Medical Abstracts ( IF > 20 )

1. Science. 2020 Apr 23:eaba9102. doi: 10.1126/science.aba9102. Online ahead of

print.

Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug

ethambutol.

Zhang L(#)(1)(2), Zhao Y(#)(1)(3)(4), Gao Y(5), Wu L(1), Gao R(4)(6), Zhang

Q(1), Wang Y(1)(4), Wu C(1), Wu F(2), Gurcha SS(7), Veerapen N(7), Batt SM(7),

Zhao W(2), Qin L(1), Yang X(1), Wang M(1), Zhu Y(1), Zhang B(1), Bi L(6), Zhang

X(6), Yang H(1), Guddat LW(8), Xu W(1), Wang Q(9)(6), Li J(9), Besra GS(10), Rao

Z(9)(2)(5)(6).

Author information:

(1)Shanghai Institute for Advanced Immunochemical Studies, iHuman Institute,

School of Life Science and Technology, ShanghaiTech University, Shanghai,

201210, China.

(2)State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center

for Cell Response, College of Life Sciences, College of Pharmacy, Nankai

University, Tianjin 300353, China.

(3)CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of

Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031,

China. …

The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium

tuberculosis cell wall synthesis and are recognized as the targets for the

anti-tuberculosis drug ethambutol. We have determined cryo-electron microscopy

and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC complexes,

in the presence of their glycosyl donor and acceptor substrates and with

ethambutol. These structures show how the donor and acceptor substrates bind in

the active site and how ethambutol inhibits by binding to the same site as both

substrates in EmbB and EmbC. The majority of drug-resistant mutations are

located nearby to the ethambutol-binding site. Collectively, our work provides a

structural basis for understanding the biochemical function and inhibition of

arabinosyltransferases and development of new anti-tuberculosis agents.

Copyright © 2020, American Association for the Advancement of Science.

DOI: 10.1126/science.aba9102

PMID: 32327601

2. Nat Biotechnol. 2020 Apr 27. doi: 10.1038/s41587-020-0505-4. Online ahead of print.

Analyzing the Mycobacterium tuberculosis immune response by T-cell receptor

clustering with GLIPH2 and genome-wide antigen screening.

Huang H(1), Wang C(1), Rubelt F(1), Scriba TJ(2), Davis MM(3)(4)(5).

Author information:

(1)Institute for Immunity, Transplantation and Infection, Stanford University

School of Medicine, Stanford, CA, USA.

(2)South African Tuberculosis Vaccine Initiative, Institute of Infectious

Disease and Molecular Medicine and Division of Immunology, Department of

Pathology, University of Cape Town, Cape Town, South Africa.

(3)Institute for Immunity, Transplantation and Infection, Stanford University

School of Medicine, Stanford, CA, USA. mmdavis@stanford.edu.

(4)Department of Microbiology and Immunology, Stanford University School of

Medicine, Stanford, CA, USA. mmdavis@stanford.edu.

(5)The Howard Hughes Medical Institute, Stanford University School of Medicine,

Stanford, CA, USA. mmdavis@stanford.edu.

CD4+ T cells are critical to fighting pathogens, but a comprehensive analysis of

human T-cell specificities is hindered by the diversity of HLA alleles (>20,000)

and the complexity of many pathogen genomes. We previously described GLIPH, an

algorithm to cluster T-cell receptors (TCRs) that recognize the same epitope and

to predict their HLA restriction, but this method loses efficiency and accuracy

when >10,000 TCRs are analyzed. Here we describe an improved algorithm, GLIPH2,

that can process millions of TCR sequences. We used GLIPH2 to analyze 19,044

unique TCRβ sequences from 58 individuals latently infected with Mycobacterium

tuberculosis (Mtb) and to group them according to their specificity. To identify

the epitopes targeted by clusters of Mtb-specific T cells, we carried out a

screen of 3,724 distinct proteins covering 95% of Mtb protein-coding genes using

artificial antigen-presenting cells (aAPCs) and reporter T cells. We found that

at least five PPE (Pro-Pro-Glu) proteins are targets for T-cell recognition in

Mtb.

