bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual intervention with a lymph node (LN) specimen collection kit and enhanced specimen dissection to improve staging of resectable non-small cell lung cancer (NSCLC).
Authors: Sareen Srishti , Ramirez Robert A. , Javed Ahmed Yasir , Miller Laura Elizabeth , Wang Christopher , Smeltzer Matthew , Khandekar Alim , Schoettle Glenn P , Robbins Samuel G , Gibson Jeffrey B , Wolf Bradley Aaron , Robbins Edward T , Osarogiagbon Raymond U
Published: March 2020

7569

Background: LN metastasis impairs survival of resectable NSCLC, but routine pathologic nodal staging is suboptimal. We tested the impact of a dual intervention (a surgical specimen collection kit with specific, pre-labeled LN collection cups, to improve intraoperative hilar/mediastinal LN dissection; and a fastidious gross dissection of the resected lung specimen for perihilar/intrapulmonary LNs) on the rate of detection of LN metastasis. Methods: We matched dual intervention cases with controls performed with standard surgical specimen collection and pathology examination protocols. Controls were hierarchically matched for extent of resection, laterality, surgeon, pathologist and T-stage. All statistical comparisons were made with Exact Conditional Logistic Regression, to account for the matched case-control design. Results: Patient demographic, tumor histology, and size characteristics were similar between the groups. The impact of the dual interventions is shown in the Table. Conclusions: The dual interventions significantly increased retrieval of N1 and N2 LNs, the rate of detection of LN metastasis, and nodal up-staging. There were strong trends towards higher aggregate stage and increased adjuvant therapy eligibility. The interventions may improve stage-adjusted survival by improving stage accuracy, and improve aggregate survival by increasing the appropriate use of post-operative adjuvant therapy. A prospective randomized trial to test survival impact of the dual interventions is at an advanced planning phase. [Table: see text]
Clinical characteristics of patients with multiple primary lung cancers: Moving beyond the Martini and Melamed criteria.
Authors: Zauderer Marjorie Glass , Drilon Alexander Edward Dela Cruz , Sima Camelia S. , Lou Feiran , Finley David J. , Kris Mark G.
Published: March 2020

7570

Background: Deciding to operate for lung cancer in patients with a prior lung cancer resection is influenced by the extent of disease at 1st resection and the certainty that the new lesion is a 2nd primary lung cancer. While the Martini and Melamed (M&M) criteria (J Thorac Cardiovasc Surg 1975) guide the decision whether a new lesion represents a 2nd lung cancer, improvements, incorporating detailed clinical and molecular analyses, are needed. Methods: From a prospective database, we identified 130 patients who underwent two curative resections from 1995 to 2009 for non-small cell lung cancers. We examined associations between clinical factors and patterns of recurrence/DFS/OS following 2nd surgery. Results: Patient characteristics: median age 66; 42% men; and 8% never smokers. See Table for stage, histology, and completeness of resection. DFS and OS were not associated with smoking status, surgical procedure, and histology. Stage at 1st resection was not associated with patterns of recurrence (none vs local vs distant, p=0.77), DFS (p=0.61), or OS (p=0.37). Earlier stage at 2nd resection was associated with improved DFS (p<0.001) and OS (p<0.001), as well as a trend toward less distant recurrence (p=0.06). As many surgeries predated routine genotyping, very few patients (5%) had genotyping from both resections. 38% of 2nd resection stage IA lung cancers recurred distantly. 20% had a third lung cancer and 47% had at least one other malignancy. Conclusions: Outcomes after 2nd primary lung cancers are unaffected by the stage of the 1st lung cancer. Pursuit of curative interventions should not be influenced by the stage of the 1st cancer. We need more detailed molecular analysis to help correctly identify new primaries. We also need additional features to help discriminate among those at most risk for another lung cancer vs local recurrence vs distant recurrence. [Table: see text]
Patient-reported symptom burdens in NSCLC patients undergoing proton, 3DCRT, or IMRT.
Authors: Wang Xin Shelley , Liao Zhongxing X. , Komaki Ritsuko , Cox James D. , Gomez Daniel Richard , Bokhari Raza H , Sailors Mary L , Cleeland Charles S.
Published: March 2020

7574

Background: Concurrent chemoradiation (CXRT) for stage III non-small-cell lung cancer (NSCLC) patients is associated with the development of systemic self-reported symptom burden as well as radiation esophagitis (RE). This longitudinal study aims to provide a profile of the symptom burden among 3 radiation techniques concurrently used with chemotherapy: 3-dimensional conformal radiation therapy (3DCRT), intensity- modulated radiation therapy (IMRT) and proton beam therapy (PBT). Methods: NSCLC patients (N=164) treated at MD Anderson Cancer Center rated symptoms via the M. D. Anderson Symptom Inventory (MDASI) weekly from pre-therapy up to 20 weeks post-therapy. Descriptive analysis identified major symptom burden, and mixed effect modeling examined change over time in symptom outcomes among the 3 types of CXRT. Results: Average total radiation dose was higher (p=.0003) for PBT (N=30, 71.6 Gy) and IMRT (N=67, 66.3 Gy) than for 3DCRT (N=24, 62.1 Gy). Over time, all patients reported a cluster of symptoms that increased as the dose accumulated, including fatigue, drowsiness, pain, difficulty swallowing, poor appetite and sore throat; symptoms generally peaked at week 7-9 and returned to pre-therapy levels at week 13. The IMRT group had significant less-severe sore throat (p=.03), while there were no significant differences in symptom severity among the 3 types of CXRT for the other major symptoms before, during and after CXRT. However, there was a trend of more patients reporting moderate to severe sickness symptoms as a component score (fatigue, pain, sore throat, poor appetite and drowsiness) in the 3DCRT group than in the IMRT or PBT groups at end of CXRT (50% vs. 44%, 31%) and at 13 weeks (53% vs. 23%, 25%). Also, there was a trend of more patients under 3DCRT than IMRT or PBT had moderate to severe sore throat (RE symptom) by end of CXRT (60% vs. 44%, 46%) and no different by 13 weeks (27% vs. 25%, 31%). Conclusions: Although clinical studies have reported the toxicities of CXRT, this is the first longitudinal study that compared symptom profiles for NSCLC patients receiving PBT, IMRT and 3DCRT. There is an impression of more severe treatment-related symptoms for 3DCRT (although in lower radiation dose) than IMRT or PBT.
Genomic characterization and high-throughput therapeutic screening of malignant mesothelioma to reveal novel tumor dependencies.
Authors: Alifrangis Constantine , Quispel Janssen Josine , de Vries Hilda , Schunselaar Laurel , Bignell Graham , Garnett Mathew , Neefjes Jacques , Berns Anton , Baas Paul , McDermott Ultan
Published: March 2020

