Imunoterapija u tretmanu ne-sitnostaničnog raka pluća

Lung cancer is leading cause of death among malignant disease Worldwide and it is responsible for more than 1, 5 million deaths each year. Lung cancer is divided in two major groups: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Despite significant improvements, for vast majority of patients chemotherapy still remains the treatment of choice in the first line setting. Progress over the last decade has led to the recognition of immunoevasion as of the leading hallmarks of cancer development. Clinical development was focused on immune checkpoint inhibitors, cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) and programmed death (PD1/PD-L1) pathway. Programmed death 1 protein is another T-cell coinhibitory receptor with a structure similar to that of CTLA-4 but with a distinct biologic function and ligand specificity and it is stimulated with PD-L1. PD-1 or PD-L1 blockade with drugs like nivolumab, pembrolizumab or atezolizumab resulted in superior efficacy comparing to standard chemotherapy in first-line setting. In patient with high PD-L1 expression (50% or more) pemborlizumab should be treatment of choice in first-line setting. PD-L1 expression is at the moment only available biomarker who can predict response to immune checkpoint inhibitors.Karcinom pluća vodeći je uzrok smrti od malignih bolesti te je odgovoran za više od 1,5 milijuna smrti. U većine bolesnika osnovu liječenja karcinoma pluća čini kemoterapija temeljena na platini. Unazad desetak godina, brojna se istraživanje provode o ulozi imunološkog sutava u karcinogenezi. Tumori uspjevaju izbjeći nadzor imunološkog sustava te tako rasti i metastazirati. Koncpet aktivacije imunološkog sutava iznimno je zanimljiv te se pokazalo da blokatori kontrolnih točaka pokazauju dobro učinkovitost u liječenju solidnih tumora poput melanoma ili bubrega. U zadnjih pet godina, inhibitori kontrolnih točaka nivolumab, pembrolizumab i atezoilizumab pokazali su se kao iznimno učinkoviti lijekovi u liječenju bolesnika s karcinomom pluća ranije liječenih klasičnom kemoterapijom. Pembrolizumab se također pokazao kao iznimno učinkovit u liječenju bolesnika sa visokom PD-L1 ekspresijom (PD-L1≥50%) u prvoj liniji liječenja. Ono što je nužno je pronaći biomarker koji bi ukazivao koji će bolesnici regirati na liječenje imunoterapijom. Danas znamo da što je viša ekspresija PD-L1 bolji je odgovor na imunoterapiju, ali i negativni bolesnici mogu odgovoriti na liječenje. Imunoterapija inhibitorima kontrolnih točaka danas je standard u drugoj liniji liječenja karcinoma pluća malih stanica, te je pembrolizumab najbolja opcija za liječenje visoko pozitivnih PD-L1 bolesnika u prvoj liniji liječenja

Imunoterapija u tretmanu ne-sitnostaničnog raka pluća

Lung cancer is leading cause of death among malignant disease Worldwide and it is responsible for more than 1, 5 million deaths each year. Lung cancer is divided in two major groups: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Despite significant improvements, for vast majority of patients chemotherapy still remains the treatment of choice in the first line setting. Progress over the last decade has led to the recognition of immunoevasion as of the leading hallmarks of cancer development. Clinical development was focused on immune checkpoint inhibitors, cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) and programmed death (PD1/PD-L1) pathway. Programmed death 1 protein is another T-cell coinhibitory receptor with a structure similar to that of CTLA-4 but with a distinct biologic function and ligand specificity and it is stimulated with PD-L1. PD-1 or PD-L1 blockade with drugs like nivolumab, pembrolizumab or atezolizumab resulted in superior efficacy comparing to standard chemotherapy in first-line setting. In patient with high PD-L1 expression (50% or more) pemborlizumab should be treatment of choice in first-line setting. PD-L1 expression is at the moment only available biomarker who can predict response to immune checkpoint inhibitors.Karcinom pluća vodeći je uzrok smrti od malignih bolesti te je odgovoran za više od 1,5 milijuna smrti. U većine bolesnika osnovu liječenja karcinoma pluća čini kemoterapija temeljena na platini. Unazad desetak godina, brojna se istraživanje provode o ulozi imunološkog sutava u karcinogenezi. Tumori uspjevaju izbjeći nadzor imunološkog sustava te tako rasti i metastazirati. Koncpet aktivacije imunološkog sutava iznimno je zanimljiv te se pokazalo da blokatori kontrolnih točaka pokazauju dobro učinkovitost u liječenju solidnih tumora poput melanoma ili bubrega. U zadnjih pet godina, inhibitori kontrolnih točaka nivolumab, pembrolizumab i atezoilizumab pokazali su se kao iznimno učinkoviti lijekovi u liječenju bolesnika s karcinomom pluća ranije liječenih klasičnom kemoterapijom. Pembrolizumab se također pokazao kao iznimno učinkovit u liječenju bolesnika sa visokom PD-L1 ekspresijom (PD-L1≥50%) u prvoj liniji liječenja. Ono što je nužno je pronaći biomarker koji bi ukazivao koji će bolesnici regirati na liječenje imunoterapijom. Danas znamo da što je viša ekspresija PD-L1 bolji je odgovor na imunoterapiju, ali i negativni bolesnici mogu odgovoriti na liječenje. Imunoterapija inhibitorima kontrolnih točaka danas je standard u drugoj liniji liječenja karcinoma pluća malih stanica, te je pembrolizumab najbolja opcija za liječenje visoko pozitivnih PD-L1 bolesnika u prvoj liniji liječenja

