2023年
No.6
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2023/6/1 - 2023/6/30.
1. N Engl J Med. 2023 Jun 28. doi: 10.1056/NEJMoa2215530. Online ahead of print.
Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung
Cancer.
Provencio M(1), Nadal E(1), González-Larriba JL(1), Martínez-Martí A(1), Bernabé
R(1), Bosch-Barrera J(1), Casal-Rubio J(1), Calvo V(1), Insa A(1),…
Author information:
(1)From Hospital Universitario Puerta de Hierro-Majadahonda (M.P., V.C.,
R.S.-B., J.M.-L., A.C.-B., A.R.), Hospital Universitario Clínico San Carlos
(J.L.G.-L., C.A.R., F.H.-T.), Hospital Universitario 12 de Octubre (S.P.),
Hospital Universitario La Paz (J.C.), and the Genetic and Molecular Epidemiology
Group, Spanish National Cancer Research Center (R. Benítez), Madrid, …
BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer
(NSCLC) receive a diagnosis of stage III disease. There is no current consensus
regarding the most appropriate treatment for these patients.
METHODS: In this open-label, phase 2 trial, we randomly assigned patients with
resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus
platinum-based chemotherapy (experimental group) or chemotherapy alone (control
group), followed by surgery. Patients in the experimental group who had R0
resections received adjuvant treatment with nivolumab for 6 months. The primary
end point was a pathological complete response (0% viable tumor in resected lung
and lymph nodes). Secondary end points included progression-free survival and
overall survival at 24 months and safety.
RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the
experimental group and 29 were assigned to the control group. A pathological
complete response occurred in 37% of the patients in the experimental group and
in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI],
1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the
experimental group and in 69% in the control group (relative risk, 1.35; 95% CI,
1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months
were 67.2% in the experimental group and 40.9% in the control group (hazard
ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25
to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in
the experimental group and 63.6% in the control group (hazard ratio for death,
0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients
in the experimental group (19%; some patients had events of both grades) and 3
patients in the control group (10%).
CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative
treatment with nivolumab plus chemotherapy resulted in a higher percentage of
patients with a pathological complete response and longer survival than
chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II
ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2215530
PMID: 37379158
2. CA Cancer J Clin. 2023 Jun 17. doi: 10.3322/caac.21785. Online ahead of print.
Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis,
therapy, and future directions.
Megyesfalvi Z(1)(2)(3), Gay CM(4), Popper H(5), Pirker R(6), Ostoros G(3), Heeke
S(4), Lang C(1)(7), Hoetzenecker K(1), Schwendenwein A(1), Boettiger K(1), Bunn
PA Jr(8), Renyi-Vamos F(2)(3), Schelch K(1)(9), Prosch H(10), Byers LA(4),
Hirsch FR(11)(12), Dome B(1)(2)(3)(13).
Author information:
(1)Department of Thoracic Surgery, Comprehensive Cancer Center, Medical
University of Vienna, Vienna, Austria.
(2)Department of Thoracic Surgery, Semmelweis University and National Institute
of Oncology, Budapest, Hungary.
(3)National Koranyi Institute of Pulmonology, Budapest, Hungary.
…
Small cell lung cancer (SCLC) is characterized by rapid growth and high
metastatic capacity. It has strong epidemiologic and biologic links to tobacco
carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an
important subset of tumors lacks these properties. Genomic profiling of SCLC
reveals genetic instability, almost universal inactivation of the tumor
suppressor genes TP53 and RB1, and a high mutation burden. Because of early
metastasis, only a small fraction of patients are amenable to curative-intent
lung resection, and these individuals require adjuvant platinum-etoposide
chemotherapy. Therefore, the vast majority of patients are currently being
treated with chemoradiation with or without immunotherapy. In patients with
disease confined to the chest, standard therapy includes thoracic radiotherapy
and concurrent platinum-etoposide chemotherapy. Patients with metastatic
(extensive-stage) disease are treated with a combination of platinum-etoposide
chemotherapy plus immunotherapy with an anti-programmed death-ligand 1
monoclonal antibody. Although SCLC is initially very responsive to
platinum-based chemotherapy, these responses are transient because of the
development of drug resistance. In recent years, the authors have witnessed an
accelerating pace of biologic insights into the disease, leading to the
redefinition of the SCLC classification scheme. This emerging knowledge of SCLC
molecular subtypes has the potential to define unique therapeutic
vulnerabilities. Synthesizing these new discoveries with the current knowledge
of SCLC biology and clinical management may lead to unprecedented advances in
SCLC patient care. Here, the authors present an overview of multimodal clinical
approaches in SCLC, with a special focus on illuminating how recent advancements
in SCLC research could accelerate clinical development.
© 2023 The Authors. CA: A Cancer Journal for Clinicians published by Wiley
Periodicals LLC on behalf of American Cancer Society.
DOI: 10.3322/caac.21785
PMID: 37329269
3. N Engl J Med. 2023 Jul 13;389(2):137-147. doi: 10.1056/NEJMoa2304594. Epub 2023 Jun 4.
Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.
Tsuboi M(1), Herbst RS(1), John T(1), Kato T(1), Majem M(1), Grohé C(1), Wang
J(1), Goldman JW(1), Lu S(1), Su WC(1), de Marinis F(1), Shepherd FA(1), Lee
KH(1), Le NT(1), Dechaphunkul A(1), Kowalski D(1), Poole L(1), Bolanos A(1),
Rukazenkov Y(1), Wu YL(1); ADAURA Investigators.
Author information:
(1)From the Department of Thoracic Surgery and Oncology, National Cancer Center
Hospital East, Kashiwa (M.T.), the Department of Thoracic Oncology, Kanagawa
Cancer Center, Yokohama (T.K.) - both in Japan; the Section of Medical Oncology,
Yale School of Medicine and Yale Cancer Center, New Haven, CT (R.S.H.);…
BACKGROUND: Among patients with resected, epidermal growth factor receptor
(EGFR)-mutated, stage IB to IIIA non-small-cell lung cancer (NSCLC), adjuvant
osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in
significantly longer disease-free survival than placebo in the ADAURA trial. We
report the results of the planned final analysis of overall survival.
METHODS: In this phase 3, double-blind trial, we randomly assigned eligible
patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo
until disease recurrence was observed, the trial regimen was completed (3
years), or a discontinuation criterion was met. The primary end point was
investigator-assessed disease-free survival among patients with stage II to IIIA
disease. Secondary end points included disease-free survival among patients with
stage IB to IIIA disease, overall survival, and safety.
RESULTS: Of 682 patients who underwent randomization, 339 received osimertinib
and 343 received placebo. Among patients with stage II to IIIA disease, the
5-year overall survival was 85% in the osimertinib group and 73% in the placebo
group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI],
0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to
IIIA disease), the 5-year overall survival was 88% in the osimertinib group and
78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34
to 0.70; P<0.001). One new serious adverse event, pneumonia related to
coronavirus disease 2019, was reported after the previously published
data-cutoff date (the event was not considered by the investigator to be related
to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had
a safety profile consistent with that in the primary analysis.
