2023年
No.2
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2023/2/1 - 2023/2/28.
1. Cell. 2023 Mar 2;186(5):1013-1025.e24. doi: 10.1016/j.cell.2023.01.043. Epub
2023 Feb 23.
Discovery of natural-product-derived sequanamycins as potent oral
anti-tuberculosis agents.
Zhang J(1), Lair C(2), Roubert C(2), Amaning K(1), Barrio MB(3), Benedetti Y(1),
Cui Z(4), Xing Z(4), Li X(4), Franzblau SG(5), Baurin N(1), Bordon-Pallier F(1),
Cantalloube C(6), Sans S(2), Silve S(2), Blanc I(2), Fraisse L(2), Rak A(1),
Jenner LB(7), Yusupova G(7), Yusupov M(7), Zhang J(4), Kaneko T(8), Yang TJ(8),
Fotouhi N(8), Nuermberger E(9), Tyagi S(9), Betoudji F(9), Upton A(10),
Sacchettini JC(11), Lagrange S(2).
Author information:
(1)Sanofi R&D, Integrated Drug Discovery, CRVA, 94403 Vitry-sur-Seine, France.
(2)Evotec ID (LYON) SAS, Lyon, France; Sanofi R&D, Infectious Diseases TSU,
31036 Toulouse, France.
(3)Sanofi R&D, Infectious Diseases TSU, 31036 Toulouse, France.
…
The emergence of drug-resistant tuberculosis has created an urgent need for new
anti-tubercular agents. Here, we report the discovery of a series of macrolides
called sequanamycins with outstanding in vitro and in vivo activity against
Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome
inhibitors that interact with the ribosome in a similar manner to classic
macrolides like erythromycin and clarithromycin, but with binding
characteristics that allow them to overcome the inherent macrolide resistance of
Mtb. Structures of the ribosome with bound inhibitors were used to optimize
sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious
in mouse models of acute and chronic TB as a single agent, and it demonstrated
bactericidal activity in a murine TB infection model in combination with other
TB drugs. These results support further investigation of this series as TB
clinical candidates, with the potential for use in new regimens against
drug-susceptible and drug-resistant TB.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2023.01.043
PMCID: PMC9994261
PMID: 36827973 [Indexed for MEDLINE]
2. N Engl J Med. 2023 Mar 9;388(10):873-887. doi: 10.1056/NEJMoa2212537. Epub 2023 Feb 20.
Treatment Strategy for Rifampin-Susceptible Tuberculosis.
Paton NI(1), Cousins C(1), Suresh C(1), Burhan E(1), Chew KL(1), Dalay VB(1), Lu
Q(1), Kusmiati T(1), Balanag VM(1), Lee SL(1), Ruslami R(1), Pokharkar Y(1),
Djaharuddin I(1), Sugiri JJR(1), Veto RS(1), Sekaggya-Wiltshire C(1),
Avihingsanon A(1), Sarin R(1), Papineni P(1), Nunn AJ(1), Crook AM(1);
TRUNCATE-TB Trial Team.
Author information:
(1)From the Infectious Diseases Translational Research Programme and Yong Loo
Lin School of Medicine, National University of Singapore (N.I.P., C.C., C.S.,
P.P.), National University Hospital (K.L.C.), and Singapore Clinical Research
Institute (Q.L., S.L.L., Y.P.) - all in Singapore; the Faculty of Medicine,
Universitas Indonesia, and Persahabatan General Hospital, Jakarta (E.B.), Dr.
Soetomo Hospital, Surabaya (T.K.), Universitas Padjadjaran, Bandung (R.R.), …
BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based
regimen. Whether a strategy involving shorter initial treatment may lead to
similar outcomes is unclear.
METHODS: In this adaptive, open-label, noninferiority trial, we randomly
assigned participants with rifampin-susceptible pulmonary tuberculosis to
undergo either standard treatment (rifampin and isoniazid for 24 weeks with
pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving
initial treatment with an 8-week regimen, extended treatment for persistent
clinical disease, monitoring after treatment, and retreatment for relapse. There
were four strategy groups with different initial regimens; noninferiority was
assessed in the two strategy groups with complete enrollment, which had initial
regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with
isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of
death, ongoing treatment, or active disease at week 96. The noninferiority
margin was 12 percentage points.
RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%)
withdrew consent or were lost to follow-up. A primary-outcome event occurred in
7 of the 181 participants (3.9%) in the standard-treatment group, as compared
with 21 of the 184 participants (11.4%) in the strategy group with an initial
rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5%
confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189
participants (5.8%) in the strategy group with an initial bedaquiline-linezolid
regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1;
noninferiority met). The mean total duration of treatment was 180 days in the
standard-treatment group, 106 days in the rifampin-linezolid strategy group, and
85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3
or 4 adverse events and serious adverse events were similar in the three groups.
CONCLUSIONS: A strategy involving initial treatment with an 8-week
bedaquiline-linezolid regimen was noninferior to standard treatment for
tuberculosis with respect to clinical outcomes. The strategy was associated with
a shorter total duration of treatment and with no evident safety concerns.
(Funded by the Singapore National Medical Research Council and others;
TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2212537
PMID: 36808186 [Indexed for MEDLINE]
3. N Engl J Med. 2023 Feb 9;388(6):489-498. doi: 10.1056/NEJMoa2212083.
Lobar or Sublobar Resection for Peripheral Stage IA Non-Small-Cell Lung Cancer.
Altorki N(1), Wang X(1), Kozono D(1), Watt C(1), Landrenau R(1), Wigle D(1),
Port J(1), Jones DR(1), Conti M(1), Ashrafi AS(1), Liberman M(1), Yasufuku K(1),
Yang S(1), Mitchell JD(1), Pass H(1), Keenan R(1), Bauer T(1), Miller D(1),
Kohman LJ(1), Stinchcombe TE(1), Vokes E(1).
Author information:
(1)From Weill Cornell Medicine, New York-Presbyterian Hospital (N.A., J.P.),
Memorial Sloan Kettering Cancer Center (D.R.J.), and New York University
Grossman School of Medicine (H.P.), New York, and SUNY Upstate Medical
University, Syracuse (L.J.K.) - all in New York; the Alliance Statistics and
Data Management Center and the Department of Biostatistics and Bioinformatics,
Duke University (X.W.), and Duke Cancer Institute, Duke University Medical
Center (T.E.S.) - both in Durham, NC; Alliance Protocol Operations Office (D.K.,
C.W.) and the University of Chicago Comprehensive Cancer Center (E.V.) - both in
Chicago; University of Pittsburgh Medical Center, Pittsburgh (R.L.); Mayo
Clinic,…
BACKGROUND: The increased detection of small-sized peripheral non-small-cell
lung cancer (NSCLC) has renewed interest in sublobar resection in lieu of
lobectomy.
METHODS: We conducted a multicenter, noninferiority, phase 3 trial in which
patients with NSCLC clinically staged as T1aN0 (tumor size, ≤2 cm) were randomly
assigned to undergo sublobar resection or lobar resection after intraoperative
confirmation of node-negative disease. The primary end point was disease-free
survival, defined as the time between randomization and disease recurrence or
death from any cause. Secondary end points were overall survival, locoregional
and systemic recurrence, and pulmonary functions.
RESULTS: From June 2007 through March 2017, a total of 697 patients were
assigned to undergo sublobar resection (340 patients) or lobar resection (357
patients). After a median follow-up of 7 years, sublobar resection was
noninferior to lobar resection for disease-free survival (hazard ratio for
disease recurrence or death, 1.01; 90% confidence interval [CI], 0.83 to 1.24).