LUNG IMMUNE PROGNOSTIC INDEX FOR ASSESSMENT OF THE RELIABILITY OF THE CLINICAL TREATMENT OUTCOME FOR NON-SMALL- CELL - LUNG CANCER

Uvod: Rak pluća jedna je od najčešće dijagnosticiranih zloćudnih bolesti čija je incidencija u svijetu u stalnom porastu. Imunoterapija je glavni terapijski pristup onkološkog liječenja uznapredovalog nesitnostaničnog raka pluća, gdje je ključno otkriće novih učinkovitih biomarkera. Dosadašnja znanstvena saznanja ukazuju na kliničku značajnost plućnog imunološkog prognostičkog indeksa (engl. Lung Immune Prognostic Index, LIPI), ali je njegov prediktivni značaj nedovoljno jasan. Cilj: Cilj istraživanja je bio utvrditi kliničku značajnost i prediktivnu vrijednost LIPI-a kao biljega u prognozi ishoda terapije bolesnika s metastatskim nesitnostaničnim rakom pluća i pozitivnom PD-L1 mutacijom liječenih prvom linijom onkološkog liječenja (imunoterapija ili kombinacija kemoterapija i imunoterapija). Nadalje, istražila se uloga LIPI-a kod pacijenata s metastatskim nesitnostaničnim rakom pluća i pozitivnom PD-L1 mutacijom koji su preboljeli COVID-19 infekciju, a nastavili se liječiti imunoterapijom ili kombinacijom kemoterapije i imunoterapije. Ispitanici i metode: Bolesnici uključeni u ovo istraživanje podijeljeni su u četiri ispitivane skupine prema strogo definiranim kliničkim parametrima, terapijskom pristupu te prisutnosti infekcije COVID-19. Određena je vrijednost LIPI-a i procijenjena je njegova prediktivna značajnost u svim ispitivanim skupinama, kao i ukupno preživljenje (OS), preživljenje bez progresije bolesti (PFS) i stopa kontrole bolesti (DCR). Rezultati: Provedeno je istraživanje potvrdilo nedovoljno istraženu i nesigurnu prediktivnu vrijednost i kliničku značajnost LIPI-a kao biomarkera u bolesnika s uznapredovalim nesitnostaničnim rakom pluća. Pacijenti zaraženi s COVID-19 imali su veću stopu preživljenja od ostalih ispitanika, neovisno o terapijskom pristupu, što se može pripisati njihovoj hospitalizaciji i intenzivnom medicinskom liječenju tijekom pandemije. Zaključak: Rezultati dobiveni ovim istraživanjem mogu doprinijeti odabiru mogućnosti liječenja u skladu s kliničkim stanjem bolesnika korištenjem vrijednosti LIPI-a kao neinvazivnog, lako dostupnog i ekonomski prihvatljivog prediktivnog biomarkera u onkologiji plućaIntroduction: Lung cancer is one of the most diagnosed malignancies with increasing incidence worldwide. Immunotherapy is the main oncological treatment for advanced non-small cell lung cancer (NSCLC), where the discovery of new efficient biomarkers is crucial. Scientific evidence points to the importance of the Lung Immune Prognostic Index (LIPI), but its predictive significance is unclear. Aim: The aim of this study was to determine the clinical significance and predictive value of LIPI as a marker of prognosis of treatment outcome in patients with metastatic non-small-cell lung cancer and a positive PD -L1 mutation treated with first-line oncologic therapy (immunotherapy or a combination of chemotherapy and immunotherapy). In addition, the role of LIPI was evaluated in patients with metastatic non-small cell lung cancer and a positive PD -L1 mutation who recovered from COVID-19 infection and continued to be treated with immunotherapy or a combination of chemotherapy and immunotherapy. Patients and Methods: Patients were divided into four study groups according to strictly defined clinical parameters, therapeutic approach, and COVID-19 infection. LIPI was determined and its predictive power was evaluated in all studied groups, as well as overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: This study confirmed the understudied and uncertain predictive power and clinical relevance of LIPI as a biomarker in patients with advanced NSCLC. Patients infected with COVID-19 had a higher survival rate than uninfected patients despite the therapeutic approach, which may be attributed to their hospitalization and intensive medical management during the pandemic. Conclusion: Findings obtained in this study may help to determine treatment options according to the clinical condition of the patient by using LIPI values as a non-invasive, readily available and economically acceptable predictive biomarker in lung oncology

