Oncology Commons^™

Tumor And Microenvironment Evolution During Immunotherapy With Nivolumab., Nadeem Riaz, Jonathan J Havel, Vladimir Makarov, Alexis Desrichard, Walter Urba, Jennifer S Sims, F Stephen Hodi, Salvador Martín-Algarra, Rajarsi Mandal, William H Sharfman, Shailender Bhatia, Wen-Jen Hwu, Thomas F Gajewski, Craig L Slingluff, Diego Chowell, Sviatoslav M Kendall, Han Chang, Rachna Shah, Fengshen Kuo, Luc G T Morris, John-William Sidhom, Jonathan P Schneck, Christine E Horak, Nils Weinhold, Timothy A Chan

Articles, Abstracts, and Reports

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific …

Efficacy And Safety Of Pembrolizumab In Patients Enrolled In Keynote-030 In The United States: An Expanded Access Program., Tara C Gangadhar, Wen-Jen Hwu, Michael A Postow, Omid Hamid, Adil Daud, Roxana Dronca, Richard Joseph, Steven J O'Day, F S Hodi, Anna C Pavlick, Harriet Kluger, Romina P Oxborough, Aiming Yang, Mihaela Gazdoiu, Debra A Kush, Scot Ebbinghaus, April K S Salama

Articles, Abstracts, and Reports

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. …

Oncolog, Volume 62, Number 11-12, November - December 2017, Joe Munch, Bryan Tutt

OncoLog MD Anderson's Report to Physicians (All issues)

• Managing Chemotherapy-Induced Neuropathy: Neuromodulation, pharmacological treatments show promise against peripheral neuropathy in cancer patients.
• Treating Tobacco Addiction: MD Anderson provides pharmacotherapy, counseling to help smokers quit plus cessation education, resources for community practitioners
• HOUSE CALL: Smoking-Related Cancers- Cancer risks from tobacco are not limited to the lungs, but quitting reduces these risks

Oncolog, Volume 62, Number 10, October 2017, Sarah Bronson, Bryan Tutt

OncoLog MD Anderson's Report to Physicians (All issues)

• Organ-Sparing Therapy for Esophageal Cancer: Endoscopic surgery, ablation treat early-stage cancer, dysplasia while avoiding esophagectomy.
• INBRIEF: Surgeons Perform Unique Allogeneic Soft Tissue Transplant Between Identical Twins
• Advances in Breast Reconstruction: New reconstruction techniques increase breast cancer surgical options, improve cosmetic outcomes.
• HOUSE CALL: Facing the Financial Burden of Cancer Treatment-Talking to care team, seeking out resources are important steps in managing cancer-related financial stress
• INBRIEF: Proton Therapy plus Chemotherapy Shows Promise in Lung Cancer Trial

Neurological Improvement Of Perineural And Leptomeningeal Spread Of Squamous Cell Carcinoma Treated With Intrathecal Chemotherapy And Systemic Egfr Inhibition., Vincent Alexander Van Vugt, Marlon Garzo Saria, Andres Javier, Navin Kesari, Tiffany Turpin, Santosh Kesari

Articles, Abstracts, and Reports

Squamous cell carcinoma (SCC) is a common cancer of the skin. Risk factors include fair skin, excessive sun and ultraviolet light exposure, and history of xeroderma pigmentosa. Perineural invasion (PNI), an uncommon manifestation of SCC, involves microscopic tumor cells invading various layers of the nerve sheath. It is associated with a poorer prognosis. Standard treatment for PNI includes radiation therapy. Here, we describe a case an older gentleman with a history of SCC with PNI successfully treated with erlotinib and intrathecal chemotherapy.

