NCI P50CA058187, NCI CCSG P30CA046934.
Two parallel randomized phase II studies of selumetinib (S) and erlotinib (E) in advanced non-small cell lung cancer selected by KRAS mutations.
Authors: Carter Corey Allan , Rajan Arun , Szabo Eva , Khozin Sean , Thomas Anish , Brzezniak Christina E. , Guha Udayan , Doyle L. Austin , Keen Corrine , Steinberg Seth M. , Xi Liqiang , Raffeld Mark , Reckamp Karen L. , Koehler Stephen , Gitlitz Barbara Jennifer , Salgia Ravi , Gandara David R. , Vokes Everett E. , Giaccone Giuseppe
Published: March 2020

8026

Background: KRAS mutations are present in 20% of NSCLC and are associated with primary resistance to erlotinib (E). KRAS mutations result in constitutive activation of the Ras/Raf/MEK/ERK pathway. Selumetinib (S) (AZD6244, ARRY-142886) is a selective and uncompetitive inhibitor of MEK kinase. Preclinical studies demonstrated increased activity in NSCLC cell lines using S+E regardless of KRAS status. Methods: Advanced NSCLC patients with progressive disease after platinum based chemotherapy +/- one other treatment were stratified by KRAS status, which was centrally assessed using macrodissection and pyrosequencing for all mutations involving codons 12, 13, and 61. Patients were randomized to receive either the standard of care E or a combination of S+E in KRAS wild type (wt) and S alone or S+E in patients with KRAS mutations. Single agent E and S were administered orally at 150 mg daily and 75 mg twice daily respectively. Combination dosing were S 150 mg every morning and E 100 mg every evening. The primary endpoint for the KRAS wt group was PFS and for the KRAS mutant group objective response rate. Results: From March 2010 to January 2013, 79 patients screened; 78 enrolled: KRAS mutant, 39; KRAS wt, 40; M/F (39:39); median age: 64 years (33-84); median WHO PS 1(0-2); 66 former and 13 never smokers; 67 adenocarcinoma, 9 squamous cell. Three patients died of complications prior to first evaluation (1 coronary disease, 1 pulmonary fibrosis, and 1 disease progression) of which none were related to S. Dose reductions occurred in 5% E, 40% S, and 56% E+S. Most grade 3/4 AEs occurred in combination therapy; diarrhea (23%), fatigue (23%) lymphopenia (13%), myositis (10%), dyspnea (10%), rash (7%). Discontinuation due to AEs was 8% all occurring in S+E cohorts. Conclusions: This study failed to show improvement of combination therapy over single agent in KRAS wt and mutant patients. Toxicity was increased in the combination arms. Interestingly, the KRAS mutant cohort had longer PFS than KRAS wt patients, although not statistically significant (p=0.11). Clinical trial information: NCT01229150. [Table: see text]
Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial.
Authors: Gandara David R. , Hiret Sandrine , Blumenschein George R. , Barlesi Fabrice , Delord Jean-Pierre , Madelaine Jeannick , Infante Jeffrey R. , Reckamp Karen L. , Lara Primo , Audebert Christine , Cho Byoung Chul , Park Keunchil , Braiteh Fadi S. , Jotte Robert M. , Wu Yuehui , Schramek Daniel J. , Piepszak Alexandra M. , Gardner Olivia S. , Peddareddigari Vijay Gopal Reddy , Leighl Natasha B.
Published: March 2020

8028

Background: KRAS-mutant NSCLC, usually reflecting tobacco-related carcinogenesis, represents an unmet medical need in lung cancer therapy. Trametinib plus docetaxel (doc) enhances growth inhibition and apoptosis of NSCLC cell lines in vitro with and without RAS/RAF mutations when compared with either agent alone. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib+doc in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib + doc at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 46 NSCLC pts (24 WT [67% had ≥ 2 prior therapies] and 22 KRAS [41% had ≥ 2 prior therapies]) have been treated at the trametinib + doc RP2D (2.0 mg + 75 mg/m2 + growth factors). Diarrhea, fatigue, asthenia, and nausea were the 4 most frequent toxicities. Dose reduction occurred in 10 pts (22%), mostly for diarrhea, fatigue, mucositis, neutropenia, and skin fissures (all 4%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed + unconfirmed) was 3 partial response (PR; RR = 17%) and 8 stable disease (SD; 44%); additionally, 4 pts had > 20% tumor shrinkage. The current disease control rate (DCR) is 61%; 4 pts have not had postbaseline scans. In WT pts, 5 PR (RR=21%) and 11 SD (46%) were observed (67% DCR). Final response and progression-free survival data will be reported upon maturity. Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib + doc (+ growth factors) demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.
Nimotuzumab plus chemotherapy versus chemotherapy alone in advanced non-small cell lung cancer: A phase II, open-label, multicenter, randomized study.
Authors: Prabhash Kumar , Govind Babu Kanaka , Vaid Ashok K. , Rangaraju Ranga Rao , Sirohi Bhawna , Diwakar Ravi , Rao Raghunadha , Kar Madhuchanda , Malhotra Hemant , Nag Shona Milon , Goswami Chanchal , Raina Vinod , Mohan Pedapenki Ravi
Published: March 2020

