DOCSLIB.ORG

Novedades En Cáncer De Pulmón Microcítico Y Mesotelioma Bartomeu Massutí [email protected] @Bmassutis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Novedades En Cáncer De Pulmón Microcítico Y Mesotelioma Bartomeu Massutí Bmassutis@Seom.Org @Bmassutis Novedades en cáncer de pulmón microcítico y mesotelioma Bartomeu Massutí [email protected] @bmassutis Indice Situación epidemiológica y resultados terapéuticos Carcinoma microcítico: estrategia terapéutica inicial Carcinoma microcítico e inmunoterapia Carcinoma microcitico pretratado Carcinoma microcítico: líneas de investigación Mesotelioma: líneas de investigación Epidemiology Worldwide age standardized mesothelioma incidence rates (per 100,000) for males in 1998–2002 SCLC 200.000 new cases/year 2/3 Stage IV Median Survival / Overall Survival 5 years (SEER) The WHO estimated that ≈ 107.000/y people in the world die from asbestos-related disease 1983-1992 1993-2003 2003-2012 EUROCARE-5 (2000-07): European mean pleural Cancers: 34.146 (Spain 226). 5y RS: 7.2% 7 months / 7 months / 7 months / 4.9% 5.9% 6.4% 2003: MPM CDDP/Pemetrexed Nothing new. No 2nd line EMPHACIS Current therapeutic strategy and outcomes for SCLC • 1L treatment for unresectable SCLC generally consists of Pt-doublet chemotherapy (±RT in LD) – Most patients relapse within 1 year of diagnosis, even when responsive to therapy – Treatment decisions in SCLC must often account for comorbidities due to smoking history • Outcomes improvement have relied on Radiotherapy • Five-year survival rates for patients with SCLC are poor – LS-SCLC: 10–13% – ES-SCLC: 1–2% • Historical lack of consensus for SOC treatment in 2L+ SCLC – Topotecan has limited efficacy in 2L setting (7% ORR) – Nivolumab monotherapy approved for 3L+ SCLC (USA, FDA) Genomic instability characteristic of SCLC Sabari et al., Nat Rev Clin Oncol. 2017 Immunotherapy DLL3 inhibitors Roval T Nocht inhibitors PARP inhibitors Aurora Kinase Veliparib Alisertib Methylation Sabari et al., Nat Rev Clin Oncol. 2017 0.5%-3.0% of patients with SCLC develop Lambert- Eaton syndrome, which involves an immune response to tumor antigens and nerve cells, and have a better prognosis, presumably due to the antitumor immune response Phase III CA184-156 trial randomized trial of platinum/ etoposide plus ipilimumab or placebo in 1L for ED-SCLC patients • No signal of efficacy was observed with the addition of ipilimumab • Toxicity was significantly higher (mainly diarrhea and rash) in the ipilimumab arm • Discontinuation rate was higher in the ipilimumab arm (18% vs 2%) Phase I/II CheckMate 032 trial: evaluation of nivolumab +/- ipilimumab in pretreated ED- SCLC population unselected for PD-L1 expression Key patient inclusion criteria Nivolumab 3 mg/kg IV q2w (n=40) •SCLC •Progressive disease Nivolumab 1 mg/kg + •≥1 prior therapy including ipilimumab 1 mg/kg IV first-line platinum-based q3w for 4 cycles (n=3) Nivolumab 3 mg/kg IV therapy Nivolumab 1 mg/kg + q2w •Unselected by PD-L1 ipilimumab 3 mg/kg IV expression q3w for 4 cycles (n=47) (n=128) Nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV q3w for 4 cycles (n=38) Primary endpoint • ORR per RECIST v1.1 