Publications by authors named "Lee M Krug"

86 Publications

Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer.

Authors:
M Catherine Pietanza Saiama N Waqar Lee M Krug Afshin Dowlati Christine L Hann Alberto Chiappori Taofeek K Owonikoko Kaitlin M Woo Robert J Cardnell Junya Fujimoto Lihong Long Lixia Diao Jing Wang Yevgeniva Bensman Brenda Hurtado Patricia de Groot Erik P Sulman Ignacio I Wistuba Alice Chen Martin Fleisher John V Heymach Mark G Kris Charles M Rudin Lauren Averett Byers

J Clin Oncol 2018 08 15;36(23):2386-2394. Epub 2018 Jun 15.

M. Catherine Pietanza, Lee M. Krug, Mark G. Kris, and Charles M. Rudin, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College; Kaitlin M. Woo, Yevgeniva Bensman, Brenda Hurtado, and Martin Fleisher, Memorial Sloan Kettering Cancer Center, New York, NY; Saiama N. Waqar, Washington University School of Medicine in St. Louis, St Louis, MO; Afshin Dowlati, Case Western Reserve University and University Hospitals Seidman Cancer Center, Cleveland, OH; Christine L. Hann, Johns Hopkins University, Baltimore; Alice Chen, National Institutes of Health, Bethesda, MD; Alberto Chiappori, H. Lee Moffitt Cancer Center, Tampa, FL; Taofeek K. Owonikoko, Emory University, Atlanta, GA; and Robert J. Cardnell, Junya Fujimoto, Lihong Long, Lixia Diao, Jing Wang, Patricia de Groot, Erik P. Sulman, Ignacio I. Wistuba, John V. Heymach, and Lauren Averett Byers, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.
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http://dx.doi.org/10.1200/JCO.2018.77.7672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085179PMC
August 2018

Making Lung Cancer Clinical Trials More Inclusive: Recommendations for Expanding Eligibility Criteria.

Authors:
Philip Bonomi Gideon Blumenthal Andrea Stern Ferris David J Stewart Wendy K D Selig Lee M Krug Jeff Allen Gwynn Ison Corey J Langer Allen Melemed Lauretta Odogwu Upal Basu Roy Alan Sandler

J Thorac Oncol 2018 06;13(6):748-751

Genentech, San Francisco, California.

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http://dx.doi.org/10.1016/j.jtho.2018.02.013DOI Listing
June 2018

A Randomized Phase II Trial of Adjuvant Galinpepimut-S, WT-1 Analogue Peptide Vaccine, After Multimodality Therapy for Patients with Malignant Pleural Mesothelioma.

Authors:
Marjorie G Zauderer Anne S Tsao Tao Dao Katherine Panageas W Victoria Lai Andreas Rimner Valerie W Rusch Prasad S Adusumilli Michelle S Ginsberg Daniel Gomez David Rice Reza Mehran David A Scheinberg Lee M Krug

Clin Cancer Res 2017 Dec 28;23(24):7483-7489. Epub 2017 Sep 28.

Division of Solid Tumor Oncology, Department of Medicine, Thoracic Oncology Service Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.

Determine the 1-year progression-free survival (PFS) rate among patients with malignant pleural mesothelioma (MPM) receiving the WT1 peptide vaccine galinpepimut-S after multimodality therapy versus those receiving control adjuvants. This double-blind, controlled, two center phase II trial randomized MPM patients after surgery and another treatment modality to galinpepimut-S with GM-CSF and Montanide or GM-CSF and Montanide alone. An improvement in 1-year PFS from 50% to 70% was the predefined efficacy threshold, and 78 patients total were planned. The study was not powered for comparison between the two arms. Forty-one patients were randomized. Treatment-related adverse events were mild, self-limited, and not clinically significant. On the basis of a stringent prespecified futility analysis (futility = ≥10 of 20 patients on one arm experiencing progression < 1 year), the control arm closed early. The treatment arm was subsequently closed because of the resultant unblinding. The PFS rate at 1 year from beginning study treatment was 33% and 45% in the control and vaccine arms, respectively. Median PFS was 7.4 months versus 10.1 months and median OS was 18.3 months versus 22.8 months in the control and vaccine arms, respectively. The favorable safety profile was confirmed. PFS and OS were greater in those who received vaccine, but the trial was neither designed nor powered for comparison between the arms. On the basis of these promising results, the investigators are planning a larger randomized trial with greater statistical power to define the optimal use and benefit of galinpepimut-S in the treatment of MPM. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732877PMC
December 2017

Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma.

Authors:
Fauzia Shaikh Marjorie G Zauderer Donata von Reibnitz Abraham J Wu Ellen D Yorke Amanda Foster Weiji Shi Zhigang Zhang Prasad S Adusumilli Kenneth E Rosenzweig Lee M Krug Valerie W Rusch Andreas Rimner

J Thorac Oncol 2017 06 21;12(6):993-1000. Epub 2017 Mar 21.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Introduction: Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicity. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) with previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/decortication (P/D).

Methods: We analyzed 209 patients who underwent P/D and adjuvant RT (131 who received CONV and 78 who received IMPRINT) for MPM between 1974 and 2015. The primary end point was overall survival (OS). The Kaplan-Meier method and Cox proportional hazards model were used to calculate OS; competing risks analysis was performed for local failure-free survival and progression-free survival. Univariate analysis and multivariate analysis were performed with relevant clinical and treatment factors.

Results: The median age was 64 years, and 80% of the patients were male. Patients receiving IMPRINT had significantly higher rates of the epithelial histological type, advanced pathological stage, and chemotherapy treatment. OS was significantly higher after IMPRINT (median 20.2 versus 12.3 months, p = 0.001). Higher Karnofsky performance score, epithelioid histological type, macroscopically complete resection, and use of chemotherapy/IMPRINT were found to be significant factors for longer OS in multivariate analysis. No significant predictive factors were identified for local failure or progression. Grade 2 or higher esophagitis developed in fewer patients after IMPRINT than after CONV (23% versus 47%).