8053

Background: To evaluate the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods: This multicenter, open-label, phase II study, randomized 110 patients to receive nimotuzumab plus chemotherapy (nimotuzumab group) or chemotherapy alone (control group), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab (200 mg) was administered once weekly for 13 weeks during the first 2 phases with 4 cycles of chemotherapy; docetaxel (75 mg/m2) and carboplatin (area under the curve [AUC] = 5 mg/ml*min), every 3 weeks for a maximum of 4 cycles during the concomitant phase. The primary endpoint was objective response rate (ORR; sum of complete response [CR] and partial response [PR]). Secondary endpoints, overall survival (OS), and progression-free survival (PFS) were estimated using Kaplan-Meier method. Efficacy was evaluated on the intent-to-treat (ITT) and efficacy-evaluable (EE) sets. Safety was assessed from adverse events (AEs) and serious adverse events (SAEs) data. Results: ORR was significantly higher in the nimotuzumab group than in the control group in the ITT (54% vs. 34.5%; P=0.04) population. CR and PR were achieved in 3.6% and 50% patients, respectively, in the nimotuzumab group, and in 4% and 30.9% patients, respectively, in the control group. No significant differences in median PFS and OS were observed. Safety profiles were comparable between the 2 groups. Conclusions: Nimotuzumab plus chemotherapy significantly improved ORR as compared to chemotherapy alone; the combination was safe and well tolerated in stage IIIB/IV NSCLC patients.
Phase II study of metronomic chemotherapy (MC) with bevacizumab (B) in patients (Pts) with advanced (Adv) nonsquamous non-small cell lung cancer (NS-NSCLC).
Authors: Marquette Carrie Lee , Grant Stefan C. , DeShazo Mollie , Reddy Vishnu , Cantor Alan , Miley Debi , Jerome Mary , Robert Francisco
Published: March 2020

8057

Background: Targeting vascular endothelial growth factor (VEGF) has shown modest improvement in pts with adv NS-NSCLC. The incorporation into MC regimens of antiangiogenic agents has been shown to further enhance efficacy in preclinical models. The goal of this pilot study was to achieve a 30% improvement in the 6.4 months (M) progression-free survival (PFS) observed in ECOG 4599. Methods: Untreated pts with stage 4 NS-NSCLC, PS 0-1 and measurable disease were treated with a 4-week (W) cycle of paclitaxel (80mg/m2 D1, 8, 15), gemcitabine (G) (200-300mg/m2 D1, 8, 15) and B (10mg/m2 D1, 15) for 6 cycles. Pts without progressive disease or significant toxicity (Tx) received maintenance B every 2 w. Primary endpoint:PFS. Secondary endpoints: ORR, OS, Tx and biomarker (BM) correlation. Blood samples for angiogenic (VEGF, sVEGFR2, BFGF, PLGF, PDGFα, Ang-2, IL-8, E-Selectin, ICAM-1, TGFβ-1, SDF-1α, endocan) and antiangiogenic (Thrombospondin-1, Ang-1) bm were collected at different intervals in 21 pts. Response assessment (RECIST) was performed every 8 w. Results: 33 evaluable pts were enrolled. Pt characteristics: median age 59 yrs (37-76), 60% female, 70% > 5% weight loss, 24% never/light smokers, 48% genetic testing (mut EGFR-4; ALK(+)-1), and 9% brain mets. Efficacy parameters are shown in the table. 24 pts had an OR (CR-1, PR-23) and 6 pts had stable disease. No significant differences were observed in the efficacy parameters between former smokers vs. never/light smokers. Worst hematologic and non-hematologic Tx: gr 3 neutropenia (N=1); gr 3/4 nausea/vomiting (N=1); gr 3/4 fatigue (N=2); ischemic colitis (N=1); cerebral ischemia (N=1); gr 3/4 pneumonitis [related to G] (N=2); gr 3/4 proteinuria (N=3), and no gr 3/4 hypertension. Conclusions: While conclusions are limited by the size of the trial, the results are consistent with the hypothesis that the addition of B to MC may result in enhanced anti-angiogenic effect and clinical benefits in adv NS-NSCLC. Analysis of prognostic or predictive bm of angiogenesis will be presented. Clinical trial information: NCT00655850. [Table: see text]
LUX-Lung 6: Patient-reported outcomes (PROs) from a randomized open-label, phase III study in first-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations.
Authors: Geater Sarayut Lucien , Zhou Caicun , Hu Cheng-Ping , Feng Ji Feng , Lu Shun , Huang Yunchao , Li Wei , Hou Mei , Shi Jian Hua , Lee Kye Young , Massey Dan , Lungershausen Juliane , Shi Yang , Zazulina Victoria , Wu Yi Long
Published: March 2020

