2023年
No.10
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2023/10/1 - 2023/10/31.
1. N Engl J Med. 2023 Oct 21. doi: 10.1056/NEJMoa2306441. Online ahead of print.
Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions.
Zhou C(1), Tang KJ(1), Cho BC(1), Liu B(1), Paz-Ares L(1), Cheng S(1), Kitazono
S(1), Thiagarajan M(1), Goldman JW(1), Sabari JK(1), Sanborn RE(1), Mansfield
AS(1), Hung JY(1), Boyer M(1), Popat S(1), Mourão Dias J(1), Felip E(1), Majem
M(1), Gumus M(1), Kim SW(1), Ono A(1), Xie J(1), Bhattacharya A(1), Agrawal
T(1), Shreeve SM(1), Knoblauch RE(1), Park K(1), Girard N(1); PAPILLON
Investigators.
Author information:
(1)From Shanghai Pulmonary Hospital, Tongji University School of Medicine,
Shanghai (C.Z.), the Division of Pulmonary and Critical Care Medicine, First
Affiliated Hospital of Sun Yat-sen University, Guangzhou (K.-J.T.), and Harbin
Medical University Cancer Hospital, Harbin (B.L.) - all in China; the Division
of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine
(B.C.C.), Asan Medical Center, University of Ulsan College of Medicine (S. Kim),
and Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.) -
all in Seoul, South Korea; Hospital Universitario 12 de Octubre, Madrid
(L.P.-A.),…
BACKGROUND: Amivantamab has been approved for the treatment of patients with
advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor
receptor (EGFR) exon 20 insertions who have had disease progression during or
after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor
activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional
data on this combination therapy are needed.
METHODS: In this phase 3, international, randomized trial, we assigned in a 1:1
ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not
received previous systemic therapy to receive intravenous amivantamab plus
chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary
outcome was progression-free survival according to blinded independent central
review. Patients in the chemotherapy group who had disease progression were
allowed to cross over to receive amivantamab monotherapy.
RESULTS: A total of 308 patients underwent randomization (153 to receive
amivantamab-chemotherapy and 155 to receive chemotherapy alone).
Progression-free survival was significantly longer in the
amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4
months and 6.7 months, respectively; hazard ratio for disease progression or
death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months,
progression-free survival was reported in 31% of the patients in the
amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete
or partial response at data cutoff was reported in 73% and 47%, respectively
(rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall
survival analysis (33% maturity), the hazard ratio for death for
amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to
1.09; P = 0.11). The predominant adverse events associated with
amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic
effects; 7% of patients discontinued amivantamab owing to adverse reactions.
CONCLUSIONS: The use of amivantamab-chemotherapy resulted in superior efficacy
as compared with chemotherapy alone as first-line treatment of patients with
advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and
Development; PAPILLON ClinicalTrials.gov number, NCT04538664.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2306441
PMID: 37870976
2. N Engl J Med. 2023 Nov 2;389(18):1672-1684. doi: 10.1056/NEJMoa2304875. Epub
2023 Oct 23.
Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer.
Heymach JV(1), Harpole D(1), Mitsudomi T(1), Taube JM(1), Galffy G(1), Hochmair
M(1), Winder T(1), Zukov R(1), Garbaos G(1), Gao S(1), Kuroda H(1), Ostoros
G(1), Tran TV(1), …
Author information:
(1)From the Department of Thoracic-Head and Neck Medical Oncology, University of
Texas M.D. Anderson Cancer Center, Houston (J.V.H.), and US Oncology Research,
the Woodlands (A.S.) - both in Texas; the Department of Surgery, Duke University
Medical Center (D.H.), and Duke Cancer Institute (J.C.) - both in Durham, NC;
the Division of Thoracic Surgery, Department of Surgery, Kindai University
Faculty of Medicine, Osaka-Sayama (T.M.), …
BACKGROUND: Neoadjuvant or adjuvant immunotherapy can improve outcomes in
patients with resectable non-small-cell lung cancer (NSCLC). Perioperative
regimens may combine benefits of both to improve long-term outcomes.
METHODS: We randomly assigned patients with resectable NSCLC (stage II to IIIB
[N2 node stage] according to the eighth edition of the AJCC Cancer Staging
Manual) to receive platinum-based chemotherapy plus durvalumab or placebo
administered intravenously every 3 weeks for 4 cycles before surgery, followed
by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles.
Randomization was stratified according to disease stage (II or III) and
programmed death ligand 1 (PD-L1) expression (≥1% or<1%). Primary end points
were event-free survival (defined as the time to the earliest occurrence of
progressive disease that precluded surgery or prevented completion of surgery,
disease recurrence [assessed in a blinded fashion by independent central
review], or death from any cause) and pathological complete response (evaluated
centrally).
RESULTS: A total of 802 patients were randomly assigned to receive durvalumab
(400 patients) or placebo (402 patients). The duration of event-free survival
was significantly longer with durvalumab than with placebo; the stratified
hazard ratio for disease progression, recurrence, or death was 0.68 (95%
confidence interval [CI], 0.53 to 0.88; P = 0.004) at the first interim
analysis. At the 12-month landmark analysis, event-free survival was observed in
73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as
compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6).
The incidence of pathological complete response was significantly greater with
durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference,
13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data
from 402 patients). Event-free survival and pathological complete response
benefit were observed regardless of stage and PD-L1 expression. Adverse events
of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in
43.2% with placebo. Data from 62 patients with documented EGFR or ALK
alterations were excluded from the efficacy analyses in the modified
intention-to-treat population.