DOI: 10.1038/s41587-020-0505-4

PMID: 32341563

3. N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004407. Online ahead of print.

Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.

Paik PK(1), Felip E(1), Veillon R(1), Sakai H(1), Cortot AB(1), Garassino MC(1),

Mazieres J(1), Viteri S(1), Senellart H(1), Van Meerbeeck J(1), Raskin J(1),

Reinmuth N(1), Conte P(1), Kowalski D(1), Cho BC(1), Patel JD(1), Horn L(1),

Griesinger F(1), Han JY(1), Kim YC(1), Chang GC(1), Tsai CL(1), Yang JC(1), Chen

YM(1), Smit EF(1), van der Wekken AJ(1), Kato T(1), Juraeva D(1), Stroh C(1),

Bruns R(1), Straub J(1), Johne A(1), Scheele J(1), Heymach JV(1), Le X(1).

Author information:

(1)From Memorial Sloan Kettering Cancer Center, New York (P.K.P.); the Oncology

Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of

Oncology (E.F.), and Dr. Rosell Oncology Institute, Dexeus University Hospital,

Quirónsalud Group (S.V.), Barcelona; Centre Hospitaliere Universitaire (CHU)

Bordeaux, Service des Maladies Respiratoires, Bordeaux (R.V.), Université de

Lille, CHU Lille, Thoracic Oncology Department, Centre National de la Recherche

Scientifique, INSERM, Institut Pasteur de Lille, UMR9020-UMR-S 1277-Canther,

Lille (A.B.C.), CHU de Toulouse, Institut Universitaire du Cancer de Toulouse,

Université Paul Sabatier, Toulouse (J.M.),…

BACKGROUND: A splice-site mutation that results in a loss of transcription of

exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with

non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of

tepotinib, a highly selective MET inhibitor, in this patient population.

METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose

of 500 mg) once daily in patients with advanced or metastatic NSCLC with a

confirmed MET exon 14 skipping mutation. The primary end point was the objective

response by independent review among patients who had undergone at least 9

months of follow-up. The response was also analyzed according to whether the

presence of a MET exon 14 skipping mutation was detected on liquid biopsy or

tissue biopsy.

RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib,

and 99 patients had been followed for at least 9 months. The response rate by

independent review was 46% (95% confidence interval [CI], 36 to 57), with a

median duration of response of 11.1 months (95% CI, 7.2 to could not be

estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36

to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63)

among 60 patients in the tissue-biopsy group; 27 patients had positive results

according to both methods. The investigator-assessed response rate was 56% (95%

CI, 45 to 66) and was similar regardless of the previous therapy received for

advanced or metastatic disease. Adverse events of grade 3 or higher that were

considered by investigators to be related to tepotinib therapy were reported in

28% of the patients, including peripheral edema in 7%. Adverse events led to

permanent discontinuation of tepotinib in 11% of the patients. A molecular

response, as measured in circulating free DNA, was observed in 67% of the

patients with matched liquid-biopsy samples at baseline and during treatment.

CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14

skipping mutation, the use of tepotinib was associated with a partial response

in approximately half the patients. Peripheral edema was the main toxic effect

of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION

ClinicalTrials.gov number, NCT02864992.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2004407

PMID: 32469185

4. Cell. 2020 Apr 16;181(2):293-305.e11. doi: 10.1016/j.cell.2020.02.026. Epub 2020

Mar 5.

Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and

Induces Cough.

Ruhl CR(1), Pasko BL(1), Khan HS(1), Kindt LM(1), Stamm CE(1), Franco LH(1),

Hsia CC(1), Zhou M(2), Davis CR(2), Qin T(2), Gautron L(3), Burton MD(4), Mejia

GL(4), Naik DK(4), Dussor G(4), Price TJ(4), Shiloh MU(5).

