bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a HER2 mutation: The ETOP NICHE trial.
Authors: Smit Egbert F. , Peters Solange , Dziadziuszko Rafal , Dafni Urania , Wolf Juergen , Wasąg Bartosz , Biernat Wojciech , Finn Stephen , Kammler Rosita , Tsourti Zoi , Rabaglio-Poretti Manuela , Ruepp Barbara Ursula , Roschitzki-Voser Heidi , Stahel Rolf A. , Felip Enriqueta 
Published: September 2018

9070 Background: HER2mutations are identified in about 2% of lung adenocarcinomas and are critical for lung carcinogenesis. Afatinib is a selective and irreversible erbB family blocker with a manageable toxicity profile and promising results in small retrospective studies targeting HER2 in NSCLC. Methods: NICHE is a single-arm phase II trial exploring the potential of afatinib to control disease (complete or partial response or disease stabilization for ≥12 weeks) in pre-treated patients with advanced NSCLC harboring HER2 exon 20 mutations. Patients were treated with afatinib 40 mg/day p.o. until tumor progression or lack of tolerability. A Simon’s two stage phase II design was adopted, to explore whether afatinib can achieve a DCR of 75%, as opposed to a DCR of 50% under the current treatment options. For a 1-sided type I error of 10% and power of 80%, a total of 22 patients were needed. Results: As of 24 November 2016, 13 patients were recruited into the trial. Median age was 60 years, 69% female and 62% never smokers. The overall toxicity profile was in the expected range, with 5 patients experiencing serious adverse events (dyspnea, diarrhea, dehydration, epistaxis, pleural, pericardial and renal insufficiency). The median follow-up was 23 weeks (IQR 12 – 39). Three patients died and 10 were still on follow-up, among them five were still on treatment. Total of 7 patients (54%) achieved DC at 12-weeks, 3 patients had PD before and 3 at 12-weeks. The 12-week PFS was 51% (95% CI: 22 - 75) and the median PFS 13 weeks (95% CI 6 - NE). In the 1st stage analysis of the Simon’s design, with 9 patients included, the stopping boundary was crossed. Therefore and upon recommendations of the ETOP IDMC, recruitment into the trial was stopped prematurely in December 2016. Treatment and follow-up of the enrolled patients continues as planned. Conclusions: Based on the interim results, afatinib did not show the expected potential to control disease in this patient population. However in the full analysis set with 13 patients, clear signs of activity were seen. A comprehensive biomolecular analysis of the tumors is currently ongoing in order to identify a subgroup of patients who might still derive benefit from afatinib treatment. Clinical trial information: NCT02369484.
Afatinib in patients with metastatic HER2-mutant lung cancers: An international multicenter study.
Authors: Lai Wei-Chu Victoria , Lebas Louisiane , Milia Julie , Barnes Tristan Alexandra , Gautschi Oliver , Peters Solange , Ferrara Roberto , Ni Ai , Sabari Joshua K. , Clarke Stephen John , Pavlakis Nick , Rudin Charles M. , Arcila Maria E. , Leighl Natasha B. , Shepherd Frances A. , Kris Mark G. , Mazieres Julien , Li Bob T. 
Published: September 2018

9071 Background: Human epidermal growth factor 2 ( HER2, ERBB2) mutations have been identified as oncogenic drivers in 3% of lung cancers. Afatinib is an irreversible tyrosine kinase inhibitor of HER1 (EGFR), HER2 and HER4 and has been described in case reports to have activity in HER2-mutant lung cancers. However, there is little data to inform the clinical use of afatinib. Methods: We reviewed patients with metastatic HER2-mutant lung cancers treated with afatinib among 7 institutions between 2009 and 2016. The primary endpoint was investigator assessed overall response rate using RECIST v1.1. Other data collected included types of HER2mutations, duration of afatinib treatment and overall survival. Results: We identified 27 patients with metastatic HER2-mutant lung cancers treated with afatinib. Median age at diagnosis was 63 (range 40 to 84); majority were men (n = 16; 59%) and never-smokers (n = 18; 67%). All tumors were adenocarcinomas, and the majority were Stage IV at initial diagnosis (n = 16; 59%). A 12-base pair (bp) in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 16 patients (59%). In addition, there were three 9-bp insertions, two 3-bp insertions and two single bp substitutions (L755F and D769H) in exon 20; two single bp substitutions (S310F) in exon 8; one exon 17 V659E mutation; and one single-nucleotide polymorphism (Ile655Val). Median duration on afatinib was 2 months (range 1 to 27); median line of prior treatment was 3 (range 1 to 6). Eight patients had previously received trastuzumab prior to afatinib and one concurrently with afatinib. Overall response rate was 15% (n = 4; 95% CI 4 to 34%); the four partial responses lasted 5, 5, 6 and 10 months. The 3 longest partial responders had a 12-bp insertion in exon 20 (YVMA); the remaining partial responder had a 9-bp insertion in exon 20. Median overall survival from diagnosis date of metastatic disease was 23 months (95% CI 18 to 62). Conclusions: Afatinib produced partial responses in 15% of patients with metastatic HER2-mutant lung cancers, including insertion YVMA. Our findings confirm the activity of afatinib and provide data supporting a framework for its use in the care of patients with HER2-mutant lung cancers.
Immune marker profiling and PD-L1, PD-L2 expression mechanisms across non-small cell lung cancer mutations.
Authors: Toki Maria , Mani Nikita , Smithy James William , Liu Yuting , Altan Mehmet , Wasserman Brad , Tuktamyshov Rasikh , Syrigos Konstantinos N. , Rimm David L. 
Published: September 2018

