bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective evaluation of RET biomarker status and outcome to vandetanib in four phase III randomized NSCLC trials.
Authors: Platt Adam , Elvin Paul , Morten John , Ji Qunsheng , Donald Emma , Womack Chris , Su Xinying , Zheng Li , Gladwin Amanda , Vasselli James Robert , Lee Jin Soo , De Boer Richard H. , Herbst Roy S. ,   The RET Analysis Team
Published: March 2020

8045

Background: The prevalence of the tumorigenic KIF5B:RET fusion gene in NSCLC tumors has been estimated at 0.2–6% (Jiu et al 2012; Lipson et al 2012). We retrospectively analyzed tumor samples from 4 Phase III NSCLC trials of vandetanib, a TKI that selectively targets RET, VEGFR and EGFR signaling, to determine the prevalence of RET fusions and other RET biomarkers, and any potential association with outcome to vandetanib (V). Methods: The studies evaluated were ZODIAC (NCT00312377; docetaxel ± V 100mg), ZEAL (NCT00418886; pemetrexed ± V 100mg), ZEPHYR (NCT00404924; V 300mg vs placebo) and ZEST (NCT00364351; V 300mg vs erlotinib). RET biomarkers evaluated included RET fusions (including KIF5B:RET) and RET gene copy number (assessed by a 4-probe FISH assay), as well as RET protein expression (by IHC). Results: Of 4089 patients randomized across the 4 studies, 1291 and 1234 had tumor samples available for FISH and IHC analysis, respectively, with evaluable data obtained for 944 and 1102. RET fusions (in >10% of tumor cells) were detected in 7 of 944 samples (vandetanib, n=3; comparator, n=4), at a prevalence of 0.7% (95% CI, 0.3–1.5%). None of the 3 vandetanib-treated RET fusion-positive patients had an objective RECIST response, although there was radiologic evidence of tumor shrinkage in 2. Overall, 2.8% (n=26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in >10% tumor cells), 8.1% (n=76) had lower RET gene copy number gain (4–6 copies in ≥40% tumor cells) and 8.3% (n=92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). There was no difference in ORR between vandetanib and comparator for the RET amplification-positive subset (both 8.3% [1/12]), the RET copy number gain subset (9.8% [4/41] vs 9.1% [3/33], respectively) or the RET protein expression-positive subset (15.2% [7/46] and 13.6% [6/44], respectively). Conclusions: The prevalence of RET fusions was estimated at 0.7%. There were too few vandetanib-treated patients with RET fusions to make any firm conclusion regarding association with efficacy. Evidence from the other RET biomarkers tested suggested that these do not infer a differential advantage in patients treated with vandetanib. Clinical trial information: NCT00312377; NCT00418886; NCT00404924.
Predictors of survival for younger patients (pts) less than 50 years of age with non-small cell lung cancer (NSCLC): A California Cancer Registry (CCR) analysis.
Authors: Lara Matthew Stephen , Brunson Ann , Tomlinson Ben Kent , Wun Theodore , Qi Lihong , Cress Rosemary , Lara Primo , Gandara David R. , Kelly Karen
Published: March 2020

8049

Background: Lung cancer is often seen in older pts, with a median age at diagnosis of 70 years (yrs). Epidemiology and outcomes are reportedly different among younger NSCLC pts (< 50 yrs). We hypothesized that these pts have longer cause-specific survival (CSS) and that baseline clinical features prognostic for CSS would be identified. Methods: NSCLC pts in the CCR diagnosed between 1/98 through 12/09 were included. The primary outcome was CSS. Hazard ratios (HR) for CSS were calculated using Cox Proportional Hazards (PH) models for all ages & for pts <50 years, adjusted for baseline variables. Results: We identified 132,671 lung cancer pts: 114,451 (86.3%) had NSCLC. 6,389 (5.6%) were < 50 yrs (median, 46 yrs). Demographics: White (3,557, 56%); Histology: AdenoCA (AC) (3,406, 53%), Squamous (781, 12%), BAC (291, 4.6%); Stage IV (3,655, 57%). Fewer pts < 50 yrs were diagnosed in later yrs: from 37% in ‘98-’01 to 29% in ‘06-‘09. Results of Cox PH models for all ages and < 50 years are shown. Conclusions: The relative proportion of pts < 50 yrs has declined by 22% over the past decade. Age < 50 years was an independent predictor of improved CSS (HR 0.83, p<0.001). In younger pts, AC histology was not prognostic for CSS (versus squamous) despite known differences in clinical and biologic behavior between subtypes.Importantly, clinical variables strongly prognostic for CSS were identified in pts < 50 yrs. [Table: see text]
A comparison of bronchofiberscopic (BFS) washing cytology (BWC) and formalin-fixed paraffin-embedded tissue (PPFE) in the analysis of EGFR mutations in advanced non-small cell lung cancer (NSCLC).
Authors: Hida Naoya , Misumi Yuuki , Agemi Yoko , Sato Akira , Ishii Mari , Shimokawa Tsuneo , Okamoto Hiroaki
Published: March 2020

