First-in-human, open-label, phase 1/2 study of the monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor cetrelimab (JNJ-63723283) in patients with advanced cancers

PURPOSE: To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study. METHODS: In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability-high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter. RESULTS: In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (C CONCLUSIONS: The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors. TRIAL REGISTRATIONS: NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016-002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017

Management of patients with advanced non-small cell lung cancer: role of gefitinib

Vamsidhar Velcheti1, Daniel Morgensztern2,3,4, Ramaswamy Govindan3,41Department of Internal Medicine, Ochsner Clinic Foundation, New Orleans, LA, USA; 2Division of Hematology-Oncology, St. Louis Veterans Hospital, St. Louis, MO, USA; 3Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA; 4Alvin J Siteman Cancer Center, St. Louis, MO, USAAbstract: Gefitinib is the first epidermal growth factor receptor tyrosine-kinase inhibitor approved for the treatment of advanced non-small cell lung cancer (NSCLC). Its failure to improve survival in a placebo-control study, however, led to its withdrawal in the United States though it is available in many other countries Subsequent studies nevertheless showed comparable efficacy for gefitinib and docetaxel in the second-line therapy. Gefitinib significantly improved progression-free survival compared to chemotherapy in patients with activating mutations in the epidermal growth factor receptor tyrosine kinase mutations. This review will discuss the results of these large randomized studies and discuss the role of gefitinib in the treatment of advanced NSCLC.Keywords: gefitinib, non-small cell lung cance

A phase 1-2 study of rovalpituzumab tesirine in combination with nivolumab plus or minus ipilimumab in patients with previously treated extensive-stage SCLC

INTRODUCTION: This open-label, phase 1-2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). METHODS: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. RESULTS: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. CONCLUSIONS: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated

Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer

PURPOSE: The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with METHODS: In this ongoing, open-label, single-arm, phase II study, patients with RESULTS: At data cutoff, 98 patients (59 treatment-naïve and 39 previously treated) with CONCLUSION: For patients with treatment-naïve and previously treate

Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-Met protein-expressing non-small-cell lung cancer

PURPOSE: Overexpression of c-Met protein and epidermal growth factor receptor ( PATIENTS AND METHODS: This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an RESULTS: As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8 to not reached). ORR for CONCLUSION: Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR TKI-pretreated patients wit

Summary of Presentations from the 46th Annual Meeting of the American Society of Clinical Oncology (2010) Focus on Tumor Biology and Biomarkers Related to Lung Cancer

Abstract:Globally, lung cancer remains the most common cause of cancer-related death. In recent years, it has become clear that development of rational molecular targeted therapies is critical to improve the outcomes of patients with lung cancer. A better understanding of the tumor biology is crucial to achieve this goal. Several new findings in the field of tumor biology were presented at the 46th Annual Meeting of the American Society of Clinical Oncology. Novel genetic mutations were identified in pleural mesothelioma using array-based technologies. Several studies on the development and testing of new molecular diagnostic tests to detect epidermal growth factor receptor tyrosine kinase mutations and EML4-ALK (Echinoderm Microtubule-associated Protein like 4 Anaplastic Lymphoma Receptor Tyrosine Kinase) fusion gene were presented as well

Improving Survival for Stage IV Non-small Cell Lung Cancer: A Surveillance, Epidemiology, and End Results Survey from 1990 to 2005

BackgroundAlthough there has been a significant survival improvement for patients with metastatic NSCLC enrolled in randomized trials, it is not clear whether a similar benefit is seen in an unselected group of patients. Therefore, we conducted a study to evaluate for survival changes in a large national cancer registry database.Patients and MethodsThe Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients with NSCLC stage IV, aged 21 years or older, and diagnosed between 1990 and 2005. We analyzed four equally divided time periods between 1990 and 2005 (1990 to 1993 or period 1, 1994 to 1997 or period 2, 1998 to 2001 or period 3, and 2002 to 2005 or period 4) to determine changes in overall survival for all patients and according to histology.ResultsWe identified 129,337 patients meeting eligibility criteria. There was a significant improvement in overall survival since period 1. One-year and 2-year overall survival increased from 13.2 and 4.5%, respectively, in period 1 to 19.4% and 7.8%, respectively, in period 4. On multivariate analysis, survival for adenocarcinoma was increased compared with squamous cell carcinoma only in period 4 (p = 0.02).ConclusionsThere has been a modest but statistically significant improvement in overall survival for stage IV NSCLC over the past 16 years. The recent differences in outcomes based on histology observed in period 4 may reflect the increased activity of epidermal growth factor receptor tyrosine kinase inhibitors in adenocarcinoma compared with squamous cell carcinoma

Phase I trial of the DLL3/CD3 bispecific T-cell engager BI 764532 in DLL3-positive small-cell lung cancer and neuroendocrine carcinomas

T-cell engager; Eeuroendocrine carcinoma; Small-cell lung cancerAcoplador de cèl·lula T; Carcinoma neuroendocrí; Càncer de pulmó de cèl·lules petitesAcoplador de célula T; Carcinoma neuroendocrino; Cáncer de pulmón de células pequeñasPoorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy.This study was funded by Boehringer Ingelheim. M Wermke received honoraria from Novartis, Pfizer, Roche, Lilly; reports consulting or advisory role for Bristol-Myers Squibb, Novartis, Pfizer, Cellex GmbH, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, GEMoaB, Roche, MSD, AstraZeneca, Amgen, Immatics; received research funding from Roche; travel, accommodations, expenses from Pfizer, Bristol-Myers Squibb, AstraZeneca, Roche Amgen, GEMoaB. E Felip received personal fees for advisory boards from AbbVie, Guardant Health, Janssen, Medscape, Merck KGaA, GlaxoSmithKline, Bayer; advisory board and speakers' bureau fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; speakers' bureau fees from Prime Oncology, Touchime; research funding from Grant for Oncology Innovation (GOI), Fundacion Merck Salud; Grífols: independent member of the board. Y Kuboki received honoraria from Taiho, ONO, Bayer, Sanofi; consulting fees from Takeda, Boehringer Ingelheim, Taiho; grants or funds from Taiho, Takeda, ONO, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GSK, Genmab, Astellas, Daiichi-Sankyo. D Morgensztern received consulting fees from AbbVie, Gilead, PharmaMar, Lilly, Bristol-Myers Squibb, G1 Therapeutics, Mirati, Boehringer Ingelheim. ZO' Hamed, M Liu and M Studeny report employment with Boehringer Ingelheim. TK Owonikoko received consulting fees from Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, XCovery, Bayer, Heron Pharmaceutical, ARMO BioSciences, Merck, Bayer, Jazz Pharmaceuticals; and research funding from Novartis, Astellas Pharma, Bayer, StemCentRx, Regeneron, AstraZeneca/MedImmune, AbbVie, G1 Therapeutics, Bristol-Myers, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Mersana, Turning Point, and Oncorus. V Gambardella reports no conflicts of interest. All authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and did not receive payment related to the development of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed