Sai-hong Ou¹, Alice Shaw¹, Ramaswamy Govindan¹, Mark Socinski¹, Ross Camidge¹, Luigi De Petris²,Dong-wan Kim³, Alberto Chiappori¹, Denis Moro-sibilot⁴,Michael Duruisseaux⁴, Lucio Crino⁵, Tommaso De Pas⁵, Eric Dansin⁴, Antje Tessmer⁶,James Yang⁷, Ji-youn Han³, Walter Bordogna⁸, Sophie Golding⁸, Ali Zeaiter⁸, Shirish Gadgeel¹

¹Medicine-Hematology/Oncology,Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine,USA, ²Sweden, ³South Korea, ⁴France,⁵Italy, ⁶Germany, ⁷Taiwan, ⁸Roche

Objective:The central nervous system (CNS) is afrequent site of progression in ALK+ NSCLC patients treated withcrizotinib, thus good CNS efficacy is of crucial importance for new ALKinhibitors. Two recent phase II studies examined the efficacy and safety ofalectinib in patients with ALK+ NSCLC who progressed after crizotinib;data from both studies were pooled to further examine the efficacy of alectinibin the CNS. Method: Both phase II, single-arm, multicenter studiesenrolled ALK+ NSCLC patients previously treated with crizotinib. Onestudy was conducted in North America only (NP28761; NCT01871805), the other wasglobal (NP28673; NCT01801111). All patients received 600mg oral alectinib twicedaily. A primary endpoint of both studies was objective response rate (ORR) byindependent review committee (IRC) and key secondary endpoints included CNS ORRby IRC and CNS duration of response (DOR). Response was determined according toRECIST v1.1. All patients underwent imaging at baseline to assess CNSmetastases. Result: The pooled analysis population comprised 225patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristicswere similar to each study population, with most patients being non-smokers,(MD) while a further 85 had non-measurable disease (NMD) at baseline; bothgroups together (M+NMD) comprised 135 patients, 60% of the overall studypopulation. In the MD group, 34 patients (68%) had received prior radiotherapy,but 24 of them had completed that radiotherapy >6 months prior to startingalectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy,with 55 completing this >6 months prior to starting alectinib. In the MDgroup, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In theM+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORRof 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1-90.7%). Complete responseswere seen in patients with and without prior radiotherapy. Median CNS DOR afteronly 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group(n=30) and 7.6 months (5.8-10.3) in the M+NMD group (n=52), which is similar tothe systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO2015). Tolerability was also similar to the overall study population. Conclusion:Alectinib showed promising efficacy in the CNS in ALK+ NSCLCpatients previously treated with crizotinib, achieving a complete response rateof 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS responsewas sustained for an equivalent duration to the systemic response, suggestingthat alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targetingCNS metastases. The ongoing phase III clinical studies will assess the systemicand CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.

Key Words: alectinib  CNS metastasis  ALK positive non-small cell