8061

Background: Afatinib (A) is an oral, irreversible, ErbB Family Blocker, blocking signaling from EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2; ErbB2) and ErbB4. In LUX-Lung 6, A was significantly better than gemcitabine/cisplatin (GC) in terms of progression free survival (PFS) and tumor response, with a more favorable safety profile. Here, we report the PRO results. Methods: 364 pts were randomized (2:1) to receive A or GC. PROs were measured using EORTC questionnaires QLQ-C30/LC13 at baseline and q3w until progression. Changes of ≥10 points (scale 0–100) were considered clinically significant. Analyses of cough, dyspnea and pain were prespecified. Time to deterioration (1st 10-point worsening from baseline) was analyzed using a stratified log-rank test. Percentage improved/worsened by ≥10 points or stable was determined. Mean scores over time were estimated using longitudinal (mixed-effects growth curve) models. Results: Compliance on treatment with questionnaires was >90%. Baseline symptom burden was low (cough: 35; dyspnea: 25; pain: 24). Compared with GC, therapy with A significantly delayed time to deterioration for cough (HR=0.45; p=0.0001), dyspnea (HR=0.54; p<0.0001) and pain (HR=0.70; p=0.03). A higher proportion of A-treated pts had ≥10-point improvements in cough (76% vs 55%; p=0.0003), dyspnea (71% vs 48%; p<0.0001) and pain (64% vs 47%; p=0.003) compared with GC, particularly among pts with baseline symptoms. Mean scores over time for cough, dyspnea and pain also significantly favored A. Consistent with their safety profiles, a significantly higher proportion of A-treated pts had worsening of diarrhea, sore mouth and dysphagia, while fatigue, nausea, and vomiting were significantly worse with GC. Overall, therapy with A significantly improved global health-related quality of life (HRQoL; p<0.0001), physical (p<0.0001), role (p=0.01) and social (p<0.001) functioning compared with GC. Conclusions: In LUX-Lung 6, prolongation of PFS with A was associated with significantly better HRQoL and significantly longer control of lung cancer-related symptoms compared with GC. Clinical trial information: NCT01121393.
First-line carboplatin, pemetrexed, and panitumumab in patients with advanced nonsquamous KRAS wild type (WT) non-small cell lung cancer (NSCLC).
Authors: Mekhail Tarek , Waterhouse David Michael , Hadley Terence J. , Webb Charles D. , Burris Howard A. , Hainsworth John D. , Greco F Anthony , Spigel David R.
Published: March 2020

