PubMed  Filters applied: from 2022/1/1 - 2022/2/28

1. CA Cancer J Clin. 2022 Feb 10. doi: 10.3322/caac.21718. Online ahead of print.

Cancer statistics for African American/Black People 2022.

Giaquinto AN(1), Miller KD(1), Tossas KY(2), Winn RA(2), Jemal A(1), Siegel

RL(1).

Author information:

(1)Surveillance and Health Equity Science, American Cancer Society, Atlanta,

Georgia, USA.

(2)Department of Health Behavior and Policy, Virginia Commonwealth University,

Richmond, Virginia, USA.

African American/Black individuals have a disproportionate cancer burden,

including the highest mortality and the lowest survival of any racial/ethnic

group for most cancers. Every 3 years, the American Cancer Society estimates the

number of new cancer cases and deaths for Black people in the United States and

compiles the most recent data on cancer incidence (herein through 2018),

mortality (through 2019), survival, screening, and risk factors using

population-based data from the National Cancer Institute and the Centers for

Disease Control and Prevention. In 2022, there will be approximately 224,080 new

cancer cases and 73,680 cancer deaths among Black people in the United States.

During the most recent 5-year period, Black men had a 6% higher incidence rate

but 19% higher mortality than White men overall, including an approximately

2-fold higher risk of death from myeloma, stomach cancer, and prostate cancer.

The overall cancer mortality disparity is narrowing between Black and White men

because of a steeper drop in Black men for lung and prostate cancers. However,

the decline in prostate cancer mortality in Black men slowed from 5% annually

during 2010 through 2014 to 1.3% during 2015 through 2019, likely reflecting the

5% annual increase in advanced-stage diagnoses since 2012. Black women have an

8% lower incidence rate than White women but a 12% higher mortality; further,

mortality rates are 2-fold higher for endometrial cancer and 41% higher for

breast cancer despite similar or lower incidence rates. The wide breast cancer

disparity reflects both later stage diagnosis (57% localized stage vs 67% in

White women) and lower 5-year survival overall (82% vs 92%, respectively) and

for every stage of disease (eg, 20% vs 30%, respectively, for distant stage).

Breast cancer surpassed lung cancer as the leading cause of cancer death among

Black women in 2019. Targeted interventions are needed to reduce stark cancer

inequalities in the Black community.

© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley

Periodicals LLC on behalf of American Cancer Society.

DOI: 10.3322/caac.21718

PMID: 35143040

2. Annu Rev Immunol. 2022 Feb 7. doi: 10.1146/annurev-immunol-093019-125148. Online ahead of print.

The Tuberculous Granuloma and Preexisting Immunity.

Cohen SB(1), Gern BH(1)(2), Urdahl KB(1)(2)(3).

Author information:

(1)Seattle Children's Research Institute, Seattle, Washington, USA; email:

kevin.urdahl@seattlechildrens.org.

(2)Department of Pediatrics, University of Washington, Seattle, Washington, USA.

(3)Department of Immunology, University of Washington, Seattle, Washington, USA.

Pulmonary granulomas are widely considered the epicenters of the immune response

to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB).

Recent animal studies have revealed factors that either promote or restrict TB

immunity within granulomas. These models, however, typically ignore the impact

of preexisting immunity on cellular organization and function, an important

consideration because most TB probably occurs through reinfection of previously

exposed individuals. Human postmortem research from the pre-antibiotic era

showed that infections in Mtb-naïve individuals (primary TB) versus those with

prior Mtb exposure (postprimary TB) have distinct pathologic features. We review

recent animal findings in TB granuloma biology, which largely reflect primary

TB. We also discuss our current understanding of postprimary TB lesions, about

which much less is known. Many knowledge gaps remain, particularly regarding how

preexisting immunity shapes granuloma structure and local immune responses at

Mtb infection sites. Expected final online publication date for the Annual

Review of Immunology, Volume 40 is April 2022. Please see

http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: 10.1146/annurev-immunol-093019-125148

PMID: 35130029

3. CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan

12.

Cancer statistics, 2022.

Siegel RL(1), Miller KD(1), Fuchs HE(1), Jemal A(1).

Author information:

(1)Surveillance and Health Equity Science, American Cancer Society, Atlanta,

Georgia.

Each year, the American Cancer Society estimates the numbers of new cancer cases

and deaths in the United States and compiles the most recent data on

population-based cancer occurrence and outcomes. Incidence data (through 2018)

were collected by the Surveillance, Epidemiology, and End Results program; the

National Program of Cancer Registries; and the North American Association of

Central Cancer Registries. Mortality data (through 2019) were collected by the

National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and

609,360 cancer deaths are projected to occur in the United States, including

approximately 350 deaths per day from lung cancer, the leading cause of cancer

death. Incidence during 2014 through 2018 continued a slow increase for female

breast cancer (by 0.5% annually) and remained stable for prostate cancer,

despite a 4% to 6% annual increase for advanced disease since 2011.

Consequently, the proportion of prostate cancer diagnosed at a distant stage

increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer

incidence continued to decline steeply for advanced disease while rates for

localized-stage increased suddenly by 4.5% annually, contributing to gains both

in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018)

and 3-year relative survival (from 21% to 31%). Mortality patterns reflect

incidence trends, with declines accelerating for lung cancer, slowing for breast

cancer, and stabilizing for prostate cancer. In summary, progress has stagnated

for breast and prostate cancers but strengthened for lung cancer, coinciding

with changes in medical practice related to cancer screening and/or treatment.

More targeted cancer control interventions and investment in improved early

detection and treatment would facilitate reductions in cancer mortality.

© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley

Periodicals LLC on behalf of American Cancer Society.

DOI: 10.3322/caac.21708

PMID: 35020204 [Indexed for MEDLINE]

4. Cell. 2022 Jan 6;185(1):169-183.e19. doi: 10.1016/j.cell.2021.12.005. Epub 2021 Dec 27.

EMSY inhibits homologous recombination repair and the interferon response,

promoting lung cancer immune evasion.

Marzio A(1), Kurz E(2), Sahni JM(3), Di Feo G(2), Puccini J(2), Jiang S(2),

Hirsch CA(2), Arbini AA(4), Wu WL(3), Pass HI(5), Bar-Sagi D(2),

Papagiannakopoulos T(6), Pagano M(7).

Author information:

(1)Department of Biochemistry and Molecular Pharmacology, New York University

Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter

NYU Cancer Center, New York University Grossman School of Medicine, New York, NY

10016, USA. Electronic address: antonio.marzio@nyulangone.org.

(2)Department of Biochemistry and Molecular Pharmacology, New York University

Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter

NYU Cancer Center, New York University Grossman School of Medicine, New York, NY

10016, USA.

(3)Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman

School of Medicine, New York, NY 10016, USA; Department of Pathology, New York

University Grossman School of Medicine, New York, NY 10016, USA.

…

Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often

resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for

ubiquitin-mediated degradation to regulate homologous recombination repair (HRR)

and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY,

producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP

inhibitors. Defective HRR contributes to a high tumor mutational burden that, in

turn, is expected to prompt an innate immune response. Notably, EMSY

accumulation suppresses the type I interferon response and impairs innate immune

signaling, fostering cancer immune evasion. Activation of the type I interferon

response in the tumor microenvironment using a STING agonist results in the

engagement of innate and adaptive immune signaling and impairs the growth of

KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways,

individually or in combination, represents a therapeutic strategy in NSCLC

patients harboring alterations in KEAP1.

Copyright © 2021 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2021.12.005

PMCID: PMC8751279

PMID: 34963055 [Indexed for MEDLINE]

5. N Engl J Med. 2022 Jan 20;386(3):241-251. doi: 10.1056/NEJMoa2112431. Epub 2021 Sep 18.

Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer.

Li BT(1), Smit EF(1), Goto Y(1), Nakagawa K(1), Udagawa H(1), Mazières J(1),

Nagasaka M(1), Bazhenova L(1), Saltos AN(1), Felip E(1), Pacheco JM(1), Pérol

M(1), Paz-Ares L(1), Saxena K(1), Shiga R(1), Cheng Y(1), Acharyya S(1), Vitazka

P(1), Shahidi J(1), Planchard D(1), Jänne PA(1); DESTINY-Lung01 Trial

Investigators.