8054

Background: In the treatment of advanced NSCLC, EGFR mutation status is one of the most predictive factors for the efficacy of EGFR tyrosine kinase inhibitors, and the evaluation of EGFR mutation status using the PPFE has been widely used for this analysis throughout the world. However, whether BWC can be used as an alternative for PPFE in the analysis of EGFR mutations is unknown. The largest study evaluating these 2 methods included only around 20 samples. Therefore, in the current study, we compared the freeze stock solution of BWC with PPFE for the determination of EGFR mutation status in a large sample set. Methods: In diagnostic BFS examinations, after curetting or brushing and biopsy to target lesions, subsequent bronchial washing by saline was performed. Thereafter, the saline fluid in which the forceps were washed and the bronchial washing fluid were mixed in a sterilized tube and were immediately frozen in a -20°C freezer. EGFR mutation testing for both BWC and PPFE was performed using high-sensitivity PCR (BML, PCR-Invader). Results: A total of 440 BFS examinations were performed from Aug 2010 to Nov 2011 in our hospital. The BWCs of 268 suspected cases of lung cancer were successfully obtained. Of these, 51 cases that were pathologically confirmed as adenocarcinoma based on both BWC and PPFE were analyzed in this study. EGFR mutations were identified in 25 cases, while the remaining 26 cases had wild-type EGFR. In 49 of 51 cases, the results of EGFR mutation status were the same for BWC and PPFE, and the concordance rate was 96%. In one case, an exon-18 mutation was detected only by BWC. In another case an exon-21 mutation was detected only by PPFE. In 24 of 25 cases of EGFR mutation, the mutation site was the same in both samples. The kappa coefficient was 0.92. Conclusions: This is the largest genetic study to date demonstrating a head-to-head comparison of BWC and PPFE for the evaluation of EGFR mutations. Both methods showed high reliability and concordance using high-sensitivity PCR. BWC is considered a simple, rapid method and represents an effective alternative for PPFE in EGFR mutation testing.
BIM deletion polymorphism to predict systemic treatment outcome in advanced non-small cell lung cancer.
Authors: Lee Jih-hsiang , Lin Yu-lin , Chen Hsuan-Yu , Chang Yeun-Chung , Yu Chong-Jen , Shih Jin-Yuan , Chen Kuan-Yu , Yang Pan-Chyr , Yang Chih-Hsin
Published: March 2020

8055

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) and chemotherapies are treatments for EGFR mutant non-small cell lung cancer (NSCLC) patients. We explored the predictive factors for progression-free survival (PFS) and overall survival (OS) on first-line EGFR-TKIs and second-line chemotherapies in NSCLC patients. Methods: One hundred and six chemonaïve NSCLC patients who received first line gefitinib in a phase II study were prospectively followed until death. Clinical and molecular biomakers were correlated with PFS and OS. Results: The OS and PFS of first-line gefitinib treatment were 19.4 (95% CI 15.6-23.3) months and 7.4 (95% CI 6.7-8.1) months, respectively. Sixty-nine patients (65%) received subsequent second-line chemotherapy. Median PFS and OS of second-line chemotherapy were 5.7 (95% CI 4.8-6.6) and 15.1 (95% CI 10.5-20.2) months. Bcl-2-like protein 11 (also named as BIM) deletion polymorphism was found in 17 out of 101 (16.8%) patients tested. The median PFS from first-line gefitinib in patients carrying normal BIM and deletion polymorphism were 8.1 months and 3.6 months, respectively (p<0.001), and the median OS were 22.1 months and 14.1 months, respectively (p=0.041); in 44 patients with common EGFR mutations (del 19 or L858R), the PFS for patients carrying normal BIM and deletion polymorphism were 9.6 months and 7.4 months, respectively (p=0.034). A multivariate analysis suggested that BIM deletion polymorphism and EGFR mutational status were independent predictors for gefitinib PFS (hazard ratio 2.83, p=0.001, and 0.63, p=0.03, respectively). Conclusions: BIM deletion polymorphism predicts shorter PFS in EGFR mutation NSCLC patients treated with first line gefitinib.
Final efficacy and safety results of pemetrexed (pem) continuation maintenance (mtc) therapy in the elderly from the PARAMOUNT phase III study.
Authors: Gridelli Cesare , Thomas Michael , Prabhash Kumar , El Kouri Claude , Blackhall Fiona Helen , Bustin Frederique , San Antonio Belen , Zimmermann Annamaria , Chouaki Nadia , Visseren-Grul Carla , Paz-Ares Luis
Published: March 2020

8068

Background: The PARAMOUNT phase III trial showed that mtc pem after pem-cisplatin induction was well tolerated and effective for patients (pts) with advanced nonsquamous NSCLC. Here we present the final OS and safety data from this study in elderly (≥70 yrs) vs. non-elderly (<70 yrs) pts. Methods: In this double-blind study, 539 pts with a PS of 0/1 were randomized (2:1, stratified for stage, PS and induction response) to receive mtc pem (n=359, 500 mg/m2, day 1, 21 day cycle) or placebo (plc) (n=180). The study was powered for PFS (previously reported) and key secondary OS. Subgroup analyses were done for pts ≥70 yrs and <70 yrs. Results: Subgroups (≥70: n=92, 17%; <70: n=447, 83%) had similar baseline characteristics except for PS and sex (elderly, PS 0/1: 22%/77%, M/F: 66%/34%; non-elderly, PS 0/1: 34%/65%, M/F: 56%/44%). The median ages were 73 yrs (≥70) and 60 yrs (<70). The mean cycles received for pts ≥70 were 7.4 (range 1-36, dose intensity (DI) 91%) for pem and 4.5 for plc, and for pts <70 were 8.0 (range 1-44, DI 94%) for pem and 5.1 for plc. The OS HRs (pem vs. plc) were 0.89 (95% CI: 0.55-1.4) for ≥70 yrs and 0.75 (95% CI: 0.60-0.95, p=0.015) for<70 yrs. The median OS (95% CI) (≥70) was 13.7 mo (10.4-19.4) for pem and 12.1 mo (8.4-16.9) for plc; the median OS (95%CI) (<70) was 13.9 mo (12.5-16.1) for pem and 10.8 mo (9.5-12.9) for plc. The 1 and 2 yr OS rates (95% CI) for the elderly were 60% (45-71%) and 34% (21-47%) for pem vs. 52% (36-66%) and 28% (15-43%) for plc, respectively. For non-elderly pts, the 1 and 2 yr OS rates were 58% (52-63%) and 31% (26-37%) for pem vs. 43% (35-52%) and 19% (13-27%) for plc, respectively. The Table shows a subset of drug-related AEs. Conclusions: Continuation mtc pem had comparable survival and toxicity profiles in the ≥70 and <70 yrs subgroups. However, Gr 3/4 anemia and neutropenia were numerically higher for pts ≥70 yrs. Clinical trial information: NCT00789373. [Table: see text]
Prognostic impact of tumor (T) and lymph node (N) status in patients with metastatic non-small-cell lung cancer (NSCLC).
Authors: Devarakonda Siddhartha , Xia Bing , Gao Feng , Govindan Ramaswamy , Morgensztern Daniel
Published: March 2020