LUNG IMMUNE PROGNOSTIC INDEX FOR ASSESSMENT OF THE RELIABILITY OF THE CLINICAL TREATMENT OUTCOME FOR NON-SMALL- CELL - LUNG CANCER

Uvod: Rak pluća jedna je od najčešće dijagnosticiranih zloćudnih bolesti čija je incidencija u svijetu u stalnom porastu. Imunoterapija je glavni terapijski pristup onkološkog liječenja uznapredovalog nesitnostaničnog raka pluća, gdje je ključno otkriće novih učinkovitih biomarkera. Dosadašnja znanstvena saznanja ukazuju na kliničku značajnost plućnog imunološkog prognostičkog indeksa (engl. Lung Immune Prognostic Index, LIPI), ali je njegov prediktivni značaj nedovoljno jasan. Cilj: Cilj istraživanja je bio utvrditi kliničku značajnost i prediktivnu vrijednost LIPI-a kao biljega u prognozi ishoda terapije bolesnika s metastatskim nesitnostaničnim rakom pluća i pozitivnom PD-L1 mutacijom liječenih prvom linijom onkološkog liječenja (imunoterapija ili kombinacija kemoterapija i imunoterapija). Nadalje, istražila se uloga LIPI-a kod pacijenata s metastatskim nesitnostaničnim rakom pluća i pozitivnom PD-L1 mutacijom koji su preboljeli COVID-19 infekciju, a nastavili se liječiti imunoterapijom ili kombinacijom kemoterapije i imunoterapije. Ispitanici i metode: Bolesnici uključeni u ovo istraživanje podijeljeni su u četiri ispitivane skupine prema strogo definiranim kliničkim parametrima, terapijskom pristupu te prisutnosti infekcije COVID-19. Određena je vrijednost LIPI-a i procijenjena je njegova prediktivna značajnost u svim ispitivanim skupinama, kao i ukupno preživljenje (OS), preživljenje bez progresije bolesti (PFS) i stopa kontrole bolesti (DCR). Rezultati: Provedeno je istraživanje potvrdilo nedovoljno istraženu i nesigurnu prediktivnu vrijednost i kliničku značajnost LIPI-a kao biomarkera u bolesnika s uznapredovalim nesitnostaničnim rakom pluća. Pacijenti zaraženi s COVID-19 imali su veću stopu preživljenja od ostalih ispitanika, neovisno o terapijskom pristupu, što se može pripisati njihovoj hospitalizaciji i intenzivnom medicinskom liječenju tijekom pandemije. Zaključak: Rezultati dobiveni ovim istraživanjem mogu doprinijeti odabiru mogućnosti liječenja u skladu s kliničkim stanjem bolesnika korištenjem vrijednosti LIPI-a kao neinvazivnog, lako dostupnog i ekonomski prihvatljivog prediktivnog biomarkera u onkologiji plućaIntroduction: Lung cancer is one of the most diagnosed malignancies with increasing incidence worldwide. Immunotherapy is the main oncological treatment for advanced non-small cell lung cancer (NSCLC), where the discovery of new efficient biomarkers is crucial. Scientific evidence points to the importance of the Lung Immune Prognostic Index (LIPI), but its predictive significance is unclear. Aim: The aim of this study was to determine the clinical significance and predictive value of LIPI as a marker of prognosis of treatment outcome in patients with metastatic non-small-cell lung cancer and a positive PD -L1 mutation treated with first-line oncologic therapy (immunotherapy or a combination of chemotherapy and immunotherapy). In addition, the role of LIPI was evaluated in patients with metastatic non-small cell lung cancer and a positive PD -L1 mutation who recovered from COVID-19 infection and continued to be treated with immunotherapy or a combination of chemotherapy and immunotherapy. Patients and Methods: Patients were divided into four study groups according to strictly defined clinical parameters, therapeutic approach, and COVID-19 infection. LIPI was determined and its predictive power was evaluated in all studied groups, as well as overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: This study confirmed the understudied and uncertain predictive power and clinical relevance of LIPI as a biomarker in patients with advanced NSCLC. Patients infected with COVID-19 had a higher survival rate than uninfected patients despite the therapeutic approach, which may be attributed to their hospitalization and intensive medical management during the pandemic. Conclusion: Findings obtained in this study may help to determine treatment options according to the clinical condition of the patient by using LIPI values as a non-invasive, readily available and economically acceptable predictive biomarker in lung oncology

