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CYIR Clinical Year in Review 2022
2022
Clinical Year in Review
Bibliography
MODERATORS
Jose L. Gomez-Villalobos, MS, MD, ATSF
Yale School of Medicine
Department of Medicine, Pulmonary, Critical Care and Sleep Section
New Haven, CT
Rupal J. Shah, MD, MSCE
University of California, San Francisco
Department of Medicine
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine
San Francisco, CA
Juliana C. Ferreira, MD, PhD, ATSF
University of Sao Paulo
Pulmonary Division
Sao Paulo, Brazil
TABLE OF CONTENTS
A1
• Pulmonary Vascular Disease .................................................................. 4
• Interstitial Lung Disease........................................................................... 9
• Lung Cancer............................................................................................... 14
• Pneumonia and Pulmonary Infections........................................... 19
This session and the International Conference are supported by
independent medical educational grants from Boehringer Ingelheim
Pharmaceuticals, Inc.; Genentech, Inc.; and Merck & Co.
B1
• COPD .......................................................................................................... 23
• Asthma ...................................................................................................... 27
• Sleep Medicine......................................................................................... 32
• Disparities in Pulmonary and Critical Care Disease.................. 37
This session and the International Conference are supported by
independent medical educational grants from Genentech, Inc.; and
Merck & Co.
Table of contents continued on next page
1SECTION Table of Contents2022
Clinical Year in Review
Bibliography
TABLE OF CONTENTS CONTINUED
C1
• General Critical Care ........................................................................... 40
• Cystic Fibrosis ........................................................................................ 44
• Sepsis..........................................................................................................48
• Bronchiectasis......................................................................................... 55
This session and the International Conference are supported by
independent medical educational grants from Insmed Incorporated; and
Vertex Pharmaceuticals.
D1
• Long COVID and Post-Intensive-Care Syndrome ....................... 58
• Medical Education................................................................................. 64
• Interventional Pulmonology...............................................................69
• ARDS............................................................................................................ 74
This session and the International Conference are supported by an
independent medical educational grant from Merck & Co.
2
SECTION Table of ContentsClinical Year in Review
Pulmonary Vascular Disease
Belinda Rivera-Lebron, MD MSCE FCCP
University of Pittsburgh
Division of Pulmonary, Allergy and Critical Care Medicine
Pittsburgh, PA
COMBINATION THERAPY IN PULMONARY ARTERIAL categorized as WHO functional class III or IV, with
HYPERTENSION intermediate- to high-risk clinical features, and PVR
Chin KM, Sitbon O, Doelberg M, Feldman J, Gibbs JSR, ≥ 6 Wood Units.
Grünig E, Hoeper MM, Martin N, Mathai SC, McLaughlin 3. Upfront triple combination therapy did not improve
VV, Perchenet L, Poch D, Saggar R, Simonneau G, Galiè N. the change in PVR at 26 weeks compared with dual
Three- Versus Two-Drug Therapy for Patients With combination therapy and had similar reductions
Newly Diagnosed Pulmonary Arterial Hypertension. J Am improvements in NT-pro BNP and 6MWD.
Coll Cardiol. 2021 Oct 5;78(14):1393-1403. doi: 4. Exploratory analysis suggested that triple therapy
10.1016/j.jacc.2021.07.057. PMID: 34593120. may decrease the risk for disease progression and
first clinical events, such as hospitalizations for
Summary
worsening PAH and death.
Randomized clinical trials have demonstrated that
5. Although TRITON did not meet its primary endpoint,
combination therapy in incident or treatment-naïve
it is unlikely to close the door on future randomized
patients with pulmonary arterial hypertension (PAH)
clinical trials of initial triple combination therapy in
alleviates symptoms and improves exercise tolerance
intermediate- to high-risk patients.
and clinical outcomes. However, the benefit of initial
triple over double therapy is less clear. TRITON, a
NEW THERAPIES IN PULMONARY ARTERIAL
multicenter, double-blind, randomized phase 3b study,
HYPERTENSION
evaluated initial triple (macitentan, tadalafil and
Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland
selexipag) versus initial double (macitentan, tadalafil
M, Hoeper MM, Preston IR, Souza R, Waxman A,
and placebo) in newly diagnosed, treatment naïve
Escribano Subias P, Feldman J, Meyer G, Montani D,
patients with PAH. The primary endpoint was change in
Olsson KM, Manimaran S, Barnes J, Linde PG, de Oliveira
pulmonary vascular resistance (PVR) at week 26. Both
Pena J, Badesch DB; PULSAR Trial Investigators.
treatment strategies reduced PVR compared with
Sotatercept for the Treatment of Pulmonary Arterial
baseline (by 54% and 52%, 95% CI 0.86-10.7, P=0.42). Six-
Hypertension. N Engl J Med. 2021 Apr 1;384(13):1204-1215.
minute walk distance (6MWD) and N-terminal pro-brain
doi: 10.1056/NEJMoa2024277. PMID: 33789009.
natriuretic peptide (BNP) improved, with no difference
between groups. Exploratory analysis suggested a signal
Summary
for reduced risk for disease progression in triple versus
Novel therapies are needed to attenuate disease
double therapy (HR 0.59, 95% CI 0.32-1.09). More
progression of PAH. Mutations in bone morphogenic
patients experienced side effects on triple versus
protein (BMP) receptor type 2 (BMPR2) play a role in the
double therapy.
pathogenesis of PAH. BMP is a member of the
Comments transforming growth-factor (TGF)-beta family.
1. TRITON is the first randomized, placebo-controlled, Sotatercept is a first-in-class ligand trap for members
head-to-head comparison, of initial triple oral of TGF-beta and restores balance between growth-
combination therapy versus double oral promoting and growth-inhibiting BMP pathways,
combination therapy, in patients with newly thereby having the potential to reverse the vascular
diagnosed PAH. remodeling in PAH. PULSAR, a multicenter, randomized,
2. Enrollment criteria ensured that patient population double-blind, phase 2 trial, evaluated the safety and
had moderate to severe disease, with the majority
Pulmonary Vascular Disease 4Clinical Year in Review
efficacy of subcutaneous sotatercept versus placebo on Summary
PAH patients who were receiving background therapy. Most therapies approved for PAH that have been
Background therapy included monotherapy, double studied in pulmonary hypertension from interstitial
therapy or triple therapy with combinations of lung disease (PH-ILD) have shown inconsistent results,
phosphodiesterase-5 inhibitors, soluble guanylate no significant benefit or even harm. INCREASE, a
cyclase stimulators, endothelin-receptor antagonists, multicenter, randomized, double-blind, placebo-
prostacyclin analogues, or prostacyclin-receptor controlled trial, studied the safety and efficacy of
agonists. Sotatercept at two doses (0.3mg/kg and inhaled treprostinil in patients with PH-ILD. Most
0.7mg/kg) was associated with significantly greater patients had idiopathic pulmonary fibrosis, connective
reduction in PVR from baseline to 24 weeks (least- tissue disease-ILD or combined pulmonary fibrosis and
squares difference of -145 dyn/sec/cm-5, P=0.003 and - emphysema. Pulmonary hypertension was established
239 dyn/sec/cm-5, P50% on triple therapy and >33% group (HR 0.61, 95% CI 0.40-0.92, P=0.04). The most
on prostacyclin infusion therapy). frequent adverse events were cough, headache,
3. Limitations of this trial were the relatively small dyspnea, dizziness, nausea, fatigue and diarrhea, and
sample size (106 patients), the lack of clinical were similar in both groups. Lung function and
outcomes such as mortality, and the short duration oxygenation were not meaningfully affected.
of follow-up.
4. A follow-up, phase 2 PULSAR, open-label extension Comments
interim results suggested that clinical efficacy is 1. INCREASE is the first clinical trial with a significant
maintained across multiple endpoints for up to 48 impact in PH-ILD, showing an improvement of 31m
weeks. (the minimal clinically important difference for
5. Ongoing phase 3 clinical trials will hopefully 6MWD in pulmonary diseases is approximately
provide insight on clinical outcomes, such as time 30m).
to clinical worsening, hospitalizations, and death. 2. No evidence of worsening oxygenation was seen,
which further allays historical concerns of
PULMONARY HYPERTENSION DUE TO INTERSTITIAL ventilation-perfusion mismatching in group 3 PH.