Author information:

(1)Department of Internal Medicine, University of Texas Southwestern Medical

Center, Dallas, TX 75390, USA.

(2)Department of Biochemistry, University of Texas Southwestern Medical Center,

Dallas, TX 75390, USA.

(3)Department of Internal Medicine, University of Texas Southwestern Medical

Center, Dallas, TX 75390, USA; Center for Hypothalamic Research, University of

Texas Southwestern Medical Center, Dallas, TX 75390, USA. …

Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb),

manifests with a persistent cough as both a primary symptom and mechanism of

transmission. The cough reflex can be triggered by nociceptive neurons

innervating the lungs, and some bacteria produce neuron-targeting molecules.

However, how pulmonary Mtb infection causes cough remains undefined, and whether

Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we

show that an Mtb organic extract activates nociceptive neurons in vitro and

identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb

organic extracts from mutants lacking SL-1 synthesis cannot activate neurons

in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea

pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a

heretofore unknown molecular mechanism for cough induction by a virulent human

pathogen via its production of a complex lipid.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2020.02.026

PMCID: PMC7102531

PMID: 32142653

Conflict of interest statement: Declaration of Interests The authors declare no

competing interests.

5. Nature. 2020 Apr;580(7802):245-251. doi: 10.1038/s41586-020-2140-0. Epub 2020

Mar 25.

Integrating genomic features for non-invasive early lung cancer detection.

Chabon JJ(1)(2), Hamilton EG(3), Kurtz DM(4)(5)(6), Esfahani MS(1)(4), …

Author information:

(1)Stanford Cancer Institute, Stanford University, Stanford, CA, USA.

(2)Institute for Stem Cell Biology and Regenerative Medicine, Stanford

University, Stanford, CA, USA.

(3)Program in Cancer Biology, Stanford University, Stanford, CA, USA.

…

Radiologic screening of high-risk adults reduces lung-cancer-related

mortality1,2; however, a small minority of eligible individuals undergo such

screening in the United States3,4. The availability of blood-based tests could

increase screening uptake. Here we introduce improvements to cancer personalized

profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of

circulating tumour DNA (ctDNA), to better facilitate screening applications. We

show that, although levels are very low in early-stage lung cancers, ctDNA is

present prior to treatment in most patients and its presence is strongly

prognostic. We also find that the majority of somatic mutations in the cell-free

DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect

clonal haematopoiesis and are non-recurrent. Compared with tumour-derived

mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and

lack mutational signatures that are associated with tobacco smoking. Integrating

these findings with other molecular features, we develop and prospectively

validate a machine-learning method termed 'lung cancer likelihood in plasma'

(Lung-CLiP), which can robustly discriminate early-stage lung cancer patients

from risk-matched controls. This approach achieves performance similar to that

of tumour-informed ctDNA detection and enables tuning of assay specificity in

order to facilitate distinct clinical applications. Our findings establish the

potential of cfDNA for lung cancer screening and highlight the importance of

risk-matching cases and controls in cfDNA-based screening studies.

DOI: 10.1038/s41586-020-2140-0

PMID: 32269342 [Indexed for MEDLINE]

6. Science. 2020 Mar 6;367(6482):1147-1151. doi: 10.1126/science.aav5912.

PE/PPE proteins mediate nutrient transport across the outer membrane of

Mycobacterium tuberculosis.

Wang Q(1), Boshoff HIM(1), Harrison JR(2), Ray PC(2)(3), Green SR(2), Wyatt

PG(2), Barry CE 3rd(4)(5).

Author information:

(1)Tuberculosis Research Section, Laboratory of Clinical Immunology and

Microbiology, National Institute of Allergy and Infectious Diseases, National

Institutes of Health, Bethesda, MD 20892, USA.