8076

Background: Although commonly reported in databases and clinical trials, T and N status do not affect the final stage or overall treatment plan for patients with metastatic NSCLC. Since there is limited data on the impact of T and N status on outcomes in this population, we conducted a Surveillance, Epidemiology, and End Results (SEER) study to address this question. Methods: The SEER database was searched for patients with stage M1b NSCLC, with known T and N status, diagnosed between 2004 and 2008. Patients with T0 and malignant pleural effusion were excluded. Overall survival (OS) was estimated by the Kaplan-Meier method, while the hazard ratios (HR) were estimated and compared using Cox proportional hazard models. Results: Among the 25,919 patients included, the frequencies of T1, T2, T3, and T4 were 15.8%, 28.2%, 33.6% and 22.4% respectively, whereas N0, N1, N2, and N3 were observed in 28.0%, 9.3%, 47.1% and 15.6% respectively. One-year OS ranged from 21.1% in T4 to 35.8% in T1, and 23.1% in N2 to 33.2% in N0 disease (Table). Both T and N were also identified as independent predictors for OS in multivariable analysis adjusted for age, gender, race, and histology. Conclusions: Both T and N status are important clinical prognostic factors that should be taken into consideration when evaluating patients with metastatic NSCLC. If confirmed in prospective studies, clinical trials and analyses of either clinical or molecular prognostic factors in the future may need to be adjusted according to the complete TNM staging. [Table: see text]
Differences in mutation patterns of diagnostic versus post-chemotherapy samples in patients with metastatic non-small cell lung cancer (NSCLC).
Authors: William William Nassib , Erickson Heidi S. , Wei Caimiao , Hanson Nana , Tang Ximing , Rodriguez Jaime , Kalhor Neda , Lee J. Jack , Hong Waun Ki , Kim Edward S. , Wistuba Ignacio Ivan
Published: March 2020

8079

Background: Many clinical trials in metastatic NSCLC patients who failed first-line chemotherapy have utilized pre-treatment, diagnostic tissues for marker assessment. BATTLE was a randomized, biopsy-driven clinical study in patients with metastatic NSCLC previously treated with systemic therapy. Fresh biopsies were obtained at the time of enrollment for biomarker evaluation. We hypothesized that molecular abnormalities found at the time of enrolment in BATTLE would differ from baseline, pre-chemotherapy, diagnostic tissue. Methods: We isolated DNA (SPRI-TE-based DNA recovery and cleanup methodology) from 82 matched pre-chemotherapy and BATTLE formalin-fixed paraffin-embedded specimens. Mutations were assessed by MALDI-TOF MS (MassArray, Sequenom Inc) using a lung cancer panel of 16 genes/140 assays (AKT1, BRAF, CTNNB1, EGFR, ERBB2, FGFR3, HRAS, KRAS, MEK1, MEK2, MET, NRAS, PIK3CA, PIK3R1, PTEN, and STK11) and were compared between pre-chemotherapy versus BATTLE samples. Results: Mutations were identified in 25 pre-chemotherapy samples (14 K-RAS, 5 EGFR, 3 PIK3CA, 1 STK11, 1 PTEN, 1 HRAS, 1 CTNNB1). Conversely, 29 BATTLE samples had at least one mutation (14 K-RAS, 7 EGFR, 5 PIK3CA, 2 STK11, 1 PTEN, 1 HRAS, 1 CTNNB1). For the matched pair analysis, 46 patients had wild-type tumors both in pre-chemotherapy and BATTLE samples. 11 patients had wild-type tumors in pre-chemotherapy samples, but had a mutation identified in BATTLE samples (4 K-RAS, 4 EGFR, 2 PIK3CA, 1 STK11). 7 patients had a mutation in pre-chemotherapy samples, but no mutations in BATTLE samples (4 K-RAS, 2 EGFR, 1 HRAS). The remaining 18 patients had mutations in both the pre-chemotherapy and BATTLE samples; of these, 2 had different mutations in the paired samples (both within the same genes, 1 KRAS, 1 PIK3CA). Overall, there was a 24% gene mutation discordance rate between pre-chemotherapy and BATTLE samples. Conclusions: Profiling of fresh biopsies may more accurately reflect molecular abnormalities present in the tumor at the time of initiation of salvage therapy, underscoring the importance of real time tissue collection in biomarker-driven studies in this setting (V Foundation, DoD).
Comparison of two chemotherapy regimens in non-small cell lung cancer patients relapsing after surgery and peri-operative chemotherapy (IFCT-0702 study).
Authors: Moro-Sibilot Denis , Audigier-Valette Clarisse , Merle Patrick , Quoix Elisabeth A. , Souquet Pierre Jean , Barlesi Fabrice , Chouaid Christos , Molinier Oliver , Lavole Armelle , Mazieres Julien , Baudrin Laurence , Morin Franck , Zalcman Gerard ,   Intergroupe Francophone de Cancérologie Thoracique (IFCT)
Published: March 2020