Ibrutinib Unmasks Critical Role Of Bruton Tyrosine Kinase In Primary Cns Lymphoma., Christian Grommes, Alessandro Pastore, Nicolaos Palaskas, Sarah S. Tang, Carl Campos, Derrek Schartz, Paolo Codega, Donna Nichol, Owen Clark, Wan-Ying Hsieh, Dan Rohle, Marc Rosenblum, Agnes Viale, Viviane S. Tabar, Cameron W. Brennan, Igor T. Gavrilovic, Thomas J. Kaley, Craig P. Nolan, Antonio Omuro, Elena Pentsova, Alissa A. Thomas, Elina Tsyvkin, Ariela Noy, M. Lia Palomba, Paul Hamlin, Craig S. Sauter, Craig H. Moskowitz, Julia Wolfe, Ahmet Dogan, Minhee Won, Jon Glass, Scott Peak, Enrico C. Lallana, Vaios Hatzoglou, Anne S. Reiner, Philip H. Gutin, Jason T. Huse, Katherine S. Panageas, Thomas G. Graeber, Nikolaus Schultz, Lisa M. Deangelis, Ingo K. Mellinghoff

Department of Neurology Faculty Papers

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated …

Hematologic Toxicity Of Concurrent Administration Of Radium-223 And Next-Generation Antiandrogen Therapies., Tu Dan, Harriet B. Eldredge-Hindy, Jean Hoffman-Censits, Jianqing Lin, William K. Kelly, Leonard G. Gomella, Costas D. Lallas, Edouard J. Trabulsi, Mark D. Hurwitz, Adam P. Dicker, Robert B. Den

Department of Radiation Oncology Faculty Papers

PURPOSE/OBJECTIVES: Radium-223 is a first-in-class radiopharmaceutical recently approved for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases. Initial studies investigating Radium-223 primarily used nonsteroidal first-generation antiandrogens. Since that time, newer antiandrogen therapies have demonstrated improved survival in patients with castration-resistant prostate cancer. It has been suggested that the rational combination of these newly approved agents with Radium-223 may lead to improved response rates and clinical outcomes. Currently, there is lack of information regarding the safety of concurrent administration of these agents with radiopharmaceuticals. Here, we report on hematologic toxicity findings from our institution in patients receiving …

Oncolog, Volume 62, Number 08, August 2017, Bryan Tutt, Sarah Bronson

OncoLog MD Anderson's Report to Physicians (All issues)

• Immunotherapy for Smoldering Myeloma: Clinical trials test PD-1, DC38 inhibitors to delay progression from premalignant disease to multiple myeloma.
• Malignant Pheochromocytoma and Sympathetic Paraganglioma Research: Studies may expand treatment options for patients with rare neuroendocrine tumors.
• Hypofractionated Partial-Breast Irradiation: Clinical trial tests 10-day external-beam radiation therapy regimen after lumpectomy for patients with early-stage breast cancer.
• HOUSE CALL: Support for Cancer Patients: Patients, caregivers find many types of support from various organizations

A Tnf-Jnk-Axl-Erk Signaling Axis Mediates Primary Resistance To Egfr Inhibition In Glioblastoma., Gao Guo, Ke Gong, Sonia Ali, Neha Ali, Shahzad Shallwani, Kimmo J Hatanpaa, Edward Pan, Bruce Mickey, Sandeep Burma, David H Wang, Santosh Kesari, Jann N Sarkaria, Dawen Zhao, Amyn A Habib

Articles, Abstracts, and Reports

Aberrant epidermal growth factor receptor (EGFR) signaling is widespread in cancer, making the EGFR an important target for therapy. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition has not been effective in treating this tumor. Here we propose that primary resistance to EGFR inhibition in glioma cells results from a rapid compensatory response to EGFR inhibition that mediates cell survival. We show that in glioma cells expressing either EGFR wild type or the mutant EGFRvIII, EGFR inhibition triggers a rapid adaptive response driven by increased tumor necrosis factor (TNF) secretion, which leads to activation in …

Adjuvant Radiation Therapy, Androgen Deprivation, And Docetaxel For High-Risk Prostate Cancer Postprostatectomy: Results Of Nrg Oncology/Rtog Study 0621., Mark D. Hurwitz, Jonathan Harris, Oliver Sartor, Ying Xiao, Bobby Shayegan, Paul W. Sperduto, Kasra R. Badiozamani, Colleen A.F. Lawton, Eric M. Horwitz, Jeff M. Michalski, Kevin Roof, David C. Beyer, Qiang Zhang, Howard M. Sandler

Department of Radiation Oncology Faculty Papers

BACKGROUND: Phase 3 trials have demonstrated a benefit from adjuvant radiation therapy (ART) for men who have adverse factors at radical prostatectomy (RP). However, some patients have a high risk of progression despite ART. The role of systemic therapy with ART in this high-risk group remains to be defined.

