Search

Shirish Gadgeel,1 Alice T Shaw,2 Fabrice Barlesi,3 Lucio Crino,4 James CH Yang,5 Anne-Marie Dingemans,6 Dong-Wan Kim,7 Filippo de Marinis,8 Mathias Schulz,8 Shiyao Liu,9 Ravindra Gupta,9 Vlatka Smoljanovic,10 Sai-Hong Ignatius Ou11 1Department of Internal Medicine, Division of Hematology and Oncology, The University of Michigan, Ann Arbor, MI 48109, USA; 2Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA, USA; 3Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille 13005, France; 4Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Srl I.R.C.C.S., Meldola, FC 47014, Italy; 5National Taiwan University Hospital and National Taiwan University Cancer Centre, Taipei City, Taiwan; 6Department of Pulmonology, Maastricht University Medical Centre, Maastricht 6229 HX, The Netherlands; 7Department of Internal Medicine, Seoul National University Hospital, Jongno-Gu, Seoul 03080, South Korea; 8Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan 20146, Italy; 9Genentech Inc., South San Francisco, CA, USA; 10F. Hoffmann-La Roche Ltd., Basel CH-4070, Switzerland; 11Division of Hematology-Medical Oncology, Department of Internal Medicine, University of California, Irvine School of Medicine, Orange, CA 92617, USACorrespondence: Sai-Hong Ignatius OuUniversity of California, Irvine School of Medicine, 1001 Health Sciences Road, Irvine, Orange, CA 92617, USATel +1 714 456 8104Email siou@uci.eduIntroduction: Alectinib is a highly selective and potent ALK inhibitor, approved for the treatment of patients with metastatic ALK+ NSCLC based on results from the Phase II global NP28673 (NCT01801111) and North American NP28761 (NCT01871805) studies.Methods: This exploratory analysis of two Phase II studies of alectinib (NP28673/NP28761) investigated time to systemic response (TTR) and time to central nervous system (CNS) response (TTCR) in patients with previously treated advanced anaplastic lymphoma kinase fusion gene-positive (ALK+) non-small-cell lung cancer. Patients (n=225) received 600 mg oral alectinib twice daily and had scans every 6/8 weeks (NP28673/NP28761).Results: For NP28673 and NP28761, respectively: median follow-up was 21.3 months/17.0 months; most responders (72.6%/82.9%) responded by the first disease assessment; median TTR was 8 weeks (95% confidence interval [CI]: 8.00–8.14)/6 weeks (95% CI: 5.86–6.14); median TTCR in responders with measurable baseline CNS disease was 8 weeks (95% CI: 7.86–10.29)/6 weeks (95% CI: 5.71–not evaluable). Similar results were observed regardless of measurable/non-measurable disease.Discussion: These data suggest that alectinib achieves a rapid response in patients, both systemically and in the CNS.Keywords: alectinib, non-small-cell lung cancer, NP28673, NP28761, time to response

Misako Nagasaka,1,2 Nadine Abdallah,3 Marcus Crosby,4 Nithin Thummala,1 Dhaval Patel,1 Antoinette J Wozniak,5 Shirish Gadgeel,6 Judith Abrams,1 Ammar Sukari1 1Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; 2Department of Advanced Medical Innovations, St. Marianna University Graduate School of Medicine, Kawasaki, Japan; 3Department of Internal Medicine, Wayne State University, Detroit, MI, USA; 4Department of Radiation Oncology, Gundersen Health System, La Crosse, WI, USA; 5Department of Oncology, University of Pittsburgh, Pittsburgh, PA, USA; 6Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USACorrespondence: Ammar SukariDepartment of Oncology, Karmanos Cancer Institute, Wayne State University, 4100 John R, Detroit, MI 48201, USATel +1 313 576 8753Fax +1 313 576 8699Email sukaria@karmanos.orgIntroduction of hypothesis: Little information is available regarding the imaging characteristics that assist in differentiating responders from non-responders. We hypothesized that patients with higher pretreatment tumor volume (PTV) would have lower response rates and shorter overall survival (OS).Methods: Data from patients who received at least one dose of program death-1 (PD-1) inhibitors before August 31, 2016 were captured from our institution’s pharmacy database. The primary objective was to determine the association of PTV with best response, evaluated utilizing RECIST v1.1 criteria. Secondary objectives were estimation of progression-free survival (PFS) and OS. PTV was measured using the Philips Intellispace Multi-Modality Tumor Tracking application.Results: 116 non-small cell lung cancer (NSCLC) patients were evaluated. 66% patients had adenocarcinoma, 28% had squamous cell carcinoma and 5% had poorly differentiated NSCLC. Median PTV was 53.7 cm3 (95% CI: 13.3–107.9). Only one individual had no metastases and the remainder had M1 disease; 38% M1a, 10% M1b, 51% M1c. Most (79%) were previously treated. There were no complete responses; among those followed for at least 6 weeks, 26% had a partial response, 39% stable disease and 34% PD; 4% had no recorded response. There were no strong associations of PTV with any of the demographic or clinical characteristics. There was no association between PTV and OS (HR 1.2, P=0.26) or PFS (HR 1.1, P=0.47). Liver metastasis was associated with shorter survival (HR=2.8, P=0.05).Conclusion: PTV in NSCLC did not prove to be a predictor of response to PD-1 inhibitors but having liver metastasis was associated with significantly shorter survival.Keywords: non-small cell lung cancer, tumor volume, tumor burden, checkpoint inhibitors

