Sistematični pregled opazovalnih raziskav učinkovitosti in varnosti zaviralcev imunskih kontrolnih točk pri zdravljenju razsejanega nedrobnoceličnega raka pljuč

Gartner, Nika (author), Knez, Lea (mentor), Locatelli, Igor (comentor)

Nedrobnocelični rak pljuč (NDRP) je najpogostejša oblika raka pljuč. Pogosto je odkrit v razsejani obliki in zanj je značilna visoka umrljivost, s 5-letnim preživetjem pod 10 %. Na področju sistemskega zdravljenja razsejanega NDRP se je po letu 2015 uveljavila imunoterapija z zaviralci imunskih kontrolnih točk (ZKT). Namen magistrskega dela je narediti sistematični pregled opazovalnih raziskav, ki poročajo o učinkovitosti in varnosti imunoterapije za zdravljenje razsejanega NDRP v realnem kliničnem okolju. Osredotočili smo se na monoterapijo z ZKT, in sicer z atezolizumabom, nivolumabom in pembrolizumabom. Izide zdravljenja opazovalnih raziskav smo primerjali z izidi iz registracijskih randomiziranih kontroliranih kliničnih raziskav, ki so bile osnova za pridobitev dovoljenja za promet zdravila za zdravljenje razsejanega NDRP. Sistematični pregled smo opravili skladno s smernicami PRISMA 2009. Po iskanju v podatkovni zbirki PubMed smo na podlagi vključitvenih in izključitvenih kriterijev izbrali 78 raziskav, ki so bile objavljene do 31. 10. 2020. Kot primarni izid učinkovitosti zdravljenja smo zbirali podatke o srednjem času celokupnega preživetja (mOS), kot primarni izid varnosti pa delež bolnikov s hudim neželenim učinkom. Izbrane raziskave smo razdelili v skupine glede na linijo zdravljenja NDRP. Izbrane raziskave se med seboj razlikujejo po številu in značilnostih bolnikov ter vključujejo od nekaj deset do več tisoč bolnikov. Prav tako se bolniki, vključeni v opazovalne raziskave, med seboj bolj razlikujejo, več jih ima slabo stanje telesne zmogljivosti in možganske metastaze kot bolniki v registracijskih kliničnih raziskavah, kjer so pogoji za vključitev običajno zelo strogi. Opazovalnih raziskav v 1. liniji zdravljenja je 11. Mediana mOS je 18,1 mesecev (razpon mOS je med 11,1 in 19,8 meseci), ki je nekoliko krajša od mediane mOS 20,2 mesecev (razpon mOS je med 20 in 30 meseci) 3 registracijskih raziskav. V 1. liniji je le 36 % raziskav poročalo o varnosti, deleži hudih neželenih učinkov so nihali med 8 % in 18,9 %, kar je primerljivo s 13 % iz registracijskih raziskav. Opazovalnih raziskav v 2. liniji zdravljenja je 36. Mediana mOS je 11,0 mesecev (razpon mOS je med 3,3 in 18,8 meseci). Registracijske raziskave iz 2. linije so 4, mediana mOS pa 11,3 mesecev (razpon mOS je med 9,2 in 13,8 meseca). V 2. liniji je 69 % raziskav poročalo o varnosti, mediana deležev hudih neželenih učinkov je 6 %, z razponom med 6 % in 42 %, kar je primerljivo z mediano deležev hudih neželenih učinkov 13 % (razpon: 7 % do 31,2 %) v registracijskih raziskavah. Rezultati opazovalnih raziskav iz realnega kliničnega okolja kažejo v grobem zgolj malo slabšo učinkovitost in primerljivo varnost ZKT kot v registracijskih kliničnih raziskavah kljub vključitvi bolnikov s slabšimi napovednimi dejavniki.

• Language: Slovenian
• Keywords: imunoterapija, zaviralci imunskih kontrolnih točk, razsejani nedrobnocelični rak pljuč, opazovalne raziskave, sistematični pregled
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-136800
• Publication date in RUL: 21.05.2022

Secondary language

• Language: English
• Title: Systematic review of observational studies evaluating the effectiveness and safety of immune checkpoint inhibitors in patients with metastatic non-small-cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. It is often diagnosed in the advanced stage that is characterised by high mortality rate with a 5-year survival below 10 %. Immunotherapy with immune checkpoint inhibitors (ICI) has been used in the field of systemic treatment of advanced NSCLC since 2015. The aim of this study is to make a systematic review of observational studies that assessed the real-world effectiveness and safety of immunotherapy in patients with advanced NSCLC. We focused on the monotherapy with ICI, namely atezolizumab, nivolumab and pembrolizumab. We compared treatment outcomes with the outcomes of the pivotal randomized controlled clinical trials performed to gain the regulatory approval of a medication in patients with advanced NSCLC. We performed a systematic review according to the PRISMA 2009 guidelines. After searching the PubMed database and applying the inclusion and exclusion criteria, we selected 78 studies, published by 31 October 2020. Studies were divided into groups according to the NSCLC treatment line. As a primary outcome of treatment efficacy and treatment safety, we collected data on median overall survival (mOS) and the share of patients with severe adverse events (sAE), respectively. The selected studies differ in the number and characteristics of included patients. Patients included in observational studies are more diverse, more have a poor performance status and have brain metastases than patients included in clinical trials where inclusion criteria are usually very strict. We have found 11 observational studies in the first treatment line. Their median mOS was 18.1 months (the mOS range is between 11.1 and 19.8 months), which is slightly shorter than the median mOS is 20.2 months (the mOS range is between 20 and 30 months) of the three pivotal clinical trials. Only 36% of the studies reported safety outcomes. The rates of sAE ranged between 8% and 18.9%, which is comparable to 13% from pivotal clinical trials. We have 36 observational studies in the second treatment line. The median mOS is 11.0 months (the mOS range is between 3.3 and 18.8 months). There are four pivotal clinical trials from second line and the median mOS is 11.3 months (the mOS range is between 9.2 and 13.8 months). In the second line, 69% of the studies reported safety outcomes with the median rate of sAE of 6%, ranging from 6% to 42%, which is comparable with the median rate of sAE of 13% (range: 7% to 31.2%) in pivotal clinical trials. The results of observational studies indicate a slightly lower effectiveness and comparable safety of ICI used in routine clinical practice than in the frame of clinical trials, despite the inclusion of patients with poorer prognostic factors.

• Keywords: immunotherapy, immune checkpoint inhibitors, advanced non-small cell lung cancer, observational studies, systematic review