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Advanced Non-Small-Cell Lung Cancer.

tir, 01/16/2018 - 05:00
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Advanced Non-Small-Cell Lung Cancer.

N Engl J Med. 2017 Nov 16;377(20):1999

Authors: Reck M, Rabe KF

PMID: 29327882 [PubMed - in process]

Advanced Non-Small-Cell Lung Cancer.

tir, 01/16/2018 - 05:00
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Advanced Non-Small-Cell Lung Cancer.

N Engl J Med. 2017 Nov 16;377(20):1998-1999

Authors: Sohal SS, Walters EH

PMID: 29327881 [PubMed - in process]

Advanced Non-Small-Cell Lung Cancer.

tir, 01/16/2018 - 05:00
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Advanced Non-Small-Cell Lung Cancer.

N Engl J Med. 2017 Nov 16;377(20):1998

Authors: Ren C, Han C, Wang D

PMID: 29327880 [PubMed - in process]

Advanced Non-Small-Cell Lung Cancer.

tir, 01/16/2018 - 05:00
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Advanced Non-Small-Cell Lung Cancer.

N Engl J Med. 2017 Nov 16;377(20):1997-1998

Authors: Kwon HW, Ham SY, Shin SW

PMID: 29327879 [PubMed - in process]

Osimertinib as First-Line Treatment in EGFR-Mutated Non-Small-Cell Lung Cancer.

tir, 01/16/2018 - 05:00
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Osimertinib as First-Line Treatment in EGFR-Mutated Non-Small-Cell Lung Cancer.

N Engl J Med. 2018 01 11;378(2):192-193

Authors: Popat S

PMID: 29320658 [PubMed - indexed for MEDLINE]

Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.

lør, 01/13/2018 - 03:30
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Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.

J Clin Oncol. 2018 Jan 10;:JCO2017753780

Authors: Hainsworth JD, Meric-Bernstam F, Swanton C, Hurwitz H, Spigel DR, Sweeney C, Burris H, Bose R, Yoo B, Stein A, Beattie M, Kurzrock R

Abstract
Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2-amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non-small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.

PMID: 29320312 [PubMed - as supplied by publisher]

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.

tor, 01/11/2018 - 02:30
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Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.

Lancet. 2017 07 01;390(10089):29-39

Authors: Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, Takiguchi Y, Nishio M, Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, Asakawa T, Asabe R, Tanaka T, Tamura T

Abstract
BACKGROUND: Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.
METHODS: J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316).
FINDINGS: Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group.
INTERPRETATION: These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study.
FUNDING: Chugai Pharmaceutical Co, Ltd.

PMID: 28501140 [PubMed - indexed for MEDLINE]

Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer.

tir, 01/09/2018 - 01:30
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Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer.

J Clin Oncol. 2018 Jan 02;:JCO2017740720

Authors: Liao Z, Lee JJ, Komaki R, Gomez DR, O'Reilly MS, Fossella FV, Blumenschein GR, Heymach JV, Vaporciyan AA, Swisher SG, Allen PK, Choi NC, DeLaney TF, Hahn SM, Cox JD, Lu CS, Mohan R

Abstract
Purpose This randomized trial compared outcomes of passive scattering proton therapy (PSPT) versus intensity-modulated (photon) radiotherapy (IMRT), both with concurrent chemotherapy, for inoperable non-small-cell lung cancer (NSCLC). We hypothesized that PSPT exposes less lung tissue to radiation than IMRT and thereby reduces toxicity without compromising tumor control. The primary end points were grade ≥ 3 radiation pneumonitis (RP) and local failure (LF). Patients and Methods Eligible patients had stage IIB to IIIB NSCLC (or stage IV NSCLC with a single brain metastasis or recurrent lung or mediastinal disease after surgery) who were candidates for concurrent chemoradiation therapy. Pairs of treatment plans for IMRT and PSPT were created for each patient. Patients were eligible for random assignment only if both plans satisfied the same prespecified dose-volume constraints for at-risk organs at the same tumor dose. Results Compared with IMRT (n = 92), PSPT (n = 57) exposed less lung tissue to doses of 5 to 10 Gy(RBE), which is the absorbed Gy dose multiplied by the relative biologic effectiveness (RBE) factor for protons; exposed more lung tissue was exposed to $ 20 Gy(RBE), but exposed less heart tissue at all dose levels between 5 and 80 Gy(RBE). The grade $ 3 RP rate for all patients was 8.1% (IMRT, 6.5%; PSPT, 10.5%); corresponding LF rates were 10.7% (all), 10.9% (IMRT), and 10.5% (PSPT). The posterior probability of IMRT being better than PSPT was 0.54. Exploratory analysis showed that the RP and LF rates at 12 months for patients enrolled before versus after the trial midpoint were 21.1% (before) versus 18.2% (after) for the IMRT group (P = .047) and 31.0% (before) versus 13.1% (after) for the PSPT group (P = .027). Conclusion PSPT did not improve dose-volume indices for lung but did for heart. No benefit was noted in RP or LF after PSPT. Improvements in both end points were observed over the course of the trial.