Conclusions: Trimodality therapy including adjuvant hemithoracic IMPRINT, chemotherapy, and P/D is associated with promising OS rates and decreased toxicity in patients with MPM. Dose constraints should be applied vigilantly to minimize serious adverse events.
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http://dx.doi.org/10.1016/j.jtho.2017.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499250PMC
June 2017

A phase I trial of the Hedgehog inhibitor, sonidegib (LDE225), in combination with etoposide and cisplatin for the initial treatment of extensive stage small cell lung cancer.

Authors:
M Catherine Pietanza Anya M Litvak Anna M Varghese Lee M Krug Martin Fleisher Jerrold B Teitcher Andrei I Holodny Cami S Sima Kaitlin M Woo Kenneth K Ng Helen H Won Michael F Berger Mark G Kris Charles M Rudin

Lung Cancer 2016 09 26;99:23-30. Epub 2016 Apr 26.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States.

Objectives: The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC.

Materials And Methods: Patients received 4-6 21-day cycles of etoposide/cisplatin with daily sonidegib. Patients with response or stable disease were continued on sonidegib until disease progression or unacceptable toxicity. Two dose levels of sonidegib were planned: 400mg and 800mg daily, with 200mg daily de-escalation if necessary. Next generation sequencing was performed on available specimens. Circulating tumor cells (CTCs) were quantified at baseline and with disease evaluation.

Results: Fifteen patients were enrolled. 800mg was established as the recommended phase II dose of sonidegib in combination with etoposide/cisplatin. Grade 3 or greater toxicities included: anemia (n=5), neutropenia (n=8), CPK elevation (n=2), fatigue (n=2), and nausea (n=2). Toxicity led to removal of one patient from study. Partial responses were confirmed in 79% (11/14; 95% CI: 49-95%). One patient with SOX2 amplification remains progression-free on maintenance sonidegib after 27 months. CTC count, at baseline, was associated with the presence of liver metastases and after 1 cycle of therapy, with overall survival.

Conclusions: Sonidegib 800mg daily was the MTD when administered with EP. Further genomic characterization of exceptional responders may reveal clinically relevant predictive biomarkers that could tailor use in patients most likely to benefit.
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http://dx.doi.org/10.1016/j.lungcan.2016.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427482PMC
September 2016

Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma.

Authors:
Andreas Rimner Marjorie G Zauderer Daniel R Gomez Prasad S Adusumilli Preeti K Parhar Abraham J Wu Kaitlin M Woo Ronglai Shen Michelle S Ginsberg Ellen D Yorke David C Rice Anne S Tsao Kenneth E Rosenzweig Valerie W Rusch Lee M Krug

J Clin Oncol 2016 08 20;34(23):2761-8. Epub 2016 Jun 20.

Andreas Rimner, Marjorie G. Zauderer, Prasad S. Adusumilli, Preeti K. Parhar, Abraham J. Wu, Kaitlin M. Woo, Ronglai Shen, Michelle S. Ginsberg, Ellen D. Yorke, Kenneth E. Rosenzweig, Valerie W. Rusch, and Lee M. Krug, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, New York, NY; and Daniel R. Gomez, David C. Rice, and Anne S. Tsao, MD Anderson Cancer Center, Houston, TX.

Purpose: We conducted a two-center phase II study to determine the safety of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) after chemotherapy and pleurectomy-decortication (P/D) as part of a multimodality lung-sparing treatment.

Patients And Methods: Patients received up to four cycles of pemetrexed plus platinum. If feasible, P/D was performed. Hemithoracic IMPRINT was administered to a planned dose of 50.4 Gy in 28 fractions. The primary end point was the incidence of grade 3 or greater radiation pneumonitis (RP).

Results: A total of 45 patients were enrolled; 18 were not evaluable (because of disease progression before radiation therapy [RT], n = 9; refusal of surgery or RT, n = 5; extrapleural pneumonectomy at time of surgery, n = 2; or chemotherapy complications, n = 2). A total of 26 patients received pemetrexed plus cisplatin, 18 received pemetrexed plus carboplatin, and four received a combination. Thirteen patients (28.9%) had a partial response, 15 patients (33.3%) experienced disease progression, one patient died during chemotherapy, and all others had stable disease. Eight patients underwent P/D or an extended P/D, and 13 underwent a partial P/D. A total of 27 patients started IMPRINT (median dose, 46.8 Gy; range, 28.8 to 50.4 Gy) and were evaluable for the primary end point (median follow-up, 21.6 months). Six patients experienced grade 2 RP, and two patients experienced grade 3 RP; all recovered after corticosteroid initiation. No grade 4 or 5 radiation-related toxicities were observed. The median progression-free survival and overall survival (OS) were 12.4 and 23.7 months, respectively; the 2-year OS was 59% in patients with resectable tumors and was 25% in patients with unresectable tumors.

Conclusions: Hemithoracic IMPRINT for malignant pleural mesothelioma (MPM) is safe and has an acceptable rate of RP. Its incorporation with chemotherapy and P/D forms a new lung-sparing treatment paradigm for patients with locally advanced MPM.
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http://dx.doi.org/10.1200/JCO.2016.67.2675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019761PMC
August 2016

Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes.

Authors:
Jarushka Naidoo Maria L Santos-Zabala Tunc Iyriboz Kaitlin M Woo Camelia S Sima John J Fiore Mark G Kris Gregory J Riely Piro Lito Afsheen Iqbal Stephen Veach Stephanie Smith-Marrone Inderpal S Sarkaria Lee M Krug Charles M Rudin William D Travis Natasha Rekhtman Maria C Pietanza

Clin Lung Cancer 2016 09 21;17(5):e121-e129. Epub 2016 Jan 21.

Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.

Background: Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC.

Materials And Methods: Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria.

Results: Forty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (n = 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had KRAS mutations (n = 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (n = 26) received platinum/etoposide and 30% (n = 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%-62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6-16.4 months) for the entire cohort.

Conclusion: Patients with stage IV LCNEC have a high incidence of brain metastases. KRAS mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.
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http://dx.doi.org/10.1016/j.cllc.2016.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474315PMC
September 2016

Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma.

Authors:
Andrea Billé Lee M Krug Kaitlin M Woo Valerie W Rusch Marjorie G Zauderer

J Thorac Oncol 2016 Feb 10;11(2):249-55. Epub 2015 Dec 10.

Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Introduction: Previous prognostic scoring systems for malignant pleural mesothelioma (MPM) included patients managed surgically and predated the use of pemetrexed. We analyzed prognostic factors in a contemporary cohort of patients with unresectable MPM who received pemetrexed-based chemotherapy.

Methods: This single-institution analysis included patients with MPM who were managed nonsurgically from 2000 to 2013. Variables correlated with overall survival (OS) included sex, performance status (PS), asbestos exposure, tumor laterality, histology, clinical stage, initial positron emission tomography maximum standardized uptake value, hemoglobin level, platelet count, lymphocyte count, white cell and neutrophil counts, treatment type, and clinical benefit from treatment. OS was analyzed by the Kaplan-Meier method, and significance (p < 0.05) of prognostic factors was analyzed by the log-rank test and Cox regression.

Results: A total of 191 patients met the study criteria: median age 71 years (range 46-90), 147 men (77%), 128 epithelioid tumors (67%), and 157 cases of stage III or IV MPM (82%). Median OS for all patients was 13.4 months. According to a univariate analysis, histology (p < 0.001), platelet count (< or = 450,000 versus >450,000, p < 0.001), initial PS (0-1 versus > or = 2), maximum standardized uptake value (< or = 8.1 versus >8.1, p = 0.037), and lymphocyte counts (p = 0.019) were associated with OS. According to a multivariable analysis, only histology, platelet count, and PS were independent prognostic factors. Epithelioid histology, PS, and elevated lymphocyte count at diagnosis were significantly associated with clinical benefit from first-line chemotherapy.

Conclusions: Our results confirm the significance of elements of the Cancer and Leukemia Group B and European Organisation for Research and Treatment of Cancer prognostic scoring systems, identify factors associated with clinical benefit from chemotherapy, and emphasize the impact of histology and clinical benefit of chemotherapy on outcomes.
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http://dx.doi.org/10.1016/j.jtho.2015.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917284PMC
February 2016

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Authors:
Paul A Bunn John D Minna Alexander Augustyn Adi F Gazdar Youcef Ouadah Mark A Krasnow Anton Berns Elisabeth Brambilla Natasha Rekhtman Pierre P Massion Matthew Niederst Martin Peifer Jun Yokota Ramaswamy Govindan John T Poirier Lauren A Byers Murry W Wynes David G McFadden David MacPherson Christine L Hann Anna F Farago Caroline Dive Beverly A Teicher Craig D Peacock Jane E Johnson Melanie H Cobb Hans-Guido Wendel David Spigel Julien Sage Ping Yang

J Thorac Oncol 2016 Apr 30;11(4):453-74. Epub 2016 Jan 30.

Mayo Clinic Cancer Center, Rochester, Minnesota.

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http://dx.doi.org/10.1016/j.jtho.2016.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836290PMC
April 2016

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors.

Authors:
Saoirse O Dolly Andrew J Wagner Johanna C Bendell Hedy L Kindler Lee M Krug Tanguy Y Seiwert Marjorie G Zauderer Martijn P Lolkema Doris Apt Ru-Fang Yeh Jill O Fredrickson Jill M Spoerke Hartmut Koeppen Joseph A Ware Jennifer O Lauchle Howard A Burris Johann S de Bono

Clin Cancer Res 2016 06 19;22(12):2874-84. Epub 2016 Jan 19.

The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.

Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases.

Experimental Design: Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed.

Results: Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas).

Conclusions: Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874-84. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876928PMC
June 2016

The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: A comprehensive analysis reveals prognostic immune markers.

Authors:
Hideki Ujiie Kyuichi Kadota Jun-Ichi Nitadori Joachim G Aerts Kaitlin M Woo Camelia S Sima William D Travis David R Jones Lee M Krug Prasad S Adusumilli

Oncoimmunology 2015 Jun 19;4(6):e1009285. Epub 2015 Mar 19.

Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA ; Center of Cell Engineering; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.

Antitumor immune responses against solid malignancies correlate with improved patient survival. We conducted a comprehensive investigation of immune responses in tumor and tumor-associated stroma in epithelioid malignant pleural mesothelioma with the goal of characterizing the tumor immune microenvironment and identifying prognostic immune markers. We investigated 8 types of tumor-infiltrating immune cells within the tumor nest and tumor-associated stroma, as well as tumor expression of 5 cytokine/chemokine receptors in 230 patients. According to univariate analyses, high densities of tumoral CD4- and CD20-expressing lymphocytes were associated with better outcomes. High expression of tumor interleukin-7 (IL-7) receptor was associated with worse outcomes. According to multivariate analyses, stage and tumoral CD20 detection were independently associated with survival. Analysis of single immune cell infiltration for CD163 tumor-associated macrophages did not correlate with survival. However, analysis of immunologically relevant cell combinations identified that: (1) high CD163 tumor-associated macrophages and low CD8 lymphocyte infiltration had worse prognosis than other groups and (2) low CD163 tumor associated macrophages and high CD20 lymphocyte infiltration had better prognosis than other groups. Multivariate analyses demonstrated that CD163/CD8 and CD163/CD20 were independent prognostic factors of survival. With a recent increase in immunotherapy investigations and clinical trials for malignant pleural mesothelioma patients, our observations that CD20 B lymphocytes and tumor-associated macrophages are prognostic markers provide important information about the tumor microenvironment of malignant pleural mesothelioma.
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http://dx.doi.org/10.1080/2162402X.2015.1009285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485766PMC
June 2015

Non-Small Cell Lung Cancer, Version 6.2015.