(2)Drug Discovery Unit, College of Life Sciences, James Black Centre, University

of Dundee, Dundee DD1 5EH, UK.

(3)Exscientia Ltd., Oxford OX1 3LD, UK.

…

Mycobacterium tuberculosis has an unusual outer membrane that lacks canonical

porin proteins for the transport of small solutes to the periplasm. We

discovered that 3,3-bis-di(methylsulfonyl)propionamide (3bMP1) inhibits the

growth of M. tuberculosis, and resistance to this compound is conferred by

mutation within a member of the proline-proline-glutamate (PPE) family, PPE51.

Deletion of PPE51 rendered M. tuberculosis cells unable to replicate on

propionamide, glucose, or glycerol. Growth was restored upon loss of the

mycobacterial cell wall component phthiocerol dimycocerosate. Mutants in other

proline-glutamate (PE)/PPE clusters, responsive to magnesium and phosphate, also

showed a phthiocerol dimycocerosate-dependent growth compromise upon limitation

of the corresponding substrate. Phthiocerol dimycocerosate determined the low

permeability of the mycobacterial outer membrane, and the PE/PPE proteins

apparently act as solute-specific channels.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/science.aav5912

PMID: 32139546 [Indexed for MEDLINE]

7. Lancet Oncol. 2020 Jun;21(6):786-795. doi: 10.1016/S1470-2045(20)30140-6. Epub

2020 May 7.

Neoadjuvant atezolizumab and chemotherapy in patients with resectable

non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2

trial.

Shu CA(1), Gainor JF(2), Awad MM(3), Chiuzan C(4), Grigg CM(5), Pabani A(6),

Garofano RF(1), Stoopler MB(1), Cheng SK(7), White A(8), Lanuti M(9), D'Ovidio

F(10), Bacchetta M(11), Sonett JR(10), Saqi A(12), Rizvi NA(13).

Author information:

(1)Division of Hematology/Oncology, Department of Medicine, Columbia University

Irving Medical Center, New York, NY, USA.

(2)Department of Medicine, Massachusetts General Hospital Cancer Center, Boston,

MA, USA.

(3)Lowe Center for Thoracic Oncology, Department of Medical Oncology,

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

…

BACKGROUND: Approximately 25% of all patients with non-small-cell lung cancer

present with resectable stage IB-IIIA disease, and although perioperative

chemotherapy is the standard of care, this treatment strategy provides only

modest survival benefits. On the basis of the activity of immune checkpoint

inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test

the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and

nab-paclitaxel given as neoadjuvant treatment before surgical resection.

METHODS: This open-label, multicentre, single-arm, phase 2 trial was done at

three hospitals in the USA. Eligible patients were aged 18 years or older and

had resectable American Joint Committee on Cancer-defined stage IB-IIIA

non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance

status of 0-1, and a history of smoking exposure. Patients received neoadjuvant

treatment with intravenous atezolizumab (1200 mg) on day 1, nab-paclitaxel (100

mg/m2) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL

per min) on day 1, of each 21-day cycle. Patients without disease progression

after two cycles proceeded to receive two further cycles, which were then

followed by surgical resection. The primary endpoint was major pathological

response, defined as the presence of 10% or less residual viable tumour at the

time of surgery. All analyses were intention to treat. This study is registered

with ClinicalTrials.gov, NCT02716038, and is ongoing but no longer recruiting

participants.

FINDINGS: Between May 26, 2016, and March 1, 2019, we assessed 39 patients for

eligibility, of whom 30 patients were enrolled. 23 (77%) of these patients had

stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and

26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019),

the median follow-up period was 12·9 months (IQR 6·2-22·9). 17 (57%; 95% CI

37-75) of 30 patients had a major pathological response. The most common

treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30

patients), increased alanine aminotransferase concentrations (two [7%]

patients), increased aspartate aminotransferase concentration (two [7%]

patients), and thrombocytopenia (two [7%] patients). Serious treatment-related

adverse events included one (3%) patient with grade 3 febrile neutropenia, one

(3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2

bronchopulmonary haemorrhage. There were no treatment-related deaths.