9076 Background: PD-1/PD-L1 axis inhibitors have been proven effective, especially in patients expressing Programmed Death Ligand 1 (PD-L1). Their clinical efficacy in patients with epidermal growth factor receptor (EGFR) activating mutations is still unclear, while KRAS mutations seem to be associated with high response rates. In this study we investigated the expression of PD-L1, PD-L2 and Tumor Infiltrating Lymphocyte (TIL) status as a function of mutation status in Non-Small Cell Lung Cancer (NSCLC). Methods: We used the AQUA method of quantitative fluorescence (QIF) to compare PD-L1 and PD-L2 expression and to characterize TILs populations and their activation status in over 150 NSCLC patient tumors with known mutation status. EGFR activation was assessed in situ using the proximity ligation assay (PLA) for EGFR and GRB2 and T cell activation was assessed using a novel multiplexed QIF assay including CD3, Granzyme B and Ki67. Results: PD-L1 tumor and stroma expression was significantly lower in EGFR mutant compared to KRAS mutant (p = 0.009) and EGFR/KRAS Wild Type (p < 0.0001) tumors, while they had a higher frequency of PD-L2 expression. Conversely, KRAS mutants had significantly lower PD-L2 tumor and stroma expression but they were also more inflamed with higher CD4+, CD8+ and CD20+ TILs. Subgroup analysis of patients by their TILs activation status revealed that EGFR mutants had a very high frequency of inactive TILs even though lymphocytes were present in the tumor microenvironment. In contrast, in KRAS mutants, when TILs were present, they were almost always active. Finally, we find that PLA-defined activated EGFR correlated with increased PD-L1 expression in EGFR mutants but not in EGFR WT, while TIL activation was associated with higher PD-L1 in EGFR/KRAS WT. Conclusions: Our findings are consistent with the unique biology of EGFR mutant tumors. The high frequency of inactive TILs could explain the low immune therapy response rates in this patient group. Similarly, in this group, the reason PD-L1 expression fails to predict response may be due to expression as a result of constitutive oncogenic signaling rather than immune signaling, which would be associated with high PD-L1 levels and TILs activation.
Factors associated with better overall survival (OS) in patients with previously treated, PD-L1–expressing, advanced NSCLC: Multivariate analysis of KEYNOTE-010.
Authors: Herbst Roy S. , Baas Paul , Kim Dong-Wan , Felip Enriqueta , Perez-Gracia Jose Luis , Han Ji-Youn , Molina Julian R. , Kim Joo-Hang , Dubos Arvis Catherine , Ahn Myung-Ju , Majem Margarita , Fidler Mary J. , Castro Gilberto , Garrido Marcelo , Ellison Misoo C. , Samkari Ayman , Lubiniecki Gregory M. , Garon Edward B. 
Published: September 2018

9090 Background: We identified factors associated with better OS for previously treated, PD-L1–expressing advanced NSCLC using data from KEYNOTE-010 (NCT01905657; Herbst et al. Lancet. 2016;387:1540-50), in which pembrolizumab had superior OS over docetaxel. Methods: 1033 patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel 75 mg/m2 Q3W. Response was assessed per RECIST v1.1 by independent central review. Multivariate analyses were performed using a Cox proportional hazards regression model on OS in the pembrolizumab arms. A set of variable selection methods was applied to 19 baseline demographic and disease characteristics, including smoking status, and identified 7 factors that contributed to OS. Data cut was September 30, 2016. Results: Adjusted hazard ratios (HRs) for the factors in the pembrolizumab arm from the model are shown in the Table. Updated OS with an additional 6 months of follow-up from this data lock for KEYNOTE-010 will be presented. Conclusions: While the overall result of KEYNOTE-010 revealed improved OS with pembrolizumab compared with docetaxel in previously treated patients with PD-L1–positive advanced NSCLC, exploratory, post hoc multivariate analyses showed that some laboratory and tumor characteristics such as nonsquamous histology, normal baseline lactate dehydrogenase (LDH), PD-L1 TPS ≥50%, and wild-type EGFR mutation status were associated with better OS among patients treated with pembrolizumab. Clinical trial information: NCT01905657. [Table: see text]
Atezolizumab (atezo) plus platinum-based chemotherapy (chemo) in non-small cell lung cancer (NSCLC): Update from a phase Ib study.
Authors: Liu Stephen V. , Camidge D. Ross , Gettinger Scott N. , Giaccone Giuseppe , Heist Rebecca Suk , Hodi F. Stephen , Ready Neal E. , Zhang Wei , Wallin Jeffrey , Funke Roel , Waterkamp Daniel , Foster Paul , Iizuka Koho , Powderly John D. 
Published: September 2018

9092 Background: Platinum-based chemo is a standard first-line (1L) therapy for NSCLC lacking actionable gene alterations. Preclinical evidence suggests that chemo can play an immunomodulatory role and induce tumor antigen release, supporting combining chemo with immunotherapy. Atezo is a humanized and Fc-region-modified monoclonal anti-programmed death-ligand-1 (PD-L1) antibody that blocks interaction with PD1 or B7.1. The GP28328 study (NCT01633970) assessed safety and efficacy of atezo plus 1L chemo regimens in multiple tumor types. Methods: In this multicenter, multi-arm study, patients (pts) with locally advanced or metastatic NSCLC with no prior chemo for advanced disease received 15 mg/kg atezo IV q3w with standard doses of chemo (Arm C: carboplatin [carbo]+paclitaxel q3w; Arm D: carbo+pemetrexed q3w; Arm E: carbo+nab-paclitaxel qw) all for ≤6 cycles followed by atezo maintenance until loss of clinical benefit (+ pemetrexed maintenance until progression, Arm D). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), PFS, and OS. Results: By the 30 Aug 2016 cut-off, 76 NSCLC pts were evaluable (n = 25, 25, 26 for Arms C, D, E, respectively). At this cut-off, the most common treatment-related grade 3–4 adverse events (AEs) were neutropenia (36% C, 36% D, 42% E) and anemia (16% C, 16% D, 31% E). Three potentially related grade 5 AEs were seen (arm C: pneumonia; arm D: systemic candida; arm E: autoimmune hepatitis). Confirmed ORRs were 36%, 64%, 46% for Arms C, D (1 CR), and E (4 CR). Median PFS (95% CI) was 7.1 months (4.2–8.3) for C, 8.4 months (4.7–11) for D, and 5.7 months (4.4–14.8) for E. Median OS (95% CI) was 12.9 months (8.8–not evaluable) for C, 19.3 months (14.7–27.4) for D, and 14.8 months (12.7–not evaluable) for E. Conclusions: Atezo was well tolerated when combined with various chemo regimens for advanced NSCLC. Clinical activity in terms of ORR was favorable supporting potential synergy between atezo and chemo. PFS and OS data show promising benefits, but are limited by small numbers and wide confidence intervals. Phase III studies that include chemotherapy and atezolizumab are currently ongoing. Clinical trial information: NCT01633970.
First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G.
Authors: Papadimitrakopoulou Vassiliki , Gadgeel Shirish M. , Borghaei Hossein , Gandhi Leena , Patnaik Amita , Powell Steven Francis , Gentzler Ryan D. , Martins Renato G. , Stevenson James , Jalal Shadia Ibrahim , Panwalkar Amit W. , Yang James Chih-Hsin , Gubens Matthew A. , Sequist Lecia V. , Awad Mark M. , Fiore Joseph , Ge Joy Yang , Raftopoulos Harry , Langer Corey J. 
Published: September 2018