In addition, overall survival after sublobar resection was similar to that after
lobar resection (hazard ratio for death, 0.95; 95% CI, 0.72 to 1.26). The 5-year
disease-free survival was 63.6% (95% CI, 57.9 to 68.8) after sublobar resection
and 64.1% (95% CI, 58.5 to 69.0) after lobar resection. The 5-year overall
survival was 80.3% (95% CI, 75.5 to 84.3) after sublobar resection and 78.9%
(95% CI, 74.1 to 82.9) after lobar resection. No substantial difference was seen
between the two groups in the incidence of locoregional or distant recurrence.
At 6 months postoperatively, a between-group difference of 2 percentage points
was measured in the median percentage of predicted forced expiratory volume in 1
second, favoring the sublobar-resection group.
CONCLUSIONS: In patients with peripheral NSCLC with a tumor size of 2 cm or less
and pathologically confirmed node-negative disease in the hilar and mediastinal
lymph nodes, sublobar resection was not inferior to lobectomy with respect to
disease-free survival. Overall survival was similar with the two procedures.
(Funded by the National Cancer Institute and others; CALGB 140503
ClinicalTrials.gov number, NCT00499330.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2212083
PMID: 36780674 [Indexed for MEDLINE]
4. Lancet. 2023 Mar 4;401(10378):733-746. doi: 10.1016/S0140-6736(23)00221-0. Epub 2023 Feb 7.
Sotorasib versus docetaxel for previously treated non-small-cell lung cancer
with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial.
de Langen AJ(1), Johnson ML(2), Mazieres J(3), Dingemans AC(4), Mountzios G(5),
Pless M(6), Wolf J(7), Schuler M(8), Lena H(9), Skoulidis F(10),…
Author information:
(1)Netherlands Cancer Institute, Amsterdam, Netherlands.
(2)Sarah Cannon Research Institute at Tennessee Oncology, Nashville, TN, USA.
(3)Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
…
Comment in
Lancet. 2023 Mar 4;401(10378):706-707.
BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase
protein, KRASG12C. We compared the efficacy and safety of sotorasib with a
standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC)
with the KRASG12C mutation who had been previously treated with other anticancer
drugs.
METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in
22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated
advanced NSCLC, who progressed after previous platinum-based chemotherapy and a
PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing
untreated brain lesions or symptomatic brain lesions, previously identified
oncogenic driver mutation other than KRASG12C for which an approved therapy is
available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or
adjuvant docetaxel was allowed if the tumour did not progress within 6 months
after the therapy was terminated), previous treatment with a direct KRASG12C
inhibitor, systemic anticancer therapy within 28 days of study day 1, and
therapeutic or palliative radiation therapy within 2 weeks of treatment
initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once
daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label
manner using interactive response technology. Randomisation was stratified by
number of previous lines of therapy in advanced disease (1 vs 2 vs >2),
ethnicity (Asian vs non-Asian), and history of CNS metastases (present or
absent). Treatment continued until an independent central confirmation of
disease progression, intolerance, initiation of another anticancer therapy,
withdrawal of consent, or death, whichever occurred first. The primary endpoint
was progression-free survival, which was assessed by a blinded, independent
central review in the intention-to-treat population. Safety was assessed in all
treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780,
and is active but no longer recruiting.
FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly
assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169
(99%) patients in the sotorasib group and 151 (87%) in the docetaxel group
received at least one dose. After a median follow-up of 17·7 months (IQR
16·4-20·1), the study met its primary endpoint of a statistically significant
increase in the progression-free survival for sotorasib, compared with docetaxel
(median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months
[3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well
tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious
treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34
[23%]). For sotorasib, the most common treatment-related adverse events of grade
3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13
[8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the
most common treatment-related adverse events of grade 3 or worse were
neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]).
INTERPRETATION: Sotorasib significantly increased progression-free survival and
had a more favourable safety profile, compared with docetaxel, in patients with
advanced NSCLC with the KRASG12C mutation and who had been previously treated
with other anticancer drugs.
FUNDING: Amgen.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(23)00221-0
PMID: 36764316 [Indexed for MEDLINE]
5. Nature. 2023 Feb;614(7948):548-554. doi: 10.1038/s41586-022-05672-3. Epub 2023
Feb 1.
Single-cell spatial landscapes of the lung tumour immune microenvironment.
Sorin M(#)(1)(2), Rezanejad M(#)(3)(4), Karimi E(#)(1), Fiset B(1), Desharnais
L(1)(2), Perus LJM(1)(5), Milette S(1)(5), Yu MW(1)(5), Maritan SM(1)(6), Doré
S(1)(2), Pichette É(7), Enlow W(8), Gagné A(8), Wei Y(1), Orain M(8), Manem
VSK(8)(9), Rayes R(1), Siegel PM(1)(6)(10), Camilleri-Broët S(11), Fiset PO(11),
Desmeules P(8), Spicer JD(1)(6)(12), Quail DF(13)(14)(15), Joubert P(16), Walsh
LA(17)(18).
Author information:
(1)Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal,
Quebec, Canada.
(2)Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
(3)Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
…
Single-cell technologies have revealed the complexity of the tumour immune
microenvironment with unparalleled resolution1-9. Most clinical strategies rely
on histopathological stratification of tumour subtypes, yet the spatial context
of single-cell phenotypes within these stratified subgroups is poorly
understood. Here we apply imaging mass cytometry to characterize the tumour and
immunological landscape of samples from 416 patients with lung adenocarcinoma
across five histological patterns. We resolve more than 1.6 million cells,
enabling spatial analysis of immune lineages and activation states with distinct
clinical correlates, including survival. Using deep learning, we can predict
with high accuracy those patients who will progress after surgery using a single
1-mm2 tumour core, which could be informative for clinical management following
surgical resection. Our dataset represents a valuable resource for the non-small
cell lung cancer research community and exemplifies the utility of spatial
resolution within single-cell analyses. This study also highlights how
artificial intelligence can improve our understanding of microenvironmental
features that underlie cancer progression and may influence future clinical
practice.
© 2023. The Author(s).
DOI: 10.1038/s41586-022-05672-3
PMCID: PMC9931585
PMID: 36725934 [Indexed for MEDLINE]
6. Lancet. 2023 Feb 4;401(10374):390-408. doi: 10.1016/S0140-6736(22)01694-4. Epub 2022 Dec 20.
Lung cancer screening.
Adams SJ(1), Stone E(2), Baldwin DR(3), Vliegenthart R(4), Lee P(5), Fintelmann
FJ(6).
Author information:
(1)Department of Radiology, Massachusetts General Hospital, Boston, MA, USA;
Harvard Medical School, Boston, MA, USA. Electronic address:
scott.adams@usask.ca.
(2)Faculty of Medicine, University of New South Wales and Department of Lung
Transplantation and Thoracic Medicine, St Vincent's Hospital, Sydney, NSW,
Australia.
(3)Respiratory Medicine Unit, David Evans Research Centre, Nottingham University
Hospitals NHS Trust, Nottingham, UK.