Long-term sustained benefit is observed in some unselected ED- SCLC patients 100 Events / No. Median OS, Minimum follow-up, at risk months (95%CI) months Nivolumab 82/98 4.1 (3.0, 6.8) 19.6 80 Nivolumab + ipilimumab 47/61 7.8 (3.6, 14.2) 20.2 60 1-yr OS = 40% OS, % 40 2-yr OS = 26% 1-yr OS = 27% 20 2-yr OS = 14% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 No. at risk Time,months Nivolumab 98 56 39 35 26 21 17 12 7 7 5 4 4 0 Nivolumab + 61 43 33 26 24 21 19 16 14 7 3 1 1 0 ipilimumab 11.9% ORR Pooled analysis of activity of pembrolizumab as 3/+ line in advanced SCLC: Results from the KEYNOTE-028 and KEYNOTE-158 studies CPI in >Second Line SCLC N ORR(%) mPFS (months) mOS 1 -Year OS (%) Atezolizumab 49 2 1.4 9.5 NR (IFCT-1603)¹ Nivolumab (CM- 98 10 1.4 4.1 33 032)² Pembrolizumab 24 1.9 9.7 38 (KN-028)³ 33 (PD-L1+) Pembrolizumab 107 19 2 9.1 40 (KN-028)⁴ Atezolizumab 17 6 NA NA NA (PCD4989)⁵ Durvalumab⁶ 21 10 1.5 4.8 28 Nivolumab (CM- 284 14 1.4 7.8 37 331)⁷ ¹Pujol JTO 2019; ²Hellman ASCO 2017 abstr 8503; ³ Ott J Clin Oncol 2017; ⁴ Chung ASCO 2018 abstr 8506; ⁵ Goldaman Asco 2018 abstr 8518; ⁶Sequist ESMO 2017 abstr 1425; ⁷ Reck ESMO IO 2018 20 IMpower133: Global Phase 1/3, double-blind, randomized, placebo-controlled trial evaluated atezolizumab + carboplatin + etoposide in 1L ES-SCLC Patients (N = Induction (4 x 21-day cycles) Maintenance 403): • Measurable ES- Atezolizumab (1200 mg IV, Day 1) SCLC + carboplatin Atezolizumab (RECIST v1.1) + etoposide up - • ECOG PS 0 or 1 Treat until • No prior systemic R PD or loss 1:1 of clinical treatment for ES- benefit SCLC Placebo • Patients with treated + carboplatin Placebo follow Survival asymptomatic brain + etoposide metastases were eligible Carboplatin: AUC 5 mg/mL/min IV, Day 1 Etoposide: 100 mg/m2 IV, Days 1–3 PCI per local standard of care Stratification: • Sex (male vs. female) Co-primary end points: Key secondary end points: • ECOG PS (0 vs. 1) • Overall survival • Objective response rate • Investigator-assessed PFS • Duration of response • Brain metastases • Safety (yes vs. no)a a Only patients with treated brain metastases were eligible. ECOG PS, Eastern Cooperative Oncology Group Performance Status; IV, intravenous; PCI, prophylactic cranial irradiation; PD, progressive disease; PFS, progression-free survival; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumors. Baseline characteristics Atezolizumab + CP/ET Placebo + CP/ET Characteristic (N = 201) (N = 202) Median age (range) — years 64 (28−90) 64 (26−87) Age group — no. (%) < 65 years 111 (55) 106 (52) ≥ 65 years 90 (45) 96 (48) Male sex — no. (%)a 129 (64) 132 (65) Smoking statusb Current smoker 74 (36.8) 75 (37.1) Former smoker 118 (58.7) 124 (61.4) Race — no. (%) White 163 (81) 159 (79) Asian 33 (16) 36 (18) Other 5 (2) 7 (3) ECOG PS — no. (%)a 0 73 (36) 67 (33) 1 128 (64) 135 (67) Brain metastases — no. (%)a Yes 17 (8) 18 (9) Liver metastases — no. (%) Yes 77 (38) 72 (36) Clinical data cutoff date: April 24, 2018. a Data reported per electronic case report form. b Nine patients in the atezolizumab group and three patients in the placebo group have never smoked. CP/ET, carboplatin + etoposide. Overall survival