PMID: 29293386 [PubMed - as supplied by publisher]

Smoking, B Vitamins, and Lung Cancer: The Chicken or the Egg Causality Dilemma.

tir, 01/02/2018 - 22:30
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Smoking, B Vitamins, and Lung Cancer: The Chicken or the Egg Causality Dilemma.

J Clin Oncol. 2017 Dec 28;:JCO2017759472

Authors: Obeid R, Pietrzik K

PMID: 29283790 [PubMed - as supplied by publisher]

Antineoplastic Treatment of Advanced-Stage Non-Small-Cell Lung Cancer: Treatment, Survival, and Spending (2000 to 2011).

tor, 12/28/2017 - 20:00
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Antineoplastic Treatment of Advanced-Stage Non-Small-Cell Lung Cancer: Treatment, Survival, and Spending (2000 to 2011).

J Clin Oncol. 2017 Feb 10;35(5):529-535

Authors: Bradley CJ, Yabroff KR, Mariotto AB, Zeruto C, Tran Q, Warren JL

Abstract
Purpose Multiple agents for advanced non-small-cell lung cancer (NSCLC) have been approved in the past decade, but little is known about their use and associated spending and survival. Methods We used SEER-Medicare data for elderly patients with a new diagnosis of advanced-stage NSCLC and were treated with antineoplastic agents between 2000 and 2011 (N = 22,163). We estimated the adjusted percentage of patients who received each agent, days while on treatment, survival, and spending in the 12 months after diagnosis. Results During the 12-year study period, a marked shift in treatment occurred along with a rapid adoption of pemetrexed (39.2%), erlotinib (20.3%), and bevacizumab (18.9%) and a decline in paclitaxel (38.7%), gemcitabine (17.0%), and vinorelbine (5.7%; all P < .05). The average total days on therapy increased by 5 days (from 103 to 108 days). Patients who received bevacizumab, erlotinib, or pemetrexed had the longest treatment durations on average (approximately 146 days v 75 days for those who did not receive these agents). Approximately 44% of patients received antineoplastic agents in the last 30 days of life throughout the study period. Acute inpatient spending declined (from $29,376 to $23,731), whereas outpatient spending increased 23% (from $37,931 to $46,642). Median survival gains of 1.5 months were observed. Conclusion Considerable shifts in the treatment of advanced-stage NSCLC occurred along with modest gains in survival and total Medicare spending. More precise outcome information is needed to inform value-based treatment decisions for advanced-stage NSCLC.

PMID: 28045621 [PubMed - indexed for MEDLINE]

Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer.

tor, 12/28/2017 - 20:00
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Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer.

J Clin Oncol. 2016 Nov 01;34(31):3740-3748

Authors: Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, Pietanza MC, Wu YL, Zielinski C, Thomas M, Felip E, Gold K, Horn L, Aerts J, Nakagawa K, Lorigan P, Pieters A, Kong Sanchez T, Fairchild J, Spigel D

Abstract
Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

PMID: 27458307 [PubMed - indexed for MEDLINE]

Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors.

ons, 12/27/2017 - 19:30
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Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors.

J Clin Oncol. 2017 Dec 18;:

Authors: Thomas A, Redon CE, Sciuto L, Padiernos E, Ji J, Lee MJ, Yuno A, Lee S, Zhang Y, Tran L, Yutzy W, Rajan A, Guha U, Chen H, Hassan R, Alewine CC, Szabo E, Bates SE, Kinders RJ, Steinberg SM, Doroshow JH, Aladjem MI, Trepel JB, Pommier Y

Abstract
Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

PMID: 29252124 [PubMed - as supplied by publisher]

Gefitinib Plus Chemotherapy Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer Resistant to First-Line Gefitinib (IMPRESS): Overall Survival and Biomarker Analyses.

ons, 12/27/2017 - 19:30
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Gefitinib Plus Chemotherapy Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer Resistant to First-Line Gefitinib (IMPRESS): Overall Survival and Biomarker Analyses.