CONCLUSIONS: Adjuvant osimertinib provided a significant overall survival
benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA
NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2304594
PMID: 37272535
4. N Engl J Med. 2023 Jun 3. doi: 10.1056/NEJMoa2302983. Online ahead of print.
Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer.
Wakelee H(1), Liberman M(1), Kato T(1), Tsuboi M(1), Lee SH(1), Gao S(1), Chen
KN(1), Dooms C(1), Majem M(1), Eigendorff E(1), Martinengo GL(1), Bylicki O(1),
Rodríguez-Abreu D(1), Chaft JE(1), Novello S(1), Yang J(1), Keller SM(1),
Samkari A(1), Spicer JD(1); KEYNOTE-671 Investigators.
Author information:
(1)From Stanford University School of Medicine, Stanford Cancer Institute,
Stanford, CA (H.W.); Centre Hospitalier de l'Université de Montréal (M.L.) and
McGill University Health Centre (J.D.S.) - both in Montreal;…
BACKGROUND: Among patients with resectable early-stage non-small-cell lung
cancer (NSCLC), a perioperative approach that includes both neoadjuvant and
adjuvant immune checkpoint inhibition may provide benefit beyond either approach
alone.
METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate
perioperative pembrolizumab in patients with early-stage NSCLC. Participants
with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1
ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3
weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles,
followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3
weeks for up to 13 cycles. The dual primary end points were event-free survival
(the time from randomization to the first occurrence of local progression that
precluded the planned surgery, unresectable tumor, progression or recurrence, or
death) and overall survival. Secondary end points included major pathological
response, pathological complete response, and safety.
RESULTS: A total of 397 participants were assigned to the pembrolizumab group,
and 400 to the placebo group. At the prespecified first interim analysis, the
median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in
the pembrolizumab group and 40.6% in the placebo group (hazard ratio for
progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to
0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the
pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet
the significance criterion). A major pathological response occurred in 30.2% of
the participants in the pembrolizumab group and in 11.0% of those in the placebo
group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001;
threshold, P = 0.0001), and a pathological complete response occurred in 18.1%
and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to
18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of
the participants in the pembrolizumab group and 37.3% of those in the placebo
group had treatment-related adverse events of grade 3 or higher, including 1.0%
and 0.8%, respectively, who had grade 5 events.
CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant
pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab
significantly improved event-free survival, major pathological response, and
pathological complete response as compared with neoadjuvant chemotherapy alone
followed by surgery. Overall survival did not differ significantly between the
groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671
ClinicalTrials.gov number, NCT03425643.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2302983
PMID: 37272513
5. Nat Commun. 2023 Jun 28;14(1):3828. doi: 10.1038/s41467-023-39300-z.
DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds
pretomanid and delamanid.
Abrahams KA(#)(1), Batt SM(#)(1), Gurcha SS(1), Veerapen N(1), Bashiri G(2),
Besra GS(3).
Author information:
(1)Institute of Microbiology and Infection, School of Biosciences, University of
Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
(2)Laboratory of Molecular and Microbial Biochemistry, School of Biological
Sciences, University of Auckland, 3A Symonds Street, Auckland, 1010, New
Zealand.
(3)Institute of Microbiology and Infection, School of Biosciences, University of
Birmingham, Edgbaston, Birmingham, B15 2TT, UK. g.besra@bham.ac.uk.
(#)Contributed equally
Mycobacterium tuberculosis is one of the global leading causes of death due to a
single infectious agent. Pretomanid and delamanid are new antitubercular agents
that have progressed through the drug discovery pipeline. These compounds are
bicyclic nitroimidazoles that act as pro-drugs, requiring activation by a
mycobacterial enzyme; however, the precise mechanisms of action of the active
metabolite(s) are unclear. Here, we identify a molecular target of activated
pretomanid and delamanid: the DprE2 subunit of
decaprenylphosphoribose-2'-epimerase, an enzyme required for the synthesis of
cell wall arabinogalactan. We also provide evidence for an NAD-adduct as the
active metabolite of pretomanid. Our results highlight DprE2 as a potential
antimycobacterial target and provide a foundation for future exploration into
the active metabolites and clinical development of pretomanid and delamanid.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-39300-z
PMCID: PMC10307805
PMID: 37380634 [Indexed for MEDLINE]
6. Nat Commun. 2023 Jun 28;14(1):3830. doi: 10.1038/s41467-023-39528-9.
A landscape of response to drug combinations in non-small cell lung cancer.
Nair NU(1), Greninger P(2), Zhang X(3), Friedman AA(2), Amzallag A(2), Cortez
E(2), Sahu AD(4), Lee JS(5), Dastur A(2), Egan RK(2), Murchie E(2), Ceribelli
M(3), Crowther GS(2), Beck E(3), McClanaghan J(2), Klump-Thomas C(3), Boisvert
JL(2), Damon LJ(2), Wilson KM(3), Ho J(2), Tam A(2), McKnight C(3), Michael
S(3), Itkin Z(3), Garnett MJ(6), Engelman JA(2), Haber DA(2)(3), Thomas
CJ(#)(7)(8), Ruppin E(#)(9), Benes CH(#)(10).
Author information:
(1)Cancer Data Science Laboratory, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD, USA.
(2)Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
(3)Howard Hughes Medical Institute, Bethesda, MD, USA.
…
Combination of anti-cancer drugs is broadly seen as way to overcome the
often-limited efficacy of single agents. The design and testing of combinations
are however very challenging. Here we present a uniquely large dataset screening
over 5000 targeted agent combinations across 81 non-small cell lung cancer cell
lines. Our analysis reveals a profound heterogeneity of response across the
tumor models. Notably, combinations very rarely result in a strong gain in
efficacy over the range of response observable with single agents. Importantly,
gain of activity over single agents is more often seen when co-targeting
functionally proximal genes, offering a strategy for designing more efficient
combinations. Because combinatorial effect is strongly context specific, tumor
specificity should be achievable. The resource provided, together with an
additional validation screen sheds light on major challenges and opportunities
in building efficacious combinations against cancer and provides an opportunity
for training computational models for synergy prediction.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-39528-9
PMCID: PMC10307832
PMID: 37380628 [Indexed for MEDLINE]
7. J Clin Oncol. 2023 Jun 28:101200JCO2300515. doi: 10.1200/JCO.23.00515. Online
ahead of print.
Lazertinib Versus Gefitinib as First-line Treatment in Patients With
EGFR-mutated Advanced Non-Small Cell Lung Cancer (NSCLC): Results From LASER301.
Cho BC(1), Ahn MJ(2), Kang JH(3), Soo RA(4), Reungwetwattana T(5), Chih-Hsin
Yang J(6), Cicin I(7), Kim DW(8), Wu YL(9), Lu S(10), Lee KH(11), Pang YK(12),
Zimina A(13), Fong CH(14), Poddubskaya E(15), Sezer A(16), How SH(17),
Danchaivijitr P(18), Kim Y(19), Lim Y(19), An T(19), Lee H(19), Byun HM(19),
Zaric B(20).
Author information:
(1)Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College
of Medicine, Seoul, Republic of Korea.
(2)Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Republic of Korea.
(3)Division of Medical Oncology, Department of Internal Medicine, Seoul St.
Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
…
PURPOSE: Lazertinib is a potent, central nervous system (CNS)-penetrant,
third-generation epidermal growth factor receptor (EGFR) tyrosine kinase
inhibitor (TKI). This global, phase 3 study (LASER301) compared lazertinib
versus gefitinib in treatment-naïve patients with EGFR-mutated (exon 19 deletion
[ex19del]/L858R) locally advanced or metastatic non-small cell lung cancer
(NSCLC).
METHODS: Patients were ≥18 years with no prior systemic anti-cancer therapy.
Neurologically stable patients with CNS metastases were allowed. Patients were
randomized 1:1 to lazertinib 240 mg once daily (qd) orally (po) or gefitinib 250
mg qd po, stratified by mutation status and race. The primary endpoint was
investigator-assessed progression-free survival (PFS) by RECIST v1.1.
RESULTS: Overall, 393 patients received double-blind study treatment across 96
sites in 13 countries. Median PFS was significantly longer with lazertinib than
with gefitinib (20.6 vs 9.7 months; hazard ratio [HR], 0.45; 95% confidence
interval [CI], 0.34 to 0.58; P<0.001). The PFS benefit of lazertinib over
gefitinib was consistent across all predefined subgroups. The objective response
rate was 76% in both groups (odds ratio, 0.99; 95% CI, 0.62 to 1.59). Median
duration of response was 19.4 months (95% CI, 16.6 to 24.9) with lazertinib
versus 8.3 months (95% CI, 6.9 to 10.9) with gefitinib. Overall survival data
were immature at the interim analysis (29% maturity). The 18-month survival rate
was 80% with lazertinib and 72% with gefitinib (HR, 0.74; 95% CI, 0.51 to 1.08;
P=0.116). Observed safety of both treatments was consistent with their
previously reported safety profiles.
CONCLUSION: Lazertinib demonstrated significant efficacy improvement compared
with gefitinib in the first-line treatment of EGFR-mutated advanced NSCLC, with
a manageable safety profile.
DOI: 10.1200/JCO.23.00515
PMID: 37379502
8. Mol Biol Evol. 2023 Jun 1;40(6):msad131. doi: 10.1093/molbev/msad131.
Analysis of Genome-Wide Mutational Dependence in Naturally Evolving
Mycobacterium tuberculosis Populations.
Green AG(1), Vargas R(1)(2), Marin MG(1), Freschi L(1), Xie J(3), Farhat
MR(1)(4).
Author information:
(1)Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
USA.
(2)Center for Computational Biomedicine, Harvard Medical School, Boston, MA,
USA.
(3)Department of Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
(4)Division of Pulmonary and Critical Care Medicine, Massachusetts General
Hospital, Boston, MA, USA.
Pathogenic microorganisms are in a perpetual struggle for survival in changing
host environments, where host pressures necessitate changes in pathogen
virulence, antibiotic resistance, or transmissibility. The genetic basis of
phenotypic adaptation by pathogens is difficult to study in vivo. In this work,
we develop a phylogenetic method to detect genetic dependencies that promote
pathogen adaptation using 31,428 in vivo sampled Mycobacterium tuberculosis
genomes, a globally prevalent bacterial pathogen with increasing levels of
antibiotic resistance. We find that dependencies between mutations are enriched
in antigenic and antibiotic resistance functions and discover 23 mutations that
potentiate the development of antibiotic resistance. Between 11% and 92% of
resistant strains harbor a dependent mutation acquired after a
resistance-conferring variant. We demonstrate the pervasiveness of genetic
dependency in adaptation of naturally evolving populations and the utility of
the proposed computational approach.
© The Author(s) 2023. Published by Oxford University Press on behalf of Society
for Molecular Biology and Evolution.
DOI: 10.1093/molbev/msad131
PMCID: PMC10292908
PMID: 37352142 [Indexed for MEDLINE]
9. J Clin Oncol. 2023 Jun 16:JCO2300059. doi: 10.1200/JCO.23.00059. Online ahead of print.
First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast
Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan
in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.
Shimizu T(1)(2), Sands J(3), Yoh K(4), Spira A(5), Garon EB(6), Kitazono S(7),
Johnson ML(8), Meric-Bernstam F(9), Tolcher AW(10), Yamamoto N(1), Greenberg
J(11), Kawasaki Y(12), Zebger-Gong H(11), Kobayashi F(13), Phillips P(12),
Lisberg AE(6), Heist RS(14).
Author information:
(1)National Cancer Center Hospital, Tokyo, Japan.
(2)Wakayama Medical University Hospital, Wakayama, Japan.
(3)Dana-Farber Cancer Institute, Boston, MA.
…
PURPOSE: This first-in-human, dose-escalation and dose-expansion study evaluated
the safety, tolerability, and antitumor activity of datopotamab deruxtecan
(Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed
antibody-drug conjugate in solid tumors, including advanced non-small-cell lung
cancer (NSCLC).
PATIENTS AND METHODS: Adults with locally advanced/metastatic NSCLC received
0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg
Dato-DXd once every 3 weeks during expansion. Primary end points were safety and
tolerability. Secondary end points included objective response rate (ORR),
survival, and pharmacokinetics.
RESULTS: Two hundred ten patients received Dato-DXd, including 180 in the 4-8
mg/kg dose-expansion cohorts. This population had a median of three prior lines
of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the
recommended dose for further development was 6 mg/kg once every 3 weeks. In
patients receiving 6 mg/kg (n = 50), median duration on study, including
follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most
frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%),
stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs
occurred in 54% and 26% of patients, respectively. Interstitial lung disease
adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of
50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of
response was 10.5 months; median progression-free survival and overall survival
were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6
months), respectively. Responses occurred regardless of TROP2 expression.
CONCLUSION: Promising antitumor activity and a manageable safety profile were
seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further
investigation as first-line combination therapy in advanced NSCLC and as
monotherapy in the second-line setting and beyond is ongoing.
DOI: 10.1200/JCO.23.00059
PMID: 37327461
10. Cell Host Microbe. 2023 Jun 14;31(6):921-923. doi: 10.1016/j.chom.2023.05.021.
BCG: From veins to correlates.
Suliman S(1).
Author information:
(1)Zuckerberg San Francisco General Hospital, Department of Medicine, Division
of Experimental Medicine, University of California San Francisco, San Francisco,
CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. Electronic address:
sara.suliman@ucsf.edu.
In this issue of Cell Host & Microbe, Darrah et al. define immune responses
against Mycobacterium tuberculosis (Mtb) infection following intravenous
Bacille-Calmette Guérin (BCG) vaccination of nonhuman primates. The results
provide candidate correlates of protection for examination in clinical trials of
TB vaccines against Mtb infection and tuberculosis (TB) disease.
Copyright © 2023 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.chom.2023.05.021
PMID: 37321176 [Indexed for MEDLINE]
11. PLoS Biol. 2023 Jun 15;21(6):e3002159. doi: 10.1371/journal.pbio.3002159.
eCollection 2023 Jun.
Autophagy prevents early proinflammatory responses and neutrophil recruitment
during Mycobacterium tuberculosis infection without affecting pathogen burden in
macrophages.