Comprehensive molecular and clinical insights into non-small cell lung cancer transformation to small cell lung cancer with an illustrative case report

Histologic transformation to small cell lung cancer (tSCLC) is a rare but increasingly recognised mechanism of acquired resistance to tyrosine kinase inhibitors (TKI) in patients with epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). Beyond its acknowledged role in TKI resistance, histologic transformation to SCLC might be an important, yet under-recognised, mechanism of resistance in NSCLC treated with immunotherapy. Our review identified 32 studies that investigated tSCLC development in patients with EGFR-mutated NSCLC treated with TKI therapy and 16 case reports of patients treated with immunotherapy. It revealed the rarity of tSCLC, with a predominance of EGFR exon 19 mutations and limited therapeutic options and outcomes. Across all analysed studies in EGFR-mutated NSCLC treated with TKI therapy, the median time to tSCLC development was similar to 17 months, with a median overall survival of 10 months. Histologic transformation of EGFR-mutated NSCLC to SCLC is a rare, but challenging clinical problem with a poor prognosis. A small number of documented cases of tSCLC after immunotherapy highlight the need for rebiopsies at progression to diagnose this potential resistance mechanism. Further research is needed to better understand the mechanisms underlying this phenomenon and to develop more effective treatment strategies for patients with tSCLC

Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid proliferation, early dissemination, acquired therapy resistance, and poor prognosis. Early diagnosis of SCLC is crucial since most patients present with advanced/metastatic disease, limiting the potential for curative treatment. While SCLC exhibits initial responsiveness to chemotherapy and radiotherapy, treatment resistance commonly emerges, leading to a five-year overall survival rate of up to 10%. New effective biomarkers, early detection, and advancements in therapeutic strategies are crucial for improving survival rates and reducing the impact of this devastating disease. This review aims to comprehensively summarize current knowledge on diagnostic options, well-known and emerging biomarkers, and SCLC treatment strategies and discuss future perspectives on this aggressive malignancy

Comprehensive genomic profiling of a metastatic small cell lung carcinoma with a complete and long-term response to atezolizumab: A case report

Small cell lung cancer (SCLC) is a highly aggressive malignancy with a poor outcome. We present the case of a 57-year-old male patient with extensive-stage (ES-SCLC) treated with chemotherapy and atezolizumab. A complete response was achieved with a long remission of ∼three years. Comprehensive genomic profiling (CGP) of the tumor revealed high tumor mutation burden (13 mutations/Mb) and mutations of TP53, RB1 and ERCC4 genes. This case study confirms that a complete response to chemoimmunotherapy may be achieved in the case of ES-SCLC. It further provides the additional value of CGP and predictive testing in the management of ES-SCLC

Significance of the Lung Immune Prognostic Index for Assessment of the Reliability of the Clinical Treatment Outcome for Advanced Non-Small-Cell Lung Cancer in Patients with COVID-19 Infection

Introduction: Lung cancer is one of the most diagnosed malignancies with increasing incidence worldwide. Immunotherapy is the main oncological treatment for advanced non-small cell lung cancer (NSCLC), for which the discovery of new efficient biomarkers is crucial. Scientific evidence points to the importance of the Lung Immune Prognostic Index (LIPI), but its predictive significance is unclear. Aim: The aim of this study was to investigate the clinical significance and predictive role of LIPI in patients with advanced NSCLC and PD-L1 mutation who are eligible for immunotherapy in combination with chemotherapy. In addition, to our knowledge, this is the first time that the association between COVID-19 infection and the course and outcome of oncologic treatment of NSCLC has been investigated. Patients and Methods: Patients were divided into four study groups according to strictly defined clinical parameters, therapeutic approach, and COVID-19 infection. LIPI was determined and its predictive power was evaluated in all studied groups, as well as overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: This study confirmed the understudied and uncertain predictive power and clinical relevance of LIPI as a biomarker in patients with advanced NSCLC. Patients infected with COVID-19 had a higher survival rate than uninfected patients despite the therapeutic approach, which may be attributed to their hospitalization and intensive medical management during the pandemic. Conclusions: Findings obtained in this study may help to determine treatment options according to the clinical condition of the patient by using LIPI values as a non-invasive, readily available and economically acceptable predictive biomarker in lung oncology