Authors:
David S Ettinger Douglas E Wood Wallace Akerley Lyudmila A Bazhenova Hossein Borghaei David Ross Camidge Richard T Cheney Lucian R Chirieac Thomas A D'Amico Todd L Demmy Thomas J Dilling M Chris Dobelbower Ramaswamy Govindan Frederic W Grannis Leora Horn Thierry M Jahan Ritsuko Komaki Lee M Krug Rudy P Lackner Michael Lanuti Rogerio Lilenbaum Jules Lin Billy W Loo Renato Martins Gregory A Otterson Jyoti D Patel Katherine M Pisters Karen Reckamp Gregory J Riely Eric Rohren

J Natl Compr Canc Netw 2015 May;13(5):515-24

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; University of Washington/Seattle Cancer Care Alliance; Huntsman Cancer Institute at the University of Utah; UC San Diego Moores Cancer Center; Fox Chase Cancer Center; University of Colorado Cancer Center; Roswell Park Cancer Institute; Dana-Farber/Brigham and Women's Cancer Center; Duke Cancer Institute; Moffitt Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; City of Hope Comprehensive Cancer Center; Vanderbilt-Ingram Cancer Center; UCSF Helen Diller Family Comprehensive Cancer Center; The University of Texas MD Anderson Cancer Center; Memorial Sloan Kettering Cancer Center; Fred & Pamela Buffett Cancer Center; Massachusetts General Hospital Cancer Center; Yale Cancer Center/Smilow Cancer Hospital; University of Michigan Comprehensive Cancer Center; Stanford Cancer Institute; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Mayo Clinic Cancer Center; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; and National Comprehensive Cancer Network.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.
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http://dx.doi.org/10.6004/jnccn.2015.0071DOI Listing
May 2015

Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.

Authors:
Lee M Krug Hedy L Kindler Hilary Calvert Christian Manegold Anne S Tsao Dean Fennell Ronny Öhman Ruth Plummer Wilfried E E Eberhardt Kazuya Fukuoka Rabab M Gaafar Jean-Jacques Lafitte Gunnar Hillerdal Quincy Chu Wieneke A Buikhuisen Gregory M Lubiniecki Xing Sun Margaret Smith Paul Baas

Lancet Oncol 2015 Apr 20;16(4):447-56. Epub 2015 Mar 20.

Cross Cancer Institute/University of Alberta, Edmonton, Alberta, Canada; The Academic Medical Center, Amsterdam, Netherlands.

Background: Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival.

Methods: This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov, number NCT00128102.

Findings: From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7-36·1) versus 27·1 weeks (23·1-31·9) for placebo (hazard ratio 0·98, 95% CI 0·83-1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 [16%] patients in the vorinostat group vs 25 [8%] in the placebo group]) and dyspnoea (35 [11%] vs 45 [14%]).

Interpretation: In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma.

Funding: Merck & Co.
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http://dx.doi.org/10.1016/S1470-2045(15)70056-2DOI Listing
April 2015

Non-small cell lung cancer, version 1.2015.

Authors:
David S Ettinger Douglas E Wood Wallace Akerley Lyudmila A Bazhenova Hossein Borghaei David Ross Camidge Richard T Cheney Lucian R Chirieac Thomas A D'Amico Todd L Demmy Thomas J Dilling Ramaswamy Govindan Frederic W Grannis Leora Horn Thierry M Jahan Ritsuko Komaki Mark G Kris Lee M Krug Rudy P Lackner Michael Lanuti Rogerio Lilenbaum Jules Lin Billy W Loo Renato Martins Gregory A Otterson Jyoti D Patel Katherine M Pisters Karen Reckamp Gregory J Riely Eric Rohren

J Natl Compr Canc Netw 2014 Dec;12(12):1738-61

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.
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http://dx.doi.org/10.6004/jnccn.2014.0176DOI Listing
December 2014

Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase.

Authors:
Marjorie G Zauderer Alex Drilon Kyuichi Kadota Kety Huberman Camelia S Sima Isabella Bergagnini Dyana K Sumner William D Travis Adriana Heguy Michelle S Ginsberg Andrei I Holodny Gregory J Riely Mark G Kris Lee M Krug M Catherine Pietanza

Lung Cancer 2014 Nov 17;86(2):237-40. Epub 2014 Aug 17.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States.

Objectives: Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O(6)-methyl-guanine-DNA methyltransferase (MGMT). Epigenetic silencing of MGMT is associated with loss of MGMT activity and improved sensitivity to alkylating agents in glioblastomas. We have reported the activity of temozolomide, a non-classical alkylating agent, in patients with relapsed sensitive or refractory SCLCs, given at 75 mg/m2/day for 21 of 28 days. However, prolonged myelosuppression was noted. We therefore evaluated a 5-day dosing schedule of temozolomide and examined MGMT as a predictive biomarker for temozolomide treatment in SCLC.

Materials And Methods: Patients with sensitive or refractory SCLCs and progression after one or two prior chemotherapy regimens received temozolomide 200 mg/m2/day for 5 consecutive days in 28-day cycles. The primary endpoint was tolerability. We also assessed MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry in tumor specimens.

Results: Of 25 patients enrolled, 5 experienced grade 3 or 4 toxicity (anemia, thrombocytopenia, neutropenia, and constipation). The partial response rate was 12% [95% CI: 3-31%], with partial responses in 2 refractory patients. We were able to obtain tumor samples for more than half of patients for MGMT testing.