CONCLUSIONS: In patients with resectable NSCLC, perioperative durvalumab plus
neoadjuvant chemotherapy was associated with significantly greater event-free
survival and pathological complete response than neoadjuvant chemotherapy alone,
with a safety profile that was consistent with the individual agents. (Funded by
AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2304875
PMID: 37870974 [Indexed for MEDLINE]
3. N Engl J Med. 2023 Nov 16;389(20):1839-1850. doi: 10.1056/NEJMoa2309457. Epub
2023 Oct 21.
First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET
Fusion-Positive NSCLC.
Zhou C(1), Solomon B(1), Loong HH(1), Park K(1), Pérol M(1), Arriola E(1),
Novello S(1), Han B(1), Zhou J(1), Ardizzoni A(1), Mak MP(1), Santini FC(1),
Elamin YY(1), Drilon A(1), Wolf J(1), Payakachat N(1), Uh MK(1), Rajakumar D(1),
Han H(1), Puri T(1), Soldatenkova V(1), Lin AB(1), Lin BK(1), Goto K(1);
LIBRETTO-431 Trial Investigators.
Author information:
(1)From Shanghai Pulmonary Hospital, Tongji University School of Medicine
(C.Z.), and the Department of Respiratory and Critical Care Medicine, Shanghai
Chest Hospital, School of Medicine, Shanghai Jiao Tong University (B.H.),
Shanghai, the Chinese University of Hong Kong, Hong Kong (H.H.L.), …
BACKGROUND: Selpercatinib, a highly selective potent and brain-penetrant RET
inhibitor, was shown to have efficacy in patients with advanced RET
fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2
study.
METHODS: In a randomized phase 3 trial, we evaluated the efficacy and safety of
first-line selpercatinib as compared with control treatment that consisted of
platinum-based chemotherapy with or without pembrolizumab at the investigator's
discretion. The primary end point was progression-free survival assessed by
blinded independent central review in both the intention-to-treat-pembrolizumab
population (i.e., patients whose physicians had planned to treat them with
pembrolizumab in the event that they were assigned to the control group) and the
overall intention-to-treat population. Crossover from the control group to the
selpercatinib group was allowed if disease progression as assessed by blinded
independent central review occurred during receipt of control treatment.
RESULTS: In total, 212 patients underwent randomization in the
intention-to-treat-pembrolizumab population. At the time of the preplanned
interim efficacy analysis, median progression-free survival was 24.8 months (95%
confidence interval [CI], 16.9 to not estimable) with selpercatinib and 11.2
months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for
progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001). The percentage of
patients with an objective response was 84% (95% CI, 76 to 90) with
selpercatinib and 65% (95% CI, 54 to 75) with control treatment. The
cause-specific hazard ratio for the time to progression affecting the central
nervous system was 0.28 (95% CI, 0.12 to 0.68). Efficacy results in the overall
intention-to-treat population (261 patients) were similar to those in the
intention-to-treat-pembrolizumab population. The adverse events that occurred
with selpercatinib and control treatment were consistent with those previously
reported.
CONCLUSIONS: Treatment with selpercatinib led to significantly longer
progression-free survival than platinum-based chemotherapy with or without
pembrolizumab among patients with advanced RET fusion-positive NSCLC. (Funded by
Eli Lilly and others; ClinicalTrials.gov number, NCT04194944.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2309457
PMID: 37870973
4. Cell. 2023 Nov 9;186(23):5135-5150.e28. doi: 10.1016/j.cell.2023.09.016. Epub
2023 Oct 20.
Mechanopathology of biofilm-like Mycobacterium tuberculosis cords.
Mishra R(1), Hannebelle M(2), Patil VP(3), Dubois A(4), Garcia-Mouton C(5),
Kirsch GM(1), Jan M(6), Sharma K(1), Guex N(6), Sordet-Dessimoz J(7), Perez-Gil
J(5), Prakash M(3), Knott GW(4), Dhar N(1), McKinney JD(1), Thacker VV(8).
Author information:
(1)Global Health Institute, École Polytechnique Fédérale de Lausanne, 1015
Lausanne, Switzerland.
(2)Global Health Institute, École Polytechnique Fédérale de Lausanne, 1015
Lausanne, Switzerland; Department of Bioengineering, Stanford University,
Stanford, CA 94305, USA.
(3)Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
…
Comment in
Cell. 2023 Nov 9;186(23):4994-4995.
Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms
biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC)
and mouse models, cords in alveolar cells contribute to suppression of innate
immune signaling via nuclear compression. Thereafter, extracellular cords cause
contact-dependent phagocyte death but grow intercellularly between epithelial
cells. The absence of these mechanopathological mechanisms explains the greater
proportion of alveolar lesions with increased immune infiltration and
dissemination defects in cording-deficient Mtb infections. Compression of Mtb
lipid monolayers induces a phase transition that enables mechanical energy
storage. Agent-based simulations demonstrate that the increased energy storage
capacity is sufficient for the formation of cords that maintain structural
integrity despite mechanical perturbation. Bacteria in cords remain
translationally active despite antibiotic exposure and regrow rapidly upon
cessation of treatment. This study provides a conceptual framework for the
biophysics and function in tuberculosis infection and therapy of cord
architectures independent of mechanisms ascribed to single bacteria.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2023.09.016
PMCID: PMC10642369
PMID: 37865090 [Indexed for MEDLINE]
5. N Engl J Med. 2023 Oct 20. doi: 10.1056/NEJMoa2307980. Online ahead of print.
Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer.
Ahn MJ(1), Cho BC(1), Felip E(1), Korantzis I(1), Ohashi K(1), Majem M(1),
Juan-Vidal O(1), Handzhiev S(1), Izumi H(1), Lee JS(1), Dziadziuszko R(1), Wolf
J(1), Blackhall F(1), Reck M(1), Bustamante Alvarez J(1), Hummel HD(1),
Dingemans AC(1), Sands J(1), Akamatsu H(1), Owonikoko TK(1), Ramalingam SS(1),
Borghaei H(1), Johnson ML(1), Huang S(1), Mukherjee S(1), Minocha M(1), Jiang
T(1), Martinez P(1), Anderson ES(1), Paz-Ares L(1); DeLLphi-301 Investigators.
Author information:
(1)From Samsung Medical Center, Sungkyunkwan University School of Medicine
(M.-J.A.), and Yonsei Cancer Center, Yonsei University College of Medicine
(B.C.C.), Seoul, and Seoul National University Bundang Hospital, Seongnam
(J.-S.L.) - all in South Korea; Vall d'Hebron University Hospital and Vall
d'Hebron Institute of Oncology (E.F.) …
BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting
delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1
trial in patients with previously treated small-cell lung cancer.
METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety
of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or
100 mg, in patients with previously treated small-cell lung cancer. The primary
end point was objective response (complete or partial response), as assessed by
blinded independent central review according to the Response Evaluation Criteria
in Solid Tumors, version 1.1.
RESULTS: Overall, 220 patients received tarlatamab; patients had previously
received a median of two lines of treatment. Among patients evaluated for
antitumor activity and survival, the median follow-up was 10.6 months in the
10-mg group and 10.3 months in the 100-mg group. An objective response occurred
in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg
group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among
patients with an objective response, the duration of response was at least 6
months in 59% (40 of 68 patients). Objective responses at the time of data
cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of
28 patients (57%) in the 100-mg group. The median progression-free survival was
4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6
to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were
68% and 66% of patients, respectively. The most common adverse events were
cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61%
of those in the 100-mg group), decreased appetite (in 29% and 44%,
respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred
primarily during treatment cycle 1, and events in most of the patients were
grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less
frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group
(in 6%). A low percentage of patients (3%) discontinued tarlatamab because of
treatment-related adverse events.
CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed
antitumor activity with durable objective responses and promising survival
outcomes in patients with previously treated small-cell lung cancer. No new
safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov
number, NCT05060016.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2307980
PMID: 37861218
6. Nat Med. 2023 Oct 30. doi: 10.1038/s41591-023-02660-6. Online ahead of print.
Association between pathologic response and survival after neoadjuvant therapy
in lung cancer.
Deutsch JS(1), Cimino-Mathews A(1), Thompson E(1), Provencio M(2), Forde PM(1),
Spicer J(3), Girard N(4), Wang D(1), Anders RA(1), Gabrielson E(1), Illei P(1),
Jedrych J(1), Danilova L(1), Sunshine J(1), Kerr KM(5), Tran M(6), Bushong J(6),
Cai J(6), Devas V(6), Neely J(6), Balli D(6), Cottrell TR(7), Baras AS(1), Taube
JM(8)(9).
Author information:
(1)Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University
School of Medicine, Baltimore, Maryland, USA.
(2)Hospital Universitario Puerta de Hierro, Madrid, Spain.
(3)McGill University Health Center, Montreal, Québec, Canada.
…
Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS)
and pathologic complete response (pCR, 0% residual viable tumor [RVT] in primary
tumor [PT]+lymph nodes [LNs]), and is approved for treatment of resectable lung
cancer. Pathologic response assessment after neoadjuvant therapy is the
potential analog to radiographic response for advanced disease. However, %RVT
thresholds beyond pCR and major pathologic response (≤10% RVT) have not been
explored. Pathologic response was prospectively assessed in the randomized,
phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab
(anti-PD-1) plus chemotherapy in patients with resectable lung cancer. RVT,
regression, and necrosis were quantified (0%-100%) in PT and LNs using a
pan-tumor scoring system and tested for association with EFS in a prespecified
exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus
>0% RVT-PT (HR = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy
(AUC = 0.74); 2-year EFS rates were 90%, 60%, 57%, and 39% for patients with
0%-5%, >5%-30%, >30%-80%, and >80% RVT, respectively. Each 1% RVT associated
with a 0.017 HR increase for EFS. Combining pathologic response from PT+LNs
helped differentiate outcomes. When compared to radiographic response and ctDNA
clearance, %RVT best approximated EFS. These findings support pathologic
response as an emerging survival surrogate. Further assessment of the full
spectrum of %RVT in lung cancer and other tumor types is warranted.
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41591-023-02660-6
PMID: 37903504
7. Cancer Cell. 2023 Oct 9;41(10):1763-1773.e4. doi: 10.1016/j.ccell.2023.09.007.
Dynamic circulating tumor DNA during chemoradiotherapy predicts clinical
outcomes for locally advanced non-small cell lung cancer patients.
Pan Y(1), Zhang JT(1), Gao X(2), Chen ZY(1), Yan B(2), Tan PX(1), Yang XR(1),
Gao W(2), Gong Y(2), Tian Z(2), Liu SM(3), Lin H(1), Sun H(1), Huang J(1), Liu
SY(1), Yan HH(1), Dong S(1), Xu CR(1), Chen HJ(1), Wang Z(1), Li P(2), Guan
Y(2), Wang BC(1), Yang JJ(1), Tu HY(1), Yang XN(1), Zhong WZ(1), Xia X(2), Yi
X(4), Zhou Q(5), Wu YL(6).
Author information:
(1)Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital
(Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou,
Guangdong, China.
(2)Geneplus-Beijing Institute, Beijing, China.
(3)Department of Hematology, First Affiliated Hospital, Institute of Hematology,
School of Medicine; Key Laboratory for Regenerative Medicine of Ministry of
Education, Jinan University, Guangzhou, Guangdong, China; Chinese Thoracic
Oncology Group (CTONG), Guangzhou, Guangdong, China.