7581

Background: Clinical trials of targeted therapeutics in mesothelioma have demonstrated limited efficacy. It has been suggested that combinations of targeted agents may be more effective in this disease, but given the unknown status of tractable oncogenic mutations it has been difficult to ascertain which key signalling nodes drive these tumours that may lend themselves to therapeutic intervention. We therefore aimed to characterise a representative panel of mesothelioma cell lines at the genomic level, and then determine critical “nodes” utilising a high throughput screen of targeted agents. Methods: 19 mesothelioma cell lines and 6 mesothelioma primary tumour early passage lines underwent Illumina whole exome sequencing and copy number analysis. In parallel a high throughput screen was performed utilising a panel of targeted therapeutics enabling each mesothelioma to be screened across 48 compounds. Efficacy was confirmed in 3D spheroid culture. Results: Exome sequencing of the mesothelioma panel revealed mutations in tumour suppressor genes previously described in mesothelioma including NF2, as well as previously unreported mutations in this disease affecting histone modifying genes MLL2 and SETD2. Notably an absence of mutated “driver” oncogenes was observed. High throughput screening demonstrated limited activity for most small molecule inhibitors as single agents. However, despite an absence of mutations in PIK3CAor related genes, PI3K/mTORC inhibition had the broadest single agent efficacy. Conclusions: We demonstrate that mutations in cell lines are similar to those found in patient-derived tumours implying fidelity at the genomic level. Mesotheliomas harbour multiple mutations in tumour suppressors, but lack commonly tractable oncogenic mutations which may explain poor efficacy seen in clinical trials to date. We further demonstrate that PI3K may represent a critical node therapeutically that may be useful in combinatorial approaches.
Platelet counts (PLT) at baseline and on treatment as predictor for progression free survival (PFS) in patients with advanced malignant pleural mesothelioma (MPM): EORTC 08052 study.
Authors: Gaafar Rabab Mohamed , Popat Sanjay , Van Meerbeeck Jan P. , Baas Paul , Fennell Dean , Pallis Athanasios G. , Hasan Baktiar , O'Brien Mary
Published: March 2020

7585

Background: PLT values at baseline are considered as a negative prognostic factor in several different tumor types (lung, colorectal, renal and endometrial cancer) in both early and advanced disease settings. This is an exploratory analysis of PLT (baseline and changes during treatment) and their value in predicting PFS and overall survival (OS) in patients with stage IV MPM treated with cisplatin/bortezomib in the context of a single-arm phase II trial (EORTC 08052). Methods: Patients participating in the clinical trial were chemo-naïve with histological proven MPM and PS 0/1 (cisplatin 75 mg/m2 d1 and bortezomib 1.3 mg/m2 on d1, 4, 8, 11 q3wks). PLT analysis was pre-planned in the protocol and was recorded at baseline and at each cycle. Nadir of change in PLT was recorded at 8 and 18 weeks according to predefined cut off points (median PLT value). The association of the PLT with PFS and OS was analyzed. Results: 82 patients from EORTC-08052 study were analyzed with 1394 records of PLT. The cut off point for baseline was median PLT 374x103/mm3. We confirmed that patients with baseline PLT less than median had longer PFS compared to patients with counts higher than median (median PFS: 5.7 vs. 3.7 months [mo]; HR: 0.55; 95% CI: 0.34-0.88; p: 0.012). There was also a trend towards higher OS for patients with baseline PLT values less than median (median OS: 14.8 vs.10.6 mo; HR: 0.62; 95% CI: 0.38-1.02; p: 0.059). The median decrease of PLT values at 8 wks of treatment was 243 x103/mm3. Patients with decrease lower than median had higher PFS (median PFS: 7.5 vs. 5.7 mo; HR: 2.2; 95% CI: 1.3-3.8; p: 0.003) and a trend towards higher OS (median OS: 14.9 vs. 10.6 mo; HR: 1.6; 95% CI 1-2.7; p: 0.06). Changes at 18 weeks had no prognostic value. Conclusions: Besides low baseline PLT values we observed that a decrease in PLT at 8 weeks (but not 18 weeks) during treatment could predict PFS and to less extent OS. Validation of this observation is planned.
Interim outcome analysis of a prospective phase I trial of surgical resection with intracavitary hyperthermic cisplatin and gemcitabine for patients with resectable malignant pleural mesothelioma.
Authors: Richards William G. , Dasilva Marcelo C , Eisen Hannah M. , Barlow Julianne C , Bueno Raphael , Sugarbaker David
Published: March 2020

7588

Background: We completed a phase I trial of cisplatin and dose-escalated gemcitabine in a hyperthermic intra-operative lavage (IOHC) following extrapleural pneumonectomy (EPP arm) or extended pleurectomy (PD arm). Primary and secondary endpoints including gemcitabine MTD (1000 mg/m2 with 175 mg/m2 cisplatin) and pharmacokinetics, toxicity and mortality were reported (IMIG congress, 9/11-14/2012, abstract IIB.4 [1]). To define phase II indications, we explored patient outcome in comparison to published phase II results of a similar trial using cisplatin IOHC alone following EPP (J Thorac Cardiovasc Surg 2009, 138:405 [2]). Methods: The protocol was registered and IRB approved. Informed consent was obtained. Overall survival was calculated from the date of surgery to the date of death or censored at the date of most recent contact. Patients who were treated on the EPP arm at 500 to 1000 mg/m2 gemcitabine dose levels were included, grouped by epithelial (E) or non-epithelial (NE) histological subtype. Median, 1-year and 2-year survival was estimated using Kaplan-Meier methods. Results: 141 patients were registered. Median age was 65 (43-85) and 22 (21%) were women. Histology was epithelial (63), biphasic (32), and sarcomatoid (8). Two patients died perioperatively (2%). 59 patients were treated on the EPP arm of which the 27 (13 censored) treated at 500 to 1000 mg/m2 gemcitabine were studied. Qualitative comparison with a prior phase II trial of cisplatin IOHC (ref [2]) suggests incremental survival benefit to adding gemcitabine for patients with epithelial but not non-epithelial tumor histology (Table). Conclusions: Patients with epithelial histology tumors who require EPP for macroscopic complete resection appear likely to benefit from the addition of gemcitabine and should be included in a phase II investigation of this combination. Patients with non-epithelial biopsy who require EPP should be considered for other treatment strategies. Clinical trial information: NCT00571298. [Table: see text]
Prophylactic cranial irradiation in patients ≥ 70 years old with limited stage small cell lung cancer: A Surveillance, Epidemiology, and End Results analysis.
Authors: Eaton Bree Ruppert , Marcus David Mitchell , Kim Sungjin , Chen Zhengjia , Ramalingam Suresh S , Curran Walter J. , Higgins Kristin
Published: March 2020