INTERPRETATION: Atezolizumab plus carboplatin and nab-paclitaxel could be a

potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a

high proportion of patients achieving a major pathological response, and

manageable treatment-related toxic effects, which did not compromise surgical

resection.

FUNDING: Genentech and Celgene.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(20)30140-6

PMID: 32386568

8. N Engl J Med. 2020 Mar 5;382(10):893-902. doi: 10.1056/NEJMoa1901814.

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.

Conradie F(1), Diacon AH(1), Ngubane N(1), Howell P(1), Everitt D(1), Crook

AM(1), Mendel CM(1), Egizi E(1), Moreira J(1), Timm J(1), McHugh TD(1), Wills

GH(1), Bateson A(1), Hunt R(1), Van Niekerk C(1), Li M(1), Olugbosi M(1),

Spigelman M(1); Nix-TB Trial Team.

Collaborators: Mvuna N, Upton C, Vanker N, Greyling L, Eriksson M, Fabiane SM,

Canseco JO, Solanki P.

Author information:

(1)From the Clinical HIV Research Unit, Faculty of Health Sciences, University

of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease

Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch

University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.),

and the TB Alliance, Pretoria (C.V.N., M.O.) - all in South Africa; the TB

Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC

Clinical Trials Unit at UCL (A.M.C., G.H.W.) and the UCL Centre for Clinical

Microbiology (T.D.M., A.B., R.H.), University College London, London.

Comment in

N Engl J Med. 2020 Mar 5;382(10):959-960.

BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have

limited treatment options and historically have had poor outcomes.

METHODS: In an open-label, single-group study in which follow-up is ongoing at

three South African sites, we investigated treatment with three oral drugs -

bedaquiline, pretomanid, and linezolid - that have bactericidal activity against

tuberculosis and to which there is little preexisting resistance. We evaluated

the safety and efficacy of the drug combination for 26 weeks in patients with

extensively drug-resistant tuberculosis and patients with multidrug-resistant

tuberculosis that was not responsive to treatment or for which a second-line

regimen had been discontinued because of side effects. The primary end point was

the incidence of an unfavorable outcome, defined as treatment failure

(bacteriologic or clinical) or relapse during follow-up, which continued until 6

months after the end of treatment. Patients were classified as having a

favorable outcome at 6 months if they had resolution of clinical disease, a

negative culture status, and had not already been classified as having had an

unfavorable outcome. Other efficacy end points and safety were also evaluated.

RESULTS: A total of 109 patients were enrolled in the study and were included in

the evaluation of efficacy and safety end points. At 6 months after the end of

treatment in the intention-to-treat analysis, 11 patients (10%) had an

unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had

a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during

treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent

during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The

expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of

patients) and myelosuppression (48%), although common, were manageable, often

leading to dose reductions or interruptions in treatment with linezolid.

CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a

favorable outcome at 6 months after the end of therapy in a high percentage of

patients with highly drug-resistant forms of tuberculosis; some associated toxic

effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov

number, NCT02333799.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1901814

PMCID: PMC6955640

PMID: 32130813 [Indexed for MEDLINE]

9. Lancet Oncol. 2020 May;21(5):645-654. doi: 10.1016/S1470-2045(20)30068-1. Epub

2020 Mar 27.

Lurbinectedin as second-line treatment for patients with small-cell lung cancer:

a single-arm, open-label, phase 2 basket trial.