…
Randomised controlled trials, including the National Lung Screening Trial (NLST)
and the NELSON trial, have shown reduced mortality with lung cancer screening
with low-dose CT compared with chest radiography or no screening. Although
research has provided clarity on key issues of lung cancer screening,
uncertainty remains about aspects that might be critical to optimise clinical
effectiveness and cost-effectiveness. This Review brings together current
evidence on lung cancer screening, including an overview of clinical trials,
considerations regarding the identification of individuals who benefit from lung
cancer screening, management of screen-detected findings, smoking cessation
interventions, cost-effectiveness, the role of artificial intelligence and
biomarkers, and current challenges, solutions, and opportunities surrounding the
implementation of lung cancer screening programmes from an international
perspective. Further research into risk models for patient selection,
personalised screening intervals, novel biomarkers, integrated cardiovascular
disease and chronic obstructive pulmonary disease assessments, smoking cessation
interventions, and artificial intelligence for lung nodule detection and risk
stratification are key opportunities to increase the efficiency of lung cancer
screening and ensure equity of access.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(22)01694-4
PMID: 36563698 [Indexed for MEDLINE]
7. Cancer Cell. 2023 Feb 13;41(2):340-355.e6. doi: 10.1016/j.ccell.2023.01.007.
CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase
inhibitor resistance.
Nilsson MB(1), Yang Y(1), Heeke S(1), Patel SA(1), Poteete A(1), Udagawa H(2),
Elamin YY(1), Moran CA(3), Kashima Y(4), Arumugam T(1), Yu X(1), Ren X(1), Diao
L(5), Shen L(5), Wang Q(5), Zhang M(1), Robichaux JP(1), Shi C(6), Pfeil AN(1),
Tran H(1), Gibbons DL(1), Bock J(7), Wang J(5), Minna JD(8), Kobayashi SS(9), Le
X(1), Heymach JV(10).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
(2)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Division of
Translational Genomics, Exploratory Oncology Research and Clinical Trial Center,
National Cancer Center, Kashiwa, Japan.
(3)Department of Pathology, The University of Texas MD Anderson Cancer Center,
Houston, TX 77030, USA.
…
Effective therapeutic strategies are needed for non-small cell lung cancer
(NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that
acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by
epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins
that could be targeted by antibody-based or adoptive cell therapy approaches and
identify CD70 as being highly upregulated in EMT-associated resistance.
Moreover, CD70 upregulation is an early event in the evolution of resistance and
occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and
invasiveness, and stimulation of CD70 triggers signal transduction pathways
known to be re-activated with acquired TKI resistance. Anti-CD70 antibody drug
conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and
CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs.
These results identify CD70 as a therapeutic target for EGFR mutant tumors with
acquired EGFR TKI resistance that merits clinical investigation.
Copyright © 2023. Published by Elsevier Inc.
DOI: 10.1016/j.ccell.2023.01.007
PMID: 36787696 [Indexed for MEDLINE]
8. Lancet Infect Dis. 2023 Feb 28:S1473-3099(22)00875-1. doi:
10.1016/S1473-3099(22)00875-1. Online ahead of print.
Clinical implications of molecular drug resistance testing for Mycobacterium
tuberculosis: a 2023 TBnet/RESIST-TB consensus statement.
Domínguez J(1), Boeree MJ(2), Cambau E(3), Chesov D(4), Conradie F(5), Cox V(6),
Dheda K(7), Dudnyk A(8), Farhat MR(9), Gagneux S(10), Grobusch MP(11), Gröschel
MI(12), Guglielmetti L(13), Kontsevaya I(14), Lange B(15), van Leth F(16),
Lienhardt C(17), Mandalakas AM(18), Maurer FP(19), Merker M(20), Miotto P(21),
Molina-Moya B(22), Morel F(13), Niemann S(23), Veziris N(13), Whitelaw A(24),
Horsburgh CR Jr(25), Lange C(18); TBnet and RESIST-TB networks.
Author information:
(1)Institut d'Investigació Germans Trias i Pujol, Universitat Autònoma de
Barcelona, CIBER Enfermedades Respiratorias, INNOVA4TB Consortium, Barcelona,
Spain. Electronic address: jadominguez@igtp.cat.
(2)Department of Lung Diseases, Radboud Institute for Health Sciences, Radboud
University Medical Center, Nijmegen, Netherlands.
(3)Centre National de Référence des Mycobactéries et de la Résistance des
Mycobactéries aux Antituberculeux, Paris, France, APHP-Hôpital Bichat,
Mycobacteriology Laboratory, INSERM, University Paris Cite, IAME UMR1137, Paris,
France.
…
Drug-resistant tuberculosis is a substantial health-care concern worldwide.
Despite culture-based methods being considered the gold standard for drug
susceptibility testing, molecular methods provide rapid information about the
Mycobacterium tuberculosis mutations associated with resistance to
anti-tuberculosis drugs. This consensus document was developed on the basis of a
comprehensive literature search, by the TBnet and RESIST-TB networks, about
reporting standards for the clinical use of molecular drug susceptibility
testing. Review and the search for evidence included hand-searching journals and
searching electronic databases. The panel identified studies that linked
mutations in genomic regions of M tuberculosis with treatment outcome data.
Implementation of molecular testing for the prediction of drug resistance in M
tuberculosis is key. Detection of mutations in clinical isolates has
implications for the clinical management of patients with multidrug-resistant or
rifampicin-resistant tuberculosis, especially in situations when phenotypic drug
susceptibility testing is not available. A multidisciplinary team including
clinicians, microbiologists, and laboratory scientists reached a consensus on
key questions relevant to molecular prediction of drug susceptibility or
resistance to M tuberculosis, and their implications for clinical practice. This
consensus document should help clinicians in the management of patients with
tuberculosis, providing guidance for the design of treatment regimens and
optimising outcomes.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00875-1
PMID: 36868253
9. Nat Commun. 2023 Feb 27;14(1):1071. doi: 10.1038/s41467-023-35962-x.
Analysis of acquired resistance mechanisms to osimertinib in patients with
EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial.
Chmielecki J(1), Mok T(2), Wu YL(3), Han JY(4), Ahn MJ(5), Ramalingam SS(6),
John T(7), Okamoto I(8), Yang JC(9), Shepherd FA(10), Bulusu KC(11), Laus
G(11)(12), Collins B(13)(14), Barrett JC(1), Hartmaier RJ(1),
Papadimitrakopoulou V(15)(16).
Author information:
(1)Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.
(2)State Key Laboratory of Translational Oncology, Department of Clinical
Oncology, Chinese University of Hong Kong, Hong Kong, China.
(3)Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital &
Guangdong Academy of Medical Sciences, Guangzhou, China.
…
Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor
(EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR
T790M resistance mutations. This analysis evaluates acquired resistance
mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M
advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a
randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples
collected at baseline and disease progression/treatment discontinuation are
analyzed using next-generation sequencing. Half (50%) of patients have
undetectable plasma EGFR T790M at disease progression and/or treatment
discontinuation. Fifteen patients (19%) have >1 resistance-related genomic
alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%).
© 2023. The Author(s).
DOI: 10.1038/s41467-023-35962-x
PMCID: PMC9971022
PMID: 36849516 [Indexed for MEDLINE]
10. Nat Commun. 2023 Feb 27;14(1):1070. doi: 10.1038/s41467-023-35961-y.
Candidate mechanisms of acquired resistance to first-line osimertinib in
EGFR-mutated advanced non-small cell lung cancer.
Chmielecki J(1), Gray JE(2), Cheng Y(3), Ohe Y(4), Imamura F(5), Cho BC(6), Lin
MC(7), Majem M(8), Shah R(9), Rukazenkov Y(10), Todd A(11), Markovets A(1),
Barrett JC(1), Hartmaier RJ(1), Ramalingam SS(12).