7589

Background: Prophylactic cranial irradiation (PCI) improves survival in patients with limited stage small cell lung cancer (SCLC) who have a complete response to chemotherapy and radiation (RT). Yet in clinical practice, concerns exist regarding PCI-related toxicity and the extent of benefit in elderly patients. This exploratory analysis evaluates the effect of PCI on survival among patients ≥ 70 years old. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 4,003 patients ≥70 years old with localized or regional SCLC diagnosed between 1988 and 1997. Patients with no brain RT information (n=974) were excluded. Patients with overall survival (OS) <6 months (n=1103) were also excluded to eliminate patients with an aggressive disease course and minimize selection bias. Survival rates for patients who received brain RT versus no brain RT were estimated by the Kaplan Meier method and compared with the Log-rank test. A Cox proportional hazards model was further fitted to estimate the effect of brain RT on OS after adjusting for age, race, gender, and stage. Results: Of the 1926 patients included, the median age was 75 years (range, 70-94). The majority of patients were white (68%) and male (52%). According to SEER Historic Stage A, 68% of patients had regional stage and 32% had localized stage. One-hundred and thirty-eight patients (7.2%) received brain RT. Patients treated with brain RT were younger at diagnosis (p<0.01) and more likely to have regional stage disease (p=0.02). Five-year OS was 11.6% (95% CI: 6.9-17.6) among patients who received brain RT versus 8.6% (95% CI: 7.32-9.91) among patients who did not (p=0.03). Younger age, female gender, white race, and localized stage were also significant factors associated with improved OS. On multi-variable analysis, receipt of brain RT remained an independent predictor of OS (HR 0.825, 95% CI: 0.69-0.98, p=0.03). Conclusions: The receipt of brain radiotherapy is associated with improved overall survival in patients ≥70 years old with localized or regional stage SCLC, suggesting the benefit of PCI is maintained in the elderly population.
A multicenter phase III randomized double-blind placebo controlled trial of pravastatin added to first-line standard chemotherapy in patients with small cell lung cancer (SCLC).
Authors: Seckl Michael , Ottensmeier Christian , Cullen Michael H. , Schmid Peter , James Lindsay E. , Wadsworth Christina , Farrant Hannah , Muthukumar Dakshinamoorthy , Thompson Joyce , Harden Susan , Middleton Gary William , Fife Kate , Crosse Barbara , Taylor Paul , Khan Iftekhar
Published: March 2020

7595

Background: Most SCLC patients initially respond to chemotherapy but then relapse and die so new therapies are urgently required. Pre-clinical data shows statins induce growth arrest and apoptosis in SCLC and several other tumour cell types and are additive with chemotherapy. This may in part be due to impaired Ras superfamily function as statins deplete mevalonate, reducing geranylgeranylation and farnesylation of these proteins. We therefore undertook this large pragmatic phase III trial in order to determine if overall survival (OS) was affected by the addition of pravastatin in SCLC. Methods: Patients with limited (LD) or extensive (ED) stage SCLC were randomised to pravastatin 40mg OD or placebo for up to 2 years and given standard chemotherapy according to local practice recommended as either cisplatin 60mg/m2 iv or carboplatin AUC 5 or 6 and etoposide 120 mg/m2iv d1 to 3 or 100 mg BD po d2 & 3; max 6 cycles plus radiotherapy as usually given. Patients were excluded if they had used statins within 12 months prior to randomisation. Stratification was: LD vs ED and ECOG 0,1 vs 2,3. Endpoints were: primary - OS; secondary - progression free survival (PFS), local PFS (local control), response rates (RR) and toxicity. Results: Between 2007 and 2012, 846 patients were randomised, 422 (49.9.%) received pravastatin and 424 (50.1%) placebo in 93 participating sites in the UK. The median age was 64 years (range 54-69); ECOG performance status: 0: 23%; 1: 54%; 2: 17% and 3: 6%; weight 72.6 kg; LD, 357 (42.2%); ED, 479 (56.6%); 211 (24.9%) had ipsilateral effusion and 201 (23.8%) had ipsilateral SCF lymph nodes; Relative Dose intensity of cisplatin/carboplatin and etoposide was 91.6% (range 80.8 to 99.7), and 94.7% (range 85.7 to 100); 83.4% vs 86.3% completed > 4 cycles of chemotherapy on the pravastatin and placebo arms respectively. Most patients completed 6 cycles of chemotherapy: 263 (62.3%) vs 265 (62.5%) in the pravastatin vs. placebo groups. Updated results showing OS, PFS, local PFS and toxicity will be presented. Conclusions: This trial will report on whether pravastatin 40 mg OD added to standard therapy alters the outcome for SCLC patients. Clinical trial information: ISRCTN56306957.
Exploratory analyses of efficacy and safety of pemetrexed (Pem) plus bevacizumab (Bev) and bev alone as maintenance therapy (MT) in patients (Pts) with stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC).
Authors: Patel Jyoti D. , Garon Edward B. , Govindan Ramaswamy , Reynolds Craig H. , Spigel David R. , Olsen Mark R. , Hermann Robert C. , Liu Jingyi , Guba Susan C. , Pennella Eduardo J. , Obasaju Coleman K. , Bonomi Philip D. , Socinski Mark A.
Published: March 2020