J Clin Oncol. 2017 Dec 20;35(36):4027-4034

Authors: Mok TSK, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Shi X, Rukazenkov Y, Haddad V, Thress KS, Soria JC

Abstract
Purpose The Iressa Mutation-Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS) compared the continuation of gefitinib plus chemotherapy with placebo plus chemotherapy in patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer with progression (Response Evaluation Criteria in Solid Tumors 1.1) after first-line gefitinib. Primary results indicated no difference between treatments in terms of progression-free survival (PFS). The current analysis presents final, mature, overall survival (OS) data, together with exploratory analyses that examined whether specific biomarkers, including T790M mutation status, were able to differentiate a relative treatment effect. Patients and Methods Patients were randomly assigned to gefitinib 250 mg or placebo, in addition to cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 (maximum of six cycles of chemotherapy). EGFR mutation status was determined from plasma-derived circulating free tumor-derived DNA samples (beads, emulsification, amplification, and magnetics digital polymerase chain reaction assay, allelic fraction analysis). Results A total of 265 patients with non-small-cell lung cancer were randomly assigned, and overall data maturity was 66%. Continuation of gefitinib plus cisplatin and pemetrexed was detrimental to OS when compared with placebo plus cisplatin and pemetrexed (hazard ratio [HR], 1.44; 95% CI, 1.07 to 1.94; P = .016; median OS, 13.4 v 19.5 months). The detriment was statistically significant in patients with T790M mutation-positive plasma samples (HR, 1.49; 95% CI, 1.02 to 2.21), whereas statistical significance was not reached in T790M mutation-negative patients (HR, 1.15; 95% CI, 0.68 to 1.94). PFS in T790M mutation-positive patients was similar between treatments, and the difference observed in T790M mutation-negative patients did not reach statistical significance (HR, 0.67; 95% CI, 0.43 to 1.03; P = .0745). Conclusion Final OS data from IMPRESS are supportive of earlier PFS results and are sufficient to warn physicians against the continuation of treatment with first-generation EGFR tyrosine kinase inhibitors beyond radiologic disease progression when chemotherapy is initiated. Plasma biomarker analyses suggest that this effect may be driven by T790M-positive status.

PMID: 28968167 [PubMed - indexed for MEDLINE]

Enrollment Trends and Disparity Among Patients With Lung Cancer in National Clinical Trials, 1990 to 2012.

man, 12/18/2017 - 15:00
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Enrollment Trends and Disparity Among Patients With Lung Cancer in National Clinical Trials, 1990 to 2012.

J Clin Oncol. 2016 Nov 20;34(33):3992-3999

Authors: Pang HH, Wang X, Stinchcombe TE, Wong ML, Cheng P, Ganti AK, Sargent DJ, Zhang Y, Hu C, Mandrekar SJ, Redman MW, Manola JB, Schilsky RL, Cohen HJ, Bradley JD, Adjei AA, Gandara D, Ramalingam SS, Vokes EE

Abstract
Purpose Under-representation of elderly, women, and racial/ethnic minority patients with cancer in clinical trials is of national concern. The goal of this study was to characterize enrollment trends and disparities by age, sex, and race/ethnicity in lung cancer trials. Methods We analyzed data for 23,006 National Cancer Institute cooperative group lung cancer trial participants and 578,476 patients with lung cancer from the SEER registry from 1990 to 2012. The enrollment disparity difference (EDD) and enrollment disparity ratio (EDR) were calculated on the basis of the proportion of each subgroup in the trial population and the US lung cancer population. Annual percentage changes (APCs) in the subgroup proportions in each population were compared over time. Results Enrollment disparity for patients ≥ 70 years of age with non-small-cell lung cancer improved from 1990 to 2012 (test of parallelism, P = .020), with a remaining EDD of 0.22 (95% CI, 0.19 to 0.25) and EDR of 1.65 (95% CI, 1.51 to 1.82) in 2010 to 2012. No improvement was seen for elderly patients with small-cell lung cancer (SCLC), with an APC of 0.20 ( P = .714) among trial participants, despite a rising proportion of elderly patients with SCLC in the US population (APC, 0.32; P = .020). Enrollment disparity for women with lung cancer improved overall, with the gap closing by 2012 (EDD, 0.03 [95% CI, 0.00 to 0.06]; EDR, 1.07 [95% CI, 1.00 to 1.16]). Enrollment disparities persisted without significant improvement for elderly women, blacks, Asians/Pacific Islanders, and Hispanics. Conclusion Under-representation in lung cancer trials improved significantly from 1990 to 2012 for elderly patients with non-small-cell lung cancer and for women, but ongoing efforts to improve the enrollment of elderly patients with SCLC and minorities are needed. Our study highlights the importance of addressing enrollment disparities by demographic and disease subgroups to better target under-represented groups of patients with lung cancer.