Author information:
(1)Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.
(2)Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research
Institute, Tampa, FL, USA. Jhanelle.Gray@moffitt.org.
(3)Jilin Provincial Cancer Hospital, Changchun, China.
…
Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor
(EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR
T790M resistance mutations. In the Phase III FLAURA study (NCT02296125),
first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm
advanced non-small cell lung cancer. This analysis identifies acquired
resistance mechanisms to first-line osimertinib. Next-generation sequencing
assesses circulating-tumor DNA from paired plasma samples (baseline and disease
progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR
T790M-mediated acquired resistance are observed; most frequent resistance
mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7;
6%). Future research investigating non-genetic acquired resistance mechanisms is
warranted.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-35961-y
PMCID: PMC9971254
PMID: 36849494 [Indexed for MEDLINE]
11. J Clin Oncol. 2023 Feb 21:JCO2201989. doi: 10.1200/JCO.22.01989. Online ahead of print.
Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung
Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study.
Garassino MC(1)(2), Gadgeel S(3), Speranza G(4), Felip E(5), Esteban E(6),
Dómine M(7), Hochmair MJ(8), Powell SF(9), Bischoff HG(10), Peled N(11), Grossi
F(12), Jennens RR(13), Reck M(14), Hui R(15), Garon EB(16), Kurata T(17), Gray
JE(18), Schwarzenberger P(19), Jensen E(19), Pietanza MC(19), Rodríguez-Abreu
D(20).
Author information:
(1)Knapp Center for Biomedical Discovery, University of Chicago Medicine &
Biological Sciences, Chicago, IL.
(2)Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
(3)Henry Ford Cancer Institute/Henry Ford Health, Detroit, MI.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically on the based on the primary end point, may
be published when key planned co-primary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.We present 5-year outcomes from the
phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible
patients with previously untreated metastatic nonsquamous non-small-cell lung
cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab
200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and
investigator's choice of carboplatin/cisplatin for four cycles, followed by
maintenance pemetrexed until disease progression or unacceptable toxicity.
Primary end points were overall survival (OS) and progression-free survival
(PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus
pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time
from random assignment to data cutoff (March 8, 2022) was 64.6 (range,
60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS
was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus
placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%.
Toxicity was manageable. Among 57 patients who completed 35 cycles of
pembrolizumab, objective response rate was 86.0% and 3-year OS rate after
completing 35 cycles (approximately 5 years after random assignment) was 71.9%.
Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus
placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1
expression. These data continue to support pembrolizumab plus
pemetrexed-platinum as a standard of care in previously untreated metastatic
non-small-cell lung cancer without EGFR/ALK alterations.
DOI: 10.1200/JCO.22.01989
PMID: 36809080
12. J Clin Oncol. 2023 Feb 21:JCO2202783. doi: 10.1200/JCO.22.02783. Online ahead of print.
Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO
Living Guideline, Version 2022.3.
Jaiyesimi IA(1)(2), Owen DH(3), Ismaila N(4), Blanchard E(5), Celano P(6),
Florez N(7), Jain D(8), Singh N(9).
Author information:
(1)Corewell Health William Beaumont University Hospital Royal Oak, MI.
(2)Oakland University William Beaumont School of Medicine, Rochester, MI.
(3)Ohio State University, Columbus, OH.
…
Update of
J Clin Oncol. 2022 Oct 1;40(28):3323-3343.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in recommended clinical practice. Living
guidelines are updated on a regular schedule by a standing expert panel that
systematically reviews the health literature on a continuous basis, as described
in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the
ASCO Conflict of Interest Policy Implementation for Clinical Practice
Guidelines. Living Guidelines and updates are not intended to substitute for
independent professional judgment of the treating provider and do not account
for individual variation among patients. See appendix for disclaimers and other
important information (Appendix 1 and Appendix 2, online only). Updates are
published regularly and can be found at
https://ascopubs.org/nsclc-non-da-living-guideline.
DOI: 10.1200/JCO.22.02783
PMID: 36809066
13. J Clin Oncol. 2023 Feb 21:JCO2202782. doi: 10.1200/JCO.22.02782. Online ahead of print.
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO
Living Guideline, Version 2022.3.
Jaiyesimi IA(1)(2), Owen DH(3), Ismaila N(4), Blanchard E(5), Celano P(6),
Florez N(7), Jain D(8), Singh N(9).
Author information:
(1)Corewell Health William Beaumont University Hospital, Royal Oak, MI.
(2)Oakland University William Beaumont School of Medicine, Rochester, MI.
(3)Ohio State University, Columbus, OH.
…
Update of
J Clin Oncol. 2022 Oct 1;40(28):3310-3322.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in clinical practice. Living guidelines are
updated on a regular schedule by a standing expert panel that systematically
reviews the health literature on a continuous basis; as described in the ASCO
Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict
of Interest Policy Implementation for Clinical Practice Guidelines. Living
Guidelines and updates are not intended to substitute for independent
professional judgment of the treating provider and do not account for individual
variation among patients. See appendix for disclaimers and other important
information (Appendix 1 and Appendix 2). Updates are published regularly and can
be found at https://ascopubs.org/nsclc-da-living-guideline.
DOI: 10.1200/JCO.22.02782
PMID: 36802359
14. Am J Respir Crit Care Med. 2023 Feb 21. doi: 10.1164/rccm.202211-2125OC. Online ahead of print.
Effectiveness of Bedaquiline Use Beyond Six Months in Patients with
Multidrug-Resistant Tuberculosis.
Trevisi L(1), Hernán MA(2), Mitnick CD(1)(3)(4), Khan U(5), Seung KJ(3)(4)(1),
Rich ML(3)(4)(1), Bastard M(6), Huerga H(6), Melikyan N(6), Atwood S(3),
Avaliani Z(7), Llanos F(8)(9), Manzur-Ul-Alam M(10), Zarli K(11), Binedgie
AB(12), Adnan S(13), Melikyan A(14), Gelin A(15), Isani AK(16), Vetushko D(17),
Daugarina Z(18), Nkundanyirazo P(19), Putri FA(20), Vilbrun C(21), Khan M(22),
Hewison C(23), Khan PY(24), Franke MF(25).
Author information:
(1)Harvard Medical School, 1811, Global Health and Social Medicine, Boston,
Massachusetts, United States.
(2)Harvard T.H. Chan School of Public Health, Department of Epidemiology and
Biostatistics, Boston, Massachusetts, United States.
(3)Brigham and Women's Hospital, 1861, Division of Global Health Equity, Boston,
Massachusetts, United States.
…
RATIONALE: Current recommendations for the treatment of rifampin- and
multidrug-resistant tuberculosis include bedaquiline used for six months or
longer. Evidence is needed to inform the optimal duration of bedaquiline.
OBJECTIVES: We emulated a target trial to estimate the effect of three
bedaquiline duration treatment strategies (6 months, 7-11 months, ≥ 12 months)
on the probability of successful treatment among patients receiving a longer
individualized regimen for multidrug-resistant tuberculosis.
METHODS: To estimate the probability of successful treatment, we implemented a
three-step approach comprising cloning, censoring, and inverse-probability
weighting.