Conclusion: Temozolomide 200 mg/m2/day for 5 days in 28-day cycles is tolerable and active in patients with relapsed SCLCs. No treatment-limiting prolonged cytopenias were observed, making this our preferred schedule for further studies. Acquisition of archived biospecimens is feasible and necessary in order to continue evaluating the role of MGMT as a predictive biomarker in SCLCs.
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http://dx.doi.org/10.1016/j.lungcan.2014.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497567PMC
November 2014

Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma.

Authors:
Andreas Rimner Daniel E Spratt Marjorie G Zauderer Kenneth E Rosenzweig Abraham J Wu Amanda Foster Ellen D Yorke Prasad Adusumilli Valerie W Rusch Lee M Krug

Int J Radiat Oncol Biol Phys 2014 Oct 26;90(2):394-401. Epub 2014 Jul 26.

Department of Medicine, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center; Weill Cornell Medical College, New York, New York.

Purpose: We previously reported our technique for delivering intensity modulated radiation therapy (IMRT) to the entire pleura while attempting to spare the lung in patients with malignant pleural mesothelioma (MPM). Herein, we report a detailed pattern-of-failure analysis in patients with MPM who were unresectable or underwent pleurectomy/decortication (P/D), uniformly treated with hemithoracic pleural IMRT.

Methods And Materials: Sixty-seven patients with MPM were treated with definitive or adjuvant hemithoracic pleural IMRT between November 2004 and May 2013. Pretreatment imaging, treatment plans, and posttreatment imaging were retrospectively reviewed to determine failure location(s). Failures were categorized as in-field (within the 90% isodose line), marginal (<90% and ≥50% isodose lines), out-of-field (outside the 50% isodose line), or distant.

Results: The median follow-up was 24 months from diagnosis and the median time to in-field local failure from the end of RT was 10 months. Forty-three in-field local failures (64%) were found with a 1- and 2-year actuarial failure rate of 56% and 74%, respectively. For patients who underwent P/D versus those who received a partial pleurectomy or were deemed unresectable, the median time to in-field local failure was 14 months versus 6 months, respectively, with 1- and 2-year actuarial in-field local failure rates of 43% and 60% versus 66% and 83%, respectively (P=.03). There were 13 marginal failures (19%). Five of the marginal failures (38%) were located within the costomediastinal recess. Marginal failures decreased with increasing institutional experience (P=.04). Twenty-five patients (37%) had out-of-field failures. Distant failures occurred in 32 patients (48%).

Conclusions: After hemithoracic pleural IMRT, local failure remains the dominant form of failure pattern. Patients treated with adjuvant hemithoracic pleural IMRT after P/D experience a significantly longer time to local and distant failure than patients treated with definitive pleural IMRT. Increasing experience and improvement in target delineation minimize the incidence of avoidable marginal failures.
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http://dx.doi.org/10.1016/j.ijrobp.2014.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560169PMC
October 2014

Phase II study of the GI-4000 KRAS vaccine after curative therapy in patients with stage I-III lung adenocarcinoma harboring a KRAS G12C, G12D, or G12V mutation.

Authors:
Jamie E Chaft Anya Litvak Maria E Arcila Payal Patel Sandra P D'Angelo Lee M Krug Valerie Rusch Alicia Mattson Claire Coeshott Bernard Park David M Apelian Mark G Kris Christopher G Azzoli

Clin Lung Cancer 2014 Nov 21;15(6):405-10. Epub 2014 Jun 21.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY.

Introduction: Patients with early-stage lung cancer have a high risk of recurrence despite multimodality therapy. KRAS-mutant lung adenocarcinomas are the largest genetically defined subgroup, representing 25% of patients. GI-4000 is a heat-killed recombinant Saccharomyces cerevisiae yeast-derived vaccine expressing mutant KRAS proteins. The present phase II study assessed the feasibility, immunogenicity, and safety of the GI-4000 vaccine in patients with early-stage, KRAS-mutant lung cancer.

Materials And Methods: Patients with stage I-III KRAS-mutant lung cancer who completed curative therapy were enrolled. The patients received the genotype matched GI-4000 vaccine for ≤ 3 years or until intolerance, disease recurrence, or death. The KRAS antigen T-cell response was assessed using the interferon-gamma enzyme-linked immunospot assay in peripheral blood mononuclear cells. The study was powered to detect an immune response in ≥ 25% of patients.

Results: A total of 24 patients were enrolled over 28 months. No vaccine-related serious adverse events occurred. One patient withdrew consent because of pain at the injection site. The study met its primary endpoint, with 50% of patients developing an immune response to mutant KRAS. The median number of vaccinations received was 15 (range, 1-19). Ten patients experienced disease recurrence, and 6 died. Compared with the genotypically matched historical controls, the recurrence rates were equivalent but overall survival showed a favorable trend.

Conclusion: GI-4000 was well tolerated and immunogenic when used as consolidation therapy in patients with stage I-III KRAS-mutant lung cancer. The patterns of recurrence and death observed in the present study can be used to design a randomized study of GI-4000 with overall survival as the primary endpoint.
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http://dx.doi.org/10.1016/j.cllc.2014.06.002DOI Listing
November 2014

Small-cell lung cancers in patients who never smoked cigarettes.

Authors:
Anna M Varghese Maureen F Zakowski Helena A Yu Helen H Won Gregory J Riely Lee M Krug Mark G Kris Natasha Rekhtman Marc Ladanyi Lu Wang Michael F Berger M Catherine Pietanza

J Thorac Oncol 2014 Jun;9(6):892-6

*Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; †Department of Medicine, Weill Cornell Medical College; ‡Department of Pathology; and §Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY.

Introduction: We describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).

Methods: We identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples.

Results: Two percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1.

Conclusions: Two percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.
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http://dx.doi.org/10.1097/JTO.0000000000000142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199745PMC
June 2014

Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma.