LUNG DISEASE 3. No significant difference in patient-reported quality
Waxman A, Restrepo-Jaramillo R, Thenappan T, of life, as assessed with the SGRQ, between groups.
Ravichandran A, Engel P, Bajwa A, Allen R, Feldman J, 4. Limitations of the trial included short duration,
Argula R, Smith P, Rollins K, Deng C, Peterson L, Bell H, premature discontinuation (21%), and lack of
Tapson V, Nathan SD. Inhaled Treprostinil in Pulmonary hemodynamic or echocardiographic outcomes.
Hypertension Due to Interstitial Lung Disease. N Engl J 5. Post-hoc analysis of the INCREASE data showed a
Med. 2021 Jan 28;384(4):325-334. doi: decrease in disease progression (defined as at least
10.1056/NEJMoa2008470. Epub 2021 Jan 13. PMID: 15% decline in 6MWD, cardiopulmonary
33440084. hospitalization, lung transplantation, or death
Pulmonary Vascular Disease 5Clinical Year in Review
during the study and a at least a 10% decline in FVC outpatient treatment over hospitalization provided
and exacerbations of underlying lung disease). access to medications, ability to access outpatient care
and home circumstances are adequate; 7) In acute VTE,
GUIDELINES FOR VENOUS THROMBOEMBOLIC DISEASE recommend apixaban, dabigatran, edoxaban or
Stevens SM, Woller SC, Kreuziger LB, Bounameaux H, rivaroxaban over VKA; 8) In acute VTE with associated
Doerschug K, Geersing GJ, Huisman MV, Kearon C, King cancer, recommend apixaban, edoxaban or rivaroxaban
CS, Knighton AJ, Lake E, Murin S, Vintch JRE, Wells PS, over LMWH; 9) In VTE with major or minor transient risk
Moores LK. Antithrombotic Therapy for VTE Disease: factor, recommend against extended-phase
Second Update of the CHEST Guideline and Expert Panel anticoagulation; 10) In VTE in the absence of transient
Report. Chest. 2021 Dec;160(6):e545-e608. doi: provocation (unprovoked VTE or provoked by persistent
10.1016/j.chest.2021.07.055. Epub 2021 Aug 2. PMID: risk factor), recommend extended-phase
34352278. anticoagulation.
Summary HEART FAILURE WITH PRESERVED EJECTION FRACTION
This is the 2nd update to the 9th edition of the CHEST Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E,
Antithrombotic Therapy for VTE guidelines. It is Böhm M, Brunner-La Rocca HP, Choi DJ, Chopra V,
endorsed by other important societies. Experts followed Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE,
a PICO (Population, Intervention, Comparator, Outcome) Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B,
framework. Strong or weak recommendations were Nicholls SJ, Perrone SV, Piña IL, Ponikowski P, Senni M,
generated based on high-, moderate-, and low-certainty Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S,
evidence, using GRADE (Grading of Recommendations, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller
Assessment, Development, and Evaluation) C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann
methodology. The expert panel generated 29 guideline M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved
statements, 13 of which are graded as strong Trial Investigators. Empagliflozin in Heart Failure with a
recommendations, covering decision to treat, Preserved Ejection Fraction. N Engl J Med. 2021 Oct
interventional treatments, initiation phase, treatment 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub
phase, extended phase, and complications of VTE. Key 2021 Aug 27. PMID: 34449189.
recommendations included: 1) In acute PE associated
with hypotension (SBP < 90 mm Hg) without a high Summary
bleeding risk, recommend treatment with systemic Treatment options for patients with heart failure with
thrombolysis; 2) In acute PE who deteriorate (decrease preserved ejection fraction (HFpEF) are limited. Sodium
in SBP, increase in HR, worsening gas exchange, signs of glucose cotransporter 2 (SGLT2) inhibitors have been
inadequate perfusion, worsening right ventricular shown to reduce heart failure progression in patients
function, or increasing cardiac biomarkers) after with a reduced ejection fraction, but the effect in HFpEF
starting anticoagulation but have yet to develop are unclear. EMPEROR-Preserved, a multicenter, double-
hypotension and have acceptable bleeding risk, blind, randomized, placebo-controlled trial examined
recommend treatment with systemic thrombolysis; 3) In the effects of the SGLT2 inhibitor empagliflozin in 5988
acute PE associated with hypotension with a high HFpEF patients with NYHA FC II-IV chronic heart failure
bleeding risk, failed systemic thrombolysis or shock that and a left ventricular ejection fraction > 40%. The
is likely to cause death before systemic thrombolysis primary outcome was a composite of cardiovascular
can take effect, if appropriate expertise and resources death or hospitalization for heart failure. During a
are available, recommend treatment with catheter- median follow up of 26 months, a primary composite
assisted thrombus removal; 4) In acute DVT of the leg outcome event occurred significantly less in the
tolerating anticoagulation, recommend against the use empagliflozin group than in the placebo (HR 0.79, 95% CI
of an IVC filter; 5) In acute proximal DVT of the leg and 0.69-0.90, PClinical Year in Review
appeared similar in patients with and without diabetes. Hoeper MM, Al-Hiti H, Benza RL, Chang SA, Corris PA,
Uncomplicated genital and urinary tract infections and Gibbs JSR, Grünig E, Jansa P, Klinger JR, Langleben D,
hypotension were more common in empagliflozin. McLaughlin VV, Meyer GMB, Ota-Arakaki J, Peacock AJ,
Pulido T, Rosenkranz S, Vizza CD, Vonk-Noordegraaf A,
Comments White RJ, Chang M, Kleinjung F, Meier C, Paraschin K,
1. Although SGLT2 inhibitors were introduced as type 2 Ghofrani HA, Simonneau G; REPLACE investigators.
diabetes medications, results of several RCT Switching to riociguat versus maintenance therapy with
indicate a clear benefit in heart failure phosphodiesterase-5 inhibitors in patients with
management, though the exact mechanism of pulmonary arterial hypertension (REPLACE): a
benefit is unclear. multicentre, open-label, randomised controlled trial.
2. EMPEROR-Preserved demonstrated that Lancet Respir Med. 2021 Jun;9(6):573-584. doi:
empagliflozin improves heart failure outcomes in 10.1016/S2213-2600(20)30532-4. Epub 2021 Mar 24. PMID:
patients with HFpEF and EF > 40%, irrespective of 33773120.
diabetes status.
3. Benefit is primarily driven by a reduction in heart Grünig E, MacKenzie A, Peacock AJ, Eichstaedt CA,
failure hospitalizations, not mortality. Benjamin N, Nechwatal R, Ulrich S, Saxer S, Bussotti M,
4. Empagliflozin also slowed down the rate of decline Sommaruga M, Ghio S, Gumbiene L, Palevičiūtė E,
in the eGFR and improved quality of life, as Jurevičienė E, Cittadini A, Stanziola AA, Marra AM, Kovacs
assessed with KCCQ. G, Olschewski H, Barberà JA, Blanco I, Spruit MA,
5. Limitations of the trial included premature Franssen FME, Vonk Noordegraaf A, Reis A, Santos M,
discontinuation (23%). Viamonte SG, Demeyer H, Delcroix M, Bossone E,
Johnson M. Standardized exercise training is feasible,
Other Articles of Interest safe, and effective in pulmonary arterial and chronic
thromboembolic pulmonary hypertension: results from
Pulmonary Hypertension a large European multicentre randomized controlled
Pi H, Kosanovich CM, Handen A, Tao M, Visina J, trial. Eur Heart J. 2021 Jun 14;42(23):2284-2295. doi:
Vanspeybroeck G, Simon MA, Risbano MG, Desai A, 10.1093/eurheartj/ehaa696. PMID: 33232470.