MAIN RESULTS: The 1,468 eligible individuals received a median of four (IQR:
4-5) likely effective drugs. In 87.1% and 77.7%, this included linezolid and
clofazimine, respectively. The adjusted probability of successful treatment (95%
CI) was 0.85 (0.81, 0.88) for 6 months of BDQ, 0.77 (0.73, 0.81) for 7-11
months, and 0.86 (0.83, 0.88) for > 12 months. Compared with 6 months of
bedaquiline, the ratio of treatment success (95% CI) was 0.91 (0.85, 0.96) for
7-11 months and 1.01 (0.96, 1.06) for > 12 months. Analyses that did not account
for immortal time bias found a higher probability of successful treatment with >
12 months: ratio 1.09 (1.05, 1.14).
CONCLUSIONS: Bedaquiline use beyond six months did not increase the probability
of successful treatment among patients receiving longer regimens that commonly
included new and repurposed drugs. When not properly accounted for, immortal
person-time can bias estimate of effects of treatment duration. Future analyses
should explore the effect of duration of bedaquiline and other drugs in
subgroups with advanced disease and/or receiving less potent regimens.
DOI: 10.1164/rccm.202211-2125OC
PMID: 36802336
15. J Clin Oncol. 2023 Feb 20;41(6):1162-1171. doi: 10.1200/JCO.22.02499.
Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously
Treated Patients With Advanced Non-Small-Cell Lung Cancer.
Fukuoka M(1), Yano S(1), Giaccone G(1), Tamura T(1), Nakagawa K(1), Douillard
JY(1), Nishiwaki Y(1), Vansteenkiste J(1), Kudoh S(1), Rischin D(1), Eek R(1),
Horai T(1), Noda K(1), Takata I(1), Smit E(1), Averbuch S(1), Macleod A(1),
Feyereislova A(1), Dong RP(1), Baselga J(1).
Author information:
(1)From the Kinki University School of Medicine, Osaka City University School of
Medicine, and AstraZeneca, Osaka, Tokushima University School of Medicine,
Tokushima, National Cancer Center, Central Hospital, and Japanese Foundation for
Cancer Research, Tokyo, National Cancer Center, East Hospital, Chiba, Kanagawa
Cancer Center, Yokohama, and National Shikoku Cancer Center, Matsuyama, Japan;
C.R.L.C.C. Rene Gauducheau, Saint-Herblain, France; University Hospital
Gasthuisberg, Leuven, Belgium; Centre for Developmental Cancer Therapeutics,
Melbourne, Australia; Mary Potter Oncology Centre, Pretoria, South Africa;
Academic Hospital Free University, Amsterdam, the Netherlands; AstraZeneca,
Wilmington, DE; AstraZeneca, Alderley Park, United Kingdom; and Vall d'Hebron
University Hospital, Barcelona, Spain.
Corrected and republished from
J Clin Oncol. 2003 Jun 15;21(12):2237-46.
PURPOSE: To evaluate the efficacy and tolerability of two doses of gefitinib
(Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor
receptor tyrosine kinase inhibitor, in patients with pretreated advanced
non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: This was a randomized, double-blind, parallel-group,
multicenter phase II trial. Two hundred ten patients with advanced NSCLC who
were previously treated with one or two chemotherapy regimens (at least one
containing platinum) were randomized to receive either 250-mg or 500-mg oral
doses of gefitinib once daily.
RESULTS: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor
response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0%
(95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were
40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median
progression-free survival times were 2.7 and 2.8 months; and median overall
survival times were 7.6 and 8.0 months, respectively. Symptom improvements were
recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor
response. Adverse events (AEs) at both dose levels were generally mild (grade 1
or 2) and consisted mainly of skin reactions and diarrhea. Drug-related
toxicities were more frequent in the higher-dose group. Withdrawal due to
drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500
mg/d, respectively.
CONCLUSION: Gefitinib showed clinically meaningful antitumor activity and
provided symptom relief as second- and third-line treatment in these patients.
At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an
important, novel treatment option for patients with pretreated advanced NSCLC.
DOI: 10.1200/JCO.22.02499
PMID: 36791474
16. Am J Respir Crit Care Med. 2023 Feb 15. doi: 10.1164/rccm.202206-1118OC. Online ahead of print.
A Standardized Approach for Collection of Objective Data to Support Outcome
Determination for Late-Phase TB Trials.
Kurbatova EV(1), Phillips PP(2)(3), Dorman SE(4), Sizemore EE(5), Bryant KE(1),
Purfield AE(1), Ricaldi J(6), Brown NE(6), Johnson JL(7)(8), Wallis CL(9), Akol
JP(8), Ocheretina O(10), Van Hung N(11), Mayanja-Kizza H(12), Lourens M(13),
Dawson R(14), Nhung NV(15), Pierre S(10), Musodza Y(16), Shenje J(17),
Badal-Faesen S(18), Vilbrun SC(10), Waja Z(19), Peddareddy L(1), Scott NA(20),
Yuan Y(21), Goldberg SV(22), Swindells S(23), Chaisson RE(24), Nahid P(25); AIDS
Clinical Trials Group and the Tuberculosis Trials Consortium.
Author information:
(1)The U.S. Centers for Disease Control and Prevention (CDC), Division of TB
Elimination, Atlanta, Georgia, United States.
(2)University of California, San Francisco, Medicine, San Francisco, United
States.
(3)United States.
…
INTRODUCTION: We developed a standardized method, "Possible poor treatment
response" (PPTR), to help ascertain efficacy endpoints in Study S31/A5349
(NCT02410772), an open-label trial comparing two 4-month rifapentine-based
regimens with a standard 6-month regimen for the treatment of pulmonary TB. We
describe the use of the PPTR process and evaluate whether the goals of
minimizing bias in efficacy endpoint assessment and attainment of relevant data
to determine outcome for all participants were achieved.
METHODS/DESIGN: A PPTR event was defined as the occurrence of one or more
pre-specified triggers. Each PPTR required initiation of a standardized
evaluation process that included obtaining multiple sputum samples for
microbiology.
RESULTS: Among 2,343 participants with culture-confirmed drug-susceptible TB,
454 individuals (19.4%) had a total of 534 individual PPTR events, of which
76.6% were microbiological (positive smear or culture at or after 17 weeks). At
least one PPTR event was experienced by 92.4% (133 of 144) of participants with
TB-related unfavorable outcome, and between 13.8 and 14.7% of participants with
favorable and not assessable outcomes. 75% of participants with TB-related
unfavorable outcomes had microbiological confirmation of failure to achieve
disease-free cure.
DISCUSSION: Standardized methodologies, such as our PPTR approach, could
facilitate unbiased efficacy outcome determinations, improve discrimination
between outcomes that are related and unrelated to regimen efficacy, and enhance
the ability to conduct pooled analyses of contemporary trials. Clinical trial
registration available at www.
CLINICALTRIALS: gov, ID: NCT02410772.
DOI: 10.1164/rccm.202206-1118OC
PMID: 36790881
17. J Clin Invest. 2023 Feb 9:e165863. doi: 10.1172/JCI165863. Online ahead of
print.
EMT-activated secretory and endocytic vesicular trafficking programs underlie a
vulnerability to PI4K2A antagonism in lung cancer.
Tan X(1), Xiao GY(1), Wang S(1), Shi L(1), Zhao Y(1), Liu X(1), Yu J(1), Russell
WK(2), Creighton CJ(3), Kurie JM(1).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, United States of America.
(2)Department of Biochemistry and Molecular Biology, The University of Texas
Medical Branch, Galveston, United States of America.
(3)Department of Medicine and Dan L Duncan Cancer Center, Baylor College of
Medicine, Houston, United States of America.