Kinsella RL(1), Kimmey JM(1), Smirnov A(1), Woodson R(1), Gaggioli MR(1), Chavez
SM(1), Kreamalmeyer D(1), Stallings CL(1).
Author information:
(1)Department of Molecular Microbiology, Center for Women's Infectious Disease
Research, Washington University School of Medicine, St. Louis, Missouri, United
States of America.
The immune response to Mycobacterium tuberculosis infection determines
tuberculosis disease outcomes, yet we have an incomplete understanding of what
immune factors contribute to a protective immune response. Neutrophilic
inflammation has been associated with poor disease prognosis in humans and in
animal models during M. tuberculosis infection and, therefore, must be tightly
regulated. ATG5 is an essential autophagy protein that is required in innate
immune cells to control neutrophil-dominated inflammation and promote survival
during M. tuberculosis infection; however, the mechanistic basis for how ATG5
regulates neutrophil recruitment is unknown. To interrogate what innate immune
cells require ATG5 to control neutrophil recruitment during M. tuberculosis
infection, we used different mouse strains that conditionally delete Atg5 in
specific cell types. We found that ATG5 is required in CD11c+ cells (lung
macrophages and dendritic cells) to control the production of proinflammatory
cytokines and chemokines during M. tuberculosis infection, which would otherwise
promote neutrophil recruitment. This role for ATG5 is autophagy dependent, but
independent of mitophagy, LC3-associated phagocytosis, and inflammasome
activation, which are the most well-characterized ways that autophagy proteins
regulate inflammation. In addition to the increased proinflammatory cytokine
production from macrophages during M. tuberculosis infection, loss of ATG5 in
innate immune cells also results in an early induction of TH17 responses.
Despite prior published in vitro cell culture experiments supporting a role for
autophagy in controlling M. tuberculosis replication in macrophages, the effects
of autophagy on inflammatory responses occur without changes in M. tuberculosis
burden in macrophages. These findings reveal new roles for autophagy proteins in
lung resident macrophages and dendritic cells that are required to suppress
inflammatory responses that are associated with poor control of M. tuberculosis
infection.
Copyright: © 2023 Kinsella et al. This is an open access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
DOI: 10.1371/journal.pbio.3002159
PMCID: PMC10306192
PMID: 37319285 [Indexed for MEDLINE]
12. Nat Commun. 2023 Jun 12;14(1):3468. doi: 10.1038/s41467-023-39139-4.
Phase 1b trial of anti-EGFR antibody JMT101 and Osimertinib in EGFR exon 20
insertion-positive non-small-cell lung cancer.
Zhao S(#)(1), Zhuang W(#)(2), Han B(#)(3), Song Z(#)(4), Guo W(#)(5), Luo
F(#)(6), Wu L(7), Hu Y(8), Wang H(9), Dong X(10), Jiang D(11), Wang M(12), Miao
L(13), Wang Q(14), Zhang J(15), Fu Z(16), Huang Y(1), Xu C(17), Hu L(18), Li
L(19), Hu R(19), Yang Y(19), Li M(19), Yang X(20), Zhang L(21), Huang Y(22),
Fang W(23).
Author information:
(1)Department of Medical Oncology, State Key Laboratory of Oncology in South
China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen
University Cancer Center, Guangzhou, China.
(2)Department of Thoracic Oncology, Fujian Cancer Hospital, Fuzhou, China.
(3)Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai, China.
…
EGFR exon 20 insertion (20ins)-positive non-small-cell lung cancer (NSCLC) is an
uncommon disease with limited therapeutic options and dismal prognosis. Here we
report the activity, tolerability, potential mechanisms of response and
resistance for dual targeting EGFR 20ins with JMT101 (anti-EGFR monoclonal
antibody) plus osimertinib from preclinical models and an open label,
multi-center phase 1b trial (NCT04448379). Primary endpoint of the trial is
tolerability. Secondary endpoints include objective response rate, duration of
response, disease control rate, progression free survival, overall survival, the
pharmacokinetic profile of JMT101, occurrence of anti-drug antibodies and
correlation between biomarkers and clinical outcomes. A total of 121 patients
are enrolled to receive JMT101 plus osimertinib 160 mg. The most common adverse
events are rash (76.9%) and diarrhea (63.6%). The confirmed objective response
rate is 36.4%. Median progression-free survival is 8.2 months. Median duration
of response is unreached. Subgroup analyses were performed by
clinicopathological features and prior treatments. In patients with
platinum-refractory diseases (n = 53), confirmed objective response rate is
34.0%, median progression-free survival is 9.2 months and median duration of
response is 13.3 months. Responses are observed in distinct 20ins variants and
intracranial lesions. Intracranial disease control rate is 87.5%. Confirmed
intracranial objective response rate is 25%.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-39139-4
PMCID: PMC10261012
PMID: 37308490 [Indexed for MEDLINE]
13. PLoS Med. 2023 Jun 9;20(6):e1004246. doi: 10.1371/journal.pmed.1004246.
eCollection 2023 Jun.
Same-day testing with initiation of antiretroviral therapy or tuberculosis
treatment versus standard care for persons presenting with tuberculosis symptoms
at HIV diagnosis: A randomized open-label trial from Haiti.
Dorvil N(1), Rivera VR(1), Riviere C(1), Berman R(2), Severe P(1), Bang H(3),
Lavoile K(1), Devieux JG(4), Faustin M(1), Saintyl G(1), Mendicuti MD(5), Pierre
S(1), Apollon A(1), Dumond E(1), Forestal GPL(1), Rouzier V(1)(6), Marcelin
A(1), McNairy ML(6), Walsh KF(6), Dupnik K(6), Reif LK(6), Byrne AL(7),
Bousleiman S(2), Orvis E(2), Joseph P(1), Cremieux PY(2), Pape JW(1)(6), Koenig
SP(5).
Author information:
(1)Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections
(GHESKIO), Port-au-Prince, Haiti.
(2)The Analysis Group, Boston, Massachusetts, United States of America.
(3)University of California, Davis School of Medicine, Davis, California, United
States of America.
(4)Florida International University, Miami, Florida, United States of America.
(5)Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts,
United States of America.
(6)Weill Cornell Medicine, New York, New York, United States of America.
(7)St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
BACKGROUND: Same-day HIV testing and antiretroviral therapy (ART) initiation is
being widely implemented. However, the optimal timing of ART among patients with
tuberculosis (TB) symptoms is unknown. We hypothesized that same-day treatment
(TB treatment for those diagnosed with TB; ART for those not diagnosed with TB)
would be superior to standard care in this population.