8012

Background: In a phase III superiority study, Pem+carboplatin (Cb)+Bev followed by Pem+Bev improved PFS compared with paclitaxel (Pac)+Cb+Bev followed by Bev in NS-NSCLC pts. Superior OS (primary endpoint) was not met. These analyses assessed the efficacy and safety in pts who received MT. Methods: Prespecified exploratory analyses were performed in the maintenance population (MP) and timed from the start of induction. Pts ≥18 years with stage IIIB/IV NS-NSCLC (ECOG status 0–1) from the multicenter, randomized, open-label, phase III superiority study were included in the MP if they received at least one dose of MT. For MT, pts received intravenous Pem 500 mg/m2+Bev 15 mg/kg (n=292) or Bev 15 mg/kg (n=298). OS, PFS, and safety were evaluated. Comparison is made to the intent-to-treat (ITT; Pem=472, Pac=467) or safety population (SP; Pem=442, Pac=443; received at least one dose of one drug). Results: Baseline pt and disease characteristics for the ITT and MP were similar between arms. In the ITT/MP population, the median number of cycles was 7/10 (range, 1-41/4–41) in the Pem arm and 6/9 (range, 1-39/5–39) in the Pac arm. In the ITT/MP, OS was 12.6/17.7 months (mos; Pem) and 13.4/15.7 mos (Pac). Survival rates (%) at 12 and 24 mos with Pem (ITT/MP) were 52.7/71.7 and 24.4/34.5; Pac, 54.1/66.5 and 21.2/26.5%. In pts not receiving MT, OS was 4.7 mos (Pem) and 6.1 mos (Pac). PFS (mos) in the ITT/MT was 6.0/8.6 (Pem) and 5.6/6.9 (Pac). In pts not receiving MT, PFS was 2.3 mos and 2.5 mos with Pem and Pac, respectively. From induction, both SP/MP had significantly more grade 3/4 thrombocytopenia, anemia, and fatigue with Pem and neutropenia and sensory neuropathy with Pac (p≤0.001). During MT only, the difference in grade 3/4 neutropenia rates between arms was no longer significant. Conclusions: Improved efficacy outcomes were consistent with previous Pem maintenance and Bev studies and no new toxicities were observed. Clinical trial information: NCT00762034.
65 plus: A randomized phase III trial of pemetrexed and bevacizumab versus pemetrexed, bevacizumab, and carboplatin as first-line treatment for elderly patients with advanced nonsquamous, non-small cell lung cancer (NSCLC).
Authors: Schuette Wolfgang , Nagel Sylke , Schneider Claus-Peter , Engel-Riedel Walburga , Schumann Christian , Kohlhaeufl Martin , Serke Monika , Hoeffken Gert , Kortsik Cornelius , Reck Martin
Published: March 2020

8013

Background: Pemetrexed (P) and bevacizumab (B) are efficacious drugs for treatment of non-squamous NSCLC. In this trial the benefit of combining PB with carboplatin (C) was investigated in elderly patients (pts) ≥ 65 years with NSCLC. Methods: In this German multicenter (27 centers), open-label phase III trial pts with stage IIIb/IV non-squamous NSCLC were recruited. Pts were randomized 1:1 to P (500 mg/m2) + B (7.5 mg/kg) or P+B+C (AUC5) d1 q3 wks for 4 to 6 cycles followed by maintenance therapy with B or P+B. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), 1-year survival rate, overall response rate (ORR) as well as tolerability (AEs/SAEs). Results: 271 pts were enrolled from Sep 2009 to Jan 2012, the ITT population consists of 251 evaluable pts, less than 10 pts are still receiving maintenance therapy. Baseline characteristics were balanced between both treatment groups (PB 118 pts, PBC 133 pts). Median age was 71 years in PB and 72 in PBC. Median PFS time was 4.8 mo in PB and 6.8 mo in PBC. Treatment comparison for ECOG performance status (PS) 0-1 subgroup (PB 112 pts, PBC 126 pts): p=0.0426 (Wilcoxon test), hazard ratio (HR) = 1.31 (95% CI 0.99-1.73). ORR was 31.4% in PB vs. 44.4% in PBC (p=0.0343). Median OS time was 11.6 mo in PB vs. 15.2 mo in PBC. Treatment comparison ECOG PS 0-1: p=0.2050, HR = 1.20 (95% CI 0.85-1.70). 1-year survival rates were 48.2% and 58.8%, respectively. Compared to this the median OS time in the small group of pts with ECOG PS 2 was 11.5 mo in PB vs. 3.8 mo in PBC. AE grade 3/4 and SAE profiles were comparable in both treatment arms, 76 pts (64.4%) with AEs grade 3/4 in PB and 87 pts (65.4%) in PBC, 58 pts (49.2%) with SAEs in PB and 64 pts (48.1%) in PBC. 46 pts (39.0%) in PB vs. 69 pts (51.9%) in PBC received maintenance therapy. Conclusions: Combination of PBC demonstrates with a median OS of 15.2 mo a strong efficacy with acceptable toxicity profile for elderly patients. Addition of carboplatin is recommended for eligible patients. However, in patients with ECOG PS 2 the administration of carboplatin must be carefully reviewed. Clinical trial information: NCT00976456.
NTRK1 gene fusions as a novel oncogene target in lung cancer.
Authors: Doebele Robert Charles , Vaishnavi Aria , Capelletti Marzia , Le Anh T. , Kako Severine , Butaney Mohit , Mahale Sakshi , Aisner Dara L. , Haas Julia , Andrews Steven W. , Lipson Doron , Stephens Philip J. , Varella-Garcia Marileila , Janne Pasi Antero , Miller Vincent A.
Published: March 2020

