Fino a poco tempo fa, la chemioterapia e la radioterapia sono state le uniche opzioni disponibili per i pazienti con diagnosi di NSCLC non suscettibili al trattamento radicale localizzato. I doppi regimi di chemioterapia di prima linea, basati su composti col platino (Cisplatino o Carboplatino) combinati con un farmaco di terza generazione (Gemcitabina, Paclitaxel, Docetaxel, Pemetrexed), hanno prolungato la sopravvivenza e migliorato la qualità di vita dei pazienti.
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Recentemente, sono stati sviluppati nuovi farmaci immunomodulanti che mirano a diversi punti di controllo immunitario, allo scopo di migliorarne la risposta, diversamente dalla chemioterapia che invece interferisce con la divisione cellulare per ridurre la proliferazione delle cellule tumorali o indurne la morte [88].
Nella chemioterapia tradizionale le risposte cliniche compaiono rapidamente, entro poche settimane, e l’eventuale sviluppo di una nuova lesione tumorale viene considerato come progressione della malattia che determina l’interruzione del trattamento in corso. Con i farmaci immunomodulanti, invece, le risposte cliniche possono manifestarsi anche alcuni mesi dopo l’inizio della somministrazione, ma in genere durano più a lungo. Una progressione della malattia non implica in questi casi la necessaria rinuncia al trattamento come accade invece per i farmaci chemioterapici. Siamo quindi di fronte a un nuovo modo di valutare la terapia in questi pazienti [140].
In particolare, sono stati fatti degli studi clinici, alcuni ancora in corso, per valutare l’efficacia del Nivolumab a diversi dosaggi in monoterapia o combinato con altri farmaci come l’Ipilimumab, nei pazienti con NSCLC avanzato, squamoso o non squamoso, che progredisce dopo la chemioterapia a base di platino.
Da questi studi è risultato che il Nivolumab, alla dose di 3 mg/kg ogni due settimane, ha migliorato il tasso di sopravvivenza, con una percentuale più alta di sopravvissuti a lungo termine e un profilo di tossicità gestibile rispetto alla chemioterapia [57] [58].
La sopravvivenza globale (OS) e il tasso di risposta obiettivo (ORR) sono stati significativamente migliori con il Nivolumab rispetto al Docetaxel per via endovenosa. Inoltre il Nivolumab ha avuto un profilo di eventi avversi gestibili ed è stato quindi meglio tollerato che il Docetaxel [62].
Invece, quando il Nivolumab viene utilizzato insieme all’Ipilimumab, gli effetti antitumorali risultano più forti rispetto a quando vengono utilizzati da soli [141].
I risultati ottenuti dagli studi hanno confermato i benefici clinici offerti dal trattamento di combinazione che ha portato ad un tasso di risposta globale più elevato e ad una migliore sopravvivenza senza progressione, sebbene si siano verificati più effetti avversi correlati al trattamento.
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Inoltre la combinazione di questi due farmaci ha portato ad un aumento dell’efficacia del trattamento nei pazienti con una maggiore espressione di PD-L1, anche se è stato visto che alcuni pazienti rispondono ugualmente anche in assenza di PD-L1 [64].
La selezione dei pazienti è attualmente uno dei problemi più importanti per l'ottimizzazione del trattamento. L'espressione di PD-L1 da parte delle cellule tumorali sembra non essere sufficiente a discriminare i responders rispetto ai nonresponders e nuove tecniche diagnostiche stanno emergendo per cercare nuovi fattori predittivi allo scopo di migliorare il trattamento [142].
Tenuto conto di questi risultati straordinari, recentemente il Nivolumab è stato approvato negli USA e in Europa come trattamento di seconda linea per NSCLC metastatico ad istologia squamosa.
L'espressione di PD-L1 è stata documentata anche in altri tipi di tumori, tra cui il melanoma, il tumore ovarico e il carcinoma delle cellule renali [143].
L'immunoterapia sta aprendo nuove prospettive per il trattamento di diverse neoplasie, dando nuove efficaci opzioni per queste malattie altamente fatali.
La sfida, nell’immediato, è capire perché metà dei pazienti non risponda ai trattamenti immuno-oncologici oggi a disposizione, cioè si vuole comprendere meglio le caratteristiche del tumore e anche le relazioni tra il tumore e il sistema immunitario che in alcuni casi rendono inefficaci questi trattamenti [144].
Rimangono molte domande circa il modo migliore per utilizzare e combinare gli inibitori di PD-1 e PD-L1, ma sulla base delle informazioni attualmente disponibili, si prevede che questi farmaci avranno in ultima analisi un ruolo chiave nella gestione dei pazienti con un range di tumori diversi [88].
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