Atezolizumab Placebo + CP/ET + CP/ET 100 (N = 201) (N = 202) OS events, n (%) 104 (51.7) 134 (66.3) 90 Median OS, 12.3 10.3 80 months (95% CI) (10.8, 15.9) (9.3, 11.3) 12-month OS 0.70 (0.54, 0.91) 70 HR (95% CI) p = 0.0069 60 51.7% Median follow-up, 13.9 monthsa 50 40 Atezolizumab 30 + CP/ET Overall survival (%) survival Overall 38.2% Placebo 20 + CP/ET 10 + Censored 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 No. at risk Months Atezolizumab 201 191 187 182 180 174 159 142 130 121 108 92 74 58 46 33 21 11 5 3 2 1 Placebo 202 194 189 186 183 171 160 146 131 114 96 81 59 36 27 21 13 8 3 3 2 2 a Clinical data cutoff date: April 24, 2018, 11 months after the last patient was enrolled. CI, confidence interval; HR, hazard ratio; CP/ET, carboplatin + etoposide. Investigator-assessed progression-free survival Atezolizumab Placebo 100 + CP/ET + CP/ET (N = 201) (N = 202) 90 PFS events, n (%) 171 (85.1) 189 (93.6) 80 Median PFS, 5.2 4.3 70 months (95% CI) (4.4, 5.6) (4.2, 4.5) 0.77 (0.62, 0.96) 60 HR (95% CI) 6-month PFS p = 0.017 50 Median follow-up, a 13.9 free survival (%) survival free months - 40 30.9% 12-month PFS Atezolizumab 30 + CP/ET Placebo 20 12.6% + CP/ET Progression 10 22.4% + Censored 5.4% 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 No. at risk Months Atezolizumab 201 190 178 158 147 98 58 48 41 32 29 26 21 15 12 11 3 3 2 2 1 1 Placebo 202 193 184 167 147 80 44 30 25 23 16 15 9 9 6 5 3 3 a Clinical data cutoff date: April 24, 2018, 11 months after the last patient was enrolled. CI, confidence interval; HR, hazard ratio; CP/ET, carboplatin + etoposide. Confirmed objective response and duration of response 70 Atezolizumab + CP/ET 60 Placebo + CP/ET Atezolizumab Placebo 50 + CP/ET + CP/ET Duration of response (N = 121) (N = 130) 40 Median duration, months 4.2 3.9 (range) (1.4a to 19.5) (2.0 to 16.1a) 30 HR (95% CI) 0.70 (0.53, 0.92) Response (%) Response 6-month event-free rate 32.2 17.1 20 — % 12-month event-free rate 14.9 6.2 10 — % Patients with ongoing 18 (14.9) 7 (5.4) 0 response — no. (%)b CR CR/PR SD PD a Censored. b At clinical cutoff date: April 24, 2018. CR, complete response; EFS, event-free survival; PD, progressive disease; PR, partial response; SD, stable disease. Overall survival in subgroups Median overall survival (months) OS hazard ratioa Population Atezolizumab + CP/ET Placebo + CP/ET (95% CI) Male (n = 261) 12.3 10.9 0.74 (0.54, 1.02) Female (n = 142) 12.5 9.5 0.65 (0.42, 1.00) < 65 years (n = 217) 12.1 11.5 0.92 (0.64, 1.32) ≥ 65 years (n = 186) 12.5 9.6 0.53 (0.36, 0.77) ECOG PS 0 (n = 140) 16.6 12.4 0.79 (0.49, 1.27) ECOG PS 1 (n = 263) 11.4 9.3 0.68 (0.50, 0.93) Brain metastases (n = 35) 8.5 9.7 1.07 (0.47, 2.43) No brain metastases (n = 368) 12.6 10.4 0.68 (0.52, 0.89) Liver metastases (n = 149) 9.3 7.8 0.81 (0.55, 1.20) No liver metastases (n = 254) 16.8 11.2 0.64 (0.45, 0.90) bTMB < 10 mut/mb (n = 139) 11.8 9.2 0.70 (0.45, 1.07) bTMB ≥ 10 mut/mb (n = 212) 14.6 11.2 0.68 (0.47, 0.97) bTMB < 16 mut/mb (n = 271) 12.5 9.9 0.71 (0.52, 0.98) bTMB ≥ 16 mut/mb (n = 80) 17.8 11.9 0.63 (0.35, 1.15) ITT (N = 403) 12.3 10.3 0.70 (0.54, 0.91) 0.1 1.0 2.5 Clinical data cutoff date: April 24, 2018.