8023

Background: The identification and therapeutic targeting of oncogenic drivers in lung adenocarcinoma has led to significant clinical improvements for patients with EGFR mutations or ALK fusions. However, many lung cancer patients do not yet have an identified oncogenic driver and the discovery of new actionable oncogenic drivers is thus an active area of investigation. Methods: Tumor samples from 36 ‘pan-negative’ (EGFR, KRAS, ALK, and ROS1) lung adenocarcinoma patients were analyzed using a next generation sequencing (NGS) test performed in a CLIA-certified lab (Foundation Medicine, Cambridge, MA). Fluorescence in situ hybridization (FISH) screening using a novel NTRK1 break-apart assay was performed on an additional 61 pan-negative samples. Cells expressing the novel NTRK1 fusions were assayed for transformation and pharmacologic inhibition. Results: Two tumor samples were identified with gene fusions containing the kinase domain of TrkA, encoded by NTRK1, including one each with an MPRIP-NTRK1 (M21;N14) and CD74-NTRK1 (C8;N12) fusion. RT-PCR confirmed mRNA expression and identity of the fusion partner and FISH analysis detected split 5’/3’ signals corresponding to the NTRK1 gene. A third sample was identified by FISH analysis. Cloning and expression of MPRIP- and CD74-NTRK1 into NIH3T3 and Ba/F3 cells show constitutive activation of the TrkA kinase domain and transformation. Treatment of cells expressing NTRK1 fusions with several candidate pan-Trk inhibitors (ARRY-772, -523, and -470) as well as CEP-701 and crizotinib demonstrate decreased phosphorylation of the fusion oncoprotein and inhibition of cell proliferation. Treatment of the index patient harboring the MPRIP-NTRK1fusion with crizotinib led to minor transient tumor shrinkage. Conclusions: We identified a novel class of oncogenes, NTRK1 fusions, in lung adenocarcinomas that can be detected by NGS or FISH. Additional studies to determine the frequency and characteristics of NTRK1 fusions in lung cancer are ongoing. Our findings suggest prospective clinical trials of Trk inhibitors in NTRK1 fusion positive patients may be warranted. Support: CO Bioscience Discovery and Evaluation Grant and CO Clinical and Translational Sciences Institute Grant.
A phase II study of HSP90 inhibitor AUY922 and erlotinib (E) for patients (pts) with EGFR-mutant lung cancer and acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).
Authors: Johnson Melissa Lynne , Hart Eric M , Rademaker Alfred , Weitner Bing Bing , Urman Alexandra , Simm Hala D , Fountas Leanne M , Worden Rebekah , Patel Jyoti D. , Miller Vincent A. , Riely Gregory J.
Published: March 2020

8036

Background: AUY922 is a synthetic HSP90 inhibitor that degrades client onco-proteins including EGFR. Preclinical studies demonstrate HSP90 inhibitors are effective agents against models of AR in EGFR-mutant lung cancer cell lines and xenografts harboring the “gatekeeper” mutation EGFR T790M. Pts with EGFR mutations who develop AR often continue E with 2nd-line therapies to avoid “disease flare” associated with discontinuing TKI. This phase II study combines AUY922 and E for the treatment of pts with EGFR-mutant lung cancer and RECIST-progression on 1st-line EGFR TKIs. Methods: Eligible pts had EGFR mutations and developed AR (Jackman, JCO 2010) after treatment with EGFR TKIs. Pts underwent tumor biopsies after developing AR and prior to study entry. Pts received AUY922 70 mg/m2 IV weekly and E 150 mg oral daily in 28-day cycles. Response assessment occurred at 4 weeks (wks), 8 wks, and every 8 wks thereafter. The primary objective was overall response rate (ORR, CR+PR) at 8 wks. A Simon mini-max design determined sample size (stage I: 16 pts (≥2 responses needed to proceed to stage II), stage II: 9 pts; α=10%, β=10%, p0=10%, p1=30%). Tumor tissue from re-biopsy at study entry was analyzed for EGFR T790M. Results: Sixteen pts have been treated (10 women, median age 58 [range 47-76]). The median time on EGFR-TKI prior to the development of AR was 12 mo (range 2-42 mo). Seven pts had EGFR T790M confirmed by tumor re-biopsy. ORR was 2/16 (13%, 95% CI 2-37%). Both pts with PR had EGFR T790M. Four other pts had stable disease for at least 8 wks, two remain on study after more than 12 wks. Adverse events reported in ≥20% of pts were diarrhea, fatigue, myalgias, nausea, and transient flashing lights or night blindness. One pt each experienced grade 3 diarrhea and cardiac abnormalities. Conclusions: AUY922 and E is a well-tolerated regimen for pts with EGFR-mutant lung cancer and AR to EGFR TKIs. Two pts remain on study and 9 additional pts will be accrued in stage II; final response rate and survival outcomes will be reported. Supported by Novartis, Inc. Clinical trial information: NCT01259089.
A randomized phase II trial comparing continuation maintenance therapy with pemetrexed and switch maintenance therapy with docetaxel after first-line therapy with carboplatin and pemetrexed in patients with advanced nonsquamous non-small cell lung cancer.
Authors: Karayama Masato , Inui Naoki , Kuroishi Shigeki , Yokomura Koshi , Toyoshima MIkio , Shirai Toshihiro , Masuda Msafumi , Yamada Takashi , Yasuda Kazumasa , Suda Takafumi , Chida Kingo
Published: March 2020

8038

Background: Emerging evidence suggests that maintenance chemotherapy could prolong survival in patients with advanced non-small-cell lung cancer (NSCLC), whereas the optimal treatment strategy remains controversial. Methods: We conducted a randomized phase II study to compare the efficacy and safety of continuation maintenance with pemetrexed (500 mg/m2) and switch maintenance with docetaxel (60 mg/m2) in patients with non-squamous NSCLC who achieved disease control after first-line chemotherapy with four cycles of carboplatin (AUC 6) and pemetrexed (500 mg/m2). Results: Eighty-five patients participated in the study, and 26 and 25 patients were randomized to the pemetrexed and the docetaxel maintenance therapies, respectively. The docetaxel group showed a trend toward longer progression-free survival (median 8.2 months, 95% CI; 3.9-12.2 months) compared with the pemetrexed group (median 4.1 months, 95% CI; 3.0-6.1 months), but not significantly (log-rank p=0.084). Grade 3/4 hematologic toxicity was significantly more frequent in the docetaxel group (80%) than the pemetrexed group (20%, p<0.0001). Conclusions: Continuation maintenance with pemetrexed after induction therapy with carboplatin and pemetrexed may be an efficacious treatment with less toxicity. In contrast, switch maintenance with docetaxel frequently causes severe hematologic toxicity but may be more efficacious. Further studies are warranted to evaluate the risks and benefits of maintenance therapies. Clinical trial information: 000004075.
Exploratory analysis of angiotensin converting enzyme (ACE) and aldosterone (Ald) serum levels as prognostic and predictive biomarkers on the NCIC CTG BR24 trial.
Authors: Bar Jair , Ding Keyue , Zhao Huijun , Laurie Scott Andrew , Han Lei , Shepherd Frances A. , Addison Christina L. , Goss Glenwood D. , Dimitroulakos Jim , Bradbury Penelope Ann
Published: March 2020

