CCO_Clin_Phase III JALEX Alectinib vs Crizotinib in ALK Inhibitor–Na

1、CCO Independent Conference Coverage*of the 2016 ASCO Annual Meeting, June 3 -7, 2016Phase III J-ALEX: Alectinib vs Crizotinib in ALK InhibitorNaive, ALK-Positive NSCLC *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals thro

2、ugh conference coverage and other educational programs.This activity is supported by educational grants from Amgen, Ariad,Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.Alectinib in ALK InhibitorNaive ALK+ NSCLC (J-ALEX): BackgroundApproxim

3、ately 4% to 5% of white and Asian pts with advanced NSCLC have ALK gene rearrangements1Crizotinib, the first ALK inhibitor to be approved, considered standard frontline treatment of pts with ALK-positive NSCLC Crizotinib has demonstrated PFS of 10.9 mos in ALK inhibitornaive pts,2 but pts eventually

4、 relapse, mainly because of secondary ALK mutations/amplification or CNS metastasesALK inhibitor, alectinib, demonstrated activity in intracranial tumors and against ALK resistance mutations in preclinical investigation3-5AF-001 JP phase I/II study: efficacy in ALK inhibitornaive ALK+ NSCLC6, 7J-ALE

5、X: randomized phase III study of alectinib vs crizotinib in ALK inhibitornaive pts with ALK-positive NSCLC81. Chia PL, et al. Clin Epidemiol. 2014;6:423-432. 2. Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177. 3. Sakamoto H, et al. Cancer Cell. 2011;19:679-690. 4. Kodama T, et al. Mol Cancer The

6、r. 2014;13:2910-2918. 5. Kodama T, et al. Cancer Chemother Pharmacol. 2014;74:1023-1028. 6. Kozuki T, et al. JSMO 2015. Abstract ISS1-2-1. 7. Takeuchi K, et al. Ann Oncol. 2016; 27:185-192. 8. Nokihara H, et al. ASCO 2016. Abstract 9008.Slide credit: Primary endpoint: PFS by independent review facil

7、ity Secondary endpoint: OS, ORR, PK, QoL, CNS PFS, safetyJ-ALEX: Study DesignAlectinib 300 mg twice daily PO28-day cycle(n = 103)Crizotinib 250 mg twice daily PO28-day cycle(n = 104)Stage IIIB/IV or recurrent ALK+ NSCLC (by IHC/FISH or RT-PCR)ECOG PS 2 1 measurable lesion (investigator assessed) 1 p

8、revious chemotherapyTreated/asymptomatic brain metastasis permitted(N = 207)Slide credit: Stratified by clinical stage (IIIB/IV vs recurrent), previous chemotherapy, ECOG PS ( 1 vs 2)1:1Nokihara H, et al. ASCO 2016. Abstract 9008.3 preplannedinterim analyses for efficacy: 33%, 50%, 75% of final even

9、ts(current report: second interim analysis)J-ALEX: Pt CharacteristicsSlide credit: CharacteristicAlectinib (n = 103)Crizotinib (n = 104)Median age, yrs (range)61.0 (27-85)59.5 (25-84)Male, n (%)41 (39.8)41 (39.4)ECOG PS, n (%)01254 (52.4)47 (45.6)2 (1.9)48 (46.2)54 (51.9)2 (1.9)Stage, n (%)IIIBIVPos

10、toperative recurrence3 (2.9)76 (73.8)24 (23.3)3 (2.9)75 (72.1)26 (25.0)Histology, n (%)%AdenocarcinomaSquamous cell carcinomaOther100 (97.1)2 (1.9)1 (1.0)103 (99.0)0 (0)1 (1.0)Brain metastasis confirmed by IRF, n (%)14 (13.6)29 (27.9)Past or current smoker, n (%)47 (45.6)43 (41.3)ALK testing method

11、IHC and FISH, n (%)96 (93.2)94 (90.4)Nokihara H, et al. ASCO 2016. Abstract 9008.J-ALEX: Efficacy Alectinib showed consistent favorable treatment effect vs crizotinib for multiple prognostic factors Brain metastases: HR: 0.08 (95% CI: 0.01-0.61)Slide credit: Nokihara H, et al. ASCO 2016. Abstract 90

12、08.OutcomeAlectinib (n = 103)Crizotinib (n = 104)HR (99.6826% CI); P ValuePFS by IRF (ITT population)Events, n (%)Median PFS, mos (95% CI)25 (24.3)NR (20.3-NR)58 (55.8)10.2 (8.2-12.0)0.34 (0.17-0.71); .0001ORR by Investigator (ITT population)ORR, % (95% CI)CR or PR, n85.4 (78.6-92.3)8870.2 (61.4-79.

13、0)73-ORRa by IRFORR, % (95% CI)CR or PR, n(n = 83)91.6 (85.6-97.5)76(n = 90)78.9 (70.5-87.3)71-a In pts with measurable disease at baseline by IRF.J-ALEX: Safety8.7% alectinib discontinuations due to AE vs 20.2% for crizotinib29.1% alectinib dose interruptions due to AE vs 74.0% for crizotinibSlide

14、credit: Nokihara H, et al. ASCO 2016. Abstract 9008.AEs ( 20%, Either Arm)Alectinib (n = 103)Crizotinib (n = 104)All GradeGrade 3/4All GradeGrade 3/4Constipation36 (35)1 (1.0)46 (44.2)1 (1.0)Nausea11 (10.7)0 (0)77 (74.0)2 (1.9)Diarrhea9 (8.7)0 (0)76 (73.1)2 (1.9)Vomiting6 (5.8)0 (0)60 (57.7)2 (1.9)A

15、ST increase11 (10.7)1 (1.0)32 (30.8)5 (4.8)ALT increase9 (8.7)1 (1.0)33 (31.7)13 (12.5)Visual disturbance1 (1.0)0 (0)57 (54.8)0 (0)Nasopharyngitis21 (20.4)0 (0)24 (23.1)0 (0)Dysgeusia19 (18.4)0 (0)54 (51.9)0 (0)Pyrexia10 (9.7)1 (1.0)21 (20.2)0 (0)Decreased appetite1 (1.0)1 (1.0)21 (20.2)1 (1.0)J-ALE

16、X: Conclusions Second preplanned interim analysis of J-ALEX shows alectinib superior to crizotinib in ALK inhibitor-naive ALK-positive NSCLC Alectinib well tolerated with fewer AE-related discontinuations or dose interruptions vs crizotinib Investigators concluded that alectinib potentially a new option for first-line therapy for ALK-positive NSCLC Global phase III ALEX trial comparing alectinib vs crizotinib in treatment-naive pts with advanced ALK-positive NSCLC ongoing (NCT02075840)Slide credit: Nokihara H, et al. ASCO