8081

Background: To evaluate the benefit of adding cisplatin or carboplatin (P) to docetaxel (D) chemotherapy (CT) in patients with the first metastatic relapse after perioperative chemotherapy and surgery. Methods: Patients (Pts) with histologically or cytologically confirmed inoperable non-small cell-lung cancer not eligible for curative radiotherapy (local or metastatic relapse), disease progression after perioperative chemotherapy and surgery and PS 0-1. Pts were randomized to D 75 mg/m² combined with cisplatin 75 mg/m² or carboplatin AUC5 every 3 weeks (Arm A) or alone (Arm B). The primary endpoint was progression-free survival (PFS). Results: Due to low accrual the trial was interrupted after inclusion of 88 patients. From November 2007 to August 2012, 68 males and 20 females, median age (range) 61 (41-75), ECOG PS 0/1/ 49%/50%, squamous histology 39%, Arm A and Arm B 44 patients each, were enrolled. Interval from last cycle of perioperative CT ou last cycle of adjuvant CT was ≥ 12 months in 69% of pts. 79.5% of patients received DP full treatment. A non-statistically significant increase in PFS favoring combined CT was observed with a HR of 0.73 (95% CI: 0.46-1.15; p = 0.18), median PFS 8 months vs 5.6. Objective response rate was increased in the P-containing arm; p <10-4). However, overall survival was not improved by the addition of P to D; the HR for death was 0.90 (95% CI: 0.55-1.48; p = 0.68) median OS 15.9 months vs 12.4 months. Overall grade 3/4 toxicity was observed in 36 pts (DP) vs 30 (D) : neutropenia (32 pts vs 26), febrile neutropenia (8 vs 3), non-hematological toxicities (18 vs 6). Conclusions: PFS and OS weresurprisingly longer than expected in this cohort of NSCLC patients with metastasis, and comparable with that observed in historical cohorts of NSCLC treated in first-line. DP resulted in a non significant 27% reduction of hazard of progression as compared to D alone. A reduced statistical power related to a slow and insufficient accrual may explain this lack of significance. Considering survival data and toxicity profile, we suggest that these patients behave like first-line patients and may probably be treated accordingly with a platinum-based doublet. Clinical trial information: NCT00535275.
Translational research (TR) results from pointbreak: A randomized, open-label, phase III study of pemetrexed (Pem)+carboplatin (Cb)+bevacizumab (Bev) followed by maintenance pem+bev (Pem Arm) versus paclitaxel (Pac)+cb+bev followed by maintenance bev (Pac Arm) in patients (pts) with stage IIIB or IV nonsquamous non-small cell lung cancer (ns-NSCLC).
Authors: Garon Edward B. , Patel Jyoti D. , Myrand Scott , Nguyen Tuan , Reynolds Craig H. , Spigel David R. , Hermann Robert C. , Liu Jingyi , Guba Susan C. , Govindan Ramaswamy , Socinski Mark A. , Bonomi Philip
Published: March 2020

8086

Background: Results of PointBreak were previously reported. Correlative tissue TR results are presented. Methods: Of 939 pts in the intent-to-treat population (ITT), 211 (22.5%) signed TR consent forms and had evaluable samples. Specimens were analyzed for: Epidermal Growth Factor Receptor (EGFR) mutations by polymerase chain reaction (n=132); thyroid transcription factor-1 (TTF-1) (n=205), thymidylate synthase (TS) (n=189), and folate receptor-alpha (FR-α) (n=180) by immunohistochemistry (IHC) (H-scores range, 0-300). H scores were dichotomized based on positive (>0)/negative (=0) cutpoint. Adjusted Cox/logistic regression determined correlations between overall survival (OS), progression-free survival (PFS), response rate (RR), and dichotomous IHC markers. A 2-sided test with α = 0.05 and 0.1 evaluated treatment and interaction effects, respectively. Results: Median (m) OS and mPFS were similar in the ITT and TR populations for both arms. 11/132 (8.3%) pts had activating EGFR mutations. For TS or FR-α, no significant between-arm differences in OS, PFS and RR were seen. 139/205 (67.8%) pts had positive TTF-1 (TTF-1+). TTF-1+ pts, compared with TTF-1-, independent of treatment, had significantly longer mOS (14.9 vs 8.7 mos, HR 0.48, p<0.001), mPFS (6.9 vs 4.5 mos, HR 0.62, p=0.006), and higher RR (38.9% vs 19.7%, OR 2.68, p=0.008). For TTF-1+ pts, compared with Pac arm, Pem arm had longer mOS (17.6 vs 12.8 mos, HR=0.7, p=0.08; interaction p=0.12) and mPFS (7.3 vs 5.8 mos, HR=0.78, p=0.20; interaction p=0.261); although not statistically significant. Conclusions: The number of pts with EGFR mutations was too small to draw conclusions. No significant between-arm differences for TS and FR-α were seen. Longer survival in TTF-1+ pts suggests TTF-1 expression is prognostic. Additional studies will be needed to better understand trends favoring pem for survival among TTF-1+ pts and other prognostic and/or predictive relationships of these markers. Clinical trial information: NCT00762034.
Patterns of second-line chemotherapy and its effect on survival in patients treated within the Veterans Health Administration (VHA).
Authors: Santana-Davila Rafael , File Danielle M. , Arce-Lara Carlos Eduardo , Kelley Michael J. , Williams Christina D. , Whittle Jeffrey C.
Published: March 2020

8090

Background: Second-line chemotherapy (2-L) improves overall survival (OS) in patients with metastatic NSCLC. In 2004, erlotinib and pemetrexed were approved as 2-L agents. In this study we analyze the utilization of anti-cancer agents and survival for patients with NSCLC who received 2-L treatment within the VHA. Methods: We identified from the VA Central Cancer Registry incident cases of metastatic NSCLC diagnosed between 2001 and 2008. We included patients who received their 1st cycle of chemotherapy within 120 days of diagnosis. A chemotherapy regimen included all chemotherapy agents prescribed during the next 28 days. We defined a subsequent line of therapy when a new agent was started after a period of more than the initial 28 days since the last drug. We divided our cohort into two based on whether they were diagnosed or treated before August of 2004 (the date pemetrexed was approved). Results: 5,893 patients fulfilled our eligibility criteria and were included for analysis. 2,200 patients were diagnosed before 2004 and 3,693 after. 2-L was administered in 35% (n=2052) of patients overall. Veterans diagnosed after 2004 were more frequently prescribed 2-L compared to those diagnosed earlier (30.2 vs. 37.6%, p<0.001). The most commonly prescribed agent in the earlier period was docetaxel in 43% (n=226) followed by gemcitabine in 22% (n=115). In contrast for patients treated after 2004 the most common agents were pemetrexed in 28% (n=421) followed by erlotinib in 27% (n=418). In this period docetaxel and gemcitabine was prescribed in 19 and 10% of cases respectively. Time from diagnosis to the start of 2-L was shorter in patients treated before 2004 (median 3.6 months (IQR 2.3-6.9) vs. 4.9 (IQR 2.6-8.2) p<0.001). Third-line chemotherapy was administered more frequently in those patients treated after 2004 (26 vs. 5.9%, p<0.001). There was no difference in survival between the two periods (Median OS 5.8 vs. 5.6 months in patients treated after 2004p=0.73) Conclusions: Since 2004 with the introduction of two new agents, which were widely adopted, patients are more likely to receive 2-L for NSCLC. In the last decade there has been no improvement in OS for patients treated with 2-L.
Randomized phase II study of pharmacodynamic separation (PDS) of pemetrexed (Pem) and erlotinib (Erl) versus pem alone in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Li Tianhong , Piperdi Bilal , Walsh William Vincent , Kim Mimi , Gucalp Rasim , Haigentz Missak , Bathini Venu Gopal , Wu Xiaoxia , Pasquinelli Patricia , Gajavelli Srikanth , Sreedhara Meera , Beckett Laurel A , Lara Primo , Gandara David R. , Perez-Soler Roman
Published: March 2020