METHODS: Patients who had either a post-RP prostate-specific antigen (PSA) nadir > 0.2 ng/mL and a Gleason score ≥7 or a PSA nadir ≤0.2 ng/mL, a Gleason score ≥8, and a pathologic tumor (pT) classification ≥ pT3 received 6 months of androgen-deprivation therapy (ADT) plus radiotherapy and 6 cycles of docetaxel. The …

Oncolog, Volume 62, Number 07, July 2017, Joe Munch, Bryan Tutt

OncoLog MD Anderson's Report to Physicians (All issues)

• RAS Mutations and Colorectal Cancer Liver Metastases: Gene mutations may have implications for local therapy for liver metastases from colorectal cancer.
• Active Surveillance for Prostate Cancer: Clinical trial may clarify which patients with prostate cancer will benefit from active surveillance rather than immediate treatment.
• Gut Microbiome May Affect Immunotherapy Response in Melanoma: Metastatic melanoma patients who experience responses to checkpoint inhibitors have a distinct gut bacterial genetic signature.
• HOUSE CALL: Cancer-Related fatigue-Tips for fighting fatigue

Lisinopril Or Coreg Cr In Reducing Cardiotoxicity In Women With Breast Cancer Receiving Trastuzumab: A Rationale And Design Of A Randomized Clinical Trial, Maya Guglin, Pamela Munster, Angelina Fink, Jeffrey Krischer

Internal Medicine Faculty Publications

Background—Trastuzumab (TZB) is an established therapy for HER2 positive breast cancer. The use of TZB is commonly associated with cardiotoxicity manifesting as asymptomatic decrease in left ventricular ejection fraction (LVEF) or overt heart failure. Several studies demonstrated favorable effects of angiotensin converting enzyme (ACE) inhibitors and beta blockers (BB) in the prevention of chemotherapy-induced cardiotoxicity. We hypothesize that patients, randomized to receive an ACE inhibitor or a beta-blocker during trastuzumab therapy for breast cancer, will maintain a higher LVEF than patients randomized to placebo.

Methods and Results—We designed a prospective, multicenter, randomized, phase II placebo-controlled clinical trial to …

Molecular-Based Recursive Partitioning Analysis Model For Glioblastoma In The Temozolomide Era: A Correlative Analysis Based On Nrg Oncology Rtog 0525., Erica Hlavin Bell, Stephanie L Pugh, Joseph P. Mcelroy, Mark R. Gilbert, Minesh Mehta, Alexander C Klimowicz, Anthony Magliocco, Markus Bredel, Pierre Robe, Anca L. Grosu, Roger Stupp, Walter Curran, Aline P. Becker, Andrea L. Salavaggione, Jill S. Barnholtz-Sloan, Kenneth Aldape, Deborah T. Blumenthal, Paul D. Brown, Jon Glass, Luis Souhami, R. Jeffrey Lee, David Brachman, John Flickinger, Minhee Won, Arnab Chakravarti

Department of Neurosurgery Faculty Papers

Importance: There is a need for a more refined, molecularly based classification model for glioblastoma (GBM) in the temozolomide era.

Objective: To refine the existing clinically based recursive partitioning analysis (RPA) model by incorporating molecular variables.

Design, Setting, and Participants: NRG Oncology RTOG 0525 specimens (n = 452) were analyzed for protein biomarkers representing key pathways in GBM by a quantitative molecular microscopy-based approach with semiquantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multimarker Cox regression analyses. To reclassify the prognostic risk groups, significant protein biomarkers on single-marker analysis were incorporated into an RPA model …

Impact Of Ibrutinib Dose Adherence On Therapeutic Efficacy In Patients With Previously Treated Cll/Sll., Paul M Barr, Jennifer R Brown, Peter Hillmen, Susan O'Brien, Jacqueline C Barrientos, Nishitha M Reddy, Steven Coutre, Stephen P Mulligan, Ulrich Jaeger, Richard R Furman, Florence Cymbalista, Marco Montillo, Claire Dearden, Tadeusz Robak, Carol Moreno, John M Pagel, Jan A Burger, Samuel Suzuki, Juthamas Sukbuntherng, George Cole, Danelle F James, John C Byrd