Collaborators: Jänne P, Li B, Kalemkerian G, Gadgeel S, Nagasaka M, Baik C,

Bazhenova L, Saltos A, Pacheco J, Waqar S, Smit E, Tomasini P, Barlesi F,

Mazières J, Planchard D, Pérol M, Felip E, Paz-Ares L, Goto K, Udagawa H, Goto

Y, Fujiwara Y, Murakami H, Nakagawa K.

Author information:

(1)From Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New

York (B.T.L.); the Netherlands Cancer Institute, Amsterdam (E.F.S); the National

Cancer Center Hospital, Tokyo (Y.G.), Kindai University Hospital, Osaka (K.N.),

and the National Cancer Center East, Kashiwa (H.U.) - all in Japan; Centre

Hospitalier Universitaire, Toulouse (J.M.), Centre Léon Bérard, Lyon (M.P.), and

the Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif

(D.P.) - all in France; Karmanos Cancer Institute, Detroit (M.N.); the

University of California, San Diego, Moores Cancer Center, San Diego (L.B.);

Moffitt Cancer Center, Tampa, FL (A.N.S.); Vall d'Hebron University Hospital and

Vall d'Hebron Institute of Oncology, Barcelona (E.F.); University of Colorado,

Aurora (J.M.P.); Hospital Universitario 12 de Octubre, H12O-Centro Nacional de

Investigaciones Oncológicas (CNIO) Lung Cancer Clinical Research Unit, and

Complutense University, Madrid (L.P.-A.); Daiichi Sankyo, Basking Ridge, NJ

(K.S., R.S., Y.C., S.A., P.V., J.S.); and Dana-Farber Cancer Institute and the

Belfer Center for Applied Cancer Science, Boston (P.A.J.).

Comment in

    Nat Rev Clin Oncol. 2021 Dec;18(12):748.

    N Engl J Med. 2022 Jan 20;386(3):286-289.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies

have not been approved for patients with non-small-cell lung cancer (NSCLC). The

efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2

antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been

investigated extensively.

METHODS: We conducted a multicenter, international, phase 2 study in which

trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to

patients who had metastatic HER2-mutant NSCLC that was refractory to standard

treatment. The primary outcome was objective response as assessed by independent

central review. Secondary outcomes included the duration of response,

progression-free survival, overall survival, and safety. Biomarkers of HER2

alterations were assessed.

RESULTS: A total of 91 patients were enrolled. The median duration of follow-up

was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response

occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The

median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median

progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median

overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was

generally consistent with those from previous studies; grade 3 or higher

drug-related adverse events occurred in 46% of patients, the most common event

being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease

occurred in 26% of patients and resulted in death in 2 patients. Responses were

observed across different HER2 mutation subtypes, as well as in patients with no

detectable HER2 expression or HER2 amplification.

CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in

patients with previously treated HER2-mutant NSCLC. The safety profile included

interstitial lung disease that was fatal in two cases. Observed toxic effects

were generally consistent with those in previously reported studies. (Funded by

Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number,

NCT03505710.).

Copyright © 2021 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2112431

PMID: 34534430 [Indexed for MEDLINE]   

6. Nat Immunol. 2022 Feb;23(2):318-329. doi: 10.1038/s41590-021-01121-x. Epub 2022 Jan 20.

The immunoregulatory landscape of human tuberculosis granulomas.

McCaffrey EF(1), Donato M(2)(3), Keren L(4), Chen Z(5), Delmastro A(1),

Fitzpatrick MB(6), Gupta S(2)(3), Greenwald NF(1), Baranski A(1), Graf W(7),

Kumar R(1), Bosse M(1), Fullaway CC(1), Ramdial PK(8), Forgó E(1), Jojic V(5),

Van Valen D(7), Mehra S(9), Khader SA(10), Bendall SC(1), van de Rijn M(1),

Kalman D(11), Kaushal D(12), Hunter RL(13), Banaei N(1)(14), Steyn AJC(8)(15),

Khatri P(2)(3), Angelo M(16).

Author information:

(1)Department of Pathology, Stanford University School of Medicine, Stanford,

CA, USA.

(2)Department of Medicine, Division of Biomedical Informatics Research, Stanford

University School of Medicine, Stanford, CA, USA.

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

School of Medicine, Stanford, CA, USA.

…

Erratum in

    Nat Immunol. 2022 Mar 11;:

Tuberculosis (TB) in humans is characterized by formation of immune-rich

granulomas in infected tissues, the architecture and composition of which are

thought to affect disease outcome. However, our understanding of the spatial

relationships that control human granulomas is limited. Here, we used

multiplexed ion beam imaging by time of flight (MIBI-TOF) to image 37 proteins

in tissues from patients with active TB. We constructed a comprehensive atlas

that maps 19 cell subsets across 8 spatial microenvironments. This atlas shows

an IFN-γ-depleted microenvironment enriched for TGF-β, regulatory T cells and

IDO1+ PD-L1+ myeloid cells. In a further transcriptomic meta-analysis of

peripheral blood from patients with TB, immunoregulatory trends mirror those

identified by granuloma imaging. Notably, PD-L1 expression is associated with

progression to active TB and treatment response. These data indicate that in TB

granulomas, there are local spatially coordinated immunoregulatory programs with

systemic manifestations that define active TB.

© 2022. The Author(s).

DOI: 10.1038/s41590-021-01121-x

PMCID: PMC8810384

PMID: 35058616 [Indexed for MEDLINE]

7. JAMA. 2022 Jan 18;327(3):264-273. doi: 10.1001/jama.2021.24287.

Evaluating the Patient With a Pulmonary Nodule: A Review.

Mazzone PJ(1), Lam L(1).

Author information:

(1)Respiratory Institute, Cleveland Clinic, Cleveland, Ohio.

IMPORTANCE: Pulmonary nodules are identified in approximately 1.6 million

patients per year in the US and are detected on approximately 30% of computed

tomographic (CT) images of the chest. Optimal treatment of an individual with a

pulmonary nodule can lead to early detection of cancer while minimizing testing

for a benign nodule.

OBSERVATIONS: At least 95% of all pulmonary nodules identified are benign, most

often granulomas or intrapulmonary lymph nodes. Smaller nodules are more likely

to be benign. Pulmonary nodules are categorized as small solid (<8 mm), larger

solid (≥8 mm), and subsolid. Subsolid nodules are divided into ground-glass

nodules (no solid component) and part-solid (both ground-glass and solid

components). The probability of malignancy is less than 1% for all nodules

smaller than 6 mm and 1% to 2% for nodules 6 mm to 8 mm. Nodules that are 6 mm

to 8 mm can be followed with a repeat chest CT in 6 to 12 months, depending on

the presence of patient risk factors and imaging characteristics associated with

lung malignancy, clinical judgment about the probability of malignancy, and

patient preferences. The treatment of an individual with a solid pulmonary

nodule 8 mm or larger is based on the estimated probability of malignancy; the

presence of patient comorbidities, such as chronic obstructive pulmonary disease

and coronary artery disease; and patient preferences. Management options include

surveillance imaging, defined as monitoring for nodule growth with chest CT

imaging, positron emission tomography-CT imaging, nonsurgical biopsy with

bronchoscopy or transthoracic needle biopsy, and surgical resection. Part-solid

pulmonary nodules are managed according to the size of the solid component.

Larger solid components are associated with a higher risk of malignancy.

Ground-glass pulmonary nodules have a probability of malignancy of 10% to 50%

when they persist beyond 3 months and are larger than 10 mm in diameter. A

malignant nodule that is entirely ground glass in appearance is typically slow

growing. Current bronchoscopy and transthoracic needle biopsy methods yield a

sensitivity of 70% to 90% for a diagnosis of lung cancer.

CONCLUSIONS AND RELEVANCE: Pulmonary nodules are identified in approximately 1.6

million people per year in the US and approximately 30% of chest CT images. The

treatment of an individual with a pulmonary nodule should be guided by the

probability that the nodule is malignant, safety of testing, the likelihood that

additional testing will be informative, and patient preferences.