9094 Background: Data from the randomized, phase 2 cohort G of KEYNOTE-021 (NCT02039674) showed that adding pembro to first-line CP in patients (pts) with advanced nonsquamous NSCLC significantly improved the primary end point of ORR (55% vs 29%, P = 0.0016) and the key secondary end point of PFS (HR 0.53, P= 0.0102) compared with CP alone and had a manageable safety profile (grade 3-4 treatment-related AEs, 39% vs 26%; treatment-related AEs leading to discontinuation, 10% vs 13%). We present updated efficacy for cohort G based on 5 mo additional follow-up. Methods: 123 pts with stage IIIB/IV, chemotherapy-naive, nonsquamous NSCLC and no EGFR mutation or ALK translocation were randomized to 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m2 Q3W ± 24 mo of pembro 200 mg Q3W; maintenance pemetrexed was permitted in both arms. Eligible pts in the CP arm who had radiologic progression could crossover to pembro monotherapy. Response was assessed per RECIST v1.1 by blinded, independent central review. All Pvalues are nominal. Results: As of Dec 31, 2016, median follow-up was 14.5 mo (range, 0.8-24.0). 36 of 48 pts (75.0%) in the CP arm who discontinued CP received subsequent anti–PD-1 or PD-L1 therapy. There was 1 additional response in each arm, and ORR was 56.7% (95% CI 43.2%-69.4%) with pembro + CP vs 30.2% (95% CI 19.2%-43.0%) with CP ( P = 0.0016). Median DOR was not reached for pembro + CP (range, 1.4+ to 18.6+ mo) and was 16.2 mo (range, 2.8 to 20.7+) for CP alone. PFS remained longer with pembro + CP (HR 0.49, 95% CI 0.29-0.83, P = 0.0035; median [95% CI] NR [9.7 mo-NR] vs 8.9 mo [6.2-10.3]; 12-mo estimate, 56% vs 34%). With 16 deaths in the pembro + CP arm and 23 deaths in the CP arm, HR for OS was 0.69 (95% CI 0.36-1.31, P= 0.13). Median OS was not reached in either arm; at 12 mo, estimated OS was 76% in the pembro + CP arm and 69% in the CP alone arm. Conclusions: With 5 mo additional follow-up, first-line pembro + CP continues to provide a substantial, clinically relevant improvement in efficacy over CP alone in pts with advanced nonquamous NSCLC, including an almost doubled ORR, halved risk of progression or death, and a trend toward improved OS despite a 75.0% crossover rate in the CP arm. Clinical trial information: NCT02039674.
Long-term outcomes in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab (pembro) treatment.
Authors: Robert Caroline , Long Georgina V. , Schachter Jacob , Arance Ana , Grob Jean Jacques , Mortier Laurent , Daud Adil , Carlino Matteo S. , McNeil Catriona M. , Lotem Michal , Larkin James M. G. , Lorigan Paul , Neyns Bart , Blank Christian U. , Petrella Teresa M. , Hamid Omid , Zhou Honghong , Homet Moreno Blanca , Ibrahim Nageatte , Ribas Antoni 
Published: September 2018

9504 Background: Pembro demonstrated superior PFS and OS vs ipi in ipi-naive pts with advanced melanoma in the phase 3 KEYNOTE-006 study (NCT01866319). Here, we present long-term outcomes for all pts and in those pts who completed pembro therapy. Methods: Eligible pts (N = 834) were randomized 1:1:1 to pembro 10 mg/kg Q2W, pembro 10 mg/kg Q3W, or ipi 3 mg/kg Q3W for 4 doses. Treatment was continued for 2 yr (pembro only) or until disease progression, intolerable toxicity, or pt/investigator decision to discontinue. Per protocol, pts could interrupt pembro for ≤12 wk before discontinuation was required. Tumor imaging was performed at wk 12, then every 6 wk up to wk 48 and every 12 wk thereafter. After the prespecified final analysis, response assessments were per immune-related response criteria (irRC) by investigator review. Results: As of the data cutoff (Nov 3, 2016), median follow-up in the total population was 33.9 mo (range, 32.1-37.6). 33-mo OS rates were 50% in the pooled pembro arms (n = 556) and 39% in the ipi arm (n = 278); 33-mo PFS rates were 31% and 14%. ORR was 42% and 16%. Median duration of response was not reached for pembro (range 1.0+ to 33.8+ mo) or ipi (1.1+ to 34.8+ mo); 46 (68%) pembro-treated pts and 7 (58%) ipi-treated pts had a response lasting ≥30 mo. Among the 104/556 (19%) pts who completed pembro, median exposure to pembro was 24.0 mo (range 22.1-25.9). After a median follow-up of 9.0 mo after completion of pembro, 102 (98%) pts were alive. Responses were durable in pts who completed pembro; 9.7 mo after completion of pembro, estimated PFS (95% CI) was 91% (80-96) in all 104 pts, 95% (69-99) in pts with complete response (n = 24), 91% (74-97) in pts with partial response (n = 68), and 83% (48-96) in pts with stable disease (n = 12). Conclusions: Pembro provides durable efficacy after stopping the protocol-specified duration of treatment in pts with ipi-naive advanced melanoma in KEYNOTE-006. The estimated risk for progression or death nearly 10 mo after completing pembro is 9% and does not appear to differ by best response to pembro. Clinical trial information: NCT01866319.
Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant unresectable or metastatic melanoma (MM).
Authors: Long Georgina V. , Eroglu Zeynep , Infante Jeffrey R. , Patel Sapna Pradyuman , Daud Adil , Johnson Douglas Buckner , Gonzalez Rene , Kefford Richard , Hamid Omid , Schuchter Lynn Mara , Cebon Jonathan S. , Sharfman William Howard , McWilliams Robert R. , Sznol Mario , Weber Jeffrey S. , Mookerjee Bijoyesh , Gasal Eduard , Redhu Suman , Flaherty Keith T. 
Published: September 2018