Authors:
Marjorie G Zauderer Samantha L Kass Kaitlin Woo Camelia S Sima Michelle S Ginsberg Lee M Krug

Lung Cancer 2014 Jun 14;84(3):271-4. Epub 2014 Mar 14.

Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, United States.

Objectives: Pemetrexed-cisplatin is the only FDA-approved regimen for malignant pleural mesothelioma (MPM), and the impact on survival is modest. No drugs have been shown to improve survival as second-line therapy, yet vinorelbine and gemcitabine are prescribed based on the results of small phase II trials. To augment the existing limited data, we examined our institutional experience with vinorelbine and gemcitabine in patients with previously treated MPM.

Materials And Methods: We reviewed charts of patients with MPM treated with vinorelbine and/or gemcitabine as second- or third-line therapy between 2003 and 2010. Toxicity was graded according to the Common Terminology Criteria for Adverse Events Version 4.0. CT scans were reviewed with a reference radiologist according to modified RECIST criteria.

Results: Sixty patients were identified: 33 treated with vinorelbine, 15 gemcitabine, and 12 both agents. Eighty-three percent initially received pemetrexed-platinum. Toxicity was substantial: 46% experienced at least one episode of grade 3-4 toxicity. Of 56 patients evaluable radiologically, there was 1 partial response (gemcitabine) giving a response rate of 2% (95% CI: 0-10%). Forty-six percent had stable disease. Median progression free survival was 1.7 months for vinorelbine and 1.6 months for gemcitabine. Median overall survival was 5.4 and 4.9 months, respectively.

Conclusions: Response to second- or third-line vinorelbine or gemcitabine is rare. The high rate of stable disease warrants the continued use of these agents in this setting, though the impact on survival is questionable. These data justify the choice of placebo control arms in randomized trials of novel agents in previously treated patients.
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http://dx.doi.org/10.1016/j.lungcan.2014.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343315PMC
June 2014

The challenge of malignant pleural mesothelioma: new directions.

Authors:
Valerie W Rusch Andreas Rimner Lee M Krug

J Thorac Oncol 2014 Mar;9(3):271-2

*Thoracic Service, Department of Surgery, †Department of Radiation Oncology, and ‡Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1097/JTO.0000000000000122DOI Listing
March 2014

Clinical characteristics of patients with malignant pleural mesothelioma harboring somatic BAP1 mutations.

Authors:
Marjorie G Zauderer Matthew Bott Robert McMillan Camelia S Sima Valerie Rusch Lee M Krug Marc Ladanyi

J Thorac Oncol 2013 Nov;8(11):1430-3

*Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York; †Department of Medicine, Weill Cornell Medical College, New York, New York; ‡Departments of Pathology, §Surgery, ‖Epidemiology and Biostatistics, ¶Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.

Introduction: Genomic studies of malignant pleural mesothelioma (MPM) have recently identified frequent mutations in the BRCA-associated protein 1(BAP1) gene. In uveal melanoma and clear cell renal cell carcinoma, BAP1 mutations are associated with poor outcomes but their clinical significance in MPM is unknown. We therefore undertook this study to define the characteristics of patients whose MPM tumors harbor somatic BAP1 mutation and to examine the relationship between BAP1 mutation and survival.

Methods: We reviewed the charts of 121 patients with MPM tumors diagnosed between 1991 and 2009 tested for BAP1 mutation, and extracted the following information: age at diagnosis, sex, histology, stage, smoking status, asbestos exposure, family or personal history of malignancy, and treatment including surgery, chemotherapy, and radiation as well as survival status.

Results: Twenty-four of the 121 tumors (20%) harbored somatic BAP1 mutations. The percentage of current or former smokers among cases with BAP1 mutations was significantly higher than in BAP1 wild-type cases, (75% versus 42%; p = 0.006). However, the types of nucleotide substitutions in BAP1 did not suggest that this association was because of a causative role of smoking in BAP1 mutations. No other clinical feature was significantly different among those with and without BAP1 mutations in their MPM. There was also no difference in survival according to somatic BAP1 mutation status.

Conclusion: There is no apparent distinct clinical phenotype for MPM with somatic BAP1 mutation. The significance of the more frequent history of smoking among patients with BAP1-mutated MPM warrants further study.
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http://dx.doi.org/10.1097/JTO.0b013e31829e7ef9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343301PMC
November 2013

Pleurectomy/decortication, chemotherapy, and intensity modulated radiation therapy for malignant pleural mesothelioma: rationale for multimodality therapy incorporating lung-sparing surgery.

Authors:
Marjorie G Zauderer Lee M Krug

Ann Cardiothorac Surg 2012 Nov;1(4):487-90

Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.

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http://dx.doi.org/10.3978/j.issn.2225-319X.2012.10.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741800PMC
November 2012

Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers.

Authors:
Jamie E Chaft Valerie Rusch Michelle S Ginsberg Paul K Paik David J Finley Mark G Kris Katharine A R Price Christopher G Azzoli Matthew G Fury Gregory J Riely Lee M Krug Robert J Downey Manjit S Bains Camelia S Sima Nabil Rizk William D Travis Naiyer A Rizvi

J Thorac Oncol 2013 Aug;8(8):1084-90

Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York 10065, USA.

Introduction: Bevacizumab improves survival in patients with advanced non-small-cell lung cancer (NSCLC). This phase II clinical trial assessed the effects of the addition of bevacizumab to neoadjuvant chemotherapy in resectable nonsquamous NSCLC.

Methods: Patients with resectable stage IB-IIIA nonsquamous NSCLC were treated with bevacizumab followed by imaging 2 weeks later to assess single-agent effect. After this they received two cycles of bevacizumab with four cycles of cisplatin and docetaxel followed by surgical resection. Resected patients were eligible for adjuvant bevacizumab. The primary endpoint was the rate of pathological downstaging (decrease from pretreatment clinical stage to post-treatment pathological stage). Secondary endpoints included overall survival, safety, and radiologic response.