Trigo J(1), Subbiah V(2), Besse B(3), Moreno V(4), López R(5), Sala MA(6),

Peters S(7), Ponce S(8), Fernández C(9), Alfaro V(9), Gómez J(9), Kahatt C(9),

Zeaiter A(9), Zaman K(7), Boni V(10), Arrondeau J(11), Martínez M(12), Delord

JP(13), Awada A(14), Kristeleit R(15), Olmedo ME(16), Wannesson L(17), Valdivia

J(18), Rubio MJ(19), Anton A(20), Sarantopoulos J(21), Chawla SP(22),

Mosquera-Martinez J(23), D'Arcangelo M(24), Santoro A(25), Villalobos VM(26),

Sands J(27), Paz-Ares L(8).

Author information:

(1)Hospital Universitario Virgen de la Victoria, Instituto de Investigación

Biomédica de Málaga, Málaga, Spain. Electronic address: jmtrigo@seom.org.

(2)MD Anderson Cancer Center, Houston, TX, USA.

(3)Gustave Roussy Cancer Campus, Villejuif, France; Paris Sud University, Orsay,

France.

…

BACKGROUND: Few options exist for treatment of patients with small-cell lung

cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective

inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the

acti and safety of lurbinectedin in patients with SCLC after failure of

platinum-based chemotherapy.

METHODS: In this single-arm, open-label, phase 2 basket trial, we recruited

patients from 26 hospitals in six European countries and the USA. Adults (aged

≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative

Oncology Group performance status of 2 or lower, measurable disease as per

Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain

metastasis, adequate organ function, and pre-treated with only one previous

chemotherapy-containing line of treatment (minimum 3 weeks before study

initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin

administered as a 1-h intravenous infusion every 3 weeks until disease

progression or unacceptable toxicity. The primary outcome was the proportion of

patients with an overall response (complete or partial response) as assessed by

the investigators according to RECIST 1.1. All treated patients were analysed

for activity and safety. This study is ongoing and is registered with

ClinicalTrials.gov, NCT02454972.

FINDINGS: Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and

treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5-25·3).

Overall response by investigator assessment was seen in 37 patients (35·2%; 95%

CI 26·2-45·2). The most common grade 3-4 adverse events (irrespective of

causality) were haematological abnormalities-namely, anaemia (in nine [9%]

patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia

(seven [7%]). Serious treatment-related adverse events occurred in 11 (10%)

patients, of which neutropenia and febrile neutropenia were the most common

(five [5%] patients for each). No treatment-related deaths were reported.

INTERPRETATION: Lurbinectedin was active as second-line therapy for SCLC in

terms of overall response and had an acceptable and manageable safety profile.

Lurbinectedin could represent a potential new treatment for patients with SCLC,

who have few options especially in the event of a relapse, and is being

investigated in combination with doxorubicin as second-line therapy in a

randomised phase 3 trial.

FUNDING: Pharma Mar.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(20)30068-1

PMID: 32224306

10. Lancet Oncol. 2020 Apr;21(4):581-592. doi: 10.1016/S1470-2045(20)30013-9. Epub

2020 Mar 12.

Imaging-based target volume reduction in chemoradiotherapy for locally advanced

non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised,

controlled trial.

Nestle U(1), Schimek-Jasch T(2), Kremp S(3), Schaefer-Schuler A(4), Mix M(5),

Küsters A(6), Tosch M(7), Hehr T(8), Eschmann SM(9), Bultel YP(10), Hass P(11),

Fleckenstein J(3), Thieme A(12), Stockinger M(13), Dieckmann K(14), Miederer

M(15), Holl G(16), Rischke HC(17), Gkika E(2), Adebahr S(18), König J(19), Grosu

AL(18); PET-Plan study group.

Author information:

(1)Department of Radiation Oncology, Faculty of Medicine, Medical Center,

University of Freiburg, Freiburg, Germany; German Cancer Consortium Partner Site

Freiburg and German Cancer Research Center, Heidelberg, Germany; Department of

Radiation Oncology, Kliniken Maria Hilf, Mönchengladbach, Germany. Electronic

address: ursula.nestle@mariahilf.de.

(2)Department of Radiation Oncology, Faculty of Medicine, Medical Center,

University of Freiburg, Freiburg, Germany.