9505 Background: D (BRAF inhibitor) + T (MEK inhibitor) combination therapy is associated with rapid clinical responses and has improved clinical outcomes in pts with BRAFV600–mutant MM, but long-term (˃ 3 y) clinical efficacy and safety data are limited. The longest follow-up to date of a randomized trial evaluating D+T at the approved dose (150 mg BID/2 mg QD [150/2]) was of the phase II study BRF113220 (part C; median, 45.6 mo) in which durable outcomes were achieved in some pts with BRAFV600–mutant MM (3-y OS, 38%). Here, we report updated 5-y landmark analyses to further characterize the impact of D+T in MM. Methods: Pts with BRAFV600–mutant mm enrolled in BRF113220 part C (NCT01072175) were randomized 1:1:1 to receive monotherapy D (150 mg BID), D+T (150 mg BID/1 mg QD), or D+T (150/2). Pts who progressed on D alone could cross over to the D+T 150/2 arm. Pt disposition, pt demographics, and 4- and 5-y efficacy and safety were analyzed for both the D-alone and D+T (approved 150/2 dose) arms. Results: This updated analysis represents an additional ≈ 2 y of follow-up (D and D+T arms; n = 54 each). As of 13 Oct 2016, 45 pts (83%) on D alone had crossed over to D+T. 20 pts were ongoing (D, n = 7 [13%]; D+T, n = 13 [24%]); 80% of D pts and 70% of D+T pts had died. D+T OS remained superior to D alone. The 4- and 5-y OS rates with D+T were 30% and 28%, respectively, demonstrating a stabilization of the OS curve. The PFS curve for D+T also remained stable (4- and 5-y: both 13%). Consistent with earlier results, the best OS for pts who received D+T was seen in pts with normal LDH (5-y, 45%) and normal LDH with disease in < 3 organ sites (5-y, 51%). At the 5-y landmark, 1 additional pt who received D+T improved from a partial to a complete response. Additional follow-up revealed no new safety signals with D+T. Detailed analyses of D crossover pts, responders, and post-progression therapy will be presented. Conclusions: This longest follow-up to date of BRAF + MEK inhibitor combination therapy in pts with BRAFV600–mutant mm revealed stable OS and PFS lasting ≥ 5 y with consistent tolerability. These results demonstrate that some pts with mm can achieve durable benefit with D+T therapy. Clinical trial information: NCT01072175.
Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204.
Authors: Tawbi Hussein Abdul-Hassan , Forsyth Peter A. J. , Algazi Alain Patrick , Hamid Omid , Hodi F. Stephen , Moschos Stergios J. , Khushalani Nikhil I. , Gonzalez Rene , Lao Christopher D. , Postow Michael Andrew , Atkins Michael B. , Ernstoff Marc S. , Puzanov Igor , Kudchadkar Ragini Reiney , Thomas Reena Parada , Tarhini Ahmad A. , Jiang Joel , Avila Alexandre , Demelo Sheena , Margolin Kim Allyson 
Published: September 2018

9507 Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial (NCT02320058), MEL pts with ≥1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] > 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months (Table). The IC objective response rate (ORR) was 56% (95% CI: 44–68); 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. Clinical trial information: NCT02320058. [Table: see text]