Correspondence

The growing multisectoral nature of Authors’ reply Heterogeneity of

Pr Michel Brauner/Ism/Science Photo

the nutrition agenda must recognise We thank Jonathan Klein for raising the
and include tobacco control as an issue of the direct and indirect effects
treatment effects in
environmental strategy to improve of tobacco smoking on maternal malignant pleural
nutrition. However, most maternal, and child undernutrition. Although mesothelioma
newborn, and child health guidelines our Series paper1 did not address the

Library
only address tobacco cessation as a effects of specific risk factors such as The results from CheckMate 7431 are
prenatal care intervention to reduce tobacco on gestational weight gain a relevant advance for the systemic
low birthweight and prematurity. and low birthweight, we recognise treatment of patients with malignant
The broader contributions of tobacco that smoking is an important pleural mesothelioma. However, we
control to constrained fiscal environ­ determinant of fetal growth. The have concerns about the presentation
ments are not addressed. In all countries, indirect effects relate to the trade- and interpretation of subgroup
smoking diverts spending from basic offs between purchasing nutritious analyses. Some further clarity would
needs and leads to catastrophic health foods and spending the limited family be helpful for the applicability of
expenditures for many households.7 To budget on tobacco, alcohol, and non- the study results in clinical practice,
truly make progress in maternal and nutritious foods (eg, sugar-sweetened beyond the unequivocal clinically
child undernutrition, social and fiscal beverages).2 Even though our Series relevant effect observed in the whole
environmental interventions should paper1 does not focus on the distal population.
recognise that evidence-based tobacco determinants of undernutrition, The investigators state that “benefit
control must be part of the nutrition poverty underlies the difficult choices with nivolumab plus ipilimumab
agenda. that families have to make, particularly was observed in most subgroups
JDK reports support for research in child health and given that unhealthy habits are assessed, with the exception of
tobacco smoke from the Flight Attendant Medical strongly promoted in many countries patients aged 75 years or older”. 1
Research Institute grant to the American Academy
of Pediatrics, Julius B Richmond Center.
globally.2 Furthermore, the prevalence However, the aim of presenting a
of smoking in most low-income and forest plot is not to show statistical
Jonathan D Klein middle-income countries is higher significance in each subgroup but to
[email protected] among men than among women;3 test if any apparent heterogeneity
Department of Pediatrics, University of Illinois at therefore, interventions targeted at among subgroups is compatible
Chicago, Chicago, IL 60612, USA
men are likely to have indirect effects with chance or not. The interaction
1 Cutler-Triggs C, Fryer GE, Miyoshi TJ,
Weitzman M. Increased rates and severity of
on the nutrition of women and test would have been useful for
child and adult food insecurity in households children. interpretation. According to our
with adult smokers. Arch Pediatr Adolesc Med calculation (RevMan, version 5·3),
REB declares funding from the Bill & Melinda Gates
2008; 162: 1056–62.
2 Kim-Mozeleski JE, Panday R. The intersection
Foundation. All other authors declare no competing treatment efficacy is not significantly
interests.
of food insecurity and tobacco use: a scoping heterogeneous among age subgroups
review. Health Promot Pract 2020;
21 (suppl 1): 124–38.
*Cesar G Victora, Robert E Black, (p=0·12). Similarly, efficacy is not
3 Sreeramareddy CT, Ramakrishnareddy N. Zulfiqar Bhutta significantly heterogeneous among
Association of adult tobacco use with [email protected] PD-L1 subgroups (p=0·20). On the
household food access insecurity: results from
Nepal Demographic and Health Survey, 2011. International Center for Equity in Health, Federal contrary, the interaction test reveals
BMC Public Health 2017; 18: 48. University of Pelotas, Pelotas 96020-220, Brazil a significant heterogeneity among
4 Semba RD, Campbell AA, Sun K, et al. (CGV); Department of International Health,
Bloomberg School of Public Health, Johns Hopkins histology subgroups (p=0·007). The
Paternal smoking is associated with greater
food insecurity among poor families in University, Baltimore, MD, USA (REB); Centre for presence of heterogeneity does not
rural Indonesia. Asia Pac J Clin Nutr 2011; Global Child Health, The Hospital for Sick Children, mean that the experimental treat­
20: 618. Toronto, ON, Canada (ZB)
5 Raghuveer G, White DA, Hayman LL, et al.
ment is not effective in epithelioid
1 Victora CG, Christian P, Vidaletti LP,
Cardiovascular consequences of childhood Gatica-Domínguez G, Menon P, Black RE.
tumours, but heterogeneity should
secondhand tobacco smoke exposure: Revisiting maternal and child undernutrition be further investigated before
prevailing evidence, burden, and racial and in low-income and middle-income countries:
socioeconomic disparities: a scientific definitive conclusions. The tumour
variable progress towards an unfinished
statement from the American Heart agenda. Lancet 2021; 397: 1388–99. immune micro­e nvironment of
Association. Circulation 2016; 134: e336–59.
6 WHO. WHO report on the global tobacco
2 Moodie R, Stuckler D, Monteiro C, et al. Profits epithelioid and non-epithelioid
and pandemics: prevention of harmful effects
epidemic, 2008: the MPOWER package. of tobacco, alcohol, and ultra-processed food
mesotheliomas is reported to be very
Geneva: World Health Organization, 2008. and drink industries. Lancet 2013; different, adding a biological basis to
7 Global Tobacco Economics Consortium. 381: 670–79.
The health, poverty, and financial further investigate such results.2,3
3 WHO. WHO global report on trends in
consequences of a cigarette price increase prevalence of tobacco smoking 2000–2025, As suggested by many experts,
among 500 million male smokers in 13 middle
income countries: compartmental model
2nd edn. Geneva: World Health Organization, analyses of the heterogeneity of
2018.
study. BMJ 2018; 361: k1162. treatment effects should be on the