Load more

Recommended publications
  • 02-09-2017 06:01:33Pm Esmo.Org Type
    08-09-2017 10:00 - 11:30 Type: Special Session Palma Title: Medical oncology as a contributor to global policy: How to improve national cancer Auditorium plans Chair(s): G. Curigliano, IT; L. Stevens, US 10:00 - 10:05 Introduction L. Stevens, Rio De Janeiro, BR 10:05 - 10:20 Overview of NCCP, including forming the multi-disciplinary and multi-sectoral partnership A. Ilbawi, Geneva, CH 10:20 - 10:35 Example from Central Asia Leadership Forum D. Kaidarova, Almaty, KZ 10:35 - 10:50 Example from Central Europe J. Jassem, Gdańsk, PL 10:50 - 11:05 Example from Eastern Europe S. Krasny, Minsk, BY 11:05 - 11:30 Interactive Q&A G. Curigliano, Milan, IT Last update: 02-09-2017 06:01:33pm esmo.org 12:00 - 13:30 Type: Opening session Madrid Auditorium Title: Opening session and Award lectures Chair(s): F. Ciardiello, IT 12:00 - 12:10 ESMO Presidential Address F. Ciardiello, Naples, IT 12:10 - 12:15 EACR Presidential Address A. Berns, Amsterdam, NL 12:15 - 12:20 Welcome to Madrid M. Martin Jimenez, Madrid, ES 12:20 - 12:25 ESMO 2017 Scientific Address A. Sobrero, Genova, IT 12:25 - 12:30 EACR 2017 Scientific Address R. Marais, Manchester, GB 12:30 - 12:32 Presentation of the ESMO Award by C. Zielinski, Vienna, AT 12:32 - 12:47 ESMO Award lecture - Oncology: The importance of teamwork M. Martin Jimenez, Madrid, ES 12:47 - 12:49 Presentation of the ESMO Translational Research Award by C. Zielinski, Vienna, AT 12:49 - 13:04 ESMO Translational Research Award lecture: Monitoring and targeting colorectal cancer evolution A.
    [Show full text]
  • Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy
    cancers Review Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy Laura Boyero 1 , Amparo Sánchez-Gastaldo 2, Miriam Alonso 2, 1 1,2,3, , 1,2, , José Francisco Noguera-Uclés , Sonia Molina-Pinelo * y and Reyes Bernabé-Caro * y 1 Institute of Biomedicine of Seville (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Seville, Spain; [email protected] (L.B.); [email protected] (J.F.N.-U.) 2 Medical Oncology Department, Hospital Universitario Virgen del Rocio, 41013 Seville, Spain; [email protected] (A.S.-G.); [email protected] (M.A.) 3 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain * Correspondence: [email protected] (S.M.-P.); [email protected] (R.B.-C.) These authors contributed equally to this work. y Received: 16 November 2020; Accepted: 9 December 2020; Published: 11 December 2020 Simple Summary: Immuno-oncology has redefined the treatment of lung cancer, with the ultimate goal being the reactivation of the anti-tumor immune response. This has led to the development of several therapeutic strategies focused in this direction. However, a high percentage of lung cancer patients do not respond to these therapies or their responses are transient. Here, we summarized the impact of immunotherapy on lung cancer patients in the latest clinical trials conducted on this disease. As well as the mechanisms of primary and acquired resistance to immunotherapy in this disease. Abstract: After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field.