PMID: 27646951 [PubMed - indexed for MEDLINE]

Sequencing of Postoperative Radiotherapy and Chemotherapy for Locally Advanced or Incompletely Resected Non-Small-Cell Lung Cancer.

fre, 12/15/2017 - 13:30
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Sequencing of Postoperative Radiotherapy and Chemotherapy for Locally Advanced or Incompletely Resected Non-Small-Cell Lung Cancer.

J Clin Oncol. 2017 Dec 13;:JCO2017744771

Authors: Francis S, Orton A, Stoddard G, Tao R, Hitchcock YJ, Akerley W, Kokeny KE

Abstract
Purpose Although several feasibility studies have demonstrated the safety of adjuvant concurrent chemoradiotherapy (CRT) for locally advanced or incompletely resected non-small-cell lung cancer (NSCLC), it remains uncertain whether this approach is superior to sequential chemotherapy followed by postoperative radiotherapy (C→PORT). We sought to determine the most effective treatment sequence. Patients and Methods Using the National Cancer Database, we selected two cohorts of patients with nonmetastatic NSCLC who had received at least a lobectomy followed by multiagent chemotherapy and radiotherapy; cohort one included patients with R0 resection and pN2 disease, whereas cohort two included patients with R1-2 resection regardless of nodal status. Overall survival (OS) was examined using a propensity score-matched analysis with a shared frailty Cox regression. Results A total of 747 patients in cohort one and 277 patients in cohort two were included, with a median follow-up of 32.8 and 27.9 months, respectively. The median OS was 58.8 months for patients who received C→PORT versus 40.4 months for patients who received CRT in cohort one (log-rank P < .001). For cohort two, the median OS was 42.6 months for patients who received C→PORT versus 38.5 months for patients who received CRT (log-rank P = .42). After propensity score matching, C→PORT remained associated with improved OS compared with CRT in cohort one (hazard ratio, 1.35; P = .019), and there was no statistical difference in OS between the sequencing groups for cohort two (hazard ratio, 1.35; P = .19). Conclusion Patients with NSCLC who undergo R0 resection and are found to have pN2 disease have improved outcomes when adjuvant chemotherapy is administered before, rather than concurrently with, radiotherapy. For patients with positive margins after surgery, there is not a clear association between treatment sequencing and survival.

PMID: 29236592 [PubMed - as supplied by publisher]

Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study.

ons, 12/13/2017 - 12:30
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Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study.

J Clin Oncol. 2017 Dec 01;35(34):3823-3829

Authors: Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, Piperdi B, Mehnert JM

Abstract
Purpose The safety and efficacy of pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), were assessed in patients with programmed death ligand 1 (PD-L1)-expressing extensive-stage small-cell lung cancer (SCLC) in the multicohort, phase Ib open-label KEYNOTE-028 study ( ClinicalTrials.gov identifier: NCT02054806). Methods Patients with SCLC received pembrolizumab 10 mg/kg every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. PD-L1 expression was assessed by immunohistochemistry. PD-L1-positive patients had membranous PD-L1 expression in ≥ 1% of tumor and associated inflammatory cells or positive staining in stroma. Response was assessed by investigator per Response Evaluation Criteria in Solid Tumors version 1.1 every 8 weeks for the first 6 months and every 12 weeks thereafter. Adverse events (AEs) were reported per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Primary end points were safety, tolerability, and objective response rate (ORR). Secondary end points included progression-free survival, overall survival, and duration of response. Results Twenty-four patients with PD-L1-expressing SCLC were enrolled and received at least one pembrolizumab dose. At the data cutoff date (June 20, 2016), the median follow-up duration was 9.8 months (range, 0.5 to 24 months). All 24 patients experienced AEs; the most common were asthenia (n = 7), fatigue (n = 7), and cough (n = 6). Two patients experienced grade 3 to 5 treatment-related AEs: one patient had elevated bilirubin, and one patient had asthenia, grade 5 colitis, and intestinal ischemia. One patient had a complete response, and seven patients had partial responses, resulting in an ORR of 33% (95% CI, 16% to 55%). Conclusion The safety of pembrolizumab was consistent with the known safety profile in other tumor types. Pembrolizumab demonstrated promising antitumor activity in patients with pretreated, PD-L1-expressing SCLC.