DOI: 10.1001/jama.2021.24287

PMID: 35040882 [Indexed for MEDLINE]

8. Lancet Oncol. 2022 Feb;23(2):220-233. doi: 10.1016/S1470-2045(21)00650-1. Epub

2022 Jan 14.

Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as

first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302):

interim and final analyses of a double-blind, randomised, phase 3 clinical

trial.

Zhou C(1), Wang Z(2), Sun Y(3), Cao L(4), Ma Z(5), Wu R(6), Yu Y(7), Yao W(8),

Chang J(9), Chen J(10), Zhuang W(11), Cui J(12), Chen X(13), Lu Y(14), Shen

H(15), Wang J(16), Li P(16), Qin M(16), Lu D(16), Yang J(16).

Author information:

(1)Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School

of Medicine, Shanghai, China. Electronic address: caicunzhoudr@163.com.

(2)Key Laboratory of Carcinogenesis and Translational Research (Ministry of

Education, Beijing), Department of Thoracic Oncology, Peking University Cancer

Hospital and Institute, Beijing, China.

(3)Department of Oncology, Jinan Central Hospital, Jinan, China; Phase I

Clinical Research Center, Shandong Cancer Hospital and Institute, Jinan, China.

…

Comment in

    Lancet Oncol. 2022 Feb;23(2):186-188.

BACKGROUND: PD-1 inhibitor plus chemotherapy had been shown to be an effective

first-line treatment for patients with metastatic non-small-cell lung cancer

(NSCLC). However, there was no robust evidence showing a PD-L1 inhibitor

combined with chemotherapy benefited patients with squamous and non-squamous

NSCLC. GEMSTONE-302 aimed to evaluate the efficacy and safety of a PD-L1

inhibitor, sugemalimab, plus chemotherapy for patients with metastatic squamous

or non-squamous NSCLC.

METHODS: This randomised, double-blind, phase 3 trial was done in 35 hospitals

and academic research centres in China. Eligible patients were aged 18-75 years,

had histologically or cytologically confirmed stage IV squamous or non-squamous

NSCLC without known EGFR sensitising mutations, ALK, ROS1, or RET fusions, no

previous systemic treatment for metastatic disease, and an Eastern Cooperative

Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly

assigned (2:1) to receive sugemalimab (1200 mg, intravenously, every 3 weeks)

plus platinum-based chemotherapy (carboplatin [area under the curve (AUC) 5

mg/mL per min, intravenously] and paclitaxel [175 mg/m2, intravenously] for

squamous NSCLC, or carboplatin [AUC 5 mg/mL per min, intravenously] and

pemetrexed [500 mg/m2, intravenously] for non-squamous NSCLC; sugemalimab group)

or placebo plus the same platinum-based chemotherapy regimens for squamous or

non-squamous NSCLC as in the sugemalimab group; placebo group) for up to four

cycles, followed by maintenance therapy with sugemalimab or placebo for squamous

NSCLC, and intravenous sugemalimab 500 mg/m2 or matching placebo plus pemetrexed

for non-squamous NSCLC. Randomisation was done by an interactive

voice-web-response system via permuted blocks (block size was a mixture of three

and six with a random order within each stratum) and stratified by ECOG

performance status, PD-L1 expression, and tumour pathology. The investigators,

patients, and the sponsor were masked to treatment assignment. The primary

endpoint was investigator-assessed progression-free survival in the

intention-to-treat population. Safety was analysed in all patients who received

at least one treatment dose. Results reported are from a prespecified interim

analysis (ie, when the study met the primary endpoint) and an updated analysis

(prespecified final analysis for progression-free survival) with a longer

follow-up. This study is registered with ClinicalTrials.gov (NCT03789604), is

closed to new participants, and follow-up is ongoing.

FINDINGS: Between Dec 13, 2018, and May 15, 2020, 846 patients were assessed for

eligibility; 367 were ineligible, and the remaining 479 patients were randomly

assigned to the sugemalimab group (n=320) or placebo group (n=159). At the

preplanned interim analysis (data cutoff June 8, 2020; median follow-up 8·6

months [IQR 6·1-11·4]), GEMSTONE-302 met its primary endpoint, with

significantly longer progression-free survival in the sugemalimab group compared

with the placebo group (median 7·8 months [95% CI 6·9-9·0] vs 4·9 months

[4·7-5·0]; stratified hazard ratio [HR] 0·50 [95% CI 0·39-0·64], p<0·0001]). At the final analysis (March 15, 2021) with a median follow-up of 17·8 months (IQR 15·1-20·9), the improvement in progression-free survival was maintained (median 9·0 months [95% CI 7·4-10·8] vs 4·9 months [4·8-5·1]; stratified HR 0·48 [95% CI 0·39-0·60], p<0·0001). The most common grade 3 or 4 any treatment-related adverse events were neutrophil count decreased (104 [33%] of 320 with

sugemalimab vs 52 [33%] of 159 with placebo), white blood cell count decreased

(45 [14%] vs 27 [17%]), anaemia (43 [13%] vs 18 [11%]), platelet count decreased

(33 [10%] vs 15 [9%]), and neutropenia (12 [4%] vs seven [4%]). Any

treatment-related serious adverse events occurred in 73 (23%) patients in the

sugemalimab group and 31 (20%) patients in the placebo group. Any

treatment-related deaths were reported in ten (3%) patients in the sugemalimab

group (pneumonia with respiratory failure in one patient; myelosuppression with

septic shock in one patient; pneumonia in two patients; respiratory failure,

abdominal pain, cardiac failure, and immune-mediated pneumonitis in one patient

each; the other two deaths had an unspecified cause) and in two (1%) patients in

the placebo group (pneumonia and multiple organ dysfunction syndrome).

INTERPRETATION: Sugemalimab plus chemotherapy showed a statistically significant

and clinically meaningful progression-free survival improvement compared with

placebo plus chemotherapy, in patients with previously untreated squamous and

non-squamous metastatic NSCLC, regardless of PD-L1 expression, and could be a

newfirst-line treatment option for both squamous and non-squamous metastatic

NSCLC.

FUNDING: CStone Pharmaceuticals.

TRANSLATION: For the Chinese translation of the abstract see Supplementary

Materials section.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(21)00650-1

PMID: 35038432 [Indexed for MEDLINE]

9. Lancet Oncol. 2022 Feb;23(2):209-219. doi: 10.1016/S1470-2045(21)00630-6. Epub

2022 Jan 14.

Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in

patients with locally advanced, unresectable, stage III non-small-cell lung

cancer in China (GEMSTONE-301): interim results of a randomised, double-blind,

multicentre, phase 3 trial.

Zhou Q(1), Chen M(2), Jiang O(3), Pan Y(1), Hu D(4), Lin Q(5), Wu G(6), Cui

J(7), Chang J(8), Cheng Y(9), Huang C(10), Liu A(11), Yang N(12), Gong Y(13),

Zhu C(14), Ma Z(15), Fang J(16), Chen G(17), Zhao J(16), Shi A(16), Lin Y(18),

Li G(19), Liu Y(20), Wang D(21), Wu R(22), Xu X(23), Shi J(24), Liu Z(25), Cui

N(26), Wang J(26), Wang Q(26), Zhang R(26), Yang J(26), Wu YL(27).

Author information:

(1)Guangdong Lung Cancer Insitute, Guangdong Provincial People's Hospital,

Guangdong Academy of Medical Sciences, Guangzhou, China.

(2)The Cancer Hospital of the University of Chinese Academy of Sciences,

Hangzhou, China; Sun Yat-sen University Cancer Centre, Guangzhou, China.

(3)The Second People's Hospital of Neijiang, Neijiang, China.

…

Comment in

    Lancet Oncol. 2022 Feb;23(2):186-188.

BACKGROUND: A substantial proportion of patients with unresectable stage III

non-small-cell lung cancer (NSCLC) cannot either tolerate or access concurrent

chemoradiotherapy, so sequential chemoradiotherapy is commonly used. We assessed

the efficacy and safety of sugemalimab, an anti-PD-L1 antibody, in patients with

stage III NSCLC whose disease had not progressed after concurrent or sequential

chemoradiotherapy.