8097

Background: Preclinical and phase I studies showed that PDS optimizes cytotoxicity of concurrent EGFR inhibitors and chemotherapy. We conducted a randomized phase II trial to assess relative efficacy of Pem alone (Arm A) versus Pem +Erl on a PDS dose-schedule (Arm B) as 2nd-line therapy in pts with advanced NSCLC (NCT00950365). Methods: Eligible pts were randomized 2:1 (Arm B: A), stratified by sex, smoking history, and performance status (0/1 vs 2). Accrual was restricted to non-squamous histology in 2009. Treatment: Arm A – Pem 500 mg/m2IV on day 1; Arm B – Pem + Erl 150 mg po QD on days 2-17. 1 cycle = 3 weeks. Primary endpoint was progression-free survival (PFS). 50 pts in Arm B were needed to detect an increase in median PFS from ~3 to 4.5 months. Results: 83 pts were entered. Age: 63 yo. Female: 42 (53%). Smoking ≥15PY: 58 (72%). Nonsquamous: 78 (99%). The primary endpoint of the study was met: Efficacy results from 79 eligible pts showed 1.6-fold longer PFS in Arm B (4.6 m) compared to Arm A (2.8 m). Although the study was not designed to directly compare two arms, p value was 0.052. Toxicity: G3/4 Hem (A/B): 8(30%)/12(23%); Neutropenia with infection (A/B): 0/3(6%). G3/4 Non-Hem (A/B): skin rash: 0/3(6%); diarrhea: 0/2(4%); joint pain: 1(4%)/6(11.5%). Treatment related death (A/B): 0/1. Interstitial lung disease (A/B): 0/1. Conclusions: PDS of Pem and Erl is well tolerated and has promising clinical activity in 2nd-line non-squamous NSCLC. Ongoing correlative studies aim to identify a subgroup of patients who might benefit most from this treatment, which will guide the design of a confirmatory phase III study. (UL1 RR024146, P30CA093373, Lilly, Astellas) Clinical trial information: NCT00950365. [Table: see text]
A French multicentric and prospective validation study for ALK translocation diagnosis in lung adenocarcinomas.
Authors: Lantuejoul Sylvie , Rouquette Isabelle , Begueret Hugues , Blons Helene , Penault-Llorca Frederique , Copin Marie-Christine , Antoine Martine , Hofman Paul , Merlio Jean-Philippe , McLeer Florin Anne , Galateau-Salle Francoise , Vignaud Jean-Michel , Garcia Stéphane , Thivolet Francoise , Shisheboran-Devouassoux Mojgan , Brevet Marie , Hofman Veronique , Mansuet-Lupo Audrey , Danel Claire
Published: March 2020

8100

Background: ALK rearrangements occur in nearly 5% of NSCLC and lead to a permanent ALK protein activation, targeted by a small molecule, the crizotinib. To date, FISH (Fluorescent In situ Hybridization) is considered as the gold standard to identify ALK abnormalities, but dual testing and pre-screening by immunohistochemistry have been proposed. Methods: The purpose of the study was to compare immunohistochemistry (IHC) using 5A4 and D5F3 Abs, with FISH and quantitative RT-PCR in a series of 500 surgical specimens, collected within one year from 15 French Thoracic Pathology Departments and INCa genetic platforms. Our study was deliberately enriched in ALK positive cases and clinicopathological data were recorded. Results: Among the 459 cases included to date, 340 were both FISH and IHC ALK negative, and 85 were ALK FISH and IHC positive. Fifteen cases were FISH neg/IHC pos, but with low staining scores; 12 cases were FISH pos/IHC neg, most provided by two centers. Seven cases were non interpretable by FISH, but 5 were ALK IHC positive. Regarding RTqPCR, nearly 50% of ALK positive cases presented a variant 1, 30% a variant 3a/b, and less than 5%, variants 2 or 7; 20%were negative or non interpretable. Discordant cases will be further discussed according to the crizotinib response. ALK positive patients were more frequently women (65 vs 42%) and younger than ALK negative patients (mean age 59 vs 64yrs); 72% were non or light smokers, whereas 75% of ALK negative patients were smokers (mean of 41PY). Histologically, most ALK positive and negative tumors presented a solid or acinar predominant architecture and were P63 negative. However, ALK positive tumors were more frequently TTF1 positive (91 vs 76%). Conclusions: 5A4 or D5F3 immunohistochemistry is a reliable and easy technique for routine diagnosis of ALK abnormalities, while FISH and RT-qPCR still dependent on pre-analytic conditions and technical expertise. However, in case of a suggestive clinical presentation, double testing with FISH remains the safer testing option as false negative IHC cases exist.
Clinical features of patients with lung adenocarcinomas harboring BRAF V600E mutations.
Authors: An Tongtong , Wang Jie , Bai Hua , Wang Zhijie , Zhao Jun , Duan Jianchun , Zhuo Minglei , Wu Meina , Wang Yuyan , Wang Shuhang
Published: March 2020