Frank Weinberg, Shirish GadgeelDivision of Hematology and Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI, USAAbstract: Until recently, the treatment of patients with advanced non-small-cell lung cancer (NSCLC) whose tumors did not have a targetable genetic alteration was cytotoxic chemotherapy alone. This treatment provided only modest survival benefit. The introduction of immune checkpoint inhibitors targeting programmed cell death 1 protein (PD-1) signaling pathway in the treatment of patients with NSCLC has had significant effect on patient survival. Atezolizumab, nivolumab and pembrolizumab have been shown to be superior to chemotherapy in patients with recurrent NSCLC. Recently, pembrolizumab has been combined with chemotherapy in the front-line setting and has demonstrated an improvement in overall survival in NSCLC patients as compared to chemotherapy alone. In this review we will focus on the clinical trials that led to approval of combination pembrolizumab and chemotherapy as first-line treatment for patients with advanced NSCLC as well as discuss other combinations of immunotherapy and chemotherapy that have also been evaluated.Keywords: NSCLC, immunotherapy, chemotherapy, clinical trials

Jennifer L Beebe-Dimmer,1,2 Jon P Fryzek,3 Cecilia L Yee,1,2 Tapashi B Dalvi,4 David H Garabrant,3 Ann G Schwartz,1,2 Shirish Gadgeel1,2 1Department of Oncology, Wayne State University School of Medicine, 2Barbara Ann Karmanos Cancer Institute, Detroit, 3EpidStat Institute, Ann Arbor, MI, 4AstraZeneca, Gaithersburg, MD, USA Introduction: Mesothelioma is a rare malignancy typically associated with exposure to asbestos and poor survival. The purpose of this investigation was to describe mesothelioma patient characteristics, treatment patterns, and overall survival (OS) utilizing the National Cancer Institute’s Surveillance, Epidemiology, and End Results–Medicare database. Materials and methods: Patients in this study were diagnosed with malignant mesothelioma of the pleura or peritoneum between January 1, 2005 and December 31, 2009 with follow-up for survival through December 31, 2010. We examined both patient and tumor characteristics at time of diagnosis and subsequent treatment patterns (surgery, radiation, and chemotherapy). Among patients treated with chemotherapy, we determined chemotherapy regimen and OS by line of therapy. Results: Of the 1,625 patients considered eligible for this investigation, the median age at diagnosis was 78 years. Nearly a third of patients (30%) had surgery as part of their treatment and 45% were given chemotherapy. The median OS was 8 months (range 1–69 months). Among chemotherapy patients, the most commonly (67%) prescribed regimen for first-line therapy was cisplatin or carboplatin (Ca/Ci) combined with pemetrexed (Pe). Among those prescribed Ca/Ci + Pe as first-line therapy, retreatment with Ca/Ci + Pe (28%) or treatment with gemcitabine (30%) were the most common second-line therapies. Median OS for those receiving first-line chemotherapy was 7 months, and among those receiving second-line therapy median OS was extended an additional 5 months. Conclusion: Irrespective of surgical resection, mesothelioma patients receiving some form of chemotherapy survived longer than patients who did not, with an additional survival benefit among those patients receiving multimodal treatment. Keywords: mesothelioma, chemotherapy, epidemiology, outcomes, mortality, morbidity, survival

Amy M Weise, Shirish Gadgeel Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA Abstract: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease and a challenging malignancy to treat, as many patients have advanced disease at the time of diagnosis. Recent advances have led to the identification of molecularly defined subtypes of NSCLC, namely for patients with adenocarcinoma histology. The most recently identified molecular target is the anaplastic lymphoma kinase (ALK) gene rearrangement, and patient responses to the ALK inhibitor crizotinib have led to its approval in this selected patient population. Like other tyrosine kinase inhibitors, resistance to crizotinib ultimately develops by various mechanisms requiring alternative therapeutic options. This review article discusses the management of patients with the ALK gene rearrangement, mechanisms of crizotinib resistance, and future potential therapeutic options. Keywords: non-small-cell lung cancer, disease management, cancer therapy