8048

Background: Benefit from angiogenesis inhibitors (AI) has been linked to high blood pressure. One of the main determinants of blood pressure is the renin-angiotensin axis. We undertook an exploratory, retrospective analysis of ACE and Ald serum levels on specimens banked during the conduct of the BR24 study. The aim was to evaluate these markers for their prognostic significance and their predictive value regarding Cediranib (Ced) treatment. Methods: The NCIC CTG BR24 study randomized advanced non-small cell lung cancer patients (pts) to carboplatin and paclitaxel (CP) +/- Ced. ACE and Ald serum levels were retrospectively tested on baseline samples using commercial ELISA kits. A graphic method, differentiating treatment effect by the range of marker, was used to determine cutoff points (JCO 2010, 28: 5247). Exploratory analyses were performed to correlate biomarkers levels with pts characteristics and overall survival (OS). Association between categorical variables was assessed by Chi-square test or Fisher’s exact test; time to event correlation with biomarkers was tested using a Cox regression model. Potential confounding factors including medications were integrated into the statistical model. Results: Biomarker data was available in 226 of 296 randomized pts. The tested pts vs. all the randomized pts were more likely to have a lower performance status (PS, p=0.03), a normal LDH (p=0.05) and to be ever-smokers (p=0.015). The determined cutoffs were ACE: 115ng/ml and Ald: 250 pg/ml. High ACE was associated with a better PS (p=0.03). High ACE levels were prognostic for longer OS (adjusted HR 0.52 [95%C.I. 0.29-0.92], p=0.025). High ACE pts had no OS benefit (HR 1.27 [95% C.I. 0.78–2.08], p=0.34), while low ACE predicted OS benefit from the addition of Ced to CP (HR 0.64 [95%CI 0.42-0.97], p=0.03). Interaction p value=0.03; this remained significant after adjustment in multivariate analyses. Ald levels were neither prognostic nor predictive. Conclusions: This exploratory analysis suggests high ACE serum levels maybe prognostic for better OS, while low ACE may predict benefit from Ced when added to CP.
Molecular marker assessments for epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) and histoscore (H-score) in the phase III SELECT trial.
Authors: Kim Edward S. , Chittoor Sreenivas , Reynolds Craig H. , Simms Lorinda , Saxman Scott
Published: March 2020

8052

Background: SELECT was a phase III study that investigated whether the addition of cetuximab (C) to pemetrexed (P) improved outcome in previously treated patients (pts) with recurrent or progressive non-small cell lung cancer (NSCLC). Clinical results have been reported previously and demonstrated that adding C to P did not improve progression-free survival (PFS) or overall survival (OS). H-score has been reported to be a potential predictor of outcome for C therapy. Prespecified biomarker analyses, including EGFR IHC and H-score, are reported here. Methods: EGFRexpression in tumor tissue was not required for eligibility; however, tissue was collected and analyzed for EGFR expression by IHC using standard methods. In addition, H-score evaluation was performed by trained central pathologists and correlated with clinical outcome using a predefined cutoff for “low” and “high” of <200 and ≥200, respectively. Results: A total of 449 (IHC) and 406 (H-score) pt specimens were evaluable. Demographics for pts with tissue available for EGFR analysis were similar to the overall population. For IHC+ pts (n=396), median PFS for C+P was 3.02 months (95% CI, 2.76–3.45) compared with 2.99 months (95% CI, 2.63–4.14) for P (HR, 1.02 [95% CI, 0.83–1.24]; p=.86). For pts with low H-score (N=99 [C+P] and N=111 [P]), median PFS was 2.7 months (95% CI, 1.8–3.2) with C+P and 3.1 months (95% CI, 2.6–4.1) with P (HR, 1.11 [95% CI, 0.84–1.46]; P=.48); median OS was 6.7 months (95% CI, 5.3–8.6) with C+P and 6.6 months (95% CI, 4.7–9.2) with P (HR, 0.96 [95% CI, 0.72–1.27]; P=.76). Among pts with high H-scores (N=101 [C+P] and N= 95 [P]), median PFS was 3.2 months (95% CI, 2.7–4.6) with C+P and 3.7 months (95% CI, 1.7–4.5) with P (HR, 1.02 [95% CI, 0.77–1.37]; P=.86); median OS was 7.7 months (95% CI, 6.5–10.9) with C+P and 8.0 months (95% CI, 7.0–9.1) with P (HR, 1.17 [95% CI, 0.86–1.57]; P=.32). Conclusions: EGFR H-score was not predictive of benefit for the addition of C to P in this population of pts with NSCLC. There was also no treatment effect in the IHC+ group. Clinical trial information: NCT00095199.
Safety and efficacy of nintedanib (BIBF 1120) plus pemetrexed in Japanese patients with advanced or recurrent non-small cell lung cancer (NSCLC): A phase I study.
Authors: Daga Haruko , Takeda Koji , Okada Hideaki , Miyazaki Masaki , Ueda Shinya , Kaneda Hiroyasu , Okamoto Isamu , Yoh Kiyotaka , Goto Koichi , Konishi Koichi , Sarashina Akiko , Yagi Nobutaka , Mera Kiyomi , Kaiser Rolf , Nakagawa Kazuhiko
Published: March 2020