    [Show full text]
  • 2017 Immuno-Oncology Medicines in Development
    2017 Immuno-Oncology Medicines in Development Adoptive Cell Therapies Drug Name Organization Indication Development Phase ACTR087 + rituximab Unum Therapeutics B-cell lymphoma Phase I (antibody-coupled T-cell receptor Cambridge, MA www.unumrx.com immunotherapy + rituximab) AFP TCR Adaptimmune liver Phase I (T-cell receptor cell therapy) Philadelphia, PA www.adaptimmune.com anti-BCMA CAR-T cell therapy Juno Therapeutics multiple myeloma Phase I Seattle, WA www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 "armored" CAR-T Juno Therapeutics recurrent/relapsed chronic Phase I cell therapy Seattle, WA lymphocytic leukemia (CLL) www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 CAR-T cell therapy Intrexon B-cell malignancies Phase I Germantown, MD www.dna.com ZIOPHARM Oncology www.ziopharm.com Boston, MA anti-CD19 CAR-T cell therapy Kite Pharma hematological malignancies Phase I (second generation) Santa Monica, CA www.kitepharma.com National Cancer Institute Bethesda, MD Medicines in Development: Immuno-Oncology 1 Adoptive Cell Therapies Drug Name Organization Indication Development Phase anti-CEA CAR-T therapy Sorrento Therapeutics liver metastases Phase I San Diego, CA www.sorrentotherapeutics.com TNK Therapeutics San Diego, CA anti-PSMA CAR-T cell therapy TNK Therapeutics cancer Phase I San Diego, CA www.sorrentotherapeutics.com Sorrento Therapeutics San Diego, CA ATA520 Atara Biotherapeutics multiple myeloma, Phase I (WT1-specific T lymphocyte South San Francisco, CA plasma cell leukemia www.atarabio.com
    [Show full text]
  • Antibody–Drug Conjugates: the Last Decade
    pharmaceuticals Review Antibody–Drug Conjugates: The Last Decade Nicolas Joubert 1,* , Alain Beck 2 , Charles Dumontet 3,4 and Caroline Denevault-Sabourin 1 1 GICC EA7501, Equipe IMT, Université de Tours, UFR des Sciences Pharmaceutiques, 31 Avenue Monge, 37200 Tours, France; [email protected] 2 Institut de Recherche Pierre Fabre, Centre d’Immunologie Pierre Fabre, 5 Avenue Napoléon III, 74160 Saint Julien en Genevois, France; [email protected] 3 Cancer Research Center of Lyon (CRCL), INSERM, 1052/CNRS 5286/UCBL, 69000 Lyon, France; [email protected] 4 Hospices Civils de Lyon, 69000 Lyon, France * Correspondence: [email protected] Received: 17 August 2020; Accepted: 10 September 2020; Published: 14 September 2020 Abstract: An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of. Keywords: antibody–drug conjugate; ADC; bioconjugation; linker; payload; cancer; resistance; combination therapies 1.
    [Show full text]
  • Antibodies for the Treatment of Brain Metastases, a Dream Or a Reality?
    pharmaceutics Review Antibodies for the Treatment of Brain Metastases, a Dream or a Reality? Marco Cavaco, Diana Gaspar, Miguel ARB Castanho * and Vera Neves * Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal * Correspondence: [email protected] (M.A.R.B.C.); [email protected] (V.N.) Received: 19 November 2019; Accepted: 28 December 2019; Published: 13 January 2020 Abstract: The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.
    [Show full text]
  • Cphi Annual Report 2018
    Part 4. The rise of the integrated CDMO and ‘ADCs the intersection of small and large’ CPhI Annual Industry Report 2018: Expert Contribution 52 CPhI Worldwide, October 2018, Madrid | Produced by Defacto PANEL MEMBER Vivek Sharma, CEO Piramal Pharma Solutions. ADCs growth driven by lack of inhouse facilities, oncology and integrated CDMOs Summary of trends forecast: the next 1-3 years • Novel payloads that target tumour-initiating cells on • Outsourcing of ADC manufacturing will continue to third generation ADCs in phase iii will come to market in rise past 70% of overall manufacturing, with increased the next couple of years co-development – driven by increased biotechs and • ADCs market forecast estimated to expand at nearly smaller companies in the pipeline needing specialist 20% CAGR until 2030 with 17 new drugs in late stage development expertise and facilities. development, and double digit approvals of ADCs over • Longer term (circa 5-years) the expansion of ADCs into next 3-years. therapeutic areas other than oncology will be the next evolution – bioconjugation in infectious disease is one potential area Abstract The past decade has seen significant advances in new and cancer cells. A strategy that combines the powerful cancer treatments through the development of highly cell-killing ability of potent cytotoxic agents with target selective small molecules that target a specific abnormality specificity would represent a potentially new paradigm in responsible for the disease. Traditional cytotoxic agents cancer treatment. Antibody Drug Conjugate (ADC) is such were another approach to treat cancer; however, unlike an approach, wherein the antibody component provides target-specific approaches, they suffered from adverse specificity for a tumour target antigen and the drug confers effects stemming from nonspecific killing of both healthy the cytotoxicity.