METHODS: GEMSTONE-301 is a randomised, double-blind, placebo-controlled, phase 3

trial in patients with locally advanced, unresectable, stage III NSCLC, done at

50 hospitals or academic research centres in China. Eligible patients were aged

18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance

status of 0 or 1 who had not progressed after concurrent or sequential

chemoradiotherapy. We randomly assigned patients (2:1, using an interactive

voice-web response system) to receive sugemalimab 1200 mg or matching placebo,

intravenously every 3 weeks for up to 24 months. Stratification factors were

ECOG performance status, previous chemoradiotherapy, and total radiotherapy

dose. The investigators, trial coordination staff, patients, and study sponsor

were masked to treatment allocation. The primary endpoint was progression-free

survival as assessed by blinded independent central review (BICR) in the

intention-to-treat population. Safety was assessed in all participants who

received at least one dose of assigned study treatment. The study has completed

enrolment and the results of a preplanned analysis of the primary endpoint are

reported here. The trial is registered with ClinicalTrials.gov, NCT03728556.

FINDINGS: Between Aug 30, 2018 and Dec 30, 2020, we screened 564 patients of

whom 381 were eligible. Study treatment was received by all patients randomly

assigned to sugemalimab (n=255) and to placebo (n=126). At data cutoff (March 8,

2021), median follow-up was 14·3 months (IQR 6·4-19·4) for patients in the

sugemalimab group and 13·7 months (7·1-18·4) for patients in the placebo group.

Progression-free survival assessed by BICR was significantly longer with

sugemalimab than with placebo (median 9·0 months [95% CI 8·1-14·1] vs 5·8 months [95% CI 4·2-6·6]; stratified hazard ratio 0·64 [95% CI 0·48-0·85], p=0·0026). Grade 3 or 4 treatment-related adverse events occurred in 22 (9%) of 255 patients in the sugemalimab group versus seven (6%) of 126 patients in the

placebo group, the most common being pneumonitis or immune-mediated pneumonitis

(seven [3%] of 255 patients in the sugemalimab group vs one [<1%] of 126 in the

placebo group). Treatment-related serious adverse events occurred in 38 (15%)

patients in the sugemalimab group and 12 (10%) in the placebo group.

Treatment-related deaths were reported in four (2%) of 255 patients (pneumonia

in two patients, pneumonia with immune-mediated pneumonitis in one patient, and

acute hepatic failure in one patient) in the sugemalimab group and none in the

placebo group.

INTERPRETATION: Sugemalimab after definitive concurrent or sequential

chemoradiotherapy could be an effective consolidation therapy for patients with

stage III NSCLC whose disease has not progressed after sequential or concurrent

chemoradiotherapy. Longer follow-up is needed to confirm this conclusion.

FUNDING: CStone Pharmaceuticals and the National Key Research and Development

Program of China.

TRANSLATION: For the Chinese translation of the abstract see Supplementary

Materials section.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(21)00630-6

PMID: 35038429 [Indexed for MEDLINE]

10. Lancet Oncol. 2022 Feb;23(2):279-291. doi: 10.1016/S1470-2045(21)00658-6. Epub 2022 Jan 13.

Durvalumab plus tremelimumab alone or in combination with low-dose or

hypofractionated radiotherapy in metastatic non-small-cell lung cancer

refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised,

phase 2 trial.

Schoenfeld JD(1), Giobbie-Hurder A(2), Ranasinghe S(3), Kao KZ(3), Lako A(3),

Tsuji J(4), Liu Y(2), Brennick RC(3), Gentzler RD(5), Lee C(6), Hubbard J(7),

Arnold SM(8), Abbruzzese JL(9), Jabbour SK(10), Uboha NV(11), Stephans KL(12),

Johnson JM(13), Park H(14), Villaruz LC(15), Sharon E(16), Streicher H(16),

Ahmed MM(16), Lyon H(4), Cibuskis C(4), Lennon N(4), Jhaveri A(2), Yang L(2),

Altreuter J(2), Gunasti L(17), Weirather JL(2), Mak RH(17), Awad MM(18), Rodig

SJ(3), Chen HX(16), Wu CJ(18), Monjazeb AM(19), Hodi FS(20).

Author information:

(1)Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA,

USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA,

USA. Electronic address: Jonathan_Schoenfeld@dfci.harvard.edu.

(2)Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.

(3)Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

…

Comment in

    Lancet Oncol. 2022 Feb;23(2):191-193.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) that is resistant

to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest

that radiotherapy could enhance antitumour immunity. Therefore, we investigated

the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition

alone or combined with radiotherapy.

METHODS: This open-label, multicentre, randomised, phase 2 trial was done by the

National Cancer Institute Experimental Therapeutics Clinical Trials Network at

18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern

Cooperative Oncology Group performance status of 0 or 1, and progression during

previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a

web-based system by the study statistician using a permuted block scheme (block

sizes of three or six) without stratification to receive either durvalumab (1500

mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75

mg intravenously every 4 weeks for a maximum of four cycles) alone or with

low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the

first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total

delivered over three 8-Gy fractions during the first cycle only), 1 week after

initial durvalumab-tremelimumab administration. Study treatment was continued

until 1 year or until progression. The primary endpoint was overall response

rate (best locally assessed confirmed response of a partial or complete

response) and, along with safety, was analysed in patients who received at least

one dose of study therapy. The trial is registered with ClinicalTrials.gov,

NCT02888743, and is now complete.

FINDINGS: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled

and randomly assigned, of whom 78 (26 per group) were treated. This trial was

stopped due to futility assessed in an interim analysis. At a median follow-up

of 12·4 months (IQR 7·8-15·1), there were no differences in overall response

rates between the durvalumab-tremelimumab alone group (three [11·5%, 90% CI

1·2-21·8] of 26 patients) and the low-dose radiotherapy group (two [7·7%,

0·0-16·3] of 26 patients; p=0·64) or the hypofractionated radiotherapy group

(three [11·5%, 1·2-21·8] of 26 patients; p=0·99). The most common grade 3-4

adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone

group; three [12%] in the low-dose radiotherapy group; and three [12%] in the

hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the

durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy

group vs three [12%] in the hypofractionated radiotherapy group).

Treatment-related serious adverse events occurred in one (4%) patient in the

durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in

the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea,

hypokalemia, and respiratory failure), and four (15%) patients in the

hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and

hyponatremia). In the low-dose radiotherapy group, there was one death from

respiratory failure potentially related to study therapy.

INTERPRETATION: Radiotherapy did not increase responses to combined PD-L1 plus

CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However,

PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future

studies should refine predictive biomarkers in this setting.

FUNDING: The US National Institutes of Health and the Dana-Farber Cancer

Institute.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(21)00658-6

PMCID: PMC8813905

PMID: 35033226 [Indexed for MEDLINE]

11. Lancet Oncol. 2022 Jan;23(1):104-114. doi: 10.1016/S1470-2045(21)00606-9. Epub 2021 Dec 15.

Postoperative radiotherapy versus no postoperative radiotherapy in patients with

completely resected non-small-cell lung cancer and proven mediastinal N2

involvement (Lung ART): an open-label, randomised, phase 3 trial.

Le Pechoux C(1), Pourel N(2), Barlesi F(3), Lerouge D(4), Antoni D(5), Lamezec

B(6), Nestle U(7), Boisselier P(8), Dansin E(9), Paumier A(10), Peignaux K(11),

Thillays F(12), Zalcman G(13), Madelaine J(14), Pichon E(15), Larrouy A(16),

Lavole A(17), Argo-Leignel D(18), Derollez M(19), Faivre-Finn C(20), Hatton

MQ(21), Riesterer O(22), Bouvier-Morel E(23), Dunant A(23), Edwards JG(24),

Thomas PA(25), Mercier O(26), Bardet A(27).

Author information:

(1)Department of Radiation Oncology, Gustave Roussy, Villejuif, France.

Electronic address: cecile.lepechoux@gustaveroussy.fr.

(2)Radiation Oncology, Institut Sainte Catherine, Avignon, France.

(3)Department of Medical Oncology, Gustave Roussy, Villejuif, France;

Aix-Marseille University, Centre National de la Recherche Scientifique, Institut

National des Sciences et de la Recherche Médicale, Centre de Recherche en

Cancérologie de Marseille, Assistance Publique - Hôpitaux de Marseille,

Marseille, France.

…

Comment in

    Lancet Oncol. 2022 Jan;23(1):8-9.