METHODS AND FINDINGS: We conducted an open-label trial among adults with TB
symptoms at initial HIV diagnosis at GHESKIO in Haiti; participants were
recruited and randomized on the same day. Participants were randomized in a 1:1
ratio to same-day treatment (same-day TB testing with same-day TB treatment if
TB diagnosed; same-day ART if TB not diagnosed) versus standard care (initiating
TB treatment within 7 days and delaying ART to day 7 if TB not diagnosed). In
both groups, ART was initiated 2 weeks after TB treatment. The primary outcome
was retention in care with 48-week HIV-1 RNA<200 copies/mL, with intention to
treat (ITT) analysis. From November 6, 2017 to January 16, 2020, 500
participants were randomized (250/group); the final study visit occurred on
March 1, 2021. Baseline TB was diagnosed in 40 (16.0%) in the standard and 48
(19.2%) in the same-day group; all initiated TB treatment. In the standard
group, 245 (98.0%) initiated ART at median of 9 days; 6 (2.4%) died, 15 (6.0%)
missed the 48-week visit, and 229 (91.6%) attended the 48-week visit. Among all
who were randomized, 220 (88.0%) received 48-week HIV-1 RNA testing; 168 had
<200 copies/mL (among randomized: 67.2%; among tested: 76.4%). In the same-day
group, 249 (99.6%) initiated ART at median of 0 days; 9 (3.6%) died, 23 (9.2%)
missed the 48-week visit, and 218 (87.2%) attended the 48-week visit. Among all
who were randomized, 211 (84.4%) received 48-week HIV-1 RNA; 152 had<200
copies/mL (among randomized: 60.8%; among tested: 72.0%). There was no
difference between groups in the primary outcome (60.8% versus 67.2%; risk
difference: -0.06; 95% CI [-0.15, 0.02]; p = 0.14). Two new grade 3 or 4 events
were reported per group; none were judged to be related to the intervention. The
main limitation of this study is that it was conducted at a single urban clinic,
and the generalizability to other settings is uncertain.
CONCLUSIONS: In patients with TB symptoms at HIV diagnosis, we found that
same-day treatment was not associated with superior retention and viral
suppression. In this study, a short delay in ART initiation did not appear to
compromise outcomes.
TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov
NCT03154320.
Copyright: © 2023 Dorvil et al. This is an open access article distributed under
the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
DOI: 10.1371/journal.pmed.1004246
PMCID: PMC10292694
PMID: 37294843 [Indexed for MEDLINE]
14. J Clin Oncol. 2023 Jun 4:JCO2300774. doi: 10.1200/JCO.23.00774. Online ahead of print.
Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With
BRAF(V600)-Mutant Metastatic Non-Small-Cell Lung Cancer.
Riely GJ(1), Smit EF(2), Ahn MJ(3), Felip E(4), Ramalingam SS(5), Tsao A(6),
Johnson M(7), Gelsomino F(8), Esper R(9), Nadal E(10), Offin M(1), Provencio
M(11), Clarke J(12), Hussain M(9), Otterson GA(13), Dagogo-Jack I(14), Goldman
JW(15), Morgensztern D(16), Alcasid A(17), Usari T(18), Wissel P(19), Wilner
K(20), Pathan N(20), Tonkovyd S(21), Johnson BE(22).
Author information:
(1)Memorial Sloan Kettering Cancer Center, New York, NY.
(2)Department of Pulmonary Diseases, Leiden University Medical Center, Leiden,
the Netherlands.
(3)Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
South Korea.
…
PURPOSE: The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK
inhibitor) has demonstrated clinical efficacy with an acceptable safety profile
in patients with BRAFV600E/K-mutant metastatic melanoma. We evaluated the
efficacy and safety of encorafenib plus binimetinib in patients with
BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC).
METHODS: In this ongoing, open-label, single-arm, phase II study, patients with
BRAFV600E-mutant metastatic NSCLC received oral encorafenib 450 mg once daily
plus binimetinib 45 mg twice daily in 28-day cycles. The primary end point was
confirmed objective response rate (ORR) by independent radiology review (IRR).
Secondary end points included duration of response (DOR), disease control rate
(DCR), progression-free survival (PFS), overall survival, time to response, and
safety.
RESULTS: At data cutoff, 98 patients (59 treatment-naïve and 39 previously
treated) with BRAFV600E-mutant metastatic NSCLC received encorafenib plus
binimetinib. Median duration of treatment was 9.2 months with encorafenib and
8.4 months with binimetinib. ORR by IRR was 75% (95% CI, 62 to 85) in
treatment-naïve and 46% (95% CI, 30 to 63) in previously treated patients;
median DOR was not estimable (NE; 95% CI, 23.1 to NE) and 16.7 months (95% CI,
7.4 to NE), respectively. DCR after 24 weeks was 64% in treatment-naïve and 41%
in previously treated patients. Median PFS was NE (95% CI, 15.7 to NE) in
treatment-naïve and 9.3 months (95% CI, 6.2 to NE) in previously treated
patients. The most frequent treatment-related adverse events (TRAEs) were nausea
(50%), diarrhea (43%), and fatigue (32%). TRAEs led to dose reductions in 24
(24%) and permanent discontinuation of encorafenib plus binimetinib in 15 (15%)
patients. One grade 5 TRAE of intracranial hemorrhage was reported. Interactive
visualization of the data presented in this article is available at the PHAROS
dashboard (https://clinical-trials.dimensions.ai/pharos/).
CONCLUSION: For patients with treatment-naïve and previously treated
BRAFV600E-mutant metastatic NSCLC, encorafenib plus binimetinib showed a
meaningful clinical benefit with a safety profile consistent with that observed
in the approved indication in melanoma.
DOI: 10.1200/JCO.23.00774
PMID: 37270692
15. Cell Host Microbe. 2023 Jun 14;31(6):978-992.e5. doi:
10.1016/j.chom.2023.05.009. Epub 2023 Jun 2.
Identification of host regulators of Mycobacterium tuberculosis phenotypes
uncovers a role for the MMGT1-GPR156 lipid droplet axis in persistence.
Kalam H(1), Chou CH(1), Kadoki M(2), Graham DB(2), Deguine J(3), Hung DT(4),
Xavier RJ(5).
Author information:
(1)Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for
Computational and Integrative Biology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA 02114, USA.
(2)Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for
Computational and Integrative Biology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA 02114, USA; Department of Molecular Biology,
Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
(3)Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
…
The ability of Mycobacterium tuberculosis (Mtb) to establish latency affects
disease and response to treatment. The host factors that influence the
establishment of latency remain elusive. We engineered a multi-fluorescent Mtb
strain that reports survival, active replication, and stressed non-replication
states and determined the host transcriptome of the infected macrophages in
these states. Additionally, we conducted a genome-wide CRISPR screen to identify
host factors that modulated the phenotypic state of Mtb. We validated hits in a
phenotype-specific manner and prioritized membrane magnesium transporter 1
(MMGT1) for a detailed mechanistic investigation. Mtb infection of
MMGT1-deficient macrophages promoted a switch to persistence, upregulated lipid
metabolism genes, and accumulated lipid droplets during infection. Targeting
triacylglycerol synthesis reduced both droplet formation and Mtb persistence.
The orphan G protein-coupled receptor GPR156 is a key inducer of droplet
accumulation in ΔMMGT1 cells. Our work uncovers the role of MMGT1-GPR156-lipid
droplets in the induction of Mtb persistence.
Copyright © 2023 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.chom.2023.05.009
PMID: 37269834 [Indexed for MEDLINE]
16. Cell Host Microbe. 2023 Jun 14;31(6):962-977.e8. doi:
10.1016/j.chom.2023.05.006. Epub 2023 Jun 1.
Airway T cells are a correlate of i.v. Bacille Calmette-Guerin-mediated
protection against tuberculosis in rhesus macaques.