Mathier MA, Rivera-Lebron BN, Nguyen Q, Kliner J,
Nouraie M, Chan SY. Outcomes of Pulmonary Arterial Pulmonary Embolism
Hypertension Are Improved in a Specialty Care Center. Jaureguízar A, Jiménez D, Bikdeli B, Ruiz-Artacho P,
Chest. 2020 Jul;158(1):330-340. doi: Muriel A, Tapson V, López-Reyes R, Valero B, Kenet G,
10.1016/j.chest.2020.01.046. Epub 2020 Feb 25. PMID: Monreal M; Registro Informatizado de la Enfermedad
32109446; PMCID: PMC7339236. TromboEmbólica Investigators. Heart Rate and Mortality
in Patients With Acute Symptomatic Pulmonary
Guth S, D'Armini AM, Delcroix M, Nakayama K, Fadel E, Embolism. Chest. 2022 Feb;161(2):524-534. doi:
Hoole SP, Jenkins DP, Kiely DG, Kim NH, Lang IM, Madani 10.1016/j.chest.2021.08.059. Epub 2021 Aug 31. PMID:
MM, Matsubara H, Ogawa A, Ota-Arakaki JS, Quarck R, 34478718.
Sadushi-Kolici R, Simonneau G, Wiedenroth CB, Yildizeli
B, Mayer E, Pepke-Zaba J. Current strategies for Lim P, Delmas C, Sanchez O, Meneveau N, Rosario R,
managing chronic thromboembolic pulmonary Bouvaist H, Bernard A, Mansourati J, Couturaud F,
hypertension: results of the worldwide prospective Sebbane M, Coste P, Rohel G, Tardy B, Biendel C, Lairez
CTEPH Registry. ERJ Open Res. 2021 Aug 16;7(3):00850- O, Ivanes F, Gallet R, Dubois-Rande JL, Fard D, Chatelier
2020. doi: 10.1183/23120541.00850-2020. PMID: 34409094; G, Simon T, Paul M, Natella PA, Layese R, Bastuji-Garin S.
PMCID: PMC8365143. Diuretic vs. placebo in intermediate-risk acute
pulmonary embolism: a randomized clinical trial. Eur
Heart J Acute Cardiovasc Care. 2022 Jan 12;11(1):2-9. doi:
10.1093/ehjacc/zuab082. PMID: 34632490.
Pulmonary Vascular Disease 7Clinical Year in Review
D'Auria S, Sezer A, Thoma F, Sharbaugh M, McKibben J, Angel W, Sarosi MG, Qaqi O, Veerina K, Brown MA, Pollak
Maholic R, Avgerinos ED, Rivera-Lebron BN, Toma C. JS. Percutaneous mechanical thrombectomy in a real-
Outcomes of catheter-directed thrombolysis vs. world pulmonary embolism population: Interim results
standard medical therapy in patients with acute of the FLASH registry. Catheter Cardiovasc Interv. 2022
submassive pulmonary embolism. Pulm Circ. 2020 Apr Feb 3. doi: 10.1002/ccd.30091. Epub ahead of print. PMID:
8;10(1):2045894019898368. doi: 35114059.
10.1177/2045894019898368. PMID: 32292583; PMCID:
PMC7144676. Klok FA, Ageno W, Ay C, Bäck M, Barco S, Bertoletti L,
Becattini C, Carlsen J, Delcroix M, van Es N, Huisman MV,
Avgerinos ED, Jaber W, Lacomis J, Markel K, McDaniel M, Jara-Palomares L, Konstantinides S, Lang I, Meyer G, Ní
Rivera-Lebron BN, Ross CB, Sechrist J, Toma C, Chaer R; Áinle F, Rosenkranz S, Pruszczyk P. Optimal follow-up
SUNSET sPE Collaborators. Randomized Trial Comparing after acute pulmonary embolism: a position paper of
Standard Versus Ultrasound-Assisted Thrombolysis for the European Society of Cardiology Working Group on
Submassive Pulmonary Embolism: The SUNSET sPE Trial. Pulmonary Circulation and Right Ventricular Function, in
JACC Cardiovasc Interv. 2021 Jun 28;14(12):1364-1373. doi: collaboration with the European Society of Cardiology
10.1016/j.jcin.2021.04.049. Erratum in: JACC Cardiovasc Working Group on Atherosclerosis and Vascular Biology,
Interv. 2021 Oct 11;14(19):2194. PMID: 34167677. endorsed by the European Respiratory Society. Eur
Heart J. 2022 Jan 25;43(3):183-189. doi:
Barco S, Schmidtmann I, Ageno W, Bauersachs RM, 10.1093/eurheartj/ehab816. PMID: 34875048; PMCID:
Becattini C, Bernardi E, Beyer-Westendorf J, Bonacchini PMC8790766.
L, Brachmann J, Christ M, Czihal M, Duerschmied D,
Empen K, Espinola-Klein C, Ficker JH, Fonseca C, Genth- COVID VTE
Zotz S, Jiménez D, Harjola VP, Held M, Iogna Prat L, ATTACC Investigators; ACTIV-4a Investigators; REMAP-
Lange TJ, Manolis A, Meyer A, Mustonen P, Rauch- CAP Investigators. Therapeutic Anticoagulation with
Kroehnert U, Ruiz-Artacho P, Schellong S, Schwaiblmair Heparin in Noncritically Ill Patients with Covid-19. N
M, Stahrenberg R, Westerweel PE, Wild PS, Engl J Med. 2021 Aug 26;385(9):790-802. doi:
Konstantinides SV, Lankeit M; HoT-PE Investigators. Early 10.1056/NEJMoa2105911. Epub 2021 Aug 4. PMID: 34351721;
discharge and home treatment of patients with low-risk PMCID: PMC8362594.
pulmonary embolism with the oral factor Xa inhibitor
rivaroxaban: an international multicentre single-arm REMAP-CAP Investigators; ACTIV-4a Investigators;
clinical trial. Eur Heart J. 2020 Jan 21;41(4):509-518. doi: ATTACC Investigators. Therapeutic Anticoagulation with
10.1093/eurheartj/ehz367. PMID: 31120118. Heparin in Critically Ill Patients with Covid-19. N Engl J
Med. 2021 Aug 26;385(9):777-789. doi:
Rali P, Sacher D, Rivera-Lebron B, Rosovsky R, Elwing JM, 10.1056/NEJMoa2103417. Epub 2021 Aug 4. PMID: 34351722;
Berkowitz J, Mina B, Dalal B, Davis GA, Dudzinski DM, PMCID: PMC8362592.
Duval A, Ichinose E, Kabrhel C, Kapoor A, Lio KU,
Lookstein R, McDaniel M, Melamed R, Naydenov S, Stevens SM, Woller SC, Kreuziger LB, Bounameaux H,
Sokolow S, Rosenfield K, Tapson V, Bossone E, Keeling B, Doerschug K, Geersing GJ, Huisman MV, Kearon C, King
Channick R, Ross CB. Interhospital Transfer of Patients CS, Knighton AJ, Lake E, Murin S, Vintch JRE, Wells PS,
With Acute Pulmonary Embolism: Challenges and Moores LK. Antithrombotic Therapy for VTE Disease:
Opportunities. Chest. 2021 Nov;160(5):1844-1852. doi: Second Update of the CHEST Guideline and Expert Panel
10.1016/j.chest.2021.07.013. Epub 2021 Jul 14. PMID: Report. Chest. 2021 Dec;160(6):e545-e608. doi:
34273391. 10.1016/j.chest.2021.07.055. Epub 2021 Aug 2. PMID:
34352278.
Toma C, Bunte MC, Cho KH, Jaber WA, Chambers J,
Stegman B, Gondi S, Leung DA, Savin M, Khandhar S,
Kado H, Koenig G, Weinberg M, Beasley RE, Roberts J,
Pulmonary Vascular Disease 8Clinical Year in Review
Interstitial Lung Disease
Rupal Shah, MD MS
University of California, San Francisco
Department of Medicine
San Francisco, CA
DIAGNOSIS OF UIP 2. Authors demonstrated that both pulmonologists
Nandy S, Raphaely RA, Muniappan A, Shih, A, Roop BW and interpreting pathologists can be easily trained
et al Diagnostic Accuracy of Endobronchial Optical in this new diagnostic procedure.
Coherence Tomography for the Microscopic Diagnosis of 3. There was excellent sensitivity and specificity for
Usual Interstitial Pneumonia. Am J Respir Crit Care Med. UIP and the clinical correlate, IPF.