BACKGROUND: In patients with non-small-cell lung cancer (NSCLC), the use of

postoperative radiotherapy (PORT) has been controversial since 1998, because of

one meta-analysis showing a deleterious effect on survival in patients with pN0

and pN1, but with an unclear effect in patients with pN2 NSCLC. Because many

changes have occurred in the management of patients with NSCLC, the role of

three-dimensional (3D) conformal PORT warrants further investigation in patients

with stage IIIAN2 NSCLC. The aim of this study was to establish whether PORT

should be part of their standard treatment.

METHODS: Lung ART is an open-label, randomised, phase 3, superiority trial

comparing mediastinal PORT to no PORT in patients with NSCLC with complete

resection, nodal exploration, and cytologically or histologically proven N2

involvement. Previous neoadjuvant or adjuvant chemotherapy was allowed. Patients

aged 18 years or older, with an WHO performance status of 0-2, were recruited

from 64 hospitals and cancer centres in five countries (France, UK, Germany,

Switzerland, and Belgium). Patients were randomly assigned (1:1) to either the

PORT or no PORT (control) groups via a web randomisation system, and

minimisation factors were the institution, administration of chemotherapy,

number of mediastinal lymph node stations involved, histology, and use of

pre-treatment PET scan. Patients received PORT at a dose of 54 Gy in 27 or 30

daily fractions, on five consecutive days a week. Three dimensional conformal

radiotherapy was mandatory, and intensity-modulated radiotherapy was permitted

in centres with expertise. The primary endpoint was disease-free survival,

analysed by intention to treat at 3 years; patients from the PORT group who did

not receive radiotherapy and patients from the control group with no follow-up

were excluded from the safety analyses. This trial is now closed. This trial is

registered with ClinicalTrials.gov number, NCT00410683.

FINDINGS: Between Aug 7, 2007, and July 17, 2018, 501 patients, predominantly

staged with 18F-fluorodeoxyglucose (18F-FDG) PET (456 [91%]; 232 (92%) in the

PORT group and 224 (90%) in the control group), were enrolled and randomly

assigned to receive PORT (252 patients) or no PORT (249 patients). At the cutoff

date of May 31, 2019, median follow-up was 4·8 years (IQR 2·9-7·0). 3-year

disease-free survival was 47% (95% CI 40-54) with PORT versus 44% (37-51)

without PORT, and the median disease-free survival was 30·5 months (95% CI

24-49) in the PORT group and 22·8 months (17-37) in the control group (hazard

ratio 0·86; 95% CI 0·68-1·08; p=0·18). The most common grade 3-4 adverse events were pneumonitis (13 [5%] of 241 patients in the PORT group vs one [<1%] of 246 in the control group), lymphopenia (nine [4%] vs 0), and fatigue (six [3%] vs one [<1%]). Late-grade 3-4 cardiopulmonary toxicity was reported in 26 patients

(11%) in the PORT group versus 12 (5%) in the control group. Two patients died

from pneumonitis, partly related to radiotherapy and infection, and one patient

died due to chemotherapy toxicity (sepsis) that was deemed to be

treatment-related, all of whom were in the PORT group.

INTERPRETATION: Lung ART evaluated 3D conformal PORT after complete resection in

patients who predominantly had been staged using (18F-FDG PET-CT and received

neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher

than expected in both groups, but PORT was not associated with an increased

disease-free survival compared with no PORT. Conformal PORT cannot be

recommended as the standard of care in patients with stage IIIAN2 NSCLC.

FUNDING: French National Cancer Institute, Programme Hospitalier de Recherche

Clinique from the French Health Ministry, Gustave Roussy, Cancer Research UK,

Swiss State Secretary for Education, Research, and Innovation, Swiss Cancer

Research Foundation, Swiss Cancer League.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(21)00606-9

PMID: 34919827 [Indexed for MEDLINE]

12. Lancet Oncol. 2022 Jan;23(1):138-148. doi: 10.1016/S1470-2045(21)00590-8. Epub 2021 Dec 11.

USPSTF2013 versus PLCOm2012 lung cancer screening eligibility criteria

(International Lung Screening Trial): interim analysis of a prospective cohort

study.

Tammemägi MC(1), Ruparel M(2), Tremblay A(3), Myers R(4), Mayo J(5), Yee J(6),

Atkar-Khattra S(7), Yuan R(8), Cressman S(9), English J(10), Bedard E(11),

MacEachern P(12), Burrowes P(13), Quaife SL(14), Marshall H(15), Yang I(15),

Bowman R(15), Passmore L(15), McWilliams A(16), Brims F(17), Lim KP(18), Mo

L(19), Melsom S(20), Saffar B(20), Teh M(21), Sheehan R(21), Kuok Y(21), Manser

R(22), Irving L(22), Steinfort D(22), McCusker M(23), Pascoe D(23), Fogarty

P(24), Stone E(25), Lam DCL(26), Ng MY(27), Vardhanabhuti V(27), Berg CD(28),

Hung RJ(29), Janes SM(2), Fong K(15), Lam S(7).

Author information:

(1)Department of Health Sciences, Brock University, St Catharines, ON, Canada.

Electronic address: martin.tammemagi@brocku.ca.

(2)Lungs for Living, UCL Respiratory, Department of Medicine, University College

London, London, UK.

(3)Division of Respiratory Medicine & Arnie Charbonneau Cancer Institute,

Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

…

Comment in

    Lancet Oncol. 2022 Jan;23(1):13-14.

BACKGROUND: Lung cancer is a major health problem. CT lung screening can reduce

lung cancer mortality through early diagnosis by at least 20%. Screening

high-risk individuals is most effective. Retrospective analyses suggest that

identifying individuals for screening by accurate prediction models is more

efficient than using categorical age-smoking criteria, such as the US Preventive

Services Task Force (USPSTF) criteria. This study prospectively compared the

effectiveness of the USPSTF2013 and PLCOm2012 model eligibility criteria.

METHODS: In this prospective cohort study, participants from the International

Lung Screening Trial (ILST), aged 55-80 years, who were current or former

smokers (ie, had ≥30 pack-years smoking history or ≤15 quit-years since last

permanently quitting), and who met USPSTF2013 criteria or a PLCOm2012 risk

threshold of at least 1·51% within 6 years of screening, were recruited from

nine screening sites in Canada, Australia, Hong Kong, and the UK. After

enrolment, patients were assessed with the USPSTF2013 criteria and the PLCOm2012

risk model with a threshold of at least 1·70% at 6 years. Data were collected

locally and centralised. Main outcomes were the comparison of lung cancer

detection rates and cumulative life expectancies in patients with lung cancer

between USPSTF2013 criteria and the PLCOm2012 model. In this Article, we present

data from an interim analysis. To estimate the incidence of lung cancers in

individuals who were USPSTF2013-negative and had PLCOm2012 of less than 1·51% at

6 years, ever-smokers in the Prostate Lung Colorectal and Ovarian Cancer

Screening Trial (PLCO) who met these criteria and their lung cancer incidence

were applied to the ILST sample size for the mean follow-up occurring in the

ILST. This trial is registered at ClinicalTrials.gov, NCT02871856. Study

enrolment is almost complete.

FINDINGS: Between June 17, 2015, and Dec 29, 2020, 5819 participants from the

International Lung Screening Trial (ILST) were enrolled on the basis of meeting

USPSTF2013 criteria or the PLCOm2012 risk threshold of at least 1·51% at 6

years. The same number of individuals was selected for the PLCOm2012 model as

for the USPSTF2013 criteria (4540 [78%] of 5819). After a mean follow-up of 2·3

years (SD 1·0), 135 lung cancers occurred in 4540 USPSTF2013-positive

participants and 162 in 4540 participants included in the PLCOm2012 of at least

1·70% at 6 years group (cancer sensitivity difference 15·8%, 95% CI 10·7-22·1%; absolute odds ratio 4·00, 95% CI 1·89-9·44; p<0·0001). Compared to

USPSTF2013-positive individuals, PLCOm2012-selected participants were older

(mean age 65·7 years [SD 5·9] vs 63·3 years [5·7]; p<0·0001), had more

comorbidities (median 2 [IQR 1-3] vs 1 [1-2]; p<0·0001), and shorter life

expectancy (13·9 years [95% CI 12·8-14·9] vs 14·8 [13·6-16·0] years).