Darrah PA(1), Zeppa JJ(2), Wang C(3), Irvine EB(4), Bucsan AN(1), Rodgers MA(2),
Pokkali S(1), Hackney JA(1), Kamath M(1), White AG(2), Borish HJ(2), Frye LJ(2),
Tomko J(2), Kracinovsky K(2), Lin PL(5), Klein E(6), Scanga CA(2), Alter G(7),
Fortune SM(4), Lauffenburger DA(8), Flynn JL(2), Seder RA(1), Maiello P(2),
Roederer M(9).
Author information:
(1)Vaccine Research Center, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
(2)Department of Microbiology and Molecular Genetics, University of Pittsburgh
School of Medicine and Center for Vaccine Research, University of Pittsburgh,
Pittsburgh, PA 15261, USA.
(3)Department of Immunology and Microbiology, University of Colorado, Anschuntz
Medical Campus, Aurora, CO 80045, USA; Department of Biological Engineering,
Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
…
Bacille Calmette-Guerin (BCG), the only approved Mycobacterium tuberculosis
(Mtb) vaccine, provides limited durable protection when administered
intradermally. However, recent work revealed that intravenous (i.v.) BCG
administration yielded greater protection in macaques. Here, we perform a
dose-ranging study of i.v. BCG vaccination in macaques to generate a range of
immune responses and define correlates of protection. Seventeen of 34 macaques
had no detectable infection after Mtb challenge. Multivariate analysis
incorporating longitudinal cellular and humoral immune parameters uncovered an
extensive and highly coordinated immune response from the bronchoalveolar lavage
(BAL). A minimal signature predicting protection contained four BAL immune
features, of which three remained significant after dose correction: frequency
of CD4 T cells producing TNF with interferon γ (IFNγ), frequency of those
producing TNF with IL-17, and the number of NK cells. Blood immune features were
less predictive of protection. We conclude that CD4 T cell immunity and NK cells
in the airway correlate with protection following i.v. BCG.
Published by Elsevier Inc.
DOI: 10.1016/j.chom.2023.05.006
PMID: 37267955 [Indexed for MEDLINE]
17. J Natl Cancer Inst. 2023 Jun 1:djad071. doi: 10.1093/jnci/djad071. Online ahead of print.
Lung cancer risk discrimination of prediagnostic proteomics measurements
compared with existing prediction tools.
Feng X(1), Wu WY(2), Onwuka JU(1), Haider Z(2), Alcala K(1), Smith-Byrne K(3),
Zahed H(1), Guida F(4), Wang R(5), Bassett JK(6), Stevens V(7), Wang Y(8),
Weinstein S(9), Freedman ND(9), Chen C(10), Tinker L(11), Nøst TH(12), Koh
WP(13)(14), Muller D(15), Colorado-Yohar SM(16)(17)(18), Tumino R(19), Hung
RJ(20)(21), Amos CI(22), Lin X(23)(24)(25), Zhang X(26), Arslan AA(27), Sánchez
MJ(17)(28)(29)(30), Sørgjerd EP(31), Severi G(32), Hveem K(31), Brennan P(1),
Langhammer A(31)(33), Milne RL(6)(34)(35), Yuan JM(5)(36), Melin B(2), Johansson
M(2), Robbins HA(1), Johansson M(1).
Author information:
(1)Genomic Epidemiology Branch, International Agency for Research on Cancer,
Lyon, France.
(2)Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden.
(3)Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
…
BACKGROUND: We sought to develop a proteomics-based risk model for lung cancer
and evaluate its risk-discriminatory performance in comparison with a
smoking-based risk model (PLCOm2012) and a commercially available autoantibody
biomarker test.
METHODS: We designed a case-control study nested in 6 prospective cohorts,
including 624 lung cancer participants who donated blood samples at most 3 years
prior to lung cancer diagnosis and 624 smoking-matched cancer free participants
who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts
to select proteins and train a protein-based risk model. We subsequently used
154 case-control pairs from 2 cohorts to compare the risk-discriminatory
performance of the protein-based model with that of the Early Cancer Detection
Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating
characteristics analysis and by estimating models' sensitivity. All tests were
2-sided.
RESULTS: The area under the curve for the protein-based risk model in the
validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81)
compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (Pdifference
= .001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a
specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same
specificity of 86%, the sensitivity for the protein-based risk model was
estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the
PLCOm2012 model.
CONCLUSION: Circulating proteins showed promise in predicting incident lung
cancer and outperformed a standard risk prediction model and the commercialized
EarlyCDT-Lung.
© The Author(s) 2023. Published by Oxford University Press.
DOI: 10.1093/jnci/djad071
PMID: 37260165
18. J Clin Invest. 2023 Jun 15;133(12):e158630. doi: 10.1172/JCI158630.
Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium
tuberculosis infection by regulating type I IFN production.
Thirunavukkarasu S(1), Ahmed M(1), Rosa BA(2)(3), Boothby M(4), Cho SH(4),
Rangel-Moreno J(5), Mbandi SK(6), Schreiber V(7), Gupta A(1), Zuniga J(8)(9),
Mitreva M(2)(3), Kaushal D(10), Scriba TJ(6), Khader SA(1).
Author information:
(1)Department of Molecular Microbiology.
(2)McDonnell Genome Institute, and.
(3)Division of Infectious Diseases, Department of Internal Medicine, Washington
University in St. Louis, St. Louis, Missouri, USA.
…
The ADP ribosyltransferases (PARPs 1-17) regulate diverse cellular processes,
including DNA damage repair. PARPs are classified on the basis of their ability
to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation
(MARylation). Although PARP9 mRNA expression is significantly increased in
progressive tuberculosis (TB) in humans, its participation in host immunity to
TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9
enzyme was upregulated during TB in humans and mice and provide evidence of a
critical modulatory role for PARP9 in DNA damage, cyclic GMP-AMP synthase (cGAS)
expression, and type I IFN production during TB. Thus, Parp9-deficient mice were
susceptible to Mycobacterium tuberculosis infection and exhibited increased TB
disease, cGAS and 2'3'-cyclic GMP-AMP (cGAMP) expression, and type I IFN
production, along with upregulation of complement and coagulation pathways.
Enhanced M. tuberculosis susceptibility is type I IFN dependent, as blockade of
IFN α receptor (IFNAR) signaling reversed the enhanced susceptibility of
Parp9-/- mice. Thus, in sharp contrast to PARP9 enhancement of type I IFN
production in viral infections, this member of the MAR family plays a protective
role by limiting type I IFN responses during TB.
DOI: 10.1172/JCI158630
PMCID: PMC10266794
PMID: 37200107 [Indexed for MEDLINE]
19. J Clin Oncol. 2023 Jun 10;41(17):3249-3259. doi: 10.1200/JCO.22.02509. Epub 2023 May 4.
US Food and Drug Administration Approval Summary: Nivolumab Plus
Platinum-Doublet Chemotherapy for the Neoadjuvant Treatment of Patients With
Resectable Non-Small-Cell Lung Cancer.