Results: Fifty patients were enrolled. Thirty-four (68%) were clinical stage IIIA. All three doses of neoadjuvant bevacizumab were delivered to 40 of 50 patients. Six patients (12%) discontinued because of bevacizumab-related adverse events. The rate of downstaging (38%), response to chemotherapy (45%), and perioperative complications (12%) were comparable with historical data. No partial responses were observed to single-agent bevacizumab, but 18% of the patients developed new intratumoral cavitation, with a trend toward improved pathologic response (57% versus 21%; p = 0.07). A major pathologic response (≥90% treatment effect) was associated with survival at 3 years (100% versus 49%; p = 0.01). No patients with KRAS-mutant NSCLC (0 of 10) had a pathologic response as compared with 11 of 31 with wild-type KRAS.

Conclusion: Although preoperative bevacizumab plus chemotherapy was feasible, it did not improve downstaging in unselected patients. New cavitation after single-agent bevacizumab is a potential biomarker. Alternative strategies are needed for KRAS-mutant tumors.
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http://dx.doi.org/10.1097/JTO.0b013e31829923ecDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191830PMC
August 2013

Risk of hemoptysis in patients with resected squamous cell and other high-risk lung cancers treated with adjuvant bevacizumab.

Authors:
Matthew D Hellmann Jamie E Chaft Valerie Rusch Michelle S Ginsberg David J Finley Mark G Kris Katharine A R Price Christopher G Azzoli Matthew G Fury Gregory J Riely Lee M Krug Robert J Downey Manjit S Bains Camelia S Sima Nabil Rizk William D Travis Naiyer A Rizvi Paul K Paik

Cancer Chemother Pharmacol 2013 Aug 28;72(2):453-61. Epub 2013 Jun 28.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical School, 300 East 66th Street, New York, NY 10065, USA.

Purpose: Bevacizumab improves survival in lung adenocarcinomas. The potential anti-tumor benefit of bevacizumab in squamous cell lung cancers (SQCLCs) is unknown because bevacizumab is contraindicated in patients with advanced SQCLC due to an increased risk of hemoptysis. The risk of hemoptysis may be eliminated in patients with resected SQCLCs. We evaluated the safety of adjuvant bevacizumab in patients with resected SQCLCs and other lung cancers at high risk of hemoptysis.

Methods: As part of a prospective, phase II trial, patients with lung cancers at high risk of hemoptysis (defined by SQCLC histology, tumor near the central blood vessels, or history of hemoptysis) were treated with adjuvant bevacizumab following neo-adjuvant chemotherapy and complete surgical resection. Bevacizumab 15 mg/kg was given once every 3 weeks for up to 1 year. Patients were followed for safety and survival.

Results: Thirteen patients with high-risk features were treated: 7 patients had SQCLC, 3 had central tumors, and 3 had previous hemoptysis. No hemoptysis of any grade was seen following treatment with bevacizumab. Five of 13 patients experienced grade 1 bleeding (epistaxis, gum bleeding). Hypertension and lymphopenia were seen.

Conclusions: In a cohort of patients with resected lung cancers at high risk of hemoptysis, including those with SQCLC, treatment with adjuvant bevacizumab did not result in hemoptysis of any grade.
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http://dx.doi.org/10.1007/s00280-013-2219-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653739PMC
August 2013

Non-small cell lung cancer, version 2.2013.

Authors:
David S Ettinger Wallace Akerley Hossein Borghaei Andrew C Chang Richard T Cheney Lucian R Chirieac Thomas A D'Amico Todd L Demmy Ramaswamy Govindan Frederic W Grannis Stefan C Grant Leora Horn Thierry M Jahan Ritsuko Komaki Feng-Ming Spring Kong Mark G Kris Lee M Krug Rudy P Lackner Inga T Lennes Billy W Loo Renato Martins Gregory A Otterson Jyoti D Patel Mary C Pinder-Schenck Katherine M Pisters Karen Reckamp Gregory J Riely Eric Rohren Theresa A Shapiro Scott J Swanson

J Natl Compr Canc Netw 2013 Jun;11(6):645-53; quiz 653

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, USA.

These NCCN Guidelines Insights focus on the diagnostic evaluation of suspected lung cancer. This topic was the subject of a major update in the 2013 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer. The NCCN Guidelines Insights focus on the major updates in the NCCN Guidelines and discuss the new updates in greater detail.
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http://dx.doi.org/10.6004/jnccn.2013.0084DOI Listing
June 2013

Thymomas and thymic carcinomas: Clinical Practice Guidelines in Oncology.

Authors:
David S Ettinger Gregory J Riely Wallace Akerley Hossein Borghaei Andrew C Chang Richard T Cheney Lucian R Chirieac Thomas A D'Amico Todd L Demmy Ramaswamy Govindan Frederic W Grannis Stefan C Grant Leora Horn Thierry M Jahan Ritsuko Komaki Feng-Ming Spring Kong Mark G Kris Lee M Krug Rudy P Lackner Inga T Lennes Billy W Loo Renato Martins Gregory A Otterson Jyoti D Patel Mary C Pinder-Schenck Katherine M Pisters Karen Reckamp Eric Rohren Theresa A Shapiro Scott J Swanson

J Natl Compr Canc Netw 2013 May;11(5):562-76

Masses in the anterior mediastinum can be neoplasms (eg, thymomas, thymic carcinomas, or lung metastases) or non-neoplastic conditions (eg, intrathoracic goiter). Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare. Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymomas have 5-year survival rates of approximately 78%. However, 5-year survival rates for thymic carcinomas are only approximately 40%. These guidelines outline the evaluation, treatment, and management of these mediastinal tumors.
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http://dx.doi.org/10.6004/jnccn.2013.0072DOI Listing
May 2013

Toxicity of initial chemotherapy in older patients with lung cancers.