Model-based difference in cumulative life expectancies for those diagnosed with

lung cancer were higher in those who had PLCOm2012 risk of at least 1·70% at 6

years than individuals who were USPSTF2013-positive (2248·6 years [95% CI

2089·6-2425·9] vs 2000·7 years [1841·2-2160·3]; difference 247·9 years,

p=0·015).

INTERPRETATION: PLCOm2012 appears to be more efficient than the USPSTF2013

criteria for selecting individuals to enrol into lung cancer screening

programmes and should be used for identifying high-risk individuals who benefit

from the inclusion in these programmes.

FUNDING: Terry Fox Research Institute, The UBC-VGH Hospital Foundation and the

BC Cancer Foundation, the Alberta Cancer Foundation, the Australian National

Health and Medical Research Council, Cancer Research UK and a consortium of

funders, and the Roy Castle Lung Cancer Foundation for the UK Lung Screen Uptake

Trial.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open

Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd..

All rights reserved.

DOI: 10.1016/S1470-2045(21)00590-8

PMCID: PMC8716337

PMID: 34902336 [Indexed for MEDLINE]

13. Annu Rev Pharmacol Toxicol. 2022 Jan 6;62:197-210. doi:

10.1146/annurev-pharmtox-041921-074800. Epub 2021 Sep 30.

Emerging Therapeutics, Technologies, and Drug Development Strategies to Address

Patient Nonadherence and Improve Tuberculosis Treatment.

Garcia-Cremades M(1), Solans BP(1), Strydom N(1), Vrijens B(2)(3), Pillai

GC(4)(5), Shaffer C(1), Thomas B(6), Savic RM(1).

Author information:

(1)Department of Bioengineering and Therapeutic Sciences, University of

California, San Francisco, California 94158, USA; email: rada.savic@ucsf.edu.

(2)AARDEX Group, B-4102 Liège Science Park, Belgium.

(3)Department of Public Health, University of Liège, B-4000 Liège, Belgium.

(4)Division of Clinical Pharmacology, University of Cape Town, 7925 Observatory,

South Africa.

(5)CP+ Associates GmbH, 4102 Basel, Switzerland.

(6)The Arcady Group, Richmond, Virginia 23226, USA.

Imperfect medication adherence remains the biggest predictor of treatment

failure for patients with tuberculosis. Missed doses during treatment lead to

relapse, tuberculosis resistance, and further spread of disease. Understanding

individual patient phenotypes, population pharmacokinetics, resistance

development, drug distribution to tuberculosis lesions, and pharmacodynamics at

the site of infection is necessary to fully measure the impact of adherence on

patient outcomes. To decrease the impact of expected variabilityin drug intake

on tuberculosis outcomes, an improvement in patient adherence and new forgiving

regimens that protect against missed doses are needed. In this review, we

summarize emerging technologies to improve medication adherence in clinical

practice and provide suggestions on how digital adherence technologies can be

incorporated in clinical trials and practice and the drug development pipeline

that will lead to more forgiving regimens and benefit patients suffering from

tuberculosis.

DOI: 10.1146/annurev-pharmtox-041921-074800

PMID: 34591605 [Indexed for MEDLINE]

14. Lancet Infect Dis. 2022 Apr;22(4):e108-e120. doi: 10.1016/S1473-3099(21)00810-0. Epub 2022 Feb 28.

Accelerating research and development of new vaccines against tuberculosis: a

global roadmap.

Cobelens F(1), Suri RK(2), Helinski M(3), Makanga M(3), Weinberg AL(3),

Schaffmeister B(4), Deege F(4), Hatherill M(5); TB Vaccine Roadmap Stakeholder

Group.

Author information:

(1)Department of Global Health and Amsterdam Institute for Global Health and

Development, Amsterdam University Medical Centers, Amsterdam, Netherlands.

Electronic address: f.g.cobelens@amsterdamumc.nl.

(2)Department of Governance and Strategy, Developing Countries Vaccine

Manufacturers' Network International, Nyon, Switzerland.

(3)European & Developing Countries Clinical Trials Partnership, The Hague,

Netherlands.

(4)Nextco, Oegstgeest, Netherlands.

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

Disease and Molecular Medicine, and Division of Immunology, Department of

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

To eliminate tuberculosis globally, a new, effective, and affordable vaccine is

urgently needed, particularly for use in adults and adolescents in low-income

and middle-income countries. We have created a roadmap that lists the actions

needed to accelerate tuberculosis vaccine research and development using a

participatory process. The vaccine pipeline needs more diverse immunological

approaches, antigens, and platforms. Clinical development can be accelerated by

validated preclinical models, agreed laboratory correlates of protection,

efficient trial designs, and validated endpoints. Determining the public health

impact of new tuberculosis vaccines requires understanding of a country's demand

for a new tuberculosis vaccine, how to integrate vaccine implementation with

ongoing tuberculosis prevention efforts, cost, and national and global demand to

stimulate vaccine production. Investments in tuberculosis vaccine research and

development need to be increased, with more diversity of funding sources and

coordination between these funders. Open science is important to enhance the

efficiency of tuberculosis vaccine research and development including early and

freely available publication of study findings and effective mechanisms for

sharing datasets and specimens. There is a need for increased engagement of

industry vaccine developers, for increased political commitment for new

tuberculosis vaccines, and to address stigma and vaccine hesitancy. The

unprecedented speed by which COVID-19 vaccines have been developed and

introduced provides important insight for tuberculosis vaccine research and

development.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(21)00810-0

PMCID: PMC8884775

PMID: 35240041

15. Am J Respir Crit Care Med. 2022 Feb 17. doi: 10.1164/rccm.202107-1779OC. Online ahead of print.

An All-Oral 6-Month Regimen for Multidrug-Resistant TB (the NExT Study): A

Multicenter, Randomized Controlled Trial.

Esmail A(1)(2), Oelofse S(3)(2), Lombard C(4)(5), Perumal R(3)(2), Mbuthini

L(3), Goolam Mahomed A(6), Variava E(7)(8), Black J(9), Oluboyo P(10), Gwentshu

N(11), Ngam E(11), Ackerman T(12), Marais L(13), Mottay L(3)(2), Meier S(14)(2),

Pooran A(3)(2), Tomasicchio M(3)(15), Te Riele J(16), Derendinger B(17), Ndjeka

N(18), Maartens G(19), Warren R(20), Martinson N(21)(22), Dheda K(23)(2)(24).

Author information:

(1)University of Cape Town, 37716, Centre for Lung Infection and Immunity,

Division of Pulmonology, Department of Medicine and UCT Lung Institute,

Rondebosch, South Africa.

(2)University of Cape Town, 37716, South African MRC Centre for the Study of

Antimicrobial Resistance, Cape Town, South Africa.

(3)University of Cape Town, 37716, Centre for Lung Infection and Immunity,

Division of Pulmonology, Department of Medicine and UCT Lung Institute, Cape

Town, South Africa.

Rationale/objectives: Improving treatment outcomes yet reducing drug toxicity

and shortening the treatment duration to ~6-months remains an aspirational goal

for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis

(MDR/RR-TB).

METHODS: We conducted a multicentre randomised controlled trial in adults with

MDR/RR-TB (i.e. without resistance to fluoroquinolones or aminoglycosides).

Participants were randomly assigned (1:1 ratio) to a ~6-month all-oral regimen

that included levofloxacin, bedaquiline and linezolid, or the standard-of-care ≥

9-month WHO-approved injectable-based regimen. The primary endpoint was a

favourable WHO-defined treatment outcome (which mandates that pre-specified drug

substitution is counted as an unfavourable outcome) 24 months after treatment

initiation. The trial was stopped prematurely when bedaquiline-based therapy

became the standard-of-care in South Africa.

MAIN RESULTS: 93 of 111 participants randomised (44/93 in comparator arm; 49/93

in interventional arm) were included in the modified intention-to-treat

analysis; 51 (55%) were HIV co-infected (median CD4 count 158 cells/mL).