8056

Background: Nintedanib (N) is a potent, orally bio-available triple angiokinase inhibitor that targets VEGFRs, PDGFRs and FGFRs, as well as RET and Flt3. The open-label phase I part of this phase I/II study was designed to determine the maximum tolerated dose (MTD) of N when combined with standard-dose pemetrexed (PEM), and to investigate safety and efficacy in Japanese patients (pts) with advanced/recurrent NSCLC. Methods: Eligible pts had histologically/cytologically confirmed stage IIIB/IV or recurrent NSCLC (any histology) after failure of first-line chemotherapy. Pts received PEM 500 mg/m2 iv on day 1 followed by N twice daily (bid) po on days 2–21 every 21 days using a standard 3+3 design. N was started at 100 mg bid and escalated to 200 mg bid in 50 mg bid intervals. Pts received ≥4 cycles of combination therapy with an option of continuing with single-agent N until disease progression or undue adverse events (AEs). Primary endpoints were MTD, defined as the highest dose at which incidence of dose-limiting toxicities (DLTs) was <33.3%, and safety. DLTs were defined as grade 3 non-hematologic or grade 4 hematologic AEs. Secondary endpoints included objective tumor response and pharmacokinetics (PKs). Results: 18 pts (14 male) were treated: 3 at N 100 mg bid, 6 at N 150 mg bid, and 9 at N 200 mg bid. DLTs were observed in 0/3, 1/6, and 2/9 pts in each cohort, respectively; 2 of these pts had liver enzyme elevations. The MTD for N (plus PEM) was 200 mg bid. The most common drug-related AEs were increased GGT, increased AST, decreased appetite, and diarrhea. Grade 3 AEs included neutropenia (22.2%), increased AST, increased ALT, and lymphopenia (each 11.1%); no pts experienced grade 4/5 AEs. Two pts (11.1%) achieved a partial response and 12 (66.7%) had stable disease. At the MTD, N exposure after PEM administration was similar to that seen with N monotherapy in a previous Japanese study. Co-administration of N did not affect the PKs of PEM. Conclusions: The combination of N and standard-dose PEM had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese pts with advanced/recurrent NSCLC. As in Caucasian pts, the MTD of N was 200 mg bid. Clinical trial information: NCT00979576.
Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined non-small cell lung cancer (NSCLC) patients.
Authors: De Greve Jacques , Moran Teresa , Graas Marie-Pascale , Galdermans Daniella , Vuylsteke Peter , Canon Jean-Luc , Chand Vikram K. , Fu Yali , Massey Dan , Vansteenkiste Johan
Published: March 2020

8063

Background: EGFR mutation+ (M+) NSCLC pts have an improved response to EGFR TKIs vs non-M+ pts. Data on EGFR FISH+ (gene amplified) and HER2 M+ pts are, however, limited. Afatinib is an irreversible ErbB Family Blocker with efficacy in Ph II/III trials in EGFR M+ NSCLC. This exploratory, open-label trial assessed afatinib in 3 genotypically and demographically defined NSCLC groups. Methods: Never/ex-smokers with stage IIIB/IV lung adenocarcinoma with EGFR M+ tumors who had failed prior EGFR TKIs, HER2 M+ tumors independent of prior therapy, or EGFR FISH+ tumors who received ≤3 prior chemotherapies were enrolled. Afatinib 50 mg qd was administered until disease progression or intolerable adverse events. Tumor assessments (RECIST 1.0) were performed every 8 wks. Pts who progressed on afatinib but experienced clinical benefit could continue treatment with afatinib 40 mg qd + paclitaxel 80 mg/m² qw on days 1, 8 and 15 every 28-day cycle. Primary endpoint: Confirmed objective response. Results: 41 pts were treated: 63% female; median age 63 yrs; 68% never smokers; 32% ex-smokers. 33 pts received afatinib monotherapy only; 8 pts received afatinib followed by afatinib/paclitaxel combination therapy. 78% (n=32) of pts were EGFR M+, 5% (n=2) were EGFR FISH+ and 17% (n=7) were HER2 M+. For afatinib monotherapy, 1 confirmed partial response (PR) was observed (EGFR FISH+), stable disease (SD) was seen in 5/7 HER2 M+, 2/2 EGFR FISH+ and 17/32 EGFR M+ pts, and overall disease control (DC) rate was 59% (n=24); mean duration of DC was 26 wks.Median PFS was 16 wks (17 wks in HER2 M+ pts). Of 8 afatinib/paclitaxel-treated pts, 1 had a confirmed PR and 2 had SD; median PFS was 7 wks. Most frequently reported drug-related AEs in afatinib monotherapy pts were diarrhea (n=39; grade ≥3 n=13), rash/acne (n=33; grade ≥3 n=4) and stomatitis (n=19; grade ≥3 n=2). In the combination arm these were diarrhea (n=4; grade ≥3 n=1) and nausea (n=3; grade ≥3 n=0). Conclusions: Efficacy of afatinib in EGFR M+ NSCLC pts has been established in previous trials. Novel activity of afatinib in HER2 M+ and EGFR FISH+ NSCLC pts has been demonstrated here, with a manageable safety profile of afatinib in the overall population. Clinical trial information: NCT00730925.
Whole-exome sequencing in tumor samples from sequenom-wild-type, ALK negative stage IV lung adenocarcinoma (ADC) patients (p).
Authors: Felip Enriqueta , Caratu Ginevra , Silberschmidt Daniel , Martinez Pablo , Martinez Marti Alex , Cedres Susana , Murtra-Garrell Nuria , Navarro-Mendivil Alejandro , Prudkin Ludmila , Jimenez Jose , de la Morena Pilar , Canela Mercedes , Nuciforo Paolo , Palmer Hector G. , Vivancos Ana
Published: March 2020