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 Correspondence

basis of tests for interaction, which with nivolumab plus ipilimumab understand the biological basis behind
should then be presented in the forest compared with chemotherapy in the differing outcomes, particularly
plot.4,5 non-epithelioid versus epithelioid differing outcomes within the patient
MDM reports advisory board fees from Eisai, subgroup. Nivolumab plus ipilimumab group with epithelioid subtype
AstraZeneca, Janssen Pharmaceuticals, and Astellas had similar effects in both groups disease.
Pharma, consultancy fees from Novartis, Roche,
Pfizer, Takeda, and Merck Sharp & Dohme, and an
(median overall survival was Nivolumab plus ipilimumab is now
institutional research grant from Tesaro– 18·1 months for the non-epithelioid approved in the USA as a first-line
GlaxoSmithKline, unrelated to this Correspondence. subgroup and 18·7 months for the treatment for unresectable MPM,
MT declares travel, accommodations, and expenses
epithelioid subgroup), whereas regardless of histology. We reaffirm
supported by Roche, Bristol-Myers Squibb,
AstraZeneca, and Takeda, and activity as a medical chemotherapy had a poor effect in that this regimen provides a new
writer supported by Novartis and Amgen, unrelated the non-epithelioid group, as reported therapeutic first-line treatment option
to this Correspondence. previously.2 for all patients with MPM; although,
*Massimo Di Maio, As interaction of treatment by further clinical and laboratory inves­
Marco Tagliamento histology was not predefined in the tigations to improve outcomes for
[email protected] statistical analysis plan, we did not patients with MPM remain a high
Department of Oncology, University of Turin, formally do these tests. We agree priority. Further prospective studies
Division of Medical Oncology, Ordine Mauriziano that forest plots represent subgroup based on biomarkers are needed
Hospital, Torino 10128, Italy (MDM); Department of
Oncology, University of Genova, IRCCS Ospedale
analyses without any correction for to decipher optimal treatment
Policlinico San Martino, Genova, Italy (MT) multiple analyses. The limitations of sequencing.
1 Baas P, Scherpereel A, Nowak AK, et al. providing results of the interaction A summary of competing interests in available in
See Online for appendix First-line nivolumab plus ipilimumab in tests are well established: false the appendix.
unresectable malignant pleural mesothelioma
(CheckMate 743): a multicentre, randomised, positives due to multiple com­ *Paul Baas, Arnaud Scherpereel,
open-label, phase 3 trial. Lancet 2021; parisons and false negatives due to Anna K Nowak, Abderrahim Oukessou,
397: 375–86. inadequate statistical power. Also,
2 Awad MM, Jones RE, Liu H, et al. Cytotoxic
Gerard Zalcman
T cells in PD-L1-positive malignant pleural as multiple characteristics might [email protected]
mesotheliomas are counterbalanced by vary simultaneously, those results Netherlands Cancer Institute, 1066 CX Amsterdam,
distinct immunosuppressive factors.
Cancer Immunol Res 2016; 4: 1038–48. have little ability to inform individual Netherlands (PB); Pulmonary and Thoracic
treatment decisions. Multivariable Oncology, University of Lille, CHU Lille, INSERM