…
Comment in
Cancer Cell. 2023 Oct 9;41(10):1699-1701.
The value of circulating tumor DNA (ctDNA) during chemoradiotherapy (CRT)
remains unclear but is critical for detecting molecular residual disease (MRD).
In this prospective study, we sequenced 761 blood samples from 139 patients with
locally advanced non-small cell lung cancer treated with definitive radiation
therapy (RT). ctDNA concentrations showed a significantly declining trend as CRT
progressed at on-RT and after-RT time points versus baseline. Thirty-eight
(27.3%) patients with early undetectable ctDNA at both on-RT (RT reached 40 Gy)
and after-RT time points, indicating early response to CRT, had better survival
outcomes for both with or without consolidation immune checkpoint inhibitors.
Longitudinal undetectable MRD was found in 20.1% patients. The 2-year
cancer-specific progression-free survival of these patients was 88.4%,
corresponding to a potentially cured population. Further analysis revealed that
pretreatment ctDNA variants serve as an essential MRD informed source. These
data provide clinical insights for ctDNA-MRD detection.
Copyright © 2023 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2023.09.007
PMID: 37816331 [Indexed for MEDLINE]
8. Nat Med. 2023 Oct;29(10):2559-2569. doi: 10.1038/s41591-023-02598-9. Epub 2023
Oct 9.
ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2
adaptive trial results.
Anagnostou V(1)(2), Ho C(3), Nicholas G(4), Juergens RA(5), Sacher A(6), Fung
AS(7), Wheatley-Price P(4), Laurie SA(4), Levy B(8), Brahmer JR(8)(9), Balan
A(8), Niknafs N(8), Avrutin E(10), Zhu L(10), Sausen M(11), Bradbury PA(6),
O'Donnell-Tormey J(12), Gaudreau PO(10), Ding K(10), Dancey J(13).
Author information:
(1)Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of
Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
(2)Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University
School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
(3)BCCA-Vancouver Cancer Centre, Vancouver, BC, Canada.
…
Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance
to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2
trial of molecular response-adaptive immuno-chemotherapy for patients with lung
cancer. In the first of two independent stages, 50 patients with advanced
non-small cell lung cancer received pembrolizumab as standard of care. The
primary objectives of stage 1 were to ascertain ctDNA response and determine
optimal timing and concordance with radiologic Response Evaluation Criteria in
Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of
time to ctDNA response and correlation with progression-free and overall
survival. Maximal mutant allele fraction clearance at the third cycle of
pembrolizumab signified molecular response (mR). The trial met its primary
endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90%
confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%).
Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients
with mR attained longer progression-free survival (5.03 months versus
2.6 months) and overall survival (not reached versus 7.23 months). These
findings are incorporated into the ctDNA-driven interventional molecular
response-adaptive second stage of the BR.36 trial in which patients at risk of
progression are randomized to treatment intensification or continuation of
therapy. ClinicalTrials.gov ID: NCT04093167 .
© 2023. The Author(s).
DOI: 10.1038/s41591-023-02598-9
PMCID: PMC10579094
PMID: 37814061 [Indexed for MEDLINE]
9. Lancet Infect Dis. 2023 Oct 30:S1473-3099(23)00491-7. doi:
10.1016/S1473-3099(23)00491-7. Online ahead of print.
Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response
cartridge using fingerstick blood for childhood tuberculosis: a multicentre
prospective study in low-income and middle-income countries.
Olbrich L(1), Verghese VP(2), Franckling-Smith Z(3), Sabi I(4), Ntinginya NE(4),
Mfinanga A(4), Banze D(5), Viegas S(5), Khosa C(5), Semphere R(6), Nliwasa M(6),
McHugh TD(7), Larsson L(8), Razid A(8), Song R(9), Corbett EL(10), Nabeta P(11),
Trollip A(11), Graham SM(12), Hoelscher M(13), Geldmacher C(14), Zar HJ(3),
Michael JS(15), Heinrich N(16); RaPaed-TB consortium.
Author information:
(1)Division of Infectious Diseases and Tropical Medicine, LMU University
Hospital, LMU Munich, Munich, Germany; German Centre for Infection Research
(DZIF), Partner Site Munich, Munich, Germany; Fraunhofer Institute ITMP,
Immunology, Infection and Pandemic Research, Munich, Germany; Oxford Vaccine
Group, Department of Paediatrics and the NIHR Oxford Biomedical Research Centre,
University of Oxford, Oxford, UK.
(2)Pediatric Infectious Diseases, Department of Pediatrics, Christian Medical
College, Vellore, India.
(3)Department of Paediatrics and Child Health, SA-MRC Unit on Child and
Adolescent Health, University of Cape Town, Cape Town, South Africa.
…
BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and
mortality in part due to missed diagnosis. Diagnostic methods with enhanced
sensitivity using easy-to-obtain specimens are needed. We aimed to assess the
diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response
prototype cartridge (MTB-HR), a candidate test measuring a three-gene
transcriptomic signature from fingerstick blood, in children with presumptive
tuberculosis disease.
METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four
sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and
one site in India. Children younger than 15 years with presumptive pulmonary or
extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30,
2021. MTB-HR was performed at baseline and at 1 month in all children and was
repeated at 3 months and 6 months in children on tuberculosis treatment.
Accuracy was compared with tuberculosis status based on standardised
microbiological, radiological, and clinical data.