Hypersecretory malignant cells underlie therapeutic resistance, metastasis, and
poor clinical outcomes. However, the molecular basis for malignant
hypersecretion remains obscure. Here, we showed that epithelial-to-mesenchymal
transition (EMT) initiates exocytic and endocytic vesicular trafficking programs
in lung cancer. The EMT-activating transcription factor ZEB1 executed a
PI4KIIIβ-to-PI4KIIα (PI4K2A)-dependency switch that drove PI4P synthesis in
Golgi and endosomes. EMT enhanced the vulnerability of lung cancer cells to
PI4K2A small molecule antagonists. PI4K2A formed a MYOIIA-containing protein
complex that facilitated secretory vesicle biogenesis in the Golgi, thereby
establishing a hypersecretory state involving osteopontin (SPP1) and other
pro-metastatic ligands. In the endosomal compartment, PI4K2A accelerated
recycling of SPP1 receptors to complete an SPP1-dependent autocrine loop and
interacted with HSP90 to prevent lysosomal degradation of AXL receptor tyrosine
kinase, a driver of cell migration. These results show that EMT coordinates
exocytic and endocytic vesicular trafficking to establish a therapeutically
actionable hypersecretory state that drives lung cancer progression.
DOI: 10.1172/JCI165863
PMID: 36757799
18. J Clin Invest. 2023 Feb 9:e161944. doi: 10.1172/JCI161944. Online ahead of
print.
A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in
foamy macrophages.
Bedard M(1), van der Niet S(2), Bernard EM(3), Babunovic GH(1), Cheng TY(1),
Aylan B(3), Grootemaat AE(3), Raman S(1), Botella L(3), Ishikawa E(4),
O'Sullivan MP(5), O'Leary S(5), Mayfield JA(1), Buter J(6), Minnaard AJ(6),
Fortune SM(7), Murphy LO(8), Ory DS(8), Keane J(5), Yamasaki S(4), Gutierrez
MG(9), van der Wel N(2), Moody DB(1).
Author information:
(1)Division of Rheumatology Immunity and Inflammation, Brigham and Women's
Hospital, Boston, United States of America.
(2)Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre,
Amsterdam, Netherlands.
(3)Host Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick
Institute, London, United Kingdom.
…
Induction of lipid-laden foamy macrophages is a cellular hallmark of
tuberculosis (TB) disease, which involves transformation of infected
phagolysomes from a site of killing into a nutrient-rich replicative niche. Here
we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis (Mtb),
1-tuberculosinyladenosine (1-TbAd), causes lysosomal maturation arrest and
autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or
infection with terpenyl nucleoside-producing Mtb, caused intralysosomal and
peribacillary lipid storage patterns that match both the molecules and
subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd
induced storage of triacylglycerides and cholesterylesters, and 1-TbAd increased
Mtb growth under conditions of restricted lipid access in macrophages. Further,
lipidomics dentified 1-TbAd induced lipid substrates that define Gaucher's
disease, Wolman's disease and other inborn lysosomal storage diseases. These
data identify genetic and molecular causes of Mtb-induced lysosomal failure,
leading to successful testing of an gonist of TRPML1 calcium channels that
reverses lipid storage in cells. These data establish the host-directed cellular
functions of an orphan effector molecule that promotes survival in macrophages,
providing both an upstream cause and detailed picture of lysosome failure in
foamy macrophages.
DOI: 10.1172/JCI161944
PMID: 36757797
19. Angew Chem Int Ed Engl. 2023 Feb 9:e202300221. doi: 10.1002/anie.202300221.
Online ahead of print.
Chemical Validation of Mycobacterium tuberculosis Phosphopantetheine
Adenylyltransferase Using Fragment Linking and CRISPR Interference.
El Bakali J(1)(2), Blaszczyk M(3)(4), Evans JC(5)(6), Boland JA(1), McCarthy
WJ(1)(7), Fathoni I(8), Dias MVB(3)(9), Johnson EO(6), Coyne AG(1), Mizrahi
V(5), Blundell TL(3), Abell C(1), Spry C(1)(8).
Author information:
(1)Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield
Road, Cambridge, CB2 1EW, UK.
(2)Present address: Univ. Lille, Inserm, CHU Lille, UMR-S 1172-LiNC-Lille
Neuroscience & Cognition, 59000, Lille, France.
(3)Department of Biochemistry, University of Cambridge, 80 Tennis Court Road,
Cambridge, CB2 1GA, UK.
…
The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential
target for much-needed novel antimicrobial drugs, including for the treatment of
tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis
(Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine
adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in
CoA biosynthesis, we performed a fragment screen. In doing so, we discovered
three series of fragments that occupy distinct regions of the MtbPPAT active
site, presenting a unique opportunity for fragment linking. Here we show how,
guided by X-ray crystal structures, we could link weakly-binding fragments to
produce an active site binder with a KD<20 μM and on-target anti-Mtb activity,
as demonstrated using CRISPR interference. This study represents a big step
toward validating MtbPPAT as a potential drug target and designing a
MtbPPAT-targeting anti-TB drug.
© 2023 The Authors. Angewandte Chemie International Edition published by
Wiley-VCH GmbH.
DOI: 10.1002/anie.202300221
PMID: 36757665
20. J Clin Oncol. 2023 Feb 3:JCO2201990. doi: 10.1200/JCO.22.01990. Online ahead of print.
Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year
Update of the Phase III KEYNOTE-407 Study.
Novello S(1), Kowalski DM(2), Luft A(3), Gümüş M(4), Vicente D(5), Mazières
J(6), Rodríguez-Cid J(7), Tafreshi A(8), Cheng Y(9), Lee KH(10), Golf A(11),
Sugawara S(12), Robinson AG(13), Halmos B(14), Jensen E(15), Schwarzenberger
P(16), Pietanza MC(16), Paz-Ares L(17).
Author information:
(1)Department of Oncology, University of Turin, Azienda Ospedaliero
Universitaria San Luigi, Turin, Italy.
(2)Department of Lung Cancer and Thoracic Tumours, Maria Sklodowska-Curie
National Research Institute of Oncology, Warsaw, Poland.
(3)Department of Oncology No. 1 (Thoracic Surgery), Leningrad Regional Clinical
Hospital, Saint Petersburg, Russia.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically based on the primary end point, may be
published when key planned co-primary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.We report 5-year efficacy and safety
outcomes from the phase III KEYNOTE-407 study (ClinicalTrials.gov identifier:
NCT02775435). Eligible patients with previously untreated, metastatic squamous
non-small-cell lung cancer (NSCLC) were randomly assigned 1:1 to pembrolizumab
200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3
weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles.
Primary end points were overall survival (OS) and progression-free survival
(PFS) per RECIST version 1.1 by blinded independent central review (BICR). Five
hundred fifty-nine patients were randomly assigned in the intention-to-treat
population (pembrolizumab plus chemotherapy, n = 278; placebo plus chemotherapy,
n = 281). The median time from random assignment to data cutoff was 56.9 (range,
49.9-66.2) months. OS and PFS were improved with pembrolizumab plus chemotherapy
versus placebo plus chemotherapy (hazard ratio [95% CI], 0.71 [0.59 to 0.85] and
0.62 [0.52 to 0.74]), with 5-year OS rates of 18.4% versus 9.7%, respectively.
Toxicity was manageable. Among 55 patients who completed 35 cycles of
pembrolizumab, the objective response rate was 90.9% and the 3-year OS rate
after completion of 35 cycles (approximately 5 years after random assignment)
was 69.5%. Pembrolizumab plus chemotherapy maintained an OS and PFS benefit
versus placebo plus chemotherapy in previously untreated, metastatic squamous
NSCLC and is a standard-of-care first-line treatment option for metastatic
squamous NSCLC regardless of programmed death ligand 1 expression.