2021 Nov 15;204(10):1164-1179. doi: 10.1164/rccm.202104- 4. Future studies should further evaluate the role of
0847OC. EB-OCT in a larger patient population, including
non-UIP pattern ILD.
Summary
Diagnostic evaluation of patients with interstitial lung TREATMENT OF IPF EXACERBATION
disease continues to be challenging, particularly in Naccache JM, Jouneau S, Didier M, Borie R, Cachando M,
patients who may be high risk for surgical lung biopsy. Bourdin A et al. Cyclophosphamide added to
Nandy et al evaluates the role of endobronchial optical glucocorticoids in acute exacerbation of idiopathic
coherence tomography (EB-OCT), a technique that pulmonary fibrosis (EXAFIP): a randomized double-blind
allows imaging of the lung via a bronchoscope, for placebo-controlled, phase 3 trial. Lancet Respiratory
diagnosis of IPF. They enrolled 27 patients with Medicine 2022; 10:26-34
unclassifiable ILD who were undergoing lung (surgical
or transbronchial) biopsy for diagnosis. Prior to biopsy, Summary
they performed EB-OCT on at least 4 regions of interest, The role of systemic immunosuppression in
including subpleural lung, which were chosen based on exacerbations of IPF is unclear. This randomized
imaging findings. Images were interpreted by a trained controlled trial of cyclophosphamide added to
ILD pathologist, who was blinded to biopsy findings. glucocorticoids vs. glucocorticoids alone included 120
Patients had mild-moderate disease (average FVC 76% patients with exacerbations of IPF. Patients receiving
predicted and DLCO 54% predicted). The average mechanical ventilation, with an active infection, cancer,
bronchoscopy time for EB-OCT was 9.5 minutes (SD 4.22 or awaiting lung transplant were excluded. All
min). EB-OCT had a sensitivity and specificity of 100% participants received methylprednisolone 10mg/kg/day
for identifying histopathologic UIP pattern, using a gold x 3 days with a taper, and those in cyclophosphamide
standard of biopsy tissue (1 transbronchial, 26 surgical). arm received a dose of 600mg/m2 and umitrexan (to
The kappa between EB-OCT diagnoses and surgical lung prevent hemorrhagic cystitis) on days 0, 15, 30 and 60.
biopsy diagnosis was also high (k=0.87) in non UIP Mortality at 3 months was 45% in the cyclophosphamide
patterns, although study was not powered to evaluate group and 31% in the placebo arm (p=0.10) and there
sensitivity and specificity of non-UIP patterns. There was no difference in mortality at 1 year. The risk of
were no adverse events during the EB-OCT. death at 3 months was higher with severe IPF and lower
with baseline antifibrotic therapy, regardless of
Comments treatment arm. There was no significant difference in
1. EB-OCT may represent a minimally invasive and adverse events, including infections, between the
safe way to differentiate between histopathologic groups. In conclusion, there was no benefit to the
patterns of ILD addition of cyclophosphamide to high dose
glucocorticoids in IPF exacerbation.
Interstitial Lung Disease 9Clinical Year in Review
Comments matched controls without chronic lung disease
1. This study demonstrates that it is feasible to early in the pandemic.
conduct randomized controlled trials in the IPF 2. Authors found that male sex and obesity
exacerbation population significantly increased risk of death in the ILD
2. Mortality after IPF exacerbation is high, and population.
addition of cyclophosphamide to high dose 3. Given the high mortality of COVID-19 in ILD patients,
glucocorticoids had no benefit on outcomes it is extremely important that ILD patients receive
3. Antifibrotic therapy prior to exacerbation was vaccinations and boosters and have access to
associated with a lower risk of death. antiviral medications
4. Future study should evaluate the utility of 4. Further work is needed on outcomes of COVD-19 in
glucocorticoids in IPF exacerbation. patients with ILD after vaccinations and widespread
use of antiviral agents, as well as long-term
COVID-19 IN PATIENTS WITH ILD morbidity and mortality outcomes for those who
Drake TM, Docherty AB, Harrison EM, Quint JK, Adamali survive COVID-19 infection.
H, Agnew S, Baby S et al Outcome of Hospitalization for
COVID-19 in Patients with Interstitial Lung Disease. An TREATMENT OF IPF
International Multicenter Study. Am J Respir Crit Care Martinez FJ, Yow E, Flaherty KR et al Effect of
Med. 2020 Dec 15;202(12):1656-1665. doi: Antimicrobial Therapy on Respiratory Hospitalization or
10.1164/rccm.202007-2794OC. Death in Adults With Idiopathic Pulmonary Fibrosis: The
Clean UP-IPF Randomized Clinical Trial. JAMA.
Summary 2021;325(18):1841-1851. doi:10.1001/jama.2021.4956
Using a retrospective cohort design, authors evaluated
Summary
outcomes of COVID-19 in patients with ILD early in the
This is a pragmatic, randomized, unblinded clinical trial
pandemic (March-May 2020). The authors utilized a 2:1
to evaluate whether the use of antibiotics reduces the
propensity score matching scheme to identify 322
risk of respiratory hospitalization or death in patients
patients hospitalized for COVID-19 during that time
with IPF. 513 patients were enrolled. Patients and
without respiratory comorbidities and matched them to
treating physicians were allowed to express a
161 patients with ILD hospitalized for COVID-19. ILD was
preference for antibiotic prior to enrollment. 272 chose
associated with a higher risk of death from COVID-19
trimethoprim/sulfamethoxazole plus folic acid, of which
(HR 1.6, 95% CI: 1.17-2.18, p=0.003). Of ILD sub-types,
128 received the drug and 114 received usual care. 241
patients with IPF had the highest mortality (HR 1.74, 95%
patients chose doxycycline, of which 126 received the
CI: 1.16-2.60, p=0.007). Obesity with ILD had an increased
drug and 115 were randomized to usual care. There was
hazard of death compared to obesity alone (HR 2.27,
no placebo drug. Treatment groups were well matched
95% CI 1.39-3.71, p=0.001) as did male sex (adjusted HR
on clinical characteristics. At the first planned efficacy
for age and comorbidity: HR 1.98, 95% CI 1.14-3.43,
analysis (300 patients with 12 months of follow up), the
p=0.015). Patients with lower lung function (FVCClinical Year in Review
Comments Comments
1. This study demonstrates the feasibility of a 1. This RCT of nebulized cromolyn sodium (RVT-1601)
pragmatic, open label approach to clinical trials in did not show an impact on objective measures of
the IPF population. cough.
2. There was no difference in outcomes in patients 2. Study was terminated early because of the COVID-
treated with antimicrobials compared to those who 19 pandemic and did not meet enrollment goal
underwent usual care 3. There were an increased number of adverse events
3. Further work on the role of antimicrobial therapy in in the treatment arm, including deaths, but analysis
IPF is needed. by an external safety monitor did not conclude
there was significant harm from the study drug.
TREATMENT OF COUGH IN IPF 4. This study highlights the importance of studying
Martinez FJ, Wijsenbeek MS, Raghu G, Flaherty KR, Maher chronic cough in IPF as it is one of the most
TM et al Phase 2b Study of Inhaled RVT-1601 for Chronic debilitating symptoms of IPF.
Cough in Idiopathic Pulmonary Fibrosis: SCENIC Trial:
Multi-Center, Randomized, Placebo-Controlled Study. TREATMENT OF IPF
Am J Respir Crit Care Med. 2022 Jan 20. doi: Dempsey, TM, Payne S, Sangaralingham L, Yao X, Shah
10.1164/rccm.202106-1485OC. Online ahead of print ND, Limper AH. Adoption of the Antifibrotic Medications
Pirfenidone and Nintedanib for Patients with Idiopathic
Summary Pulmonary Fibrosis. Ann Am Thorac Soc. 2021
Chronic cough is one of the most disabling symptoms in Jul;18(7):1121-1128. doi: 10.1513/AnnalsATS.202007-901OC.