FINDINGS: 5313 potentially eligible children were screened, of whom 975 were
eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic
classification and were included in the analysis. MTB-HR differentiated children
with culture-confirmed tuberculosis from those with unlikely tuberculosis with a
sensitivity of 59·8% (95% CI 50·8-68·4). Using any microbiological confirmation
(culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7-48·7), and using
a composite clinical reference standard, sensitivity was 29·6%
(25·4-34·2). Specificity for all three reference standards was 90·3% (95% CI
85·5-94·0). Performance was similar in different age groups and by malnutrition
status. Among children living with HIV, accuracy against the strict reference
standard tended to be lower (sensitivity 50·0%, 15·7-84·3) compared with those
without HIV (61·0%, 51·6-69·9), although the difference did not reach
statistical significance. Combining baseline MTB-HR result with one Ultra result
identified 71·2% of children with microbiologically confirmed tuberculosis.
INTERPRETATION: MTB-HR showed promising diagnostic accuracy for
culture-confirmed tuberculosis in this large, geographically diverse, paediatric
cohort and hard-to-diagnose subgroups.
FUNDING: European and Developing Countries Clinical Trials Partnership, UK
Medical Research Council, Swedish International Development Cooperation Agency,
Bundesministerium für Bildung und Forschung; German Center for Infection
Research (DZIF).
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S1473-3099(23)00491-7
PMID: 37918414
10. J Clin Oncol. 2023 Oct 20:101200JCO2301891. doi: 10.1200/JCO.23.01891. Online
ahead of print.
A Phase 3, Randomized study of atezolizumab plus bevacizumab and chemotherapy in
patients with EGFR or ALK mutated in non-small cell lung cancer (ATTLAS,
KCSG-LU19-04).
Park S(1), Kim TM(2), Han JY(3), Lee GW(4), Shim BY(5), Lee YG(6), Kim SW(7),
Kim IH(8), Lee S(9), Kim YJ(10), Park JH(11), Park SG(12), Lee KH(13), Kang
EJ(14), Kim JW(15), Shin SH(16), Ock CY(17), Nam BH(18), Lee J(19), Jung HA(1),
Sun JM(1), Lee SH(1), Ahn JS(1), Ahn MJ(1).
Author information:
(1)Division of Hematology-Oncology, Department of Medicine, Samsung Medical
Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
(2)Department of Internal Medicine, Seoul National University Hospital, Seoul
National University Cancer Research Institute, Seoul, Korea.
(3)Center for Lung Cancer, Research Institute and Hospital, National Cancer
Center, Goyang-si Gyeonggi-do, Korea.
…
PURPOSE: In the treatment of non-small cell lung cancer (NSCLC) with a driver
mutation, the role of anti-PD-(L)1 antibody following tyrosine kinase inhibitor
(TKI) remains unclear. This randomized, open-label, multicenter, phase 3 study
evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel and
carboplatin (ABCP) in EGFR or ALK-mutated NSCLC that progressed prior to TKI
therapy.
METHODS: We compared the clinical efficacy of ABCP followed by maintenance
therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or
cisplatin (PC arm) followed by pemetrexed maintenance. The primary endpoint was
progression-free survival (PFS).
RESULTS: A total of 228 patients with activating EGFR mutation (n=215) or ALK
translocation (n=13) were enrolled from 16 sites in the Republic of Korea and
randomized at 2:1 ratio to either ABCP (n=154) or PC arm (n=74). The median
follow-up duration was 26.1 months (95%CI 24.7-28.2). Objective response rates
(69.5% vs 41.9%, P<0.001) and median PFS (8.48 vs. 5.62 months, hazard ratio
[HR] 0.62 [0.45-0.86], P=0.004) were significantly better in the ABCP than PC
arm. PFS benefit increased as PD-L1 expression increased, with HR of 0.47, 0.41,
and 0.24 for PD-L1 ≥1%, ≥10% and ≥50%, respectively. Overall survival was
similar between ABCP and PC arm (20.63 vs. 20.27 months, HR 1.01 [0.69-1.46],
P=0.975). The safety profile of the ABCP arm was comparable to that previously
reported, with no additional safety signals, but higher rates of
treatment-related adverse events were observed compared to the PC arm.
CONCLUSION: This study is the first randomized phase 3 study to demonstrate the
clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and
chemotherapy in EGFR or ALK mutated NSCLC who have progressed on relevant
targeted therapy.
DOI: 10.1200/JCO.23.01891
PMID: 37861993
11. Cell Host Microbe. 2023 Nov 8;31(11):1820-1836.e10. doi:
10.1016/j.chom.2023.09.010. Epub 2023 Oct 16.
Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular
survival.
Liu S(1), Guan L(1), Peng C(1), Cheng Y(1), Cheng H(1), Wang F(1), Ma M(1),
Zheng R(1), Ji Z(2), Cui P(1), Ren Y(1), Li L(1), Shi C(1), Wang J(3), Huang
X(3), Cai X(4), Qu D(4), Zhang H(5), Mao Z(5), Liu H(6), Wang P(7), Sha W(7),
Yang H(8), Wang L(9), Ge B(10).
Author information:
(1)Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Key
Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji
University School of Medicine, Shanghai 200433, P.R. China; Department of
Microbiology and Immunology, Tongji University School of Medicine, Shanghai
200092, P.R. China.
(2)Department of Microbiology and Immunology, Tongji University School of
Medicine, Shanghai 200092, P.R. China.
(3)Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Key
Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji
University School of Medicine, Shanghai 200433, P.R. China.
…
Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages,
resulting in the formation of lipid droplets that serve as a nutrient source. We
discover that Mtb promotes lipid droplets by inhibiting DNA repair responses,
resulting in the activation of the type-I IFN pathway and scavenger receptor-A1
(SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850)
inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and
impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The
suppression of this repair pathway increases the abundance of micronuclei that
trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes
(STING) pathway and subsequent interferon-β (IFN-β) production. UreC-mediated
activation of the IFN-β pathway upregulates the expression of SR-A1 to form
lipid droplets that facilitate Mtb replication. UreC inhibition via a urease
inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings
identify mechanisms by which Mtb triggers a cascade of cellular events that
establish a nutrient-rich replicative niche.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.chom.2023.09.010
PMID: 37848028 [Indexed for MEDLINE]
12. J Clin Oncol. 2023 Oct 11:JCO2301435. doi: 10.1200/JCO.23.01435. Online ahead of print.
Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care
Ontario) Guideline.