Akinboro O(1), Drezner N(1), Amatya A(1), Runyan J(1), Fourie-Zirkelbach J(1),
Zhao M(1), Bi Y(1), Korsah K(1), Mixter B(2), Tang S(1), Larkins E(1), Pazdur
R(1)(2), Beaver JA(1)(2), Singh H(1)(2).
Author information:
(1)Center for Drug Evaluation and Research (CDER), U.S. Food and Drug
Administration, Silver Spring, MD.
(2)Oncology Center of Excellence, U.S. Food and Drug Administration, Silver
Spring, MD.
PURPOSE: On March 4, 2022, the US Food and Drug Administration (FDA) approved
nivolumab plus platinum-doublet chemotherapy for the neoadjuvant treatment of
patients with resectable non-small-cell lung cancer (NSCLC). We discuss the
FDA's review of the key data and regulatory considerations supporting this
approval.
PATIENTS AND METHODS: The approval was based on the results of CheckMate 816, an
international, multiregional, active-controlled trial that randomly assigned 358
patients with resectable NSCLC, stage IB (≥4 cm) to IIIA (N2) per the American
Joint Committee on Cancer seventh staging edition to receive either nivolumab
plus platinum-doublet or platinum-doublet chemotherapy alone for three cycles
before planned surgical resection. The major efficacy end point that supported
this approval was event-free survival (EFS).
RESULTS: At the first planned interim analysis (IA), the hazard ratio (HR) for
EFS was 0.63 (95% CI, 0.45 to 0.87; P = .0052; statistical significance boundary
= .0262) favoring the nivolumab plus chemotherapy arm; the median EFS was 31.6
months (95% CI, 30.2 to not reached) in the nivolumab plus chemotherapy arm
versus 20.8 months (95% CI, 14.0 to 26.7) in the chemotherapy-only arm. At the
time of a prespecified IA for overall survival (OS), 26% of patients had died,
and the HR for OS was 0.57 (95% CI, 0.38 to 0.87; P = .0079; statistical
significance boundary = .0033). Eighty-three percent of patients in the
nivolumab-containing arm versus 75% in the chemotherapy-only arm received
definitive surgery.
CONCLUSION: This approval, the first for any regimen for the neoadjuvant
treatment of NSCLC in the United States, was supported by a statistically
significant and clinically meaningful improvement in EFS with no evidence of
detriment in OS or negative impact on patients' receipt and timing of surgery or
surgical outcomes.
DOI: 10.1200/JCO.22.02509
PMCID: PMC10256356
PMID: 37141544 [Indexed for MEDLINE]
20. J Clin Oncol. 2023 Jun 20;41(18):3311-3317. doi: 10.1200/JCO.22.02524. Epub 2023 Apr 25.
Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients
With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of
CodeBreaK 100.
Dy GK(1), Govindan R(2), Velcheti V(3), Falchook GS(4), Italiano A(5), Wolf
J(6), Sacher AG(7), Takahashi T(8), Ramalingam SS(9), Dooms C(10), Kim DW(11),
Addeo A(12), Desai J(13), Schuler M(14), Tomasini P(15), Hong DS(16), Lito
P(17), Tran Q(18), Jones S(18), Anderson A(18), Hindoyan A(18), Snyder W(18),
Skoulidis F(16), Li BT(17).
Author information:
(1)Roswell Park Comprehensive Cancer Center, Buffalo, NY.
(2)Siteman Cancer Center, Washington University School of Medicine, St Louis,
MO.
(3)Perlmutter Cancer Center, New York University Langone, New York, NY.
…
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.In the longest follow-up, to our
knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety,
and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced
non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial
(ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group,
open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated,
locally advanced or metastatic NSCLC after progression on prior therapies.
Patients (N = 174) received sotorasib 960 mg once daily with the primary end
points for phase I of safety and tolerability and for phase II of objective
response rate (ORR). Sotorasib produced an ORR of 41%, median duration of
response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall
survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical
benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1
expression levels, in a proportion of patients with somatic STK11 and/or KEAP1
alterations, and was associated with lower baseline circulating tumor DNA
levels. Sotorasib was well tolerated, with few late-onset treatment-related
toxicities, none of which led to treatment discontinuation. These results
demonstrate the long-term benefit of sotorasib, including in subgroups with poor
prognosis.
DOI: 10.1200/JCO.22.02524
PMID: 37098232 [Indexed for MEDLINE]
21. J Exp Med. 2023 Jun 5;220(6):e20221392. doi: 10.1084/jem.20221392. Epub 2023 Mar 15.
Spatial mapping reveals granuloma diversity and histopathological superstructure
in human tuberculosis.
Sawyer AJ(1)(2)(3), Patrick E(4)(5)(6), Edwards J(1)(7), Wilmott JS(1)(3)(7),
Fielder T(8), Yang Q(9), Barber DL(10), Ernst JD(11), Britton WJ(2)(12),
Palendira U(1)(2)(3), Chen X(13), Feng CG(1)(2)(3)(14).
Author information:
(1)School of Medical Sciences, Faculty of Medicine and Health, The University of
Sydney , Sydney, Australia.
(2)Centenary Institute, The University of Sydney , Sydney, Australia.
(3)Charles Perkins Centre, The University of Sydney , Sydney, Australia.
…
The hallmark of tuberculosis (TB) is the formation of immune cell-enriched
aggregates called granulomas. While granulomas are pathologically diverse, their
tissue-wide heterogeneity has not been spatially resolved at the single-cell
level in human tissues. By spatially mapping individual immune cells in every
lesion across entire tissue sections, we report that in addition to necrotizing
granulomas, the human TB lung contains abundant non-necrotizing leukocyte
aggregates surrounding areas of necrotizing tissue. These cellular lesions were
more diverse in composition than necrotizing lesions and could be stratified
into four general classes based on cellular composition and spatial distribution
of B cells and macrophages. The cellular composition of non-necrotizing
structures also correlates with their proximity to necrotizing lesions,
indicating these are foci of distinct immune reactions adjacent to necrotizing
granulomas. Together, we show that during TB, diseased lung tissue develops a
histopathological superstructure comprising at least four different types of
non-necrotizing cellular aggregates organized as satellites of necrotizing
granulomas.
© 2023 Sawyer et al.
DOI: 10.1084/jem.20221392
PMCID: PMC10035589
PMID: 36920308 [Indexed for MEDLINE]
22. Am J Respir Crit Care Med. 2023 Jun 1;207(11):1525-1532. doi:
10.1164/rccm.202211-2125OC.
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(1)(3)(4),
Rich ML(1)(3)(4), Bastard M(6), Huerga H(6), Melikyan N(6), Atwood SA(3),
Avaliani Z(7), Llanos F(8)(9), Manzur-Ul-Alam M(10), Zarli K(11), Binegdie
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(5), Vilbrun C(20), Khan M(21),
Hewison C(22), Khan PY(23), Franke MF(1).
Author information:
(1)Department of Global Health and Social Medicine, Harvard Medical School,
Boston, Massachusetts.
(2)CAUSALab, Departments of Epidemiology, Harvard T.H. Chan School of Public
Health, Harvard University, Boston, Massachusetts.
(3)Division of Global Health Equity, Brigham and Women's Hospital, Boston,
Massachusetts.