DOI: 10.1200/JCO.22.01990
PMID: 36735893
21. Nat Commun. 2023 Feb 1;14(1):549. doi: 10.1038/s41467-023-36282-w.
Genome-wide host-pathogen analyses reveal genetic interaction points in
tuberculosis disease.
Phelan J(1), Gomez-Gonzalez PJ(1), Andreu N(1), Omae Y(2), Toyo-Oka L(2), Yanai
H(3), Miyahara R(4), Nedsuwan S(5), de Sessions PF(6), Campino S(1), Sallah
N(1), Parkhill J(7), Smittipat N(8), Palittapongarnpim P(8), Mushiroda T(9),
Kubo M(9), Tokunaga K(2), Mahasirimongkol S(10), Hibberd ML(11), Clark
TG(12)(13).
Author information:
(1)Faculty of Infectious and Tropical Diseases, London School of Hygiene and
Tropical Medicine, London, United Kingdom.
(2)Department of Human Genetics, Graduate School of Medicine, The University of
Tokyo, Tokyo, Japan.
(3)Fukujuji Hospital and Research Institute of Tuberculosis, Japan
Anti-Tuberculosis Association, Kiyose, Japan.
…
The genetics underlying tuberculosis (TB) pathophysiology are poorly understood.
Human genome-wide association studies have failed so far to reveal reproducible
susceptibility loci, attributed in part to the influence of the underlying
Mycobacterium tuberculosis (Mtb) bacterial genotype on the outcome of the
infection. Several studies have found associations of human genetic
polymorphisms with Mtb phylo-lineages, but studies analysing genome-genome
interactions are needed. By implementing a phylogenetic tree-based Mtb-to-human
analysis for 714 TB patients from Thailand, we identify eight putative genetic
interaction points (P < 5 × 10-8) including human loci DAP and RIMS3, both
linked to the IFNγ cytokine and host immune system, as well as FSTL5, previously
associated with susceptibility to TB. Many of the corresponding Mtb markers are
lineage specific. The genome-to-genome analysis reveals a complex interactome
picture, supports host-pathogen adaptation and co-evolution in TB, and has
potential applications to large-scale studies across many TB endemic populations
matched for host-pathogen genomic diversity.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-36282-w
PMCID: PMC9892022
PMID: 36725857 [Indexed for MEDLINE]
22. J Clin Oncol. 2023 Feb 1;41(4):715-723. doi: 10.1200/JCO.22.02270.
Phase I Study of Single-Agent Anti-Programmed Death-1 (MDX-1106) in Refractory
Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic
Correlates.
Brahmer JR(1), Drake CG(1), Wollner I(1), Powderly JD(1), Picus J(1), Sharfman
WH(1), Stankevich E(1), Pons A(1), Salay TM(1), McMiller TL(1), Gilson MM(1),
Wang C(1), Selby M(1), Taube JM(1), Anders R(1), Chen L(1), Korman AJ(1),
Pardoll DM(1), Lowy I(1), Topalian SL(1).
Author information:
(1)From the Johns Hopkins University School of Medicine and the Sidney Kimmel
Comprehensive Cancer Center, Baltimore, MD; Henry Ford Health Systems, Detroit,
MI; Carolina BioOncology Institute, Huntersville, NC; Washington University
School of Medicine Siteman Cancer Center, St Louis, MO; and Medarex, Bloomsbury,
NJ, and Milpitas, CA.
Corrected and republished from
J Clin Oncol. 2010 Jul 1;28(19):3167-75.
PURPOSE: Programmed death-1 (PD-1), an inhibitory receptor expressed on
activated T cells, may suppress antitumor immunity. This phase I study sought to
determine the safety and tolerability of anti-PD-1 blockade in patients with
treatment-refractory solid tumors and to preliminarily assess antitumor
activity, pharmacodynamics, and immunologic correlates.
PATIENTS AND METHODS: Thirty-nine patients with advanced metastatic melanoma,
colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung
cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous
infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3,
1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg.
Patients with evidence of clinical benefit at 3 months were eligible for
repeated therapy.
RESULTS: Anti-PD-1 was well tolerated: one serious adverse event, inflammatory
colitis, was observed in a patient with melanoma who received five doses at 1
mg/kg. One durable complete response (CRC) and two partial responses (PRs;
melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had
significant lesional tumor regressions not meeting PR criteria. The serum
half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a
sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2
months following infusion, regardless of dose. In nine patients examined, tumor
cell surface B7-H1 expression appeared to correlate with the likelihood of
response to treatment.
CONCLUSION: Blocking the PD-1 immune checkpoint with intermittent antibody
dosing is well tolerated and associated with evidence of antitumor activity.
Exploration of alternative dosing regimens and combinatorial therapies with
vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.
DOI: 10.1200/JCO.22.02270
PMID: 36706735
23. J Clin Oncol. 2023 Feb 10;41(5):e10-e20. doi: 10.1200/JCO.22.02124. Epub 2022
Dec 19.
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO
Living Guideline, Version 2022.2.
Owen DH(1), Singh N(2), Ismaila N(3), Blanchard E(4), Celano P(5), Florez N(6),
Jain D(7), Leighl NB(8), Mamdani H(9), Masters G(10), Moffitt PR(11), Naidoo
J(12), Phillips T(13), Riely GJ(14), Robinson AG(15), Schenk E(16), Schneider
BJ(17), Sequist L(18), Spigel DR(19), Jaiyesimi IA(20).
Author information:
(1)Ohio State University, Columbus, OH.
(2)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
(3)American Society of Clinical Oncology, Alexandria, VA.
…
Update of
J Clin Oncol. 2022 Oct 1;40(28):3310-3322.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in recommended clinical practice. Living
guidelines are updated on a regular schedule by a standing expert panel that
systematically reviews the health literature on a continuous basis, as described
in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the
ASCO Conflict of Interest Policy Implementation for Clinical Practice
Guidelines. Living Guidelines and updates are not intended to substitute for
independent professional judgment of the treating provider and do not account
for individual variation among patients. See Appendix 1 (online only) for
disclaimers and other important information. Updates are published regularly and
can be found at https://ascopubs.org/nsclc-da-living-guideline.
DOI: 10.1200/JCO.22.02124
PMID: 36534938 [Indexed for MEDLINE]
24. J Clin Oncol. 2023 Feb 10;41(5):e1-e9. doi: 10.1200/JCO.22.02121. Epub 2022 Dec 19.
Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO
Living Guideline, Version 2022.2.
Owen DH(1), Singh N(2), Ismaila N(3), Blanchard E(4), Celano P(5), Florez N(6),
Jain D(7), Leighl NB(8), Mamdani H(9), Masters G(10), Moffitt PR(11), Naidoo
J(12), Phillips T(13), Riely GJ(14), Robinson AG(15), Schenk E(16), Schneider
BJ(17), Sequist L(18), Spigel DR(19), Jaiyesimi IA(20).
Author information:
(1)Ohio State University, Columbus, OH.
(2)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
(3)American Society of Clinical Oncology, Alexandria, VA.