ILD with few effective treatments. This multicenter,
Summary
randomized, placebo-controlled phase 2b trial
This study evaluated the adoption, treatment duration,
evaluated the efficacy and safety of RVT-1601 (nebulized
and cost of nintedanib and pirfenidone in patients with
cromolyn sodium) for treatment of chronic cough in
IPF. The authors used a database with deidentified
patients with IPF. Patients were enrolled who had IPF
administrative claims data for patients enrolled in
with significant cough and FVC > 45% predicted. Patients
private and Medicare Advantage health plans, using ICD
were randomly assigned to receive study drug (10mg,
codes to identify IPF. Codes were validated in a local
40mg, or 80mg) or placebo, nebulized three times per
cohort by chart and imaging review. Adult patients who
day. The study duration was 12 weeks with a 12 week
filled a prescription for pirfenidone or nintedanib
open label extension. The primary outcome was least
between 10/1/14 and 7/31/19 and had IPF diagnosis
squares mean change in 24-hour average cough count.
code were included. 8,095 of 10,996 patients (74%) with
Enrollment was stopped after 108 patients due to
IPF were not on treatment. There were equal numbers
pandemic (goal 180), and 61% of patients completed the
on pirfenidone (13.2%) and nintedanib (13.2%) in the
study. Adherence was high, and demographics of
treated patients. Treated patients were younger (72 vs.
placebo and treatment arms were similar. There was no
73.9, pClinical Year in Review
Comments Khanna D, Lin CJF, Furst DE, Wagner B, Zucchetto M,
1. Adoption of antifibrotics is low in a retrospective Raghu G, Martinez FJ, Goldin J Siegel J, Denton CP et al.
cohort study using insurance claims data with rates Long-Term Safety and Efficacy of Tocilizumab in Early
remaining at 21% in 2019, with no difference in Systemic Sclerosis-Interstitial Lung Disease: Open Lab
prescribing patterns between nintedanib and Extension of a Phase 3 Randomized Controlled Trial Am
pirfenidone. J Respir Crit Care Med. 2022 Mar 15;205(6):674-684. doi:
2. The average duration of treatment was 302 days, 10.1164/rccm.202103-0714OC.
which was not attributable to patient mortality as
the average time between treatment end and death Lok SD, Wong AW, Khor YH, Ryerson CJ, Johannson KA;
was 505 days CARE-PF Investigators. Malignancy Risk Associated With
3. The annual cost of pirfenidone and nintedanib is Mycophenolate Mofetil or Azathioprine in Patients With
over $100,000 with about $400/month in out of Fibrotic Interstitial Lung Disease. Chest. 2021 Dec
pocket costs for patients 16:S0012-3692(21)05085-6. doi: 10.1016/j.chest.2021.12.636.
4. 52% of untreated patients in this cohort did not see Epub ahead of print. PMID: 34921905.
a pulmonologist.
Swaminatha A, Hellkamp AS, Neely ML, Bender S,
5. Use of insurance claims data is a limitation,
Paoletti L et al Disparities in Lung Transplant among
however, this study provides important information
Patients with Idiopathic Pulmonary Fibrosis: An Analysis
on real world prescribing practices of antifibrotic
of the IPF-PRO Registry Ann Am Thorac Soc. 2022 Jan 24.
medications.
doi: 10.1513/AnnalsATS.202105-589OC. Online ahead of
print.
OTHER ARTICLES OF INTEREST
Tomassetti S, Ravagli C, Puglisi S, Ryu JH, Colby TV et al
Diagnosis of ILD
Impact of Lung Biopsy Information on Treatment
Hunninghake GM, Goldin JG, Kadoch MA, Kropski JA, Strategy of Patients with Interstitial Lung Disease Ann
Rosas IO, et al. Detection and Early Referral of Patients Am Thorac Soc. 2021 Nov 5. doi:
With Interstitial Lung Abnormalities: An Expert Survey 10.1513/AnnalsATS.202104-466OC. Online ahead of print
Initiative. Chest. 2022 Feb;161(2):470-482. doi:
Waxman, A, Restrepo-Jaramillo R, Thenappan T,
10.1016/j.chest.2021.06.035. Epub 2021 Jun 29.
Ravichandran A, Engel P et al Inhaled Treprostinil in
Teoh AKY, Holland AE, Morisset J, Flaherty KR et al Pulmonary Hypertension Due to Interstitial Lung
Essential Features of an ILD Multidisciplinary Meeting: Disease N Engl J Med 2021; 384:325-334
An International Dephi Survey Ann Am Thorac Soc. 2022 DOI: 10.1056/NEJMoa2008470 *Discussed in the
Jan;19(1):66-73. doi: 10.1513/AnnalsATS.202011-1421OC. Pulmonary Hypertension Year in Review
Treatment of ILD Outcomes of ILD
Assayag D, Garlick K, Johannson KA, Fell CD, Kolb et al Cutting CC, Bowman WS, Dao N, Pugashetti JV, Garcia CK,
Treatment Initiation in Patients with ILD in Canada Ann Oldham JM, Newton CA. Family History of Pulmonary
Am Thorac Soc. 2021 Oct;18(10):1661-1668. doi: Fibrosis Predicts Worse Survival in Patients With
10.1513/AnnalsATS.202009-1122OC. Interstitial Lung Disease. Chest. 2021 05; 159(5):1913-1921.
Behr JB, Prasse A, Kreuter M, Johow J, Rabe KF, Bonella F Johannson KA, Lethebe BC, Assaya D, Fisher, JH, Kolb M
et al Pirfenidone in patients with progressive fibrotic et al Travel Distance to Subspecialty Clinic and
ILD other than IPF (RELIEF): a double-blind, randomized, Outcomes in Patients with Fibrotic Interstitial Lung
placebo-controlled, phase 2b trial. Lancet Respir Med. Disease Ann Am Thorac Soc. 2022 Jan;19(1):20-27. doi:
2021 May;9(5):476-486. doi: 10.1016/S2213-2600(20)30554- 10.1513/AnnalsATS.202102-216OC.
3. Epub 2021 Mar 30.
Interstitial Lung Disease 12Clinical Year in Review
Kaul B, Lee JS, Zhang N, Vittinghoff E, Sarmiento K et al COVID 19 in ILD
Epidemiology of Idiopathic Pulmonary Fibrosis among
US Veterans, 2010-2019. Ann Am Thorac Soc. 2022 Lee H, Choi H, Yang B, Lee S, Park TS, Park DW, et al
Feb;19(2):196-203. doi: 10.1513/AnnalsATS.202103-295OC. Interstitial lung disease increases susceptibility to and
severity of COVID-19 ERJ 2021; 58(6) PMID: 33888524
Nasser M, Larrieu S, Si-Mohamed S, Ahma K, Boussel L
Progressive fibrosing interstitial lung disease: a clinical Myall KJ, Mukherjee B, Catanheira AM, Lam JL, Benedetti
cohort (the PROGRESS study) ERJ 2021 Feb 11;57 (2): G et al Persistent Post-COVID-19 Interstitial Lung
2002718 Disease. An Observational Study of Corticosteroid
Treatment. AATS 2021 May; 18(5).
Oldham JM, Lee CT, Wu Z, Bowman WS, Vu Pugashetti J,
et al. Lung function trajectory in progressive fibrosing Wild JM, Porter JC, Molyneaux PL, George PM, Stewart I,
interstitial lung disease. Eur Respir J. 2021 Nov 04. et al. Understanding the burden of interstitial lung
disease post-COVID-19: the UK Interstitial Lung Disease-
Simpson T, Barratt SL, Beirne P, Chaudhuri N, Crawhsaw Long COVID Study (UKILD-Long COVID). BMJ Open Respir
A et al The Burden of Progressive Fibrotic Interstitial Res. 2021 Sep;8(1):e001049. doi: 10.1136/bmjresp-2021-
Lung Disease Across the UK ERJ 2021 Jul 8;58 001049. PMID: 34556492; PMCID: PMC8461362.
Interstitial Lung Disease 13Clinical Year in Review
Lung Cancer
Neal Navani, MA (Cantab.), MBBS, MSc, PhD, FRCP
University College London Hospital
Department of Thoracic Medicine
London, United Kingdom
LUNG CANCER SCREENING 2. This study is an improvement over the analyses
Meza R, Jeon J, Toumazis I, Ten Haaf K, Cao P, Bastani M, conducted in 2013 because the new risk factor–
Han SS, Blom EF, Jonas DE, Feuer EJ, Plevritis SK, de based strategy considers both lung cancer deaths
Koning HJ, Kong CY. Evaluation of the Benefits and averted as well as life-years gained and applies
Harms of Lung Cancer Screening With Low-Dose them to a 1960 cohort which is more similar to
Computed Tomography: Modeling Study for the US current population.