Participants in the intervention arm were 2.2 times more likely to experience a

favourable 24-month outcome than participants in the standard-of-care arm [51%

(25/49) versus 22.7% (10/44); RR 2.2 (1.2-4.1); p=0.006]. Toxicity-related drug

substitution occurred more frequently in the standard-of-care arm [(65·9%

(29/44) versus 34·7% (17/49), p= 0·001)]; 82.8% (24/29) due to kanamycin (mainly

hearing loss; replaced by bedaquiline) in the standard-of-care arm, and 64.7%

(11/17) due to linezolid (mainly anaemia) in the interventional arm. Adverse

event-related treatment discontinuation in safety population was more common in

the standard-of-care arm [56.4% (31/55) vs 32.1% (17/56, p=0.007]. However,

grade 3 adverse events were more common in the interventional arm (55.4% (31/56)

versus 32.7 (18/55); p= 0.022). Culture conversion was significantly better in

the intervention arm [HR 2.6 (1.4-4.9); p= 0.003] after censoring those with

bedaquiline replacement in the standard-of-care arm (and this pattern remained

consistent after censoring for drug replacement in both arms; p= 0.01).

CONCLUSIONS: Compared with traditional injectable-containing regimens, an

all-oral 6-month levofloxacin, bedaquiline and linezolid-containing MDR/RR-TB

regimen was associated with a significantly improved 24-month WHO-defined

treatment outcome (predominantly due to toxicity-related drug substitution).

However, drug toxicity occurred frequently in both arms. These findings inform

strategies to develop future regimens for MDR/RR-TB. Clinical trial registration

available at www.clinicaltrials.gov, ID: NCT02454205.

DOI: 10.1164/rccm.202107-1779OC

PMID: 35175905

16. Nat Commun. 2022 Jan 21;13(1):432. doi: 10.1038/s41467-022-28078-1.

Interplay between an ATP-binding cassette F protein and the ribosome from

Mycobacterium tuberculosis.

Cui Z(1), Li X(1), Shin J(1), Gamper H(2), Hou YM(2), Sacchettini JC(1), Zhang

J(3).

Author information:

(1)Department of Biochemistry and Biophysics, Texas A&M University, College

Station, TX, 77843, USA.

(2)Department of Biochemistry and Molecular Biology, Thomas Jefferson

University, Philadelphia, PA, 19107, USA.

(3)Department of Biochemistry and Biophysics, Texas A&M University, College

Station, TX, 77843, USA. junjiez@tamu.edu.

EttA, energy-dependent translational throttle A, is a ribosomal factor that

gates ribosome entry into the translation elongation cycle. A detailed

understanding of its mechanism of action is limited due to the lack of

high-resolution structures along its ATPase cycle. Here we present the

cryo-electron microscopy (cryo-EM) structures of EttA from Mycobacterium

tuberculosis (Mtb), referred to as MtbEttA, in complex with the Mtb 70S ribosome

initiation complex (70SIC) at the pre-hydrolysis (ADPNP) and transition

(ADP-VO4) states, and the crystal structure of MtbEttA alone in the

post-hydrolysis (ADP) state. We observe that MtbEttA binds the E-site of the Mtb

70SIC, remodeling the P-site tRNA and the ribosomal intersubunit bridge B7a

during the ribosomal ratcheting. In return, the rotation of the 30S causes

conformational changes in MtbEttA, forcing the two nucleotide-binding sites

(NBSs) to alternate to engage each ADPNP in the pre-hydrolysis states, followed

by complete engagements of both ADP-VO4 molecules in the ATP-hydrolysis

transition states. In the post-hydrolysis state, the conserved ATP-hydrolysis

motifs of MtbEttA dissociate from both ADP molecules, leaving two

nucleotide-binding domains (NBDs) in an open conformation. These structures

reveal a dynamic interplay between MtbEttA and the Mtb ribosome, providing

insights into the mechanism of translational regulation by EttA-like proteins.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-28078-1

PMCID: PMC8782954

PMID: 35064151 [Indexed for MEDLINE]

17. Lancet Infect Dis. 2022 Feb;22(2):242-249. doi: 10.1016/S1473-3099(21)00452-7. Epub 2021 Oct 7.

Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and

capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre

diagnostic accuracy study.

Penn-Nicholson A(1), Georghiou SB(2), Ciobanu N(3), Kazi M(4), Bhalla M(5),

David A(6), Conradie F(6), Ruhwald M(2), Crudu V(3), Rodrigues C(4), Myneedu

VP(5), Scott L(6), Denkinger CM(7), Schumacher SG(2); Xpert XDR Trial

Consortium.

Author information:

(1)FIND, Geneva, Switzerland. Electronic address:

adam.penn-nicholson@finddx.org.

(2)FIND, Geneva, Switzerland.

(3)Phthisiopneumology Institute "Chiril Draganiuc", Chișinău, Moldova.

…

BACKGROUND: The WHO End TB Strategy requires drug susceptibility testing and

treatment of all people with tuberculosis, but second-line diagnostic testing

with line-probe assays needs to be done in experienced laboratories with

advanced infrastructure. Fewer than half of people with drug-resistant

tuberculosis receive appropriate treatment. We assessed the diagnostic accuracy

of the rapid Xpert MTB/XDR automated molecular assay (Cepheid, Sunnyvale, CA,

USA) to overcome these limitations.

METHODS: We did a prospective study involving individuals presenting with

pulmonary tuberculosis symptoms and at least one risk factor for drug resistance

in four sites in India (New Delhi and Mumbai), Moldova, and South Africa between

July 31, 2019, and March 21, 2020. The Xpert MTB/XDR assay was used as a reflex

test to detect resistance to isoniazid, fluoroquinolones, ethionamide, amikacin,

kanamycin, and capreomycin in adults with positive results for Mycobacterium

tuberculosis complex on Xpert MTB/RIF or Ultra (Cepheid). Diagnostic performance

was assessed against a composite reference standard of phenotypic

drug-susceptibility testing and whole-genome sequencing. This study is

registered with ClinicalTrials.gov, number NCT03728725.

FINDINGS: Of 710 participants, 611 (86%) had results from both Xpert MTB/XDR and

the reference standard for any drug and were included in analysis. Sensitivity

for Xpert MTB/XDR detection of resistance was 94% (460 of 488, 95% CI 92-96) for

isoniazid, 94% (222 of 235, 90-96%) for fluoroquinolones, 54% (178 of 328,

50-61) for ethionamide, 73% (60 of 82, 62-81) for amikacin, 86% (181 of 210,

81-91) for kanamycin, and 61% (53 of 87, 49-70) for capreomycin. Specificity was

98-100% for all drugs. Performance was equivalent to that of line-probe assays.

The non-determinate rate of Xpert MTB/XDR (ie, invalid M tuberculosis complex

detection) was 2·96%.

INTERPRETATION: The Xpert MTB/XDR assay showed high diagnostic accuracy and met

WHO's minimum target product profile criteria for a next-generation drug

susceptibility test. The assay has the potential to diagnose drug-resistant

tuberculosis rapidly and accurately and enable optimum treatment.

FUNDING: German Federal Ministry of Education and Research through KfW, Dutch

Ministry of Foreign Affairs, and Australian Department of Foreign Affairs and

Trade.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(21)00452-7

PMID: 34627496

18. Lancet Infect Dis. 2022 Feb;22(2):250-264. doi: 10.1016/S1473-3099(21)00261-9. Epub 2021 Oct 1.

The diagnostic performance of novel skin-based in-vivo tests for tuberculosis

infection compared with purified protein derivative tuberculin skin tests and

blood-based in vitro interferon-γ release assays: a systematic review and

meta-analysis.

Krutikov M(1), Faust L(2), Nikolayevskyy V(3), Hamada Y(1), Gupta RK(1), Cirillo

D(4), Mateelli A(5), Korobitsyn A(6), Denkinger CM(7), Rangaka MX(8).

Author information:

(1)Institute for Global Health, University College London, London, UK.

(2)McGill International Tuberculosis Centre and Department of Epidemiology,

Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.

(3)UK National Mycobacterium Reference Service, Public Health England, London,

UK; Department of Infectious Diseases, Imperial College London, London, UK.

…

Erratum in

    Lancet Infect Dis. 2022 Feb;22(2):e41.

    Lancet Infect Dis. 2022 Feb 15;:

BACKGROUND: Novel skin-based tests for tuberculosis infection might present

suitable alternatives to current tests; however, diagnostic performance of new

tests compared with the purified protein derivative-tuberculin skin test (TST)

or interferon-γ release assays (IGRA) needs systematic assessment.