Khurshid H(1), Ismaila N(2), Bian J(3), Dabney R(4), Das M(5), Ellis P(6),
Feldman J(7), Hann C(8), Kulkarni S(9), Laskin J(10), Manochakian R(11), Mishra
DR(12), Preeshagul I(13), Reddy P(14), Saxena A(15), Weinberg F(16), Kalemkerian
GP(17).
Author information:
(1)Brown University, Providence, RI.
(2)American Society of Clinical Oncology (ASCO), Alexandria, VA.
(3)Maine Health, South Portland, ME.
…
PURPOSE: To provide evidence-based recommendations to practicing clinicians on
the management of patients with small-cell lung cancer.
METHODS: An Expert Panel of medical oncology, thoracic surgery, radiation
oncology, pulmonary, community oncology, research methodology, and advocacy
experts were convened to conduct a literature search, which included systematic
reviews, meta-analyses, and randomized controlled trials published from 1990
through 2022. Outcomes of interest included response rates, overall survival,
disease-free survival or recurrence-free survival, and quality of life. Expert
Panel members used available evidence and informal consensus to develop
evidence-based guideline recommendations.
RESULTS: The literature search identified 95 relevant studies to inform the
evidence base for this guideline.
RECOMMENDATIONS: Evidence-based recommendations were developed to address
systemic therapy options, timing of therapy, treatment in patients who are older
or with poor performance status, role of biomarkers, and use of
myeloid-supporting agents in patients with small-cell lung cancer.Additional
information is available at www.asco.org/thoracic-cancer-guidelines.
DOI: 10.1200/JCO.23.01435
PMID: 37820295
13. Nat Commun. 2023 Oct 4;14(1):6182. doi: 10.1038/s41467-023-41937-9.
Global burden of disease due to rifampicin-resistant tuberculosis: a
mathematical modeling analysis.
Menzies NA(1)(2), Allwood BW(#)(3), Dean AS(#)(4), Dodd PJ(#)(5), Houben
RMGJ(#)(6)(7), James LP(#)(8)(9), Knight GM(#)(10), Meghji J(#)(11), Nguyen
LN(#)(4), Rachow A(#)(12)(13)(14), Schumacher SG(#)(4), Mirzayev F(4), Cohen
T(15).
Author information:
(1)Department of Global Health and Population, Harvard T. H. Chan School of
Public Health, Boston, USA. nmenzies@hsph.harvard.edu.
(2)Center for Health Decision Science, Harvard T. H. Chan School of Public
Health, Boston, USA. nmenzies@hsph.harvard.edu.
(3)Division of Pulmonology, Department of Medicine, Stellenbosch University &
Tygerberg Hospital, Cape Town, South Africa.
…
In 2020, almost half a million individuals developed rifampicin-resistant
tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime
of affected individuals. We synthesized data on incidence, case detection, and
treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a
mathematical model, we projected disability-adjusted life years (DALYs) over the
lifetime for individuals developing tuberculosis in 2020 stratified by country,
age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in
2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5)
million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an
average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater
than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was
highest in former Soviet Union countries and southern African countries. While
RR-TB causes substantial short-term morbidity and mortality, nearly half of the
overall disease burden of RR-TB accrues among tuberculosis survivors. The
substantial long-term health impacts among those surviving RR-TB disease suggest
the need for improved post-treatment care and further justify increased health
expenditures to prevent RR-TB transmission.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-41937-9
PMCID: PMC10550952
PMID: 37794037 [Indexed for MEDLINE]
14. J Clin Oncol. 2023 Oct 3:JCO2300910. doi: 10.1200/JCO.23.00910. Online ahead of print.
Canakinumab as Adjuvant Therapy in Patients With Completely Resected
Non-Small-Cell Lung Cancer: Results From the CANOPY-A Double-Blind, Randomized
Clinical Trial.
Garon EB(1), Lu S(2), Goto Y(3), De Marchi P(4), Paz-Ares L(5), Spigel DR(6),
Thomas M(7), Yang JC(8), Ardizzoni A(9), Barlesi F(10)(11), Orlov S(12),
Yoshioka H(13), Mountzios G(14), Khanna S(15), Bossen C(16), Carbini M(16),
Turri S(15), Myers A(17), Cho BC(18).
Author information:
(1)David Geffen School of Medicine at UCLA/TRIO-US/TRIO-Global Network, Los
Angeles, CA.
(2)Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University,
Shanghai, China.
(3)National Cancer Center, Tokyo, Japan.
…
PURPOSE: Effective treatments for resectable non-small-cell lung cancer (NSCLC)
are limited and relapse rates are high. The interleukin (IL)-1β pathway has been
linked with tumor development and progression, including in the Canakinumab
Anti-Inflammatory Thrombosis Outcomes cardiovascular study in which IL-1β
pathway inhibition with canakinumab reduced lung cancer incidence and mortality
in an exploratory analysis.
METHODS: CANOPY-A (ClinicalTrials.gov identifier: NCT03447769) is a phase III,
randomized, double-blind, multicenter study of canakinumab versus placebo for
adult patients with stage II-IIIA or IIIB (T >5 cm, N2-positives II-IIIB;
American Joint Committee on Cancer/Union for International Cancer Control
version 8), completely resected NSCLC who had received adjuvant cisplatin-based
chemotherapy. The primary end point was disease-free survival (DFS) and the key
secondary end point was overall survival (OS).