Preventive Services Task Force. JAMA 2021 Mar 3. Compared to the 2013 criteria, the 2021 criteria are
9;325(10):988-997. estimated to increase screening eligibility with a
greater reduction in mortality and more life-years
Summary gained.
Meza et al used 4 lung cancer simulation models that 4. Full uptake and adherence were assumed for all
predict age- and sex-specific lung cancer incidence and scenarios in the evaluation while in practice, uptake
mortality according to an individual’s smoking history, is much lower e.g. 6-18%
to assess the benefits and harms of lung cancer
screening using 2 different screening strategies. The LUNG CANCER RISK FACTORS
first screening strategy was based on risk factors and Myers R, Brauer M, Dummer T, Atkar-Khattra S, Yee J,
used criteria similar to the 2013 recommendation Melosky B, Ho C, McGuire AL, Sun S, Grant K, Lee A, Lee
criteria. The second, a risk model–based strategy, M, Yuchi W, Tammemagi M, Lam S. High-Ambient Air
evaluated eligibility criteria based on 3 multivariable Pollution Exposure Among Never Smokers Versus Ever
risk prediction models to estimate lung cancer risk. The Smokers With Lung Cancer. J Thorac Oncol. 2021
models were simplified to incorporate only smoking Nov;16(11):1850-1858.
history, sex, and age but excluded other risk variables
such as race, ethnicity, chronic obstructive pulmonary Summary
disease, family history, and personal history of cancer. The proportion of patients with lung cancer who have
Using these 2 strategies, Meza and colleagues identified never smoked is increasing in Asian countries and lung
a set of screening criteria estimated to be associated cancer in never smokers is now the 7th leading cause of
with a reduction in lung cancer mortality and an cancer death worldwide in both sexes. This case series
increase in life-years gained. The risk factor–based study compared the air pollution exposure in never
strategy identified as efficient was an approach that smokers with lung cancer versus ever smokers with lung
included beginning screening at age 50 or 55 years and cancer, adjusting for sex, race/ethnicity, and additional
stopping at age 80 years, with 20 pack-year smoking factors. Patients were prospectively recruited from 2017-
intensity minimum. 2019 in Vancouver. Street and city address or postal
codes allow accurate linking of residential locations to
Comments satellite derived PM2.5 exposure data that were
1. This study supports the new 2021 USPSTF available from 1996 onward. Household exposure was
recommendation of “annual screening for lung obtained by questionnaire. In multivariable logistic
cancer with LDCT [low-dose CT] in adults aged 50 to regression analysis, there was a significant association
80 years who have a 20 pack-year smoking history with never-smoker lung cancer and being female (OR
and currently smoke or have quit within the past 15 4.01), Asian (OR 6.48) and greater exposure to air
years.”
Lung Cancer 14Clinical Year in Review
pollution (OR 1.79). Exposure to ambient air pollution rib spreading. The primary outcome was physical
should be considered when evaluating risk for function at 5 weeks as a measure of recovery using the
developing lung cancer. European Organization for Research and Treatment of
Cancer core health-related quality of life questionnaire
Comments (QLQ-C30). For this primary endpoint, participants
1. In this study, compared with ever smokers with lung allocated to VATS had significantly better physical
cancer, never smokers with lung cancer were more functioning at 5 weeks (median score 73 vs 67 in open
likely females who were significantly younger with surgery group) and those undergoing VATS had less
adenocarcinoma, more frequently East Asian, better pain. Median length of stay was 1 day shorter for the
educated, less likely to have COPD or a family VATS group (4 days vs 5 days for the open group).
history of lung cancer, and had higher exposure to Oncological outcomes including number of lymph
outdoor PM2.5 but lower exposure to second-hand nodes harvested, R0 and upstaging rates, adjuvant
smoke. chemotherapy rates and recurrence rates at 12 months
2. The Global Burden of Disease 2019 study revealed were similar between the groups. In conclusion, VATS
that the percent of the global lung cancers lobectomy results in better physical recovery at 5 weeks
attributable to each risk factor is 62.4% for smoking, compared with open surgery.
5.8% for second-hand smoking, 15.3% for air
pollution exposure, and 4% for household air Comments
pollution from use of solid fuels for cooking. 1. Lobectomy via VATS rather than open lobectomy led
3. Residential radon exposure is also known to be to a shorter length of stay with better physical
associated with lung cancer in never smokers but function at 5 weeks.
varies from hour to hour and in the absence of 2. From 6 months to 1 year after surgery, the benefit of
direct measurements was not included in this VATS over open lobectomy were lost and the groups
study. had similar physical function.
4. Never smokers with lung cancer in this study were 3. There was more bleeding and more patients with
more likely to live near truck routes where diesel air leaks in the VATS group but these did not appear
fumes are concentrated to impact patient outcomes.
5. Although this study was able to estimate PM2.5 4. Although a wound dressing sufficiently large to
exposure in the 20 years prior to lung cancer conceal a thoracotomy incision (regardless of
diagnosis, the etiologically relevant period for actual access used) was applied, the dressing was
exposure is not known. removed on discharge and so the participants were
not blinded for the primary endpoint.
MANAGEMENT OF EARLY STAGE LUNG CANCER 5. Longer term oncological outcomes e.g. 5 year
Lim E, Batchelor TJP, Dunning J, Shackcloth M et al. survival will be important and are awaited.
Video-assisted thoracoscopic or open lobectomy in
early-stage lung cancer. NEJM Evidence 2022; 1 (3) MANAGEMENT OF EARLY STAGE NON-SMALL CELL LUNG
CANCER
Summary Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I,
While surgery is established as the standard of care for Goloborodko O, Luft A, Akopov A, Martinez-Marti A,
early-stage lung cancer, previous trials of a video- Kenmotsu H, Chen YM, Chella A, Sugawara S, Voong D,
assisted thorascopic (VATS) vs open approach have Wu F, Yi J, Deng Y, McCleland M, Bennett E, Gitlitz B,
been inconclusive. In this U.K. multicenter pragmatic Wakelee H; IMpower010 Investigators. Adjuvant
trial, 503 participants were randomly assigned to VATS atezolizumab after adjuvant chemotherapy in resected
(n=247) or open lobectomy (n=256). In the VATS group, stage IB-IIIA non-small-cell lung cancer (IMpower010): a
there was one to four incisions without rib spreading randomised, multicentre, open-label, phase 3 trial.
while participants in the open surgery group underwent Lancet. 2021 Oct 9;398(10308):1344-1357.
lobectomy through a single thoracotomy incision with
Lung Cancer 15Clinical Year in Review
Summary 4. In Impower010 8% of patients developed grade 3-4
No new therapies have been approved over the past immune-related adverse events and risk of chronic
decade for patients with completely resected NSCLC adverse events should be considered in shared
without oncogenic drivers. Immune-checkpoint decision-making.
inhibitors are used routinely used in patients with 5. Use of immunotherapy in the adjuvant setting
advanced lung cancer and this IMpower010 trial is the raises questions about the efficacy of
first positive trial of immunotherapy in the adjuvant immunotherapy in patients who subsequently
setting. In this trial, 1,005 patients with completely develop disease progression.
resected stage IB–IIIA NSCLC were randomly assigned
(1:1) to receive adjuvant atezolizumab (1200 mg every 21 MANAGEMENT OF ADVANCED NSCLC
days for 16 cycles or 1 year) or best supportive care, Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J,
after adjuvant platinum-based chemotherapy. The Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T,
primary end point was investigator-assessed disease- Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS,
free survival (DFS) and was tested in a complex Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather
hierarchy. In the first analysis, atezolizumab prolonged O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V,
DFS in the subpopulation of patients with stage II–IIIA Govindan R. Sotorasib for Lung Cancers with KRAS
NSCLC and PD-L1 expression on ≥1% tumor cells (HR p.G12C Mutation. N Engl J Med. 2021 Jun 24;384(25):2371-
0.66, 95% CI 0.50–0.88; P = 0.0039). In the second 2381.