8062

Background: KRAS WT colorectal cancer (CRC) is responsive to the EGFR inhibitors panitumumab (P) and cetuximab. Phase III data suggest a small, but statistically significant overall survival (OS) advantage with cetuximab + chemotherapy in KRAS unselected NSCLC (Pirker, Lancet 2009); and phase I data suggest P alone has activity in non-CRC tumors including NSCLC (Weiner, Clin Ca Res. 2008). This single-arm phase II trial examined the safety and efficacy of P in combination with carboplatin (C) and pemetrexed (Pem) in patients (pts) with advanced non-squamous KRAS WT NSCLC. The addition of P was hypothesized to improve the median time-to-progression (TTP) from 3.6 months (mos) (historical) to 5.4 mos (1-sided α .10, 80% power). Methods: Pts with previously untreated, unresectable stage IIIB/IV non squamous KRAS WT NSCLC received P 9 mg/kg, Pem 500 mg/m2, and C AUC=6 IV day 1 every 21 days for 6 cycles, followed by P and Pem maintenance every 21 days until progressive disease or unacceptable toxicity. Responses were evaluated every 2 cycles per RECIST 1.1. KRAS mutation testing was performed centrally (DxS kit). Tissue was also collected for EGFR FISH testing. Results: 60 pts were enrolled; median age, 65 years; 58% female, ECOG PS 0-1 (98%), and prior adjuvant chemotherapy (10%). Median number of cycles was 5 (range 1-22). At a median follow-up of 8.7 mos, the median TTP was 6.2 mos (95% CI: 3.7, 9.5), PFS 6.2 mos (95% CI 3.0, 9.0), 1 year OS 65.5% (95% CI 44.8%, 80%). 23 pts (38%) had partial responses (PR); the disease control rate (PR + proportion with stable disease) was 68%. Treatment-related toxicity (TRT) included (all grades) nausea (38%), fatigue (30%), rash (30%), and mucositis (23%). Severe (grade 3/4) TRT in > 2 pts included: thrombocytopenia (11%), neutropenia (7%), and dehydration (5%). There were no treatment-related deaths. EGFR mutation and FISH analyses will be presented. Conclusions: The addition of panitumumab to carboplatin and pemetrexed in the first-line treatment of advanced KRAS WT NSCLC was safe and well-tolerated; the median TTP of 6.2 mos met the primary endpoint. Definitive assessment of the value of panitumumab in this setting requires a randomized trial. Clinical trial information: NCT01042288.
Phase II study of gefitinib and inserted cisplatin plus docetaxel as a first-line treatment for advanced non-small cell lung cancer haboring an epidermal growth factor receptor activating mutation.
Authors: Kanda Shintaro , Ohe Yuichiro , Horinouchi Hidehito , Fujiwara Yutaka , Nokihara Hiroshi , Yamamoto Noboru , Sekine Ikuo , Kunitoh Hideo , Kubota Kaoru , Tamura Tomohide
Published: March 2020

8064

Background: Gefitinib yields a longer progression-free survival (PFS) period than platinum–doublet chemotherapy as a first–line treatment for patients with advanced non–small–cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) activating mutation, but most patients develop resistance against gefitinib after the initial response. We hypothesized that the insertion of platinum–doublet chemotherapy during the initial response could prevent the emergence of acquired resistance and prolong survival, compared with gefitinib alone. Methods: We performed a phase ΙΙ study of the following first–line treatment for patients with advanced NSCLC with EGFR mutation. Gefitinib (250 mg) was administrated on days 1–56. After a two–week rest, three cycles of cisplatin (80 mg/m2) and docetaxel (60 mg/m2) were administered on days 71, 92, and 113. Gefitinib was re–started on day 134 and was continued until progression. The primary endpoint was the two–year PFS rate. The sample size was estimated at 33, and this treatment was considered worthy for further development if more than 11 of the 33 patients who started treatment had a 2–year PFS. Results: Thirty–three Japanese patients were enrolled. Twenty–five patients could re–start gefitinib, 12 achieved a PFS period of over 2 years, and 9 continued to receive the protocol treatment without experiencing progression. The 1–, 2–, and 3–year estimated PFS rates were 59.4%, 37.5%, and 33.8%, respectively, and the median PFS time was 19.2 months. The 1–, 2–, and 3–year estimated survival rates were 90.0%, 82.9%, and 62.4%, respectively, and the median survival time had not been reached at the time of analysis. Treatment–related deaths and unexpected severe toxicities were not seen. Conclusions: Our results indicated that first–line treatment consisting of gefitinib and inserted cisplatin plus docetaxel is promising for patients with advanced NSCLC with EGFR mutation. A phase ΙΙΙ study of this treatment compared with gefitinib alone is warranted. Clinical trial information: 000001738.
Rebiopsy in TKI-resistance: A retrospective analysis.
Authors: Kuiper Justine Leonie , Heideman Danielle , Thunnissen Erik , Paul M A , Smit Egbert F.
Published: March 2020