8101

Background: To investigate the prevalence, distribution, and prognostic role of activating BRAF mutations in Chinese patients with lung adenocarcinomas (ADCs). Methods: This retrospective study included 192 lung ADCs (97 males 50.5%, 95 females 49.5%). BRAF gene mutations were screened using AmoyDx BRAF V600E mutations detection kit. Mutations of EGFR and KRAS gene were also analyzed. Results: BRAF mutations were present in 8(4.17%) lung ADCs patients. V600E mutations were significantly more prevalent in females (6 of 96; 6.25%) than in males (2 of 97; 2.06%), as indicated by multivariate logistic regression analysis. Other clinocopathologic parameters, including age, smoking history, and tumor stage, were not significantly associated with V600E BRAF mutations. V600E-mutated tumors were not associated with different progression-free and overall survival rates comparing with non V600E-mutated tumors in this study. The frequency of EGFR and KRAS mutations in all patients were 42.7%(82/192) and 8.3%(16/192), respectivelyBRAF and EGFR were concomitantly mutated in three tumors. All tumors with BRAF mutations were found to be negative for KRAS mutations. Conclusions: We report for the first time to our knowledge that V600E BRAF mutation has high concomitant occurrence rate with EGFR mutations in Chinese lung ADCs patients. BRAF mutations were found to be independently associated only with female gender.
SORAVE: Sorafenib and everolimus for treatment of patients with relapsed solid tumors and with KRAS mutated NSCLC—A phase I study.
Authors: Nogova Lucia , Mattonet Christian , Gardizi Masyar , Scheffler Matthias , Bos Marc Christiaan Allardt , Toepelt Karin , Heukamp Lukas Carl , Suleiman Ahmed Abbas , Frechen Sebastian , Soergel Fritz , Fuhr Uwe , Schnell Roland , Katay Ildiko , Behringer Dirk M. , Geist Thomas , Kaminsky Britta , Eichstaedt Martina , Tummes Dirk , Buettner Reinhard , Wolf Jurgen
Published: March 2020

8112

Background: Dual inhibition of signaling pathways interfering with cell proliferation and angiogenesis may increase anti-tumor efficacy. Sorafenib and mTOR inhibitors showed preliminary activity in KRAS mutated NSCLC. Methods: In the dose escalation part patients with relapsed solid tumors were treated with escalating doses of everolimus from 2.5-10.0 mg daily p.o. in a 14 days run-in phase followed by the combination with a fixed dose of sorafenib 400 mg bid p.o. Extension phase is currently recruiting patients with KRAS mutated NSCLC. The KRAS mutation status was determined by PCR based high resolution melting curve analysis (HRM) on DNA extracted from FFPE material and validated using Sanger sequencing. The HRM has now been replaced by a multiplex PCR. Pharmacokinetic (PK) analyses are performed during run-in and during the combination. Treatment outcome is validated with CT scans on day 57. Results: (I) In the dose escalation part, 19 patients were recruited. The dose limiting toxicity (DLT) was not reached. At everolimus dose level of 10 mg/day, increased rates of grade 3 thrombocytopenia (3 patients), leukocytopenia (2 patients) and anaemia (2 patients) occurred after the DLT interval of 29 days. Based on these observations, the dose level of 7.5 mg/day everolimus in combination with 400 mg sorafenib bid was defined as a maximal tolerated dose. The AUC and Cmax values of everolimus at all dose levels were comparable on days 5 and 14. On day 29, AUC and Cmaxof everolimus showed a 20 - 40% reduction when co-administered with sorafenib. The best treatment outcome was stable disease in 11 patients. Median PFS and OS were 3.7 and 5.5 months, respectively. (II) The extension phase in KRAS mutated NSCLC is currently ongoing. Nine patients have been recruited so far. The CT response at day 57 compared to the baseline of 4 evaluable patients is ranging from -22% to +5% in the sum of the longest diameter of all targeted lesions. Conclusions: Treatment with the combination of 7.5 mg everolimus p.o. daily and 400 mg sorafenib p.o. bid is safe and feasible. Current results of an extension phase in KRAS mutated NSCLC patients show preliminary clinical activity in this patient group with an unfavorable prognosis. Clinical trial information: NCT00933777.
Predicting fitness for chemotherapy in older cancer patients.
Authors: Thomson Damien B. , McCarthy Alexandra , Yates Patsy , Skerman Helen , Walpole Euan Thomas
Published: March 2020

9516

Background: The Vulnerable Elders Survey-13 (VES-13) is increasingly used to screen for older patients who can proceed to intensive chemotherapy without further comprehensive assessment. This study compared the VES-13 determination of fitness for treatment with the oncologist's assessments of fitness. Methods: Sample: Consecutive series of solid tumour patients ≥65 years (n=175; M=72; range=65-86) from an Australian cancer centre. Patients were screened with the VES-13 before proceeding to usual treatment. Blinded to screening, oncologists concurrently predicted patient fitness for chemotherapy. A sample of 175 can detect, with 90% power, kappa coefficients of agreement between VES-13 & oncologists’ assessments >0.90 ("almost perfect agreement"). Separate backward stepwise logistic regression analyses assessed potential predictors of VES-13 & oncologists’ ratings of fitness. Results: Kappa coefficient for agreement between VES-13 & oncologists’ ratings of fitness was 0.41 (p<0.001). VES-13 & oncologists’ assessments agreed in 71% of ratings. VES-13 sensitivity = 83.3%; specificity = 57%; positive predictive value = 69%; negative predictive value = 75%. Logistic regression modelling indicated that the odds of being vulnerable to chemotherapy (VES-13) increased with increasing depression (OR=1.42; 95% CI: 1.18, 1.71) & decreased with increased functional independence assessed on the Bartel Index (OR=0.82; CI: 0.74, 0.92) & Lawton instrumental activities of daily living (OR=0.44; CI: 0.30, 0.65); RSquare=.65. Similarly, the odds of a patient being vulnerable to chemotherapy, when assessed by physicians, increased with increasing age (OR=1.15; CI: 1.07, 1.23) & depression (OR=1.23; CI: 1.06, 1.43), & decreased with increasing functional independence (OR=0.91; CI: 0.85, 0.98); RSquare=.32. Conclusions: Our data indicate moderate agreement between VES-13 & clinician assessments of patients’ fitness for chemotherapy. Current ‘one-step’ screening processes to determine fitness have limits. Nonetheless, screening tools do have the potential for modification & enhanced predictive properties in cancer care by adding relevant items, thus enabling fit patients to be immediately referred for chemotherapy.
Patients’ perceptions of caregivers’ preference for comfort care at the EOL: Impact on DNR completion.
Authors: Fletcher Kalen Michele , Prigerson Holly Gwen , Maciejewski Paul K
Published: March 2020