3 Pasello G, Zago G, Lunardi F, et al.
U1189, Lille, France (AS); Medical School, University
Malignant pleural mesothelioma immune analyses would be needed to better of Western Australia, Perth, WA, Australia (AKN);
microenvironment and checkpoint expression:
correlation with clinical-pathological features account for possible confounding Bristol Myers Squibb, Princeton, NJ, USA (AO);
and intratumor heterogeneity over time. of various demographics or disease Bichat–Claude Bernard University Hospital,
Ann Oncol 2018; 29: 1258–65. Université de Paris, Paris, France (GZ)
4 Wang R, Lagakos SW, Ware JH, Hunter DJ,
characteristics.
1 Baas P, Scherpereel A, Nowak AK, et al.
Drazen JM. Statistics in medicine—reporting of Although the data on novel bio­ First-line nivolumab plus ipilimumab in
subgroup analyses in clinical trials. N Engl J Med markers provided by Di Maio and unresectable malignant pleural mesothelioma
2007; 357: 2189–94. (CheckMate 743): a multicentre, randomised,
5 Sormani MP, Bruzzi P. Reporting of subgroup
Tagliamento are intriguing, these open-label, phase 3 trial. Lancet 2021;
analyses from clinical trials. Lancet Neurol 2012; analyses are derived from small 397: 375–86.
11: 747. patient numbers and need further 2 Pasello G, Zago G, Lunardi F, et al.
Malignant pleural mesothelioma immune
assessment. We agree that the tumour microenvironment and checkpoint expression:
Authors’ reply immune microenvironment should correlation with clinical-pathological features
and intratumor heterogeneity over time.
We thank Massimo Di Maio and be further characterised; additional Ann Oncol 2018; 29: 1258–65.
Marco Tagliamento for their Correspon­ analyses are warranted to evaluate the 3 Blum Y, Meiller C, Quetel L, et al. Dissecting
dence regarding CheckMate 743, predictive value of PD-L1 by histology, heterogeneity in malignant pleural
mesothelioma through histo-molecular
a global, open-label, randomised, with sufficient patient numbers gradients for clinical applications. Nat Commun
phase 3 study of first-line nivolumab whose tumours express PD-L1 along 2019; 10: 1333.
plus ipilimumab versus chemotherapy a continuum of levels. Mesothelioma 4 Alay A, Cordero D, Hijazo-Pechero S, et al.
Integrative transcriptome analysis of
in unresectable malignant pleural transcriptomic studies have suggested malignant pleural mesothelioma reveals a
mesothelioma (MPM).1 We appreciate that, beyond PD-L1 expression or clinically relevant immune-based classification.
J Immunother Cancer 2021; 9: e001601.
their remarks on the interaction test histological subgrouping, there is 5 Alcala N, Mangiante L, Le-Stang N, et al.
to investigate heterogeneity across substantial heterogeneity based Redefining malignant pleural mesothelioma
histological subtypes. either on histomolecular continuous types as a continuum uncovers immune-
vascular interactions. EBioMedicine 2019;
We agree that treatment efficacy gradients, 3 cytotoxic T-cell and 48: 191–202.
by histology is of interest and T-helper 2 marker expression,4 or
acknowledged in our Article the both immune and angiogenic marker
greater magnitude of benefit observed expression.5 It will now be crucial to

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