8065

Background: EGFR-TKI provides a clinical benefit in patients with EGFR-mutated NSCLC with median progression-free survival (PFS) of 12 months. Several resistance mechanisms (e.g. T790M mutation) have been described, however data are sparse. We analysed EGFR-mutation spectra in NSCLC patients with acquired resistance to TKI. Methods: Biopsies from patients with EGFR-mutation or TKI-response>24 weeks with both pre- and post TKI biopsy available were retrospectively analysed. Information was collected from the medical record. Response to TKI-treatment was assessed according to RECIST. PFS after TKI-treatment was calculated with a Kaplan-Meier curve. Results: 63 patients were included for analysis. Pre- and post TKI biopsy results are described in the Table. 32 patients received 1 (38%), 2 (10%) or 3 (3%) lines of chemotherapy before start of TKI and 18 patients received 1 (13%), 2 (11%), 3 (3%), or 5 (2%) lines of therapy after TKI treatment. Median PFS on TKI-treatment was 12,3 months (range: 1,4 – 43,2). Objective response rate was 61,9%. 47,6% of patients developed the T790M mutation. One patient developed transformation to SCLC with the original exon 19 deletion. One patient with pre-TKI an exon 18 + exon 21 mutation was found to have a KRAS-mutation post-TKI. Conclusions: In this cohort, frequency of development of T790M mutation was consistent with earlier reports. Transformation to SCLC occurred less than described earlier. Two patients did not retain their original mutation. Surprisingly, one patient developed a KRAS mutation: a second primary tumor is not excluded in this case. Rebiopsy in TKI-resistance provides important information on dynamic tumour characteristics and has management implications in certain patients. [Table: see text]
A phase II trial of second-line erlotinib in combination with stereotactic body radiation therapy (SBRT) for patients with metastatic non-small cell lung cancer (NSCLC).
Authors: Iyengar Puneeth , Kavanagh Brian D. , Smith Irma , Ahn Chul , Gerber David E. , Dowell Johnathan , Hughes Randall S. , Abdulrahman Ramzi , Camidge D. Ross , Gaspar Laurie E. , Doebele Robert Charles , Bunn Paul A. , Choy Hak , Timmerman Robert D.
Published: March 2020

8074

Background: Stage IV NSCLC patients who progress through first-line therapy have poor progression-free survival (PFS) and overall survival (OS), most commonly failing in existing sites of gross disease after systemic therapy. Cytoreduction with SBRT may aid systemic agents in prolonging survival. We decided to test this hypothesis in a multi-institutional phase II study with SBRT and erlotinib. Methods: Stage IV NSCLC patients with ≤ 6 sites of extracranial disease who failed first-line systemic therapy were eligible to receive SBRT to all sites of clinically apparent disease, utilizing equipotent fractionation schemes based on location of disease and risk of toxicity to critical normal structures, and erlotinib given daily (150 mg OD) until disease progression. Frequent SBRT fractionation schemes used included 33 Gy in 11 Gy fractions and 40 Gy in 8 Gy fractions. Safety and clinical endpoints were evaluated. Results: 23 patients (12 M: 11 F) with a median age of 67 (56-86) were enrolled in this trial with median follow-up of 14.7 months. All patients progressed through platinum-based chemotherapy, 14 with paclitaxel and 7 with pemetrexed as part of the doublet regimen. 20/23 patients received SBRT to 3 or fewer sites. Lung parenchyma and mediastinal lymph nodes represented most common sites of irradiation. Median PFS was 10.7 months and median OS was 20.8 months.A majority of patients progressed in new sites with only 4 patients failing locally. Most distant failures manifested in the liver. Only one grade 3 toxicity, pneumonitis, was radiation-related. The trial commenced before molecular profiling became standard; 5/10 patient tumors tested, however, had EGFR alterations by IHC/FISH, 0/10 were positive for an EGFR mutation. Conclusions: Use of SBRT with erlotinib for unselected stage IV NSCLC patients as a second-line therapy was well tolerated and resulted in significant PFS and OS, substantially greater than historical values for patients who only received second-line systemic agents. Debulking gross disease with local therapy results in a median PFS of nearly a year with patients relapsing most commonly in new rather than existing sites. Clinical trial information: NCT00547105.