9521

Background: Research has shown that informal caregivers provide substantial psychosocial and material support to advanced cancer patients. Few studies have examined how family caregivers influence patients’ advance care planning. Here we test whether patients’ perceptions of their caregivers’ preference for comfort (vs. life-extending) end-of-life (EOL) care is associated with DNR order completion. We also evaluated whether caregivers’ actual agreement with patients on preference for comfort EOL care was associated with their rates of DNR order completion. Methods: Coping with Cancer II is an NCI –funded, multi-site, prospective cohort study of patients with advanced cancer and their informal family caregivers. Patients are interviewed after receiving restaging scan results and asked if they would prefer a plan of EOL care focused on life-extension or one focused on relieving pain. Patients are also asked what type of EOL care they think their family caregivers would prefer for them and whether or not a DNR order has been completed for them. Caregivers are interviewed separately after patients receive restaging scan results and asked what type of EOL care they would want for the patient. Results: Based on patient data alone (N=72), patients who preferred comfort care at the EOL and who believe that their family caregiver agrees with them on this were significantly more likely than others to report DNR order completion (OR=3.67, p=0.013). Based on data from both patients and caregivers, patients’ perception of agreement with their caregivers on desire for comfort EOL care was more strongly associated with patients’ reports of DNR completion (rs=0.51, p=0.004) than was actual agreement with their caregivers on desire for comfort EOL care (rs=0.36, p=0.045). Conclusions: Patients who prefer comfort care to life-extending care at the EOL, and who think that their caregivers also want them to pursue comfort care, are more likely to have a DNR order completed. Interestingly, patients’ perception of this agreement had a stronger influence on DNR completion than the caregivers’ actual agreement with patients’ preference for comfort EOL care. DNR completion is influenced by patients’ perceptions of family support.
Outcomes of patients ≥ 65 yrs with advanced cancer treated on phase I clinical trials.
Authors: Subbiah Ishwaria Mohan , Wheler Jennifer J. , Hess Kenneth R. , Hong David S. , Fu Siqing , Wolff Robert A. , Kurzrock Razelle , Tsimberidou Apostolia Maria
Published: March 2020

9544

Background: Older patients with cancer are underrepresented in clinical trials; their disease biology and comorbidities may impact the decision to consider a clinical trial. Here we systematically analyze outcomes of elderly pts treated on phase I clinical trials. Methods: The characteristics, toxicity, survival, and response of pts with advanced cancer treated on phase I clinical trials from 1/04 – 12/09 were studied. Results: Overall,347 of 1,182 pts (29%) were >65 yrs old. The Table lists pt characteristics by treatment regimen. 251 pts received a targeted agent, of which 241 (96%) received an investigational, non-FDA approved drug. Of 347 pts, 3 (1%) had a CR, 15 (4%) a PR, 127 (37%) SD, of which 43 (12%) had SD ≥ 6mos. Of 347 pts, 194 (56%) had >1 drug-related toxicity, of which 89 (26%) had a Grade 3-4 toxicity, most often hematologic; 72% of toxicities on targeted therapies were Grade 1-2. Six pts had a DLT; there was one death (<0.01%) “possibly” attributed to the study drug. Median OS from 1st phase I Clinic visit was 8.8mos (95% CI, 7.8-10.6). Median TTF on 1st phase I trial was 1.9mos (95% CI, 1.8-2.1). Multivariate analyses demonstrated that ECOG PS 2-3 (vs. 01) (p <0.001) and liver mets (vs. no liver mets) (p <0.01) were independent factors predicting shorter TTF and OS. Conclusions: Our results suggest that phase I clinical trials are well tolerated and offer a reasonable therapeutic option for pts > 65 yrs. [Table: see text]
Measures of polypharmacy and chemotherapy toxicity in older adults with cancer.
Authors: Maggiore Ronald John , Feng Tao , Dale William , Gross Cary Philip , Tew William P. , Mohile Supriya Gupta , Owusu Cynthia , Klepin Heidi D. , Lichtman Stuart M. , Gajra Ajeet , McKoy June M , Katheria Vani , Ramani Rupal , Jayani Reena , Brown Jaycen , Hurria Arti
Published: March 2020

9545

Background: Polypharmacy is common and associated with adverse clinical outcomes in older adults. Potentially inappropriate medication (PIM) use serves as an adjunctive assessment of polypharmacy. The goals of this study in an outpatient population of older adults with cancer (CA) were: 1) to estimate the prevalence of polypharmacy using multiple measures; and 2) to determine the relationship between polypharmacy and chemotherapy (chemo) toxicity. Methods: Medication use was evaluated in 500 patients (pts) age ≥65 years with invasive CA who were starting a new chemo regimen. Polypharmacy was defined by number of daily medications (meds), including non-prescription meds. PIM use was defined by 4 indices: Beers (2003 and 2012 update), Zhan, and HEDIS Drugs to Avoid in the Elderly (DAE) criteria. Prevalence of polypharmacy, PIM, and their association with grade 3-5 chemo toxicity [NCI Common Toxicity Criteria (v. 3.0)] were analyzed using chi square test and unconditional logistic regression. Results: All 500 pts were evaluable [mean age, 73 years (range 65-91); 56% female; 61% stage IV]. The mean number of daily meds was 5 (range 0-23); 38% used ≤3 daily meds, 51% used 4-9 meds, and 11% using ≥10 meds. Using 0-3 daily meds as the referent group, no association was found between daily meds and chemo tox: 4-9 meds, OR 1.34 (95% CI: 0.92-1.97); ≥10, OR 0.82 (95% CI: 0.45-1.49). PIM use was identified in 87 (17%), 147 (29%), 54 (11%), and 69 (13%) patients utilizing the 2003 Beers, 2012 Beers, Zhan, and HEDIS DAE criteria, respectively. There was no association between each PIM use index and chemo toxicity (p>0.10 for all). Conclusions: Polypharmacy and PIM use were common in the geriatric oncology population. Although polypharmacy did not increase the risk of chemotherapy toxicity in this sample, further studies of polypharmacy’s impact on additional outcomes, including non-chemotherapy adverse drug events, in older persons with cancer are warranted.
The prognostic value of rapid screening tests (RST) in geriatric assessment of patients with cancer over 70.
Authors: Bononi Antonio , Inno Alessandro , Borghi Massimo , Tesi Paolo , Barile Carmen , Crepaldi Giorgio , Menon Daniela , Modena Yasmina , Fraccon Anna Paola , Gusella Milena , Raschella' Guido , Pasini Felice
Published: March 2020