analysis, a lower level of benefit from atezolizumab was
demonstrated among all patients in the stage II–IIIA Summary
population (HR 0.79, 95% CI 0.64–0.96; P = 0.02), KRASG12C mutations can be found in approximately 13%
including ~45% with PD-L1 expression on ≤1% of tumour of patients with NSCLC and are associated with poor
cells. In the third analysis, in the intention-to-treat prognosis. This phase II study, CodeBreaK 100,
population that additionally included the patients with demonstrates the efficacy of the novel KRASG12C
stage IB disease, the HR was 0.81, 95% CI 0.67–0.99 (P = specific inhibitor sotorasib. In this single-arm study, a
0.04). Finally, a fourth analysis revealed no benefit with total of 126 patients with disease progression on an
adjuvant atezolizumab for the secondary endpoint of anti-PD-1 or anti-PD-L1 antibody and/or platinum-
overall survival (HR 1.07, 95% CI 0.80–1.42). The 3rd and based chemotherapy received a 960 mg daily dose of
4th analyses are immature and will be updated. sotorasib until death, disease progression,
unacceptable adverse events or withdrawal. Objective
Comments response rate was the primary end point. Secondary
1. IMpower010 showed a disease-free survival benefit end points included duration of response, disease
with atezolizumab versus best supportive care after control (defined as complete response, partial
adjuvant chemotherapy in patients with resected response, or stable disease), progression-free survival,
stage II–IIIA NSCLC, with particular benefit in the overall survival, and safety. An objective response was
subgroup whose tumours expressed PD-L1≥1% observed in 46 patients (37.1%, 95% CI 28.6-46.2%).
2. Although DFS is an accepted endpoint for drug Median duration of response was 11.1 months and
approval, overall survival benefit should be the aim responses were significant with a median 60% decrease
for adjuvant treatment and it is difficult to in tumor burden from baseline. Median progression-
anticipate whether the DFS seen in this trial will free survival was 6.8 months, with a median overall
translate into an OS benefit. survival of 12.5 months. Adverse events deemed to be
3. A post hoc exploratory analysis in the stage II–IIIA treatment-related of any grade occurred in 69.8% of
population of IMpower010 showed a positive patients, including grade 3–4 events in 20.6%.
correlation between the DFS benefit from CodeBreak 100 demonstrates the safety and efficacy of
atezolizumab and PD-L1 expression on tumor cells sotorasib in patients with pretreated advanced
(PD-L1Clinical Year in Review
Comments Coker-Schwimmer M, Middleton JC, Voisin C, Harris RP.
1. KRAS mutant lung cancers are common but have Screening for Lung Cancer With Low-Dose Computed
proved difficult to target and this is the first report Tomography: Updated Evidence Report and Systematic
of a novel agent with significant activity after Review for the US Preventive Services Task Force. JAMA.
disease progression on immunotherapy and/or 2021 Mar 9;325(10):971-987.
chemotherapy.
2. Disease control occurred in 81% of patients and Tammemägi MC, Ruparel M, Tremblay A, Myers R, Mayo J,
tumour shrinkage of any magnitude was observed Yee J, Atkar-Khattra S, Yuan R, Cressman S, English J,
in 82% of participants. Bedard E, MacEachern P, Burrowes P, Quaife SL,
3. Although encouraging, the response rate (37%) is Marshall H, Yang I, Bowman R, Passmore L, McWilliams
lower than for other personalized therapies in A, Brims F, Lim KP, Mo L, Melsom S, Saffar B, Teh M,
NSCLC e.g. EGFR-TKIs Sheehan R, Kuok Y, Manser R, Irving L, Steinfort D,
4. A variety of resistance mechanisms are likely to McCusker M, Pascoe D, Fogarty P, Stone E, Lam DCL, Ng
exist that may limit efficacy including lesions that MY, Vardhanabhuti V, Berg CD, Hung RJ, Janes SM, Fong
activate RAS by a non-G12C mechanism and KRAS K, Lam S. USPSTF2013 versus PLCOm2012 lung cancer
amplification. screening eligibility criteria (International Lung
5. The efficacy of combinations of sotorasib with Screening Trial): interim analysis of a prospective
immune-checkpoint inhibitors and/or cohort study. Lancet Oncol. 2022 Jan;23(1):138-148.
chemotherapy is to be determined, while newer
Fahrmann JF, Marsh T, Irajizad E, Patel N, Murage E,
generations of KRAS inhibitors are also in
Vykoukal J, Dennison JB, Do KA, Ostrin E, Spitz MR, Lam S,
development
Shete S, Meza R, Tammemägi MC, Feng Z, Hanash SM.
OTHER ARTICLES OF INTEREST Blood-Based Biomarker Panel for Personalized Lung
Cancer Risk Assessment. J Clin Oncol. 2022 Mar
Epidemiology 10;40(8):876-883.
Ganti AK, Klein AB, Cotarla I, Seal B, Chou E. Update of
Incidence, Prevalence, Survival, and Initial Treatment in Management of Operable Non-Small Cell Lung Cancer
Patients With Non-Small Cell Lung Cancer in the US. Le Pechoux C, Pourel N, Barlesi F, Lerouge D, Antoni D,
JAMA Oncol. 2021 Dec 1;7(12):1824-1832. Lamezec B, Nestle U, Boisselier P, Dansin E, Paumier A,
Peignaux K, Thillays F, Zalcman G, Madelaine J, Pichon E,
Huang Y, Zhu M, Ji M, Fan J, Xie J, Wei X, Jiang X, Xu J, Larrouy A, Lavole A, Argo-Leignel D, Derollez M, Faivre-
Chen L, Yin R, Wang Y, Dai J, Jin G, Xu L, Hu Z, Ma H, Shen Finn C, Hatton MQ, Riesterer O, Bouvier-Morel E, Dunant
H. Air Pollution, Genetic Factors, and the Risk of Lung A, Edwards JG, Thomas PA, Mercier O, Bardet A.
Cancer: A Prospective Study in the UK Biobank. Am J Postoperative radiotherapy versus no postoperative
Respir Crit Care Med. 2021 Oct 1;204(7):817-825. radiotherapy in patients with completely resected non-
small-cell lung cancer and proven mediastinal N2
Screening involvement (Lung ART): an open-label, randomised,
US Preventive Services Task Force, Krist AH, Davidson phase 3 trial. Lancet Oncol. 2022 Jan;23(1):104-114.
KW, Mangione CM, Barry MJ, Cabana M, Caughey AB,
Davis EM, Donahue KE, Doubeni CA, Kubik M, Landefeld Xia L, Mei J, Kang R, Deng S, Chen Y, Yang Y, Feng G, Deng
CS, Li L, Ogedegbe G, Owens DK, Pbert L, Silverstein M, Y, Gan F, Lin Y, Pu Q, Ma L, Lin F, Yuan Y, Hu Y, Guo C,
Stevermer J, Tseng CW, Wong JB. Screening for Lung Liao H, Liu C, Zhu Y, Wang W, Liu Z, Xu Y, Li K, Li C, Li Q,
Cancer: US Preventive Services Task Force He J, Chen W, Zhang X, Kou Y, Wang Y, Wu Z, Che G, Chen
Recommendation Statement. JAMA. 2021 Mar L, Liu L. Perioperative ctDNA-Based Molecular Residual
9;325(10):962-970. Disease Detection for Non-Small Cell Lung Cancer: A
Prospective Multicenter Cohort Study (LUNGCA-1). Clin
Jonas DE, Reuland DS, Reddy SM, Nagle M, Clark SD, Cancer Res. 2021 Nov 29.