…
Comment in
Am J Respir Crit Care Med. 2023 Jun 1;207(11):1423-1424.
Rationale: Current recommendations for the treatment of rifampicin- and
multidrug-resistant tuberculosis include bedaquiline (BDQ) used for 6 months or
longer. Evidence is needed to inform the optimal duration of BDQ. Objectives: We
emulated a target trial to estimate the effect of three BDQ duration treatment
strategies (6, 7-11, and ⩾12 mo) 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. Measurements and Main Results: The 1,468 eligible
individuals received a median of 4 (interquartile range, 4-5) likely effective
drugs. In 87.1% and 77.7% of participants, this included linezolid and
clofazimine, respectively. The adjusted probability of successful treatment was
0.85 (95% confidence interval [CI], 0.81-0.88) for 6 months of BDQ, 0.77 (95%
CI, 0.73-0.81) for 7-11 months, and 0.86 (95% CI, 0.83-0.88) for ⩾12 months.
Compared with 6 months of BDQ, the ratio of treatment success was 0.91 (95% CI,
0.85-0.96) for 7-11 months and 1.01 (95% CI, 0.96-1.06) for ⩾12 months. Naive
analyses that did not account for bias revealed a higher probability of
successful treatment with ⩾12 months (ratio, 1.09 [95% CI, 1.05-1.14]).
Conclusions: BDQ use beyond 6 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 bias can influence estimates of the effects of treatment duration.
Future analyses should explore the effect of treatment duration of BDQ and other
drugs in subgroups with advanced disease and/or receiving less potent regimens.
DOI: 10.1164/rccm.202211-2125OC
PMCID: PMC10263131
PMID: 36802336 [Indexed for MEDLINE]
23. J Clin Oncol. 2023 Jun 1;41(16):2893-2903. doi: 10.1200/JCO.22.02823. Epub 2023 Jan 23.
Tarlatamab, a First-in-Class DLL3-Targeted Bispecific T-Cell Engager, in
Recurrent Small-Cell Lung Cancer: An Open-Label, Phase I Study.
Paz-Ares L(1), Champiat S(2), Lai WV(3), Izumi H(4), Govindan R(5), Boyer M(6),
Hummel HD(7), Borghaei H(8), Johnson ML(9), Steeghs N(10), Blackhall F(11),
Dowlati A(12), Reguart N(13), Yoshida T(14), He K(15), Gadgeel SM(16), Felip
E(17), Zhang Y(18), Pati A(18), Minocha M(18), Mukherjee S(18), Goldrick A(18),
Nagorsen D(18), Hashemi Sadraei N(18), Owonikoko TK(19).
Author information:
(1)Hospital Universitario 12 de Octubre, CNIO-H120 Lung Cancer Unit, Ciberonc
and Universidad Complutense, Madrid, Spain.
(2)Gustave Roussy, DC(c)partement d'Innovation ThC(c)rapeutique et d'Essais
PrC(c)coces (DITEP), Villejuif, France.
(3)Thoracic Oncology Service, Department of Medicine, Division of Solid Tumor
Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
…
Comment in
J Clin Oncol. 2023 Jun 1;41(16):2877-2880.
Transl Lung Cancer Res. 2023 Jun 30;12(6):1355-1357.
PURPOSE: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited
treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC.
Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and
CD3 leading to T-cellb-mediated tumor lysis. Herein, we report phase I results
of tarlatamab in patients with SCLC.
PATIENTS AND METHODS: This study evaluated tarlatamab in patients with
relapsed/refractory SCLC. The primary end point was safety. Secondary end points
included antitumor activity by modified RECIST 1.1, overall survival, and
pharmacokinetics.
RESULTS: By July 19, 2022, 107 patients received tarlatamab in dose exploration
(0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior
lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed
death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse
events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%).
One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most
common treatment-related adverse event, occurring in 56 patients (52%) including
grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective
response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23
partial responses. The median duration of response was 12.3 months (95% CI, 6.6
to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median
progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to
5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory
analysis suggests that selecting for increased DLL3 expression can result in
increased clinical benefit.
CONCLUSION: In patients with heavily pretreated SCLC, tarlatamab demonstrated
manageable safety with encouraging response durability. Further evaluation of
this promising molecule is ongoing.
DOI: 10.1200/JCO.22.02823
PMID: 36689692 [Indexed for MEDLINE]
24. J Natl Cancer Inst. 2023 Jun 8;115(6):742-748. doi: 10.1093/jnci/djac015.
Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without
Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung
Cancer.
Wang XS(1), Bai YF(1), Verma V(2), Yu RL(1), Tian W(1), Ao R(1), Deng Y(1), Zhu
XQ(1), Liu H(1), Pan HX(1), Yang L(1), Bai HS(3), Luo X(3), Guo Y(3), Zhou
MX(3), Sun YM(4), Zhang ZC(4), Li SM(3)(5), Cheng X(3), Tan BX(3), Han LF(6),
Liu YY(7), Zhang K(8), Zeng FX(9), Jia L(10), Hao XB(11), Wang YY(1), Feng G(1),
Xie K(1), Lu Y(12), Zeng M(1).
Author information:
(1)Cancer Center, Sichuan Provincial People's Hospital, University of Electronic
Science and Technology of China, Chengdu, China.
(2)Department of Radiation Oncology, University of Nebraska Medical Center,
Omaha, NE, USA.
(3)School of Medicine, University of Electronic Science and Technology of China,
Chengdu, China.
…
Erratum in
J Natl Cancer Inst. 2023 May 18;:
Expression of concern in
J Natl Cancer Inst. 2022 Apr 01;:
Comment in
J Natl Cancer Inst. 2023 Jun 8;115(6):605-607.
BACKGROUND: Adding radiotherapy (RT) to systemic therapy improves
progression-free survival (PFS) and overall survival (OS) in oligometastatic
non-small cell lung cancer (NSCLC). Whether these findings translate to
epidermal growth factor receptor (EGFR)-mutated NSCLC remains unknown. The
SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI)
therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to
upfront RT vs no RT; we now report the prespecified interim analysis at 68%
accrual.
METHODS: Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per
amplification refractory mutation system or next generation sequencing), with
synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases;
≤2 lesions in any one organ) NSCLC without brain metastases. All patients
received a first-generation TKI (gefitinib, erlotinib, or icotinib), and
randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on
tumor size and location) to all metastases and the primary tumor/involved
regional lymphatics. The primary endpoint (intention to treat) was PFS.
Secondary endpoints included OS and toxicities. All statistical tests were
2-sided.
RESULTS: A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were
enrolled (2016-2019). The median follow-up was 23.6 months. The respective
median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was
17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment
yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in
the TKI with RT arm. Based on the efficacy results of this prespecified interim
analysis, the ethics committee recommended premature cessation of this trial.
CONCLUSIONS: As compared with a first-line TKI alone, addition of upfront local
therapy using RT statistically significantly improved PFS and OS for
EGFR-mutated NSCLC.
© The Author(s) 2022. Published by Oxford University Press.
DOI: 10.1093/jnci/djac015
PMCID: PMC10248839
PMID: 35094066 [Indexed for MEDLINE]