RESULTS: In total, 1,382 patients were randomized to 200 mg canakinumab (n =
693) or placebo (n = 689) once every 3 weeks for 18 cycles. Grade ≥3 adverse
events (AEs) were reported in 20.8% and 19.6% of patients receiving canakinumab
and placebo, respectively; AEs led to discontinuation in 4.3% and 4.1% of
patients in these groups, respectively. This study did not meet its primary end
point. Median DFS was 35.0 months (canakinumab arm) and 29.7 months (placebo
arm; hazard ratio, 0.94; 95% CI, 0.78 to 1.14; one-sided P = .258). DFS subgroup
analyses did not show any meaningful differences between arms. As expected,
because of canakinumab-driven IL-1β pathway inhibition, C-reactive protein and
IL-6 levels decreased in the canakinumab arm versus placebo arm, but had no
correlation with differential clinical outcomes. OS was not formally tested as
DFS was not statistically significant.
CONCLUSION: CANOPY-A did not show a DFS benefit of adding canakinumab after
surgery and adjuvant cisplatin-based chemotherapy in patients with resected,
stage II-III NSCLC. No new safety signals were identified with canakinumab.
DOI: 10.1200/JCO.23.00910
PMID: 37788412
15. PLoS Med. 2023 Oct 3;20(10):e1004287. doi: 10.1371/journal.pmed.1004287.
eCollection 2023 Oct.
Assessing eligibility for lung cancer screening using parsimonious ensemble
machine learning models: A development and validation study.
Callender T(1), Imrie F(2), Cebere B(3), Pashayan N(4), Navani N(1), van der
Schaar M(3)(5)(6), Janes SM(1).
Author information:
(1)Department of Respiratory Medicine, University College London, London, United
Kingdom.
(2)Department of Electrical and Computer Engineering, University of California,
Los Angeles, California, United States of America.
(3)Department of Applied Mathematics and Theoretical Physics, University of
Cambridge, Cambridge, United Kingdom.
(4)Department of Applied Health Research, University College London, London,
United Kingdom.
(5)Cambridge Centre for AI in Medicine, University of Cambridge, Cambridge,
United Kingdom.
(6)Alan Turing Institute, London, United Kingdom.
BACKGROUND: Risk-based screening for lung cancer is currently being considered
in several countries; however, the optimal approach to determine eligibility
remains unclear. Ensemble machine learning could support the development of
highly parsimonious prediction models that maintain the performance of more
complex models while maximising simplicity and generalisability, supporting the
widespread adoption of personalised screening. In this work, we aimed to develop
and validate ensemble machine learning models to determine eligibility for
risk-based lung cancer screening.
METHODS AND FINDINGS: For model development, we used data from 216,714
ever-smokers recruited between 2006 and 2010 to the UK Biobank prospective
cohort and 26,616 high-risk ever-smokers recruited between 2002 and 2004 to the
control arm of the US National Lung Screening (NLST) randomised controlled
trial. The NLST trial randomised high-risk smokers from 33 US centres with at
least a 30 pack-year smoking history and fewer than 15 quit-years to annual CT
or chest radiography screening for lung cancer. We externally validated our
models among 49,593 participants in the chest radiography arm and all 80,659
ever-smoking participants in the US Prostate, Lung, Colorectal and Ovarian
(PLCO) Screening Trial. The PLCO trial, recruiting from 1993 to 2001, analysed
the impact of chest radiography or no chest radiography for lung cancer
screening. We primarily validated in the PLCO chest radiography arm such that we
could benchmark against comparator models developed within the PLCO control arm.
Models were developed to predict the risk of 2 outcomes within 5 years from
baseline: diagnosis of lung cancer and death from lung cancer. We assessed model
discrimination (area under the receiver operating curve, AUC), calibration
(calibration curves and expected/observed ratio), overall performance (Brier
scores), and net benefit with decision curve analysis. Models predicting lung
cancer death (UCL-D) and incidence (UCL-I) using 3 variables-age, smoking
duration, and pack-years-achieved or exceeded parity in discrimination, overall
performance, and net benefit with comparators currently in use, despite
requiring only one-quarter of the predictors. In external validation in the PLCO
trial, UCL-D had an AUC of 0.803 (95% CI: 0.783, 0.824) and was well calibrated
with an expected/observed (E/O) ratio of 1.05 (95% CI: 0.95, 1.19). UCL-I had an
AUC of 0.787 (95% CI: 0.771, 0.802), an E/O ratio of 1.0 (95% CI: 0.92, 1.07).
The sensitivity of UCL-D was 85.5% and UCL-I was 83.9%, at 5-year risk
thresholds of 0.68% and 1.17%, respectively, 7.9% and 6.2% higher than the
USPSTF-2021 criteria at the same specificity. The main limitation of this study
is that the models have not been validated outside of UK and US cohorts.
CONCLUSIONS: We present parsimonious ensemble machine learning models to predict
the risk of lung cancer in ever-smokers, demonstrating a novel approach that
could simplify the implementation of risk-based lung cancer screening in
multiple settings.
Copyright: © 2023 Callender 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.1004287
PMCID: PMC10547178
PMID: 37788223 [Indexed for MEDLINE]
16. J Clin Invest. 2023 Oct 2;133(19):e173156. doi: 10.1172/JCI173156.
The Mycobacterium tuberculosis genome at 25 years: lessons and lingering
questions.
Koleske BN(1), Jacobs WR Jr(2), Bishai WR(1).
Author information:
(1)Center for Tuberculosis Research, Department of Medicine, Johns Hopkins
School of Medicine, Baltimore, Maryland, USA.
(2)Department of Microbiology and Immunology, Albert Einstein College of
Medicine, Bronx, New York, USA.