Authors:
Marjorie G Zauderer Camelia S Sima Beatriz Korc-Grodzicki Mark G Kris Lee M Krug

J Geriatr Oncol 2013 Jan;4(1):64-70

Objectives: Despite the growing number of elderly patientswith lung cancers,we lack adequate information about how best to treat them. A phase III trial demonstrated a survival benefit of doublet chemotherapy in elderly patients with lung cancers compared to single agents at the cost of increased toxicity. We undertook this study to identify and describe chemotherapyassociated toxicity patterns among elderly patients treated for lung cancers.

Materials And Methods: We reviewed records of patients age 70 or older with metastatic lung cancers who received initial chemotherapy at the Memorial Sloan-Kettering Cancer Center during 2008 and 2009.

Results: We identified 70 patients: 28 (40%) completed at least 4 cycles of chemotherapy without dose reduction but 31 (44%) required hospitalization for toxicity. Baseline albumin <3.5 g/dL and anemiawere associatedwith grade 3–5 chemotherapy-associated toxicity. Also, an increase in platelets from cycle 1 to cycle 2 was associated with chemotherapy-associated toxicity. No other statistically significant associations between chemotherapy-associated toxicity and putative biologic and functional risk factors, including age and performance status, were identified.

Conclusion: Patients deemed eligible for chemotherapy by their physicianswere just as likely to have severe chemotherapy-associated toxicity requiring hospitalization as to finish an initial course of therapy without any serious problems. An increase in platelet count from cycle 1 to cycle 2 was associated with increased toxicity. Additional research, such as exploration of inflammatory cytokines (PDGF, IL6, and IGF-1) to identify the mechanisms of chemotherapy tolerance and prospective evaluation and validation of existing metrics, is needed so that all patients can be appropriately risk stratified.
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http://dx.doi.org/10.1016/j.jgo.2012.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601754PMC
January 2013

Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors.

Authors:
Helena A Yu Camelia S Sima James Huang Stephen B Solomon Andreas Rimner Paul Paik M Catherine Pietanza Christopher G Azzoli Naiyer A Rizvi Lee M Krug Vincent A Miller Mark G Kris Gregory J Riely

J Thorac Oncol 2013 Mar;8(3):346-51

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.

Background: Development of acquired resistance limits the utility of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for the treatment of EGFR-mutant lung cancers. There are no accepted targeted therapies for use after acquired resistance develops. Metastasectomy is used in other cancers to manage oligometastatic disease. We hypothesized that local therapy is associated with improved outcomes in patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI.

Methods: Patients who received non-central nervous system local therapy were identified by a review of data from a prospective biopsy protocol for patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy and other institutional biospecimen registry protocols.

Results: Eighteen patients were identified, who received elective local therapy (surgical resection, radiofrequency ablation, or radiation). Local therapy was well tolerated, with 85% of patients restarting TKI therapy within 1 month of local therapy. The median time to progression after local therapy was 10 months (95% confidence interval [CI]: 2-27 months). The median time until a subsequent change in systemic therapy was 22 months (95% CI: 6-30 months). The median overall survival from local therapy was 41 months (95% CI: 26-not reached).

Conclusions: EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy are amenable to local therapy to treat oligometastatic disease when used in conjunction with continued EGFR inhibition. Local therapy followed by continued treatment with an EGFR TKI is well tolerated and associated with long PFS and OS. Further study in selected individuals in the context of other systemic options is required.
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http://dx.doi.org/10.1097/JTO.0b013e31827e1f83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673295PMC
March 2013

Non-small cell lung cancer.

Authors:
David S Ettinger Wallace Akerley Hossein Borghaei Andrew C Chang Richard T Cheney Lucian R Chirieac Thomas A D'Amico Todd L Demmy Apar Kishor P Ganti Ramaswamy Govindan Frederic W Grannis Leora Horn Thierry M Jahan Mohammad Jahanzeb Anne Kessinger Ritsuko Komaki Feng-Ming Kong Mark G Kris Lee M Krug Inga T Lennes Billy W Loo Renato Martins Janis O'Malley Raymond U Osarogiagbon Gregory A Otterson Jyoti D Patel Mary C Pinder-Schenck Katherine M Pisters Karen Reckamp Gregory J Riely

J Natl Compr Canc Netw 2012 Oct;10(10):1236-71

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

Most patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced cancer. These guidelines only include information about stage IV NSCLC. Patients with widespread metastatic disease (stage IV) are candidates for systemic therapy, clinical trials, and/or palliative treatment. The goal is to identify patients with metastatic disease before initiating aggressive treatment, thus sparing these patients from unnecessary futile treatment. If metastatic disease is discovered during surgery, then extensive surgery is often aborted. Decisions about treatment should be based on multidisciplinary discussion.
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http://dx.doi.org/10.6004/jnccn.2012.0130DOI Listing
October 2012

New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment.

Authors:
Marc Ladanyi Marjorie G Zauderer Lee M Krug Tatsuo Ito Robert McMillan Matthew Bott Filippo Giancotti

Clin Cancer Res 2012 Sep 23;18(17):4485-90. Epub 2012 Jul 23.

Departments of Pathology and Human Oncology & Pathogenesis Program, Surgery, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, NY 10065, USA.

Malignant pleural mesothelioma (MPM) is a highly lethal cancer with limited therapeutic options. Recent work has focused on the frequent somatic inactivation of two tumor suppressor genes in MPM-NF2 (Neurofibromatosis type 2) and the recently identified BAP1 (BRCA associated protein 1). In addition, germline mutations in BAP1 have been identified that define a new familial cancer syndrome, which includes MPM, ocular melanoma, and other cancers. These recent advances may allow screening of high-risk individuals and the development of new therapies that target key pathways in MPM.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-2375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432735PMC
September 2012