(3)Department of Radiotherapy and Radiation Oncology, Saarland University

Medical Center and Faculty of Medicine, Homburg/Saar, Germany.

…

BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging,

the concept of radiotherapy target volume planning might be redefined with the

aim of improving outcomes. We aimed to investigate whether target volume

reduction is feasible and effective compared with conventional planning in the

context of radical chemoradiotherapy for patients with locally advanced

non-small-cell lung cancer.

METHODS: We did a multicentre, open-label, randomised, controlled trial

(PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland.

Previously untreated patients (aged older than 18 years) with inoperable locally

advanced non-small-cell lung cancer suitable for chemoradiotherapy and an

Eastern Cooperative Oncology Group performance status of less than 3 were

included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment

planning, patients were randomly assigned (1:1) using a random number generator

and block sizes between four and six to target volume delineation informed by

18F-FDG PET and CT plus elective nodal irradiation (conventional target group)

or target volumes informed by PET alone (18F-FDG PET-based target group).

Randomisation was stratified by centre and Union for International Cancer

Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per

fraction) was planned to the respective target volumes and applied with

concurrent platinum-based chemotherapy. The primary endpoint was time to

locoregional progression from randomisation with the objective to test

non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio

(HR) margin of 1·25. The per-protocol set was included in the primary analysis.

The safety set included all patients receiving any study-specific treatment.

Patients and study staff were not masked to treatment assignment. This study is

registered with ClinicalTrials.gov, NCT00697333.

FINDINGS: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were

randomly assigned to the conventional target group (n=99) or the 18F-FDG

PET-based target group (n=106; the intention-to-treat set), and 172 patients

were treated per protocol (84 patients in the conventional target group and 88

in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR

9-54), the risk of locoregional progression in the 18F-FDG PET-based target

group was non-inferior to, and in fact lower than, that in the conventional

target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1

year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the

18F-FDG PET-based target group was also non-inferior to that in the conventional

target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at

1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse

toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the

conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based

target group); the most common late toxicities were lung-related (12 [12%] vs 11

[10%]). 20 deaths potentially related to study treatment were reported (seven vs

13).

INTERPRETATION: 18F-FDG PET-based planning could potentially improve local

control and does not seem to increase toxicity in patients with

chemoradiotherapy-treated locally advanced non-small-cell lung cancer.

Imaging-based target volume reduction in this setting is, therefore, feasible,

and could potentially be considered standard of care. The procedures established

might also support imaging-based target volume reduction concepts for other

tumours.

FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(20)30013-9

PMID: 32171429

11. Nature. 2020 Jan;577(7788):95-102. doi: 10.1038/s41586-019-1817-8. Epub 2020 Jan

1.

Prevention of tuberculosis in macaques after intravenous BCG immunization.

Darrah PA(1), Zeppa JJ(2), Maiello P(2), Hackney JA(1), Wadsworth MH

2nd(3)(4)(5), Hughes TK(3)(4)(5), Pokkali S(1), Swanson PA 2nd(1), Grant NL(6),

Rodgers MA(2), Kamath M(1), Causgrove CM(2), Laddy DJ(7), Bonavia A(7), Casimiro

D(7), Lin PL(8), Klein E(9), White AG(2), Scanga CA(2), Shalek AK(3)(4)(5)(10),

Roederer M(1), Flynn JL(2), Seder RA(11).

Author information:

(1)Vaccine Research Center, National Institute of Allergy and Infectious

Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.

(2)Department of Microbiology and Molecular Genetics and Center for Vaccine

Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

(3)Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA.

…

Comment in

Nature. 2020 Jan;577(7788):31-32.

Nature. 2020 Jan;577(7789):145.

Immunity. 2020 Feb 18;52(2):219-221.