PMID: 28813164 [PubMed - indexed for MEDLINE]

Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in Non-Small-Cell Lung Cancer.

ons, 12/13/2017 - 12:30
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Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in Non-Small-Cell Lung Cancer.

J Clin Oncol. 2017 Dec 01;35(34):3867-3876

Authors: Büttner R, Gosney JR, Skov BG, Adam J, Motoi N, Bloom KJ, Dietel M, Longshore JW, López-Ríos F, Penault-Llorca F, Viale G, Wotherspoon AC, Kerr KM, Tsao MS

Abstract
Purpose Three programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of non-small-cell lung cancer (NSCLC). Treatment with pembrolizumab in NSCLC requires PD-L1 immunohistochemistry (IHC) testing. Nivolumab and atezolizumab are approved without PD-L1 testing, though US Food and Drug Administration-cleared complementary PD-L1 tests are available for both. PD-L1 IHC assays used to assess PD-L1 expression in patients treated with programmed death-1/PD-L1 inhibitors in clinical trials include PD-L1 IHC 28-8 pharmDx (28-8), PD-L1 IHC 22C3 pharmDx (22C3), Ventana PD-L1 SP142 (SP142), and Ventana PD-L1 SP263 (SP263). Differences in antibodies and IHC platforms have raised questions about comparability among these assays and their diagnostic use. This review provides practical information to help physicians and pathologists understand analytical features and comparability of various PD-L1 IHC assays and their diagnostic use. Methods We reviewed and summarized published or otherwise reported studies (January 2016 to January 2017) on clinical trial and laboratory-developed PD-L1 IHC assays (LDAs). Studies assessing the effect of diagnostic methods on PD-L1 expression levels were analyzed to address practical issues related to tissue samples used for testing. Results High concordance and interobserver reproducibility were observed with the 28-8, 22C3, and SP263 clinical trial assays for PD-L1 expression on tumor cell membranes, whereas lower PD-L1 expression was detected with SP142. Immune-cell PD-L1 expression was variable and interobserver concordance was poor. Inter- and intratumoral heterogeneity had variable effects on PD-L1 expression. Concordance among LDAs was variable. Conclusion High concordance among 28-8, 22C3, and SP263 when assessing PD-L1 expression on tumor cell membranes suggests possible interchangeability of their clinical use for NSCLC but not for assessment of PD-L1 expression on immune cells. Development of LDAs requires stringent standardization before their recommendation for routine clinical use.

PMID: 29053400 [PubMed - indexed for MEDLINE]

Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057).

man, 12/11/2017 - 11:30
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Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057).

J Clin Oncol. 2017 Dec 10;35(35):3924-3933

Authors: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE

Abstract
Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non-small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death with nivolumab versus docetaxel remained similar to those reported in the primary analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years' minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooled analysis, the relative reduction in the risk of death with nivolumab versus docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.

PMID: 29023213 [PubMed - indexed for MEDLINE]

Programmed death of chemotherapy in non-small-cell lung cancer?

lør, 12/09/2017 - 10:30
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Programmed death of chemotherapy in non-small-cell lung cancer?

Lancet. 2017 01 21;389(10066):227-228

Authors: Leduc C, Quoix E

PMID: 27979385 [PubMed - indexed for MEDLINE]

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

lør, 12/09/2017 - 10:30
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Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

N Engl J Med. 2017 11 16;377(20):1919-1929

Authors: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M, PACIFIC Investigators

Abstract
BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.
METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety.
RESULTS: Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.
CONCLUSIONS: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

PMID: 28885881 [PubMed - indexed for MEDLINE]