    [Show full text]
  • Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody–Drug Conjugate, in Relapsed/ Refractory B-Cell Non-Hodgkin Lymphoma Brad S
    Published OnlineFirst November 4, 2019; DOI: 10.1158/1078-0432.CCR-19-0711 Clinical Trials: Targeted Therapy Clinical Cancer Research A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody–Drug Conjugate, in Relapsed/ Refractory B-Cell Non-Hodgkin Lymphoma Brad S. Kahl1, Mehdi Hamadani2, John Radford3, Carmelo Carlo-Stella4, Paolo Caimi5, Erin Reid6, Jay M. Feingold7, Kirit M. Ardeshna8, Melhem Solh9, Leonard T. Heffner10, David Ungar7, Shui He7, Joseph Boni7, Karin Havenith11, and Owen A. O'Connor12 Abstract Purpose: ADCT-402 (loncastuximab tesirine) is an anti- 200 mg/kg. Treatment-emergent adverse events (TEAEs) were body–drug conjugate comprising a CD19-targeting antibody experienced by 87/88 (98.9%) patients. Most common TEAEs and pyrrolobenzodiazepine dimers. A first-in-human study (20% of patients) were hematologic abnormalities, fatigue, evaluated the safety and preliminary clinical activity of lon- edema, liver test abnormalities, nausea, rash, and dyspnea. castuximab tesirine in patients with B-cell non-Hodgkin lym- Grade 3 TEAEs (5% of patients) included hematologic phoma (NHL). abnormalities, liver test abnormalities, fatigue, and dyspnea. Experimental Design: A multicenter, phase I, dose- Overall response rate at doses 120 mg/kg was 59.4% (41 of 69 escalation and dose-expansion study enrolled patients ages patients; 40.6% complete response; 18.8% partial response). 18 years with relapsed/refractory (R/R) B-cell NHL. Patients Median duration of response, progression-free survival, and received loncastuximab tesirine every 3 weeks at doses overall survival (all doses) were 4.8, 5.5, and 11.6 months, assigned by a 3þ3 dose-escalation design.
    [Show full text]
  • Antibody–Drug Conjugates (Adcs) for Personalized Treatment of Solid Tumors: a Review
    Adv Ther DOI 10.1007/s12325-017-0519-6 REVIEW Antibody–Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review John M. Lambert . Charles Q. Morris Received: January 5, 2017 Ó The Author(s) 2017. This article is an open access publication ABSTRACT ADCs have advanced into pivotal clinical trials for treating various solid tumors—platinum-re- Attaching a cytotoxic ‘‘payload’’ to an antibody sistant ovarian cancer, mesothelioma, to form an antibody–drug conjugate (ADC) triple-negative breast cancer, glioblastoma, and provides a mechanism for selective delivery of small cell lung cancer. The level of target the cytotoxic agent to cancer cells via the expression is a key parameter in predicting the specific binding of the antibody to cancer-se- likelihood of patient benefit for all these ADCs, lective cell surface molecules. The first ADC to as well as for the approved compound, ado- receive marketing authorization was gem- trastuzumab emtansine. The development of a tuzumab ozogamicin, which comprises an patient selection strategy linked to target anti-CD33 antibody conjugated to a highly expression on the tumor is thus critically potent DNA-targeting antibiotic, calicheamicin, important for identifying the population approved in 2000 for treating acute myeloid appropriate for receiving treatment. leukemia. It was withdrawn from the US market in 2010 following an unsuccessful confirmatory trial. The development of two classes of highly Keywords: ADC; Antibody–drug conjugate; potent microtubule-disrupting agents, may- Auristatin; Calicheamicin; Cancer therapy; tansinoids and auristatins, as payloads for ADCs Maytansine; Monoclonal antibodies; Payload; resulted in approval of brentuximab vedotin in Oncology; Targeted drug delivery 2011 for treating Hodgkin lymphoma and anaplastic large cell lymphoma, and approval of ado-trastuzumab emtansine in 2013 for treating INTRODUCTION HER2-positive breast cancer.