9554

Background: Comprehensive Geriatric Assessment (CGA) may help to evaluate the functional status of elderly patients, but, because time-consuming, RST have been proposed. However, whether these instruments may predict survival is still unclear. The aim of this study was to correlate overall survival (OS) with the results of 3 rapid tests: G8 (1), VES-13 (2, aCGA (3) in patients over 70. Methods: From April 2009 to April 2012, 530 unelected outpatients over 70, 263 males and 267 females, were evaluated. During the first oncologic visit, they were homogeneously assessed by a trained oncogeriatric team using a dedicated, expressly developed web-based software (www: oncoger.ro.it) including all of the 3 rapid tests. Survival curves were drawn using Kaplan-Meier method and compared with log rank test; multivariate analysis was performed according to Cox regression method. Results: The tests identified frail patients as follows: VES-13 69%, aCGA 50%, G8 68.5%. Frailty was significantly associated with poor OS, with different hazard ratios (HR) for each test. HRs for death of frail vs non-frail pts were for aCGA 1.45 (95%CI 1.09-1.89, p=0.008), for VES-13 1.55 (95%CI 1.12-2.00, p=0.005) and for G8 2.57 (95%CI 1.66-2.93, p<0.0001). In the multivariate analysis including the 8 items of the G8 test, appetite loss (HR 1.44, p=0.002), weight loss (HR 1.28, p=0.003), and personal perception of poor health (HR 1.58, p=0.002) were significantly associated with a higher risk of death. Conclusions: i) Frailty, as identified by RST (VES-13, aCGA, G8), is statistically associated with poor OS; ii) G8 presents the most meaningful HR for OS; iii) appetite loss, weight loss and personal perception of poor health are significantly associated with lower OS.Our data show that RST and in particular G8 represent a useful prognostic tool for the assessment of geriatric patients with cancer.
Integrated oncopalliative care versus standard care for patients with metastatic lung cancer: A single institution retrospective review.
Authors: King Jonathan Douglas , Retseck Janet , Eickhoff Jens C. , Hoang Tien , Traynor Anne M. , Campbell Toby Christopher
Published: March 2020

9566

Background: Patients with metastatic non-small cell lung cancer (NSCLC) receiving early palliative care (PC) demonstrated improved anxiety, quality of life, and survival compared to standard oncology care (SOC). ASCO clinical practice guidelines recommend concurrent PC and SC be offered to patients with metastatic NSCLC. Our lung cancer clinic is partially integrated with PC. We performed retrospective chart review comparing patients seen in our integrated clinic with SOC patients for survival, trial participation, chemotherapy and hospice utilization. Methods: Charts of all patients with advanced lung cancer from July 2007-June 2011 were reviewed. Eligible patients were those who received any care at our center. Demographic, treatment details, survival, and hospice utilization data were obtained. Overall survival and length of hospice enrollment were calculated for patients treated with PC compared to SOC. Results: Of 207 patients, 82 received PC. Overall survival favored PC (11.9 months vs. 10.1 months, p=0.032). Hospice length of stay (LOS) favored PC (38.5 days vs. 24 days in SOC, p=0.047). There was not a significant difference in lines of chemotherapy, chemotherapy in the last 30 days of life, or trial participation. Conclusions: Our chart review provides confirmatory evidence that early integrated PC in lung cancer patients increases survival and hospice LOS without affecting chemotherapy utilization or trial participation. [Table: see text]
Spiritual/religious struggle in hematopoietic cell transplant survivors.
Authors: King Stephen Duane Watkins , Fitchett George , Pargament Kenneth I. , Peterson Do , Harrison David A. , Johnson Rebecca H. , Martin Paul J. , Loggers Elizabeth Trice
Published: March 2020

9573

Background: Spiritual/religious (SR) struggle (e.g., feeling abandoned or punished by God) has been associated with poorer coping and quality of life (QOL), greater depression and pain, and health declines in general cancer populations. Few studies have been conducted among survivors of hematopoietic cell transplantation (HCT). This study examined the prevalence and predictors of SR struggle in HCT survivors. Methods: Data were collected as part of an annual questionnaire of adult (age >18 years) survivors of HCT at Fred Hutchinson Cancer Research Center in Seattle, WA. The 2011 survey included a SR module that incorporated the following items: Negative Religious Coping subscale of Brief RCOPE, subscales from the McGill QOL Questionnaire and the SF-36, Patient Health Questionnaire-8, disease information and socio-demographics. SR struggle was defined as any non-zero response on the Negative Religious Coping subscale of the Brief RCOPE. A multi-variable logistic regression model was used to determine factors associated with SR struggle. Results: Of 2113 returned surveys (52% response rate), 83% returned the SR module (n=1745) and of those 1586 were included in this analysis. Subjects were 49% female; 67% Christian and 20% Agnostic/Atheist/No preference; and 91% white. Mean age was 55 years; survivors ranged from 6 months to 40 years post-transplant. Primary indications for transplant were leukemia (49%), lymphoma (20%), and multiple myeloma (15%). Twenty-eight percent indicated SR struggle. In a multi-variable model, SR struggle showed statistically significant associations with age >=65 years (odds ratio [OR] .57, p=.02); patient report of being religious only (OR 3.5, p<.001) or spiritual only (OR 1.8, p<.001) compared to being both religious and spiritual; depression (OR 1.1, p<.001); and better social support (OR 0.77, p<.001). Time since HCT, religious affiliation and race/ethnicity did not show statistically significant associations with SR struggle. Conclusions: SR struggle is common among HCT survivors, even years after HCT.Further study is needed to determine causal relations, longitudinal trajectory, impact of struggle intensity, and effects of SR struggle on health, mood and social roles for HCT survivors.