METHODS: In this systematic review and meta-analysis, we searched English

(Medline OVID), Chinese (Chinese Biomedical Literature Database and the China

National Knowledge Infrastructure), and Russian (e-library) databases from the

inception of each database to May 15, 2019, (with updated search of the Russian

and English databases on Oct, 20 2020) using terms "ESAT6" OR "CFP10" AND "skin

test" AND "Tuberculosis" OR "C-Tb" OR "Diaskintest". We included studies

reporting on the performance of index tests alone or compared with a comparator.

Inclusion criteria varied according to review objectives and performance

outcome, but reporting of test cut-offs for positivity applied to study

population was required from all studies. We used a hierarchy of reference

standards for tuberculosis infection consistent with the 2020 WHO framework to

evaluate diagnostic performance. Two authors independently reviewed the titles

and abstracts for English and Chinese (LF and MK) and Russian studies (MK and

VN). Study quality was assessed with QUADAS-2. Pooled random-effects estimates

are presented when appropriate for total agreement proportion, sensitivity in

microbiologically confirmed tuberculosis and specificity in cohorts with low

risk of tuberculosis infection. This study is registered with PROSPERO,

CRD42019135572.

FINDINGS: We identified 1466 original articles, of which 37 (2·5%) studies,

including 10 915 individuals (7111 Diaskintest, 2744 C-Tb, 887 EC, 173 DPPD),

were included in the qualitative analysis (29 [78%] studies of Diaskintest, five

[15%] studies of C-Tb, two [5%] studies of EC-skintest, and one [3%] study of

DPPD). 22 (1·5%) studies including 5810 individuals (3143 Diaskintest, 2129

C-Tb, 538 EC-skintest) were included in the quantitative analysis: 15 (68%) of

Diaskintest, five (23%) of C-Tb, and two (9%) of EC-skintest. Tested

sub-populations included individuals with HIV, children (0-18 years), and

individuals exposed to tuberculosis. Studies were heterogeneous with moderate to

high risk of bias. Nine head-to-head studies of index test versus TST and IGRA

permitted direct comparisons and pooling. In a mixed cohort of people with and

without tuberculosis, Diaskintest pooled agreement with IGRA was 87·16% (95% CI

79·47-92·24) and 55·45% (46·08-64·45) with TST-5 mm cut-off (TST5 mm).

Diaskintest sensitivity was 91·18% (95% CI 81·72-95·98) compared with 88·24%

(78·20-94·01) for TST5 mm, 89·66 (78·83-95·28) for IGRA QuantiFERON, and 90·91% (79·95-96·16) for TSPOT.TB. C-Tb agreement with IGRA in individuals with active tuberculosis was 79·80% (95% CI 76·10-83·07) compared with 78·92% (74·65-82·63) for TST5 mm/15 mm cut-off (TST5 mm/15 mm). TST5/15mm reflects threshold in cohorts that applied stratified cutoffs: 5 mm for HIV-infected,

immunocompromised, or BCG-naive individuals, and 15mm for BCG-vaccinated

immunocompetent individuals. C-Tb sensitivity was 74·52% (95% CI 70·39-78·25)

compared with a sensitivity of 78·18% (67·75-85·94) for TST5 mm/15 mm, and

71·67% (63·44-78·68) for IGRA. Specificity was 97·85% (95% CI 93·96-99·25) for C-Tb versus 93·31% (90·22-95·48) for TST 15 mm cut-off and 99·15% (79·66-99·97) for IGRA. EC-skintest sensitivity was 86·06% (95% CI 82·39-89·07).

INTERPRETATION: Novel skin-based tests for tuberculosis infection appear to

perform similarly to IGRA or TST; however, study quality varied. Evaluation of

test performance, patient-important outcomes, and diagnostic use in current

clinical algorithms will inform implementation in key populations.

FUNDING: StopTB (New Diagnostics Working Group) and FIND.

TRANSLATIONS: For the Chinese and Russian translations of the abstract see

Supplementary Materials section.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(21)00261-9

PMID: 34606768

19. Lancet Infect Dis. 2022 Feb;22(2):222-241. doi: 10.1016/S1473-3099(21)00449-7. Epub 2021 Sep 23.

Global, regional, and national sex differences in the global burden of

tuberculosis by HIV status, 1990-2019: results from the Global Burden of Disease

Study 2019.

GBD 2019 Tuberculosis Collaborators.

BACKGROUND: Tuberculosis is a major contributor to the global burden of disease,

causing more than a million deaths annually. Given an emphasis on equity in

access to diagnosis and treatment of tuberculosis in global health targets,

evaluations of differences in tuberculosis burden by sex are crucial. We aimed

to assess the levels and trends of the global burden of tuberculosis, with an

emphasis on investigating differences in sex by HIV status for 204 countries and

territories from 1990 to 2019.

METHODS: We used a Bayesian hierarchical Cause of Death Ensemble model (CODEm)

platform to analyse 21 505 site-years of vital registration data, 705 site-years

of verbal autopsy data, 825 site-years of sample-based vital registration data,

and 680 site-years of mortality surveillance data to estimate mortality due to

tuberculosis among HIV-negative individuals. We used a population attributable

fraction approach to estimate mortality related to HIV and tuberculosis

coinfection. A compartmental meta-regression tool (DisMod-MR 2.1) was then used

to synthesise all available data sources, including prevalence surveys, annual

case notifications, population-based tuberculin surveys, and tuberculosis

cause-specific mortality, to produce estimates of incidence, prevalence, and

mortality that were internally consistent. We further estimated the fraction of

tuberculosis mortality that is attributable to independent effects of risk

factors, including smoking, alcohol use, and diabetes, for HIV-negative

individuals. For individuals with HIV and tuberculosis coinfection, we assessed

mortality attributable to HIV risk factors including unsafe sex, intimate

partner violence (only estimated among females), and injection drug use. We

present 95% uncertainty intervals for all estimates.

FINDINGS: Globally, in 2019, among HIV-negative individuals, there were 1·18

million (95% uncertainty interval 1·08-1·29) deaths due to tuberculosis and 8·50 million (7·45-9·73) incident cases of tuberculosis. Among HIV-positive

individuals, there were 217 000 (153 000-279 000) deaths due to tuberculosis and

1·15 million (1·01-1·32) incident cases in 2019. More deaths and incident cases

occurred in males than in females among HIV-negative individuals globally in

2019, with 342 000 (234 000-425 000) more deaths and 1·01 million (0·82-1·23)

more incident cases in males than in females. Among HIV-positive individuals,

6250 (1820-11 400) more deaths and 81 100 (63 300-100 000) more incident cases

occurred among females than among males in 2019. Age-standardised mortality

rates among HIV-negative males were more than two times greater in 105 countries

and age-standardised incidence rates were more than 1·5 times greater in 74

countries than among HIV-negative females in 2019. The fraction of global

tuberculosis deaths among HIV-negative individuals attributable to alcohol use,

smoking, and diabetes was 4·27 (3·69-5·02), 6·17 (5·48-7·02), and 1·17

(1·07-1·28) times higher, respectively, among males than among females in 2019.

Among individuals with HIV and tuberculosis coinfection, the fraction of

mortality attributable to injection drug use was 2·23 (2·03-2·44) times greater

among males than females, whereas the fraction due to unsafe sex was 1·06

(1·05-1·08) times greater among females than males.

INTERPRETATION: As countries refine national tuberculosis programmes and

strategies to end the tuberculosis epidemic, the excess burden experienced by

males is important. Interventions are needed to actively communicate, especially

to men, the importance of early diagnosis and treatment. These interventions

should occur in parallel with efforts to minimise excess HIV burden among women

in the highest HIV burden countries that are contributing to excess HIV and

tuberculosis coinfection burden for females. Placing a focus on tuberculosis

burden among HIV-negative males and HIV and tuberculosis coinfection among

females might help to diminish the overall burden of tuberculosis. This strategy

will be crucial in reaching both equity and burden targets outlined by global

health milestones.

FUNDING: Bill & Melinda Gates Foundation.

Copyright © 2022 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(21)00449-7

PMCID: PMC8799634

PMID: 34563275