First achieved in 1998 by Cole et al., the complete genome sequence of
Mycobacterium tuberculosis continues to provide an invaluable resource to
understand tuberculosis (TB), the leading cause of global infectious disease
mortality. At the 25-year anniversary of this accomplishment, we describe how
insights gleaned from the M. tuberculosis genome have led to vital tools for TB
research, epidemiology, and clinical practice. The increasing accessibility of
whole-genome sequencing across research and clinical settings has improved our
ability to predict antibacterial susceptibility, to track epidemics at the level
of individual outbreaks and wider historical trends, to query the efficacy of
the bacille Calmette-Guérin (BCG) vaccine, and to uncover targets for novel
antitubercular therapeutics. Likewise, we discuss several recent efforts to
extract further discoveries from this powerful resource.
DOI: 10.1172/JCI173156
PMCID: PMC10541200
PMID: 37781921 [Indexed for MEDLINE]
17. Nat Rev Clin Oncol. 2023 Oct;20(10):716-732. doi: 10.1038/s41571-023-00808-4. Epub 2023 Aug 17.
Emerging therapeutics and evolving assessment criteria for intracranial
metastases in patients with oncogene-driven non-small-cell lung cancer.
Pan K(1), Concannon K(1), Li J(2), Zhang J(3), Heymach JV(3), Le X(4).
Author information:
(1)Department of Cancer Medicine, University of Texas MD Anderson Cancer Center,
Houston, TX, USA.
(2)Department of Radiation Oncology, University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
(3)Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD
Anderson Cancer Center, Houston, TX, USA.
(4)Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD
Anderson Cancer Center, Houston, TX, USA. xle1@mdanderson.org.
The improved survival outcomes of patients with non-small-cell lung cancer
(NSCLC), largely owing to the improved control of systemic disease provided by
immune-checkpoint inhibitors and novel targeted therapies, have highlighted the
challenges posed by central nervous system (CNS) metastases as a devastating yet
common complication, with up to 50% of patients developing such lesions during
the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs)
often provide robust systemic disease control in patients with oncogene-driven
NSCLCs, although these agents are usually unable to accumulate to
therapeutically relevant concentrations in the CNS owing to an inability to
cross the blood-brain barrier. However, the past few years have seen a paradigm
shift with the emergence of several novel or later-generation TKIs with improved
CNS penetrance. Such agents have promising levels of activity against brain
metastases, as demonstrated by data from preclinical and clinical studies. In
this Review, we describe current preclinical and clinical evidence of the
intracranial activity of TKIs targeting various oncogenic drivers in patients
with NSCLC, with a focus on newer agents with enhanced CNS penetration,
leptomeningeal disease and the need for intrathecal treatment options. We also
discuss evolving assessment criteria and regulatory considerations for future
clinical investigations.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41571-023-00808-4
PMID: 37592034 [Indexed for MEDLINE]
18. J Clin Oncol. 2023 Oct 1;41(28):4472-4477. doi: 10.1200/JCO.23.00046. Epub 2023 Jun 16.
Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With
KRAS(G12C)-Mutated Non-Small-Cell Lung Cancer Who Have Untreated CNS Metastases.
Negrao MV(1), Spira AI(2)(3)(4), Heist RS(5), Jänne PA(6), Pacheco JM(7), Weiss
J(8), Gadgeel SM(9), Velastegui K(10), Yang W(10), Der-Torossian H(10),
Christensen JG(10), Sabari JK(11).
Author information:
(1)Department of Thoracic/Head & Neck Medical Oncology, MD Anderson Cancer
Center, University of Texas, Houston, TX.
(2)Virginia Cancer Specialists, Fairfax, VA.
(3)US Oncology Research, The Woodlands, TX.
…
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.Patients with Kirsten rat sarcoma
viral oncogene homolog (KRAS)-mutated non-small-cell lung cancer (NSCLC) and
untreated CNS metastases have a worse prognosis than similar patients without
KRAS mutations. Adagrasib has previously demonstrated CNS penetration
preclinically and cerebral spinal fluid penetration clinically. We evaluated
adagrasib in patients with KRASG12C-mutated NSCLC and untreated CNS metastases
from the KRYSTAL-1 trial (ClinicalTrials.gov identifier: NCT03785249; phase Ib
cohort), in which adagrasib 600 mg was administered orally, twice daily. Study
outcomes included the safety and clinical activity (intracranial [IC] and
systemic) by blinded independent central review. Twenty-five patients with
KRASG12C-mutated NSCLC and untreated CNS metastases were enrolled and evaluated
(median follow-up, 13.7 months); 19 patients were radiographically evaluable for
IC activity. Safety was consistent with previous reports of adagrasib, with
grade 3 treatment-related adverse events (TRAEs) in 10 patients (40%) and one
grade 4 (4%) and no grade 5 TRAEs. The most common CNS-specific TRAEs included
dysgeusia (24%) and dizziness (20%). Adagrasib demonstrated an IC objective
response rate of 42%, disease control rate of 90%, progression-free survival of
5.4 months, and median overall survival of 11.4 months. Adagrasib is the first
KRASG12C inhibitor to prospectively demonstrate IC activity in patients with
KRASG12C-mutated NSCLC and untreated CNS metastases, supporting further
investigation in this population.
DOI: 10.1200/JCO.23.00046
PMCID: PMC10553074
PMID: 37327468 [Indexed for MEDLINE]
19. J Clin Oncol. 2023 Oct 10;41(29):4678-4687. doi: 10.1200/JCO.23.00059. Epub 2023 Jun 16.
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.
…
Comment in
doi: 10.1200/JCO.23.01207.
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
PMCID: PMC10564307
PMID: 37327461 [Indexed for MEDLINE]