8070

Background: The majority of lung ADC tumors are characterized by specific genetic features with KRAS mutations (mut) seen in 20-30%, EGFR mut in 15%, EML4-ALK translocations in 5%, and ERBB2 mut in 2%, among others. Some of these genetic alterations are already being used for selecting targeted therapies. However, identification of additional genomic alterations is required. Methods: In the present ongoing study we perform whole-exome sequencing in paraffin-embedded tumor samples from OncoCarta v1.0 panel wild-type (no mut in hotspots of KRAS, EGFR, ERBB2, AKT1, BRAF, PIK3CA genes) and ALK negative (by FISH) stage IV ADC lung cancer p, and in their matched normal tissue samples. Results: To date, a total of 7 tumors and matched normal tissues have been successfully analyzed. We have detected mut in previously identified ADC genes, such as ERBB2, CTNNB1, TP53, SMAD4 or APC. Interestingly, mut were found in genes belonging to the proposed new cancer hallmark ‘epigenetic and RNA regulation’, such as BRD3, EPC1, PHF1 in almost every p included in our study. Regarding alterations that could be considered relevant for lung tumor pathogenesis/growth or as potential targets for treatment therapies, we were able to identify candidates in 4 of the 7 p. In one p, a case of a transmembrane domain ERBB2mut in exon 20 (p.E770delinsEAYVM) not previously detected by the OncoCarta v1.0 panel (that interrogates L755P, G776S/L/V/C, A775_G776insYVMA, P780_Y781insGSP, S779_P780insVGS mut) was found. In another p, three somatic mut in the BRCA1/2 genes were detected. Additionally, one p had an ALK point mut (p.P336K), for which no functional information is available, together with an APC mutation. In the remaining p, a non-hotspot mutation (although previously detected in a colorectal tumor) was found in CTNNB1. Conclusions: In this limited experience of whole-exome sequencing of a subgroup of stage IV lung ADC p, potentially targetable alterations not formerly detected by other techniques were found. We believe that genomic approaches to detecting alterations may be useful in clinical practice and will hopefully provide assistance in making treatment decisions.
First-line pemetrexed plus cisplatin followed by maintenance pemetrexed versus carboplatin-paclitaxel plus bevacizumab followed by maintenance bevacizumab (ERACLE) in advanced nonsquamous NSCLC: A quality-of-life-oriented, multicenter randomized phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale).
Authors: Galetta Domenico , Pisconti Salvatore , Cinieri Saverio , Gebbia Vittorio , Morabito Alessandro , Borsellino Nicolo , Maiello Evaristo , Febbraro Antonio , Catino Annamaria , Rizzo Pietro , Montrone Michele , Simone Giovanni , Lorusso Vito , Rizzi Daniele , Pappagallo Giovanni L. , Colucci Giuseppe
Published: March 2020

8071

Background: In absence of oncogenic driver chemotherapy (CT) for advanced non-squamous non-small cell lung cancer (NS-NSCLC) remains palliative with similar efficacy and survival among different regimens. Histotype, maintenance therapy (m) and quality of life (QoL) have been explored to improve patients (pts) outcome. ERACLE trial (NCT01303926), a QoL-oriented phase III trial was designed to compare the QoL for two CT regimens. Methods: Pts with stage IIIB/IV NS-NSCLC (ECOG 0/1) were randomized (1:1) to receive first-line CT. ARM A received 6 cycles of Cisplatin (C) (75 mg/m2) - Pemetrexed (P) (500 mg/m2) q3w, followed by mP (500 mg/m2) while ARM B received Carboplatin (Cb) AUC 6 - Paclitaxel (T) 200 mg/m2plus Bevacizumab (Be) 15 mg/kg q3w for 6 cycles and mBe 15 mg/kg. Both treatments were administered until progression, unacceptable toxicity or death. Stratification was based on Study Centre and disease stage. Co-Primary endpoints were EQ5D Index (EQ5D-I) and EQ5D-VAS (Euro-QoL questionnaire) at 12 weeks during m. Secondary endpoints were QoL over time, activity and safety of CT arms. A sample of 49 pts per arm (not progressed during initial CT and during m therapy for at least 12 weeks) will have 91% chance to have 12-point Minimal Interesting Difference (MID) between arms for EQ5D-VAS, and 87% chance to find 0.137 MID between arms for EQ5D-I. It is assumed that about 20% of pts in both arms experienced a PD before to evaluate primary endpoint. The study sample was then increased to 118. Results: From 1/2011 to 3/2012, 118 pts were randomized to CP (n=60) or CbTBe (n=58). Baseline demographics were well balanced across arms; overall 74% male, 79% PS 0 and 94% stage IV. Treatment differences (mean change from baseline), EQ5D-VAS = 1.82 (95%CI -8.60 to 12.24; P=0.73), EQ5D-I = 0.15 (95%CI 0.01 to 0.29), favoured arm A. Conclusions: CP-mP showed better (over the MID) health profile (EQ5D-I) at 12 weeks as compared to CbBe-mBe. EQ5D-VAS didn’t find any significant difference between treatment arms. Clinical trial information: NCT01303926.
KRAS subset analysis from randomized phase II trials of erlotinib versus erlotinib plus sorafenib or pazopanib in refractory non-small cell lung cancer (NSCLC).
Authors: Waterhouse David Michael , Stults Dawn Michelle , Daniel Davey B. , Griner Paula L. , Greco F Anthony , Burris Howard A. , Hainsworth John D. , Spigel David R.
Published: March 2020

8091

Background: KRAS mutations are among the most common genetic alterations in NSCLC; however no targeted therapies have been approved to benefit this lung cancer subset. Between 2/2008 and 2/2011 our center conducted two consecutive multicenter randomized phase II trials in patients (pts) with refractory NSCLC comparing erlotinib/placebo versus erlotinib + either sorafenib or pazopanib, both oral multikinase inhibitors (Spigel et al, JCO 2011; Chicago MSTO 2012). Progression-free survival (PFS) was improved with the multikinase regimens in the EGFR wild-type (WT) subsets, but not in the overall populations. An unplanned analysis of the combined KRAS subset data is the subject of this report. Methods: Eligibility criteria for both trials included: stage IIIB/IV NSCLC; 1 to 2 prior regimens; ECOG performance status 0–2; measurable disease. PFS was the primary endpoint of each trial. Treatment groups included: erlotinib/placebo (N=121), erlotinib/sorafenib (N=112), and erlotinib/pazopanib (N=127). 168 pts (47%) in these three groups had sufficient tumor specimens for KRAS analysis. Results: The PFS and OS results based on KRAS results are shown in the Table below. Conclusions: Patients in whom the KRAS mutation status was known achieved a significantly longer PFS with erlotinib and a multikinase inhibitor than with erlotinib alone. Although this unplanned combined analysis has several limitations, the greater PFS and OS benefits in pts with KRAS mutations warrant further study. Clinical trial information: NCT00600015; NCT01027598. [Table: see text]