title: Tackling ALK in non-small cell lung cancer: the role of novel inhibitors.
abstract: Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.
authors.affiliation: 1 INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France ; 2 Medical Oncology Unit, University Hospital of Parma, Parma, Italy ; 3 Department of Oncology, AOU San Luigi (Orbassano), University of Turin, Italy ; 4 Medical Oncology, AO Ordine Mauriziano, Turin, Italy ; 5 Division of Pathology, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy ; 6 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy ; 7 Operative Unit of Pathology, Azienda USL Valle d'Aosta, Aosta, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facchinetti
authors.affiliation: 1 INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France ; 2 Medical Oncology Unit, University Hospital of Parma, Parma, Italy ; 3 Department of Oncology, AOU San Luigi (Orbassano), University of Turin, Italy ; 4 Medical Oncology, AO Ordine Mauriziano, Turin, Italy ; 5 Division of Pathology, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy ; 6 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy ; 7 Operative Unit of Pathology, Azienda USL Valle d'Aosta, Aosta, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.affiliation: 1 INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France ; 2 Medical Oncology Unit, University Hospital of Parma, Parma, Italy ; 3 Department of Oncology, AOU San Luigi (Orbassano), University of Turin, Italy ; 4 Medical Oncology, AO Ordine Mauriziano, Turin, Italy ; 5 Division of Pathology, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy ; 6 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy ; 7 Operative Unit of Pathology, Azienda USL Valle d'Aosta, Aosta, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
authors.affiliation: 1 INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France ; 2 Medical Oncology Unit, University Hospital of Parma, Parma, Italy ; 3 Department of Oncology, AOU San Luigi (Orbassano), University of Turin, Italy ; 4 Medical Oncology, AO Ordine Mauriziano, Turin, Italy ; 5 Division of Pathology, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy ; 6 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy ; 7 Operative Unit of Pathology, Azienda USL Valle d'Aosta, Aosta, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Graziano
authors.affiliation: 1 INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France ; 2 Medical Oncology Unit, University Hospital of Parma, Parma, Italy ; 3 Department of Oncology, AOU San Luigi (Orbassano), University of Turin, Italy ; 4 Medical Oncology, AO Ordine Mauriziano, Turin, Italy ; 5 Division of Pathology, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy ; 6 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy ; 7 Operative Unit of Pathology, Azienda USL Valle d'Aosta, Aosta, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.affiliation: 1 INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France ; 2 Medical Oncology Unit, University Hospital of Parma, Parma, Italy ; 3 Department of Oncology, AOU San Luigi (Orbassano), University of Turin, Italy ; 4 Medical Oncology, AO Ordine Mauriziano, Turin, Italy ; 5 Division of Pathology, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy ; 6 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy ; 7 Operative Unit of Pathology, Azienda USL Valle d'Aosta, Aosta, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
authors.affiliation: 1 INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France ; 2 Medical Oncology Unit, University Hospital of Parma, Parma, Italy ; 3 Department of Oncology, AOU San Luigi (Orbassano), University of Turin, Italy ; 4 Medical Oncology, AO Ordine Mauriziano, Turin, Italy ; 5 Division of Pathology, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy ; 6 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy ; 7 Operative Unit of Pathology, Azienda USL Valle d'Aosta, Aosta, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
keywords: EML4-ALK rearrangement; Non-small-cell lung cancer (NSCLC); anaplastic lymphoma kinase inhibitors (ALK inhibitors); crizotinib