…
Update of
J Clin Oncol. 2022 Oct 1;40(28):3323-3343.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in recommended clinical practice. Living
guidelines are updated on a regular schedule by a standing expert panel that
systematically reviews the health literature on a continuous basis, as described
in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the
ASCO Conflict of Interest Policy Implementation for Clinical Practice
Guidelines. Living Guidelines and updates are not intended to substitute for
independent professional judgment of the treating provider and do not account
for individual variation among patients. See Appendix 1 (online only) for
disclaimers and other important information. Updates are published regularly and
can be found at https://ascopubs.org/nsclc-non-da-living-guideline.
DOI: 10.1200/JCO.22.02121
PMID: 36534935 [Indexed for MEDLINE]
25. J Clin Oncol. 2023 Feb 20;41(6):1213-1227. doi: 10.1200/JCO.22.00975. Epub 2022 Nov 3.
Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as
First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III
POSEIDON Study.
Johnson ML(1), Cho BC(2), Luft A(3), Alatorre-Alexander J(4), Geater SL(5),
Laktionov K(6), Kim SW(7), Ursol G(8), Hussein M(9), Lim FL(10), Yang CT(11),
Araujo LH(12), Saito H(13), Reinmuth N(14), Shi X(15), Poole L(16), Peters
S(17), Garon EB(18), Mok T(19); POSEIDON investigators.
Author information:
(1)Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN.
(2)Yonsei Cancer Center, Seoul, South Korea.
(3)Leningrad Regional Clinical Hospital, St Petersburg, Russia.
…
Comment in
1176.
PURPOSE: The open-label, phase III POSEIDON study evaluated tremelimumab plus
durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D +
CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung
cancer (mNSCLC).
METHODS: Patients (n = 1,013) with EGFR/ALK wild-type mNSCLC were randomly
assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and
platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab
once every 4 weeks until progression and one additional tremelimumab dose;
durvalumab plus chemotherapy for up to four 21-day cycles, followed by
durvalumab once every 4 weeks until progression; or chemotherapy for up to six
21-day cycles (with or without maintenance pemetrexed; all arms). Primary end
points were progression-free survival (PFS) and overall survival (OS) for D + CT
versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D +
CT versus CT.
RESULTS: PFS was significantly improved with D + CT versus CT (hazard ratio
[HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend
for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72
to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS
(HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS
(HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month
OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT.
Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and
44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%,
14.1%, and 9.9%, respectively, discontinued treatment because of
treatment-related adverse events.
CONCLUSION: D + CT significantly improved PFS versus CT. A limited course of
tremelimumab added to durvalumab and chemotherapy significantly improved OS and
PFS versus CT, without meaningful additional tolerability burden, representing a
potential new option in first-line mNSCLC.
DOI: 10.1200/JCO.22.00975
PMCID: PMC9937097
PMID: 36327426 [Indexed for MEDLINE]
26. J Clin Oncol. 2023 Feb 10;41(5):1105-1115. doi: 10.1200/JCO.22.00739. Epub 2022 Oct 26.
Phase Ib Study of Telisotuzumab Vedotin in Combination With Erlotinib in
Patients With c-Met Protein-Expressing Non-Small-Cell Lung Cancer.
Camidge DR(1), Barlesi F(2)(3), Goldman JW(4), Morgensztern D(5), Heist R(6),
Vokes E(7), Spira A(8), Angevin E(9), Su WC(10), Hong DS(11), Strickler JH(12),
Motwani M(13), Dunbar M(13), Parikh A(14), Noon E(13), Blot V(13), Wu J(13),
Kelly K(15).
Author information:
(1)University of Colorado Cancer Center, Aurora, CO.
(2)Multidisciplinary Oncology and Therapeutic Innovations Department, Aix
Marseille University, Assistance Publique Hôpitaux de Marseille, Inserm U911
CRO2, Marseille, France.
(3)Medical Oncology Department, Gustave Roussy, Villejuif, France.
…
Comment in
1129.
PURPOSE: Overexpression of c-Met protein and epidermal growth factor receptor
(EGFR) mutations can co-occur in non-small-cell lung cancer (NSCLC), providing
strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a
first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable
safety profile and antitumor activity as monotherapy. Herein, we report the
results of a phase Ib study (ClinicalTrials.gov identifier: NCT02099058)
evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in
patients with c-Met-positive (+) NSCLC.
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 EGFR-activating mutation
(EGFR-M+) and progression on a prior EGFR TKI. End points included safety,
pharmacokinetics, objective response rate (ORR), and progression-free survival
(PFS). The efficacy-evaluable population consisted of c-Met+ patients (confirmed
histology [H]-score ≥ 150) who had at least one postbaseline scan; c-Met+
patients with H-scores ≥ 225 were classified as c-Met high.
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 EGFR-M+ patients (n = 28) was 32.1%. Of EGFR-M+
patients, those who were c-Met high (n = 15) had an ORR of 52.6%. Median PFS was
6.8 months for non-T790M+ and for those whose T790M status was unknown, versus
3.7 months for T790M+.
CONCLUSION: Teliso-V plus erlotinib showed encouraging antitumor activity and
acceptable toxicity in EGFR TKI-pretreated patients with EGFR-M+, c-Met+ NSCLC.
DOI: 10.1200/JCO.22.00739
PMCID: PMC9928626
PMID: 36288547 [Indexed for MEDLINE]
27. J Clin Oncol. 2023 Feb 20;41(6):1200-1212. doi: 10.1200/JCO.22.01503. Epub 2022 Oct 12.
Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy
as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate
227.
Brahmer JR(1), Lee JS(2), Ciuleanu TE(3), Bernabe Caro R(4), Nishio M(5), Urban
L(6), Audigier-Valette C(7), Lupinacci L(8), Sangha R(9), Pluzanski A(10),
Burgers J(11), Mahave M(12), Ahmed S(13), Schoenfeld AJ(14), Paz-Ares LG(15),
Reck M(16), Borghaei H(17), O'Byrne KJ(18), Gupta RG(19), Bushong J(19), Li
L(19), Blum SI(19), Eccles LJ(19), Ramalingam SS(20).
Author information:
(1)Johns Hopkins Kimmel Cancer Center, Baltimore, MD.
(2)National University Bundang Hospital, Seongnam, Republic of Korea.
(3)Institutul Oncologic Prof Dr Ion Chiricuta and University of Medicine and
Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania.
…
Comment in
1172.
PURPOSE: We present 5-year results from CheckMate 227 Part 1, in which nivolumab
plus ipilimumab improved overall survival (OS) versus chemotherapy in patients
with metastatic non-small-cell lung cancer, regardless of tumor programmed death
ligand 1 (PD-L1) status.
METHODS: Adults with stage IV/recurrent non-small-cell lung cancer without EGFR
mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were
randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to
first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients
with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab,
nivolumab plus chemotherapy, or chemotherapy. End points included exploratory
5-year results for efficacy, safety, and quality of life.
RESULTS: At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus
14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19%
versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7
months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients
surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus
ipilimumab without initiating subsequent systemic anticancer treatment by the
5-year time point. Survival benefit continued after nivolumab plus ipilimumab
discontinuation because of treatment-related adverse events, with a 5-year OS
rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in
5-year survivors treated with nivolumab plus ipilimumab was similar to that in
the general US population through the 5-year follow-up. No new safety signals
were observed.
CONCLUSION: With all patients off immunotherapy treatment for ≥ 3 years,
nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy,
including long-term, durable clinical benefit regardless of tumor PD-L1
expression. These data support nivolumab plus ipilimumab as an effective
first-line treatment for patients with metastatic non-small-cell lung cancer.
DOI: 10.1200/JCO.22.01503
PMCID: PMC9937094
PMID: 36223558 [Indexed for MEDLINE]