    [Show full text]
  • Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer
    cancers Review Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer Arik Bernard Schulze * , Georg Evers, Andrea Kerkhoff, Michael Mohr, Christoph Schliemann, Wolfgang E. Berdel and Lars Henning Schmidt * Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany; [email protected] (G.E.); andrea.kerkhoff@ukmuenster.de (A.K.); [email protected] (M.M.); [email protected] (C.S.); [email protected] (W.E.B.) * Correspondence: [email protected] (A.B.S.); [email protected] (L.H.S.); Tel.: +49-251-83-44827 (L.H.S.) Received: 29 March 2019; Accepted: 14 May 2019; Published: 17 May 2019 Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13).
    [Show full text]
  • List Item Minutes of the COMP Meeting 19-21 April 2016 (PDF
    2 June 2016 EMA/COMP/278477/2016 Procedure Management and Committees Support Division Committee for Orphan Medicinal Products (COMP) Minutes for the meeting on 19-21 April 2016 Chair: Bruno Sepodes – Vice-Chair: Lesley Greene 19 April 2016, 09:00-18:30, room 2F 20 April 2016, 09:00-18:30, room 2F 21 April 2016, 08:30-12:30, room 2F Disclaimers Some of the information contained in this set of minutes is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the COMP meeting reports once the procedures are finalised. Of note, this set of minutes is a working document primarily designed for COMP members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the minutes cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on- going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006). 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2016.
    [Show full text]
  • Extrapulmonary Poorly Differentiated Necs, Including Molecular and Immune Aspects
    27 7 Endocrine-Related M G McNamara et al. EP-PD-NECs: molecular/ 27:7 R219–R238 Cancer immune landscape REVIEW Extrapulmonary poorly differentiated NECs, including molecular and immune aspects Mairéad G McNamara1,2, Jean-Yves Scoazec3,4 and Thomas Walter5 1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK 2Division of Cancer Sciences, University of Manchester, Manchester, UK 3Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France 4Université Paris Sud, Faculté de Médecine de Bicêtre, Le Kremlin-Bicêtre, France 5Department of Gastroenterology and Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France Correspondence should be addressed to M G McNamara: [email protected] Abstract Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas Key Words (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, f extra-pulmonary but the majority of patients present with advanced disease. Treatment strategies adopted f poorly differentiated are analogous to that of high grade NECs of the lung, with platinum/etoposide-based f neuroendocrine carcinoma regimens advocated in the first-line setting for advanced disease. There is no standard f treatment second-line therapy. Research into their molecular and immune pathways may pave the f molecular profile way for novel drug discovery. The molecular drivers of NEC are best identified in small cell f immune landscape lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder.
    [Show full text]
  • WO 2018/107109 Al 14 June 2018 (14.06.2018) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/107109 Al 14 June 2018 (14.06.2018) W !P O PCT (51) International Patent Classification: (74) Agent: MEIGS, Julie Broadus et al; Womble Bond A61K 39/395 (2006.01) C07K 14/705 (2006.01) Dickinson (US) LLP, P.O. Box 7037, Atlanta, Georgia A61K 47/48 (2006.01) C07K 16/28 (2006.01) 30357-0037 (US). A61P 35/00 (2006.01) C07K 16/30 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US20 17/065445 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 0 8 December 2017 (08.12.2017) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (25) Filing Language: English KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/432,050 0 9 December 20 16 (09. 12. 20 16) U S TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]