Weber RP, Enyioha C, Malo TL, Brenner AT, Armstrong C,
Lung Cancer 17Clinical Year in Review
Management of Advanced Non-Small Cell Lung Cancer A, Nakachi I, Kuyama S, Furuya N, Sakakibara-Konishi J,
Creelan BC, Wang C, Teer JK, Toloza EM, Yao J, Kim S, Okamoto I, Taima K, Ebi N, Daga H, Yamasaki A, Kodani
Landin AM, Mullinax JE, Saller JJ, Saltos AN, Noyes DR, M, Udagawa H, Kirita K, Zenke Y, Nosaki K, Sugiyama E,
Montoya LB, Curry W, Pilon-Thomas SA, Chiappori AA, Sakai T, Nakai T, Ishii G, Niho S, Ohtsu A, Kobayashi SS,
Tanvetyanon T, Kaye FJ, Thompson ZJ, Yoder SJ, Fang B, Goto K. The CLIP1-LTK fusion is an oncogenic driver in
Koomen JM, Sarnaik AA, Chen DT, Conejo-Garcia JR, non-small-cell lung cancer. Nature. 2021
Haura EB, Antonia SJ. Tumor-infiltrating lymphocyte Dec;600(7888):319-323.
treatment for anti-PD-1-resistant metastatic lung
cancer: a phase 1 trial. Nat Med. 2021 Aug;27(8):1410-1418. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C,
Adkins S, Anadkat M, Atkins MB, Brassil KJ, Caterino JM,
Park K, Haura EB, Leighl NB, Mitchell P, Shu CA, Girard N, Chau I, Davies MJ, Ernstoff MS, Fecher L, Ghosh M,
Viteri S, Han JY, Kim SW, Lee CK, Sabari JK, Spira AI, Yang Jaiyesimi I, Mammen JS, Naing A, Nastoupil LJ, Phillips T,
TY, Kim DW, Lee KH, Sanborn RE, Trigo J, Goto K, Lee JS, Porter LD, Reichner CA, Seigel C, Song JM, Spira A,
Yang JC, Govindan R, Bauml JM, Garrido P, Krebs MG, Suarez-Almazor M, Swami U, Thompson JA, Vikas P,
Reckamp KL, Xie J, Curtin JC, Haddish-Berhane N, Roshak Wang Y, Weber JS, Funchain P, Bollin K. Management of
A, Millington D, Lorenzini P, Thayu M, Knoblauch RE, Cho Immune-Related Adverse Events in Patients Treated
BC. Amivantamab in EGFR Exon 20 Insertion-Mutated With Immune Checkpoint Inhibitor Therapy: ASCO
Non-Small-Cell Lung Cancer Progressing on Platinum Guideline Update. J Clin Oncol. 2021 Dec 20;39(36):4073-
Chemotherapy: Initial Results From the CHRYSALIS 4126.
Phase I Study. J Clin Oncol. 2021 Oct 20;39(30):3391-3402.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi
Bentham R, Litchfield K, Watkins TBK, Lim EL, Rosenthal T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S,
R, Martínez-Ruiz C, Hiley CT, Bakir MA, Salgado R, Moore O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E,
DA, Jamal-Hanjani M; TRACERx Consortium, Swanton C, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes
McGranahan N. Using DNA sequencing data to quantify With Pembrolizumab Versus Chemotherapy for
T cell fraction and therapy response. Nature. 2021 Metastatic Non-Small-Cell Lung Cancer With PD-L1
Sep;597(7877):555-560. Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul
20;39(21):2339-2349.
Li BT, Smit EF, Goto Y, Nakagawa K, Udagawa H, Mazières
J, Nagasaka M, Bazhenova L, Saltos AN, Felip E, Pacheco Malignant Mesothelioma
JM, Pérol M, Paz-Ares L, Saxena K, Shiga R, Cheng Y, Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S,
Acharyya S, Vitazka P, Shahidi J, Planchard D, Jänne PA; Tsao AS, Mansfield AS, Popat S, Jahan T, Antonia S,
DESTINY-Lung01 Trial Investigators. Trastuzumab Oulkhouir Y, Bautista Y, Cornelissen R, Greillier L, Grossi
Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer F, Kowalski D, Rodríguez-Cid J, Aanur P, Oukessou A,
N Engl J Med. 2022 Jan 20;386(3):241-251. Baudelet C, Zalcman G. First-line nivolumab plus
ipilimumab in unresectable malignant pleural
Izumi H, Matsumoto S, Liu J, Tanaka K, Mori S, Hayashi K, mesothelioma (CheckMate 743): a multicentre,
Kumagai S, Shibata Y, Hayashida T, Watanabe K, randomised, open-label, phase 3 trial. Lancet. 2021 Jan
Fukuhara T, Ikeda T, Yoh K, Kato T, Nishino K, Nakamura 30;397(10272):375-386.
Lung Cancer 18Clinical Year in Review
Pneumonia and Pulmonary Infections
Francesco Amati, MD
Humanitas Research Hospital
Department of Biomedical Sciences, Respiratory Unit
Milan, Italy
DURATION OF ANTIBIOTIC TREATMENT IN ADULT 4. The study was performed in France where microbial
PATIENTS WITH NON-SEVERE CAP resistance rates and patient-level characteristics
Dinh A et al. Discontinuing β-Lactam Treatment After 3 may differ from an individual physician’s practice
Days for Patients with Community-Acquired Pneumonia population
in Non-Critical Care Wards (PTC): A Double-Blind, 5. European treatment guidelines used in the study
Randomised, Placebo-Controlled, Non-Inferiority Trial. differ from the U.S.
Lancet 2021. PMID: 33773631
DURATION OF ANTIBIOTIC TREATMENT IN PEDIATRIC
Summary
PATIENTS WITH NON-HOSPITALIZED CAP
Clinical Question: Is a 3-day course of β-lactam therapy
Pernica JM, Harman S, Kam AJ, et al. Short-Course
non inferior compared to an 8-day course for admitted
Antimicrobial Therapy for Pediatric Community-
patients with non-severe CAP?
Acquired Pneumonia: The SAFER Randomized Clinical
Methods and design: Multi-center, double-blind,
Trial. JAMA Pediatr. 2021;175(5):475-482.
randomized, placebo-controlled non-inferiority trial
doi:10.1001/jamapediatrics.2020.6735
comparing 3 days of β-lactam treatment to 8 days of β-
lactam treatment in non-ICU patients admitted with
Summary
CAP. Randomized adult patients (≥ 18 years old)
Clinical question: Is 5 days of high-dose amoxicillin for
admitted to the hospital with CAP after 3 days of IV or
non-hospitalized CAP in pediatric community
oral β-lactam treatment.
associated with non-inferior rates of clinical cure
Primary outcome: Cure at 15 days after start of
compared with 10 days of high-dose amoxicillin?
antibiotic treatment.
Methods and design: The SAFER (Short-Course
Results: 706 patients assessed for eligibility; 396
Antimicrobial Therapy for Pediatric Respiratory
excluded; 310 patients randomized to a placebo group
Infections) study was a 2-center, parallel-group, non-
or β-lactam group. 117 of 152 (77%) of patients in the 3
inferiority randomized clinical trial. Patients were
day β-lactam group, followed by 5 days of placebo
randomized to 5 days of high-dose amoxicillin therapy
(placebo) were cured whereas 102 of 151 (68%) of
followed by 5 days of placebo (intervention group) vs 5
patients in the 8 day β-lactam group were cured. The
days of high-dose amoxicillin followed by a different
difference was 9.42% (95 % CI -0.38 – 20.04) indicating
formulation of 5 days of high-dose amoxicillin (control
non-inferiority. No differences in the secondary
group).
outcomes were recorded, including 30-day cure, all-
Primary outcome: Clinical cure at 14 to 21 days.
cause mortality, frequency and severity of adverse
Results: Among the 281 participants, the median age
events, length of hospital stay and recovery time.
was 2.6 (interquartile range, 1.6-4.9) years (160 boys
Comments [57.7%] of 279 with sex listed). Clinical cure was
1. This RCT attempts to tackle a relevant clinical observed in 101 of 114 children (88.6%) in the
question: reducing antibiotic usage for CAP. intervention group and in 99 of 109 (90.8%) in the
2. Primary and secondary outcomes of the study are control group in per-protocol analysis (risk difference, -
patient-oriented. 0.016; 97.5% confidence limit, -0.087). Clinical cure at 14
3. Adherence to protocol and inclusion criteria reflects to 21 days was observed in 108 of 126 (85.7%) in the
the fact that the study might be easily replicated in intervention group and in 106 of 126 (84.1%) in the
clinical practice
Pneumonia and Pulmonary Infections 19You can also read