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection

worldwide1. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given

intradermally and has variable efficacy against pulmonary tuberculosis, the

major cause of mortality and disease transmission1,2. Here we show that

intravenous administration of BCG profoundly alters the protective outcome of

Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal

or aerosol delivery, intravenous immunization induced substantially more

antigen-responsive CD4 and CD8 T cell responses in blood, spleen,

bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization

induced a high frequency of antigen-responsive T cells across all lung

parenchymal tissues. Six months after BCG vaccination, macaques were challenged

with virulent Mtb. Notably, nine out of ten macaques that received intravenous

BCG vaccination were highly protected, with six macaques showing no detectable

levels of infection, as determined by positron emission tomography-computed

tomography imaging, mycobacterial growth, pathology and granuloma formation. The

finding that intravenous BCG prevents or substantially limits Mtb infection in

highly susceptible rhesus macaques has important implications for vaccine

delivery and clinical development, and provides a model for defining immune

correlates and mechanisms of vaccine-elicited protection against tuberculosis.

DOI: 10.1038/s41586-019-1817-8

PMCID: PMC7015856

PMID: 31894150 [Indexed for MEDLINE]

12. Lancet Oncol. 2020 Mar;21(3):373-386. doi: 10.1016/S1470-2045(19)30785-5. Epub

2020 Feb 3.

Osimertinib plus savolitinib in patients with EGFR mutation-positive,

MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine

kinase inhibitors: interim results from a multicentre, open-label, phase 1b

study.

Sequist LV(1), Han JY(2), Ahn MJ(3), Cho BC(4), Yu H(5), Kim SW(6), Yang JC(7),

Lee JS(8), Su WC(9), Kowalski D(10), Orlov S(11), Cantarini M(12), Verheijen

RB(12), Mellemgaard A(12), Ottesen L(12), Frewer P(13), Ou X(13), Oxnard G(14).

Author information:

(1)Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

(2)Center for Lung Cancer, National Cancer Center, Goyang, South Korea.

(3)Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul,

South Korea.

…

BACKGROUND: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs)

plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers

with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also

known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus

osimertinib, a third-generation EGFR TKI, have provided recommended doses for

study. Here, we report the assessment of osimertinib plus savolitinib in two

global expansion cohorts of the TATTON study.

METHODS: In this multi-arm, multicentre, open-label, phase 1b study, we enrolled

adult patients (aged ≥18 years) with locally advanced or metastatic,

MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had

progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D.

Part B consisted of three cohorts of patients: those who had been previously

treated with a third-generation EGFR TKI (B1) and those who had not been

previously treated with a third-generation EGFR TKI who were either Thr790Met

negative (B2) or Thr790Met positive (B3). In part B, patients received oral

osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment

(March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose

of savolitinib. Part D enrolled patients who had not previously received a

third-generation EGFR TKI and were Thr790Met negative; these patients received

osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and

tolerability, which were assessed in all dosed patients. Secondary endpoints

included the proportion of patients who had an objective response per RECIST 1.1

and was assessed in all dosed patients and all patients with centrally confirmed

MET amplification. Here, we present an interim analysis with data cutoff on

March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466.

FINDINGS: Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into

part B and 42 patients into part D. In part B, 138 patients received osimertinib

plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received

osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16

(38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%)

patients in part B and 25 (60%) patients in part D had adverse events possibly

related to savolitinib and serious adverse events were reported in 62 (45%)

patients in part B and 11 (26%) patients in part D; two adverse events leading

to death (acute renal failure and death, cause unknown) were possibly related to

treatment in part B. Objective partial responses were observed in 66 (48%; 95%

CI 39-56) patients in part B and 23 (64%; 46-79) in part D.

INTERPRETATION: The combination of osimertinib and savolitinib has acceptable

risk-benefit profile and encouraging antitumour activity in patients with

MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease

progression on a previous EGFR TKI. This combination might be a potential

treatment option for patients with MET-driven resistance to EGFR TKIs.

FUNDING: AstraZeneca.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30785-5

PMID: 32027846