Articles, Abstracts, and Reports

Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ∼9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. …

Dysregulated Gpcr Signaling And Therapeutic Options In Uveal Melanoma., Vivian Chua, Dominic Lapadula, Clinita Randolph, Jeffrey L. Benovic, Philip B. Wedegaertner, Andrew E. Aplin

Department of Biochemistry and Molecular Biology Faculty Papers

Uveal melanoma is the most common primary intraocular malignant tumor in adults and arises from the transformation of melanocytes in the uveal tract. Even after treatment of the primary tumor, up to 50% of patients succumb to metastatic disease. The liver is the predominant organ of metastasis. There is an important need to provide effective treatment options for advanced stage uveal melanoma. To provide the preclinical basis for new treatments, it is important to understand the molecular underpinnings of the disease. Recent genomic studies have shown that mutations within components of G protein-coupled receptor (GPCR) signaling are early events associated …

A Phase Ib/Ii Study Of Cabozantinib (Xl184) With Or Without Erlotinib In Patients With Non-Small Cell Lung Cancer., Heather A Wakelee, Scott Gettinger, Jeffrey Engelman, Pasi A Jänne, Howard J. West, Deepa S Subramaniam, Joseph Leach, Michael Wax, Yifah Yaron, Dale R Miles, Primo N Lara

Articles, Abstracts, and Reports

PURPOSE: Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.

METHODS: This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent …

Oncolog, Volume 62, Number 04, April 2017, Bryan Tutt, Sarah Bronson

OncoLog MD Anderson's Report to Physicians (All issues)

• Advances in Surgical Management of Lymphedema: New options reduce edema in limbs, improve quality of life for cancer patients with lymphedema.
• Noncytotoxic First-Line Therapy for Mantle Cell Lymphoma: First-line therapy with targeted and immunotherapy agents produces high response rates in mantle cell lymphoma.
• Reports from the Survivorship Research Symposium: Research on BK virus, heart failure, and aspiration in cancer survivors.
• HOUSE CALL: Types of Immunotherapy for Cancer: Understanding different approaches to immunotherapy

Phase I First-In-Human Study Of Venetoclax In Patients With Relapsed Or Refractory Non-Hodgkin Lymphoma., Matthew S Davids, Andrew W Roberts, John F Seymour, John M Pagel, Brad S Kahl, William G Wierda, Soham Puvvada, Thomas J Kipps, Mary Ann Anderson, Ahmed Hamed Salem, Martin Dunbar, Ming Zhu, Franklin Peale, Jeremy A Ross, Lori Gressick, Monali Desai, Su Young Kim, Maria Verdugo, Rod A Humerickhouse, Gary B Gordon, John F Gerecitano

Articles, Abstracts, and Reports

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included …

Co-Targeting Hgf/Cmet Signaling With Mek Inhibitors In Metastatic Uveal Melanoma., Hanyin Cheng, Vivian Chua, Connie Liao, Timothy J. Purwin, Mizue Terai, Ken Kageyama, Michael A. Davies, Takami Sato, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a …

Impact Of Sequencing Targeted Therapies With High-Dose Interleukin-2 Immunotherapy: An Analysis Of Outcome And Survival Of Patients With Metastatic Renal Cell Carcinoma From An On-Going Observational Il-2 Clinical Trial: Proclaim, Joseph I Clark, Michael K K Wong, Howard L Kaufman, Gregory A Daniels, Michael A Morse, David F Mcdermott, Sanjiv S Agarwala, Lionel D Lewis, John H Stewart, Ulka Vaishampayan, Brendan Curti, René Gonzalez, Jose Lutzky, Venkatesh Rudraptna, Lee D Cranmer, Joanne M Jeter, Ralph J Hauke, Gerald Miletello, Mohammed M Milhem, Asim Amin, John M Richart, Mayer Fishman, Sigrun Hallmeyer, Sapna P Patel, Peter Van Veldhuizen, Neeraj Agarwal, Bret Taback, Jonathan S Treisman, Marc S Ernstoff, Jessica C Perritt, Hong Hua, Tharak B Rao, Janice P Dutcher, Sandra Aung

Articles, Abstracts, and Reports

BACKGROUND: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2).

PATIENTS AND METHODS: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin

RESULTS: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an …