Phase II ALTA: Brigatinib Has Promising Activity in Crizotinib-Refractory ALK+ NSCLC CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. NSCLC, non-small-cell lung cancer. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

Brigatinib for Crizotinib-Refractory ALK+ NSCLC (ALTA): Background Progression after crizotinib treatment typical in ALK+ NSCLC because of acquired ALK resistance mutations, poor penetration of CNS[1,2] Secondary ALK resistance also develops with current post-crizotinib ALK inhibitors[3] Brigatinib: potent ALK TKI with activity against common resistance mutations, including G1202R[4] Survival enhanced vs crizotinib and tumor burden reduced in orthotopic brain tumor mouse model Multicenter, open-label, single-arm phase I/II study demonstrated antitumor activity of brigatinib in ALK+ NSCLC pts[5] Current study evaluated efficacy, safety of brigatinib in crizotinib- refractory ALK+ NSCLC[6] CNS, central nervous system; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor. 1. Costa DB, et al. J Clin Oncol. 2015;33:1881-1888. 2. Zhang I, et al. Lancet Oncol. 2015;16:e510-e521. 3. Katayama R, et al. Clin Cancer Res. 2014;20:5686-5696. 4. Zhang S, et al. AACR 2015.Abstract 781. 5. Camidge DR, et al. ASCO 2015. Abstract 8062. 6. Kim D-W, et al. ASCO 2016. Abstract 9007. Slide credit: clinicaloptions.com

ALTA: Study Design Randomized, multicenter, open-label, international phase II trial Primary endpoint: confirmed ORR per RECIST v1.1 by investigator Secondary endpoints: confirmed ORR by IRC, intracranial ORR/PR by IRC in pts with active brain mets,† PFS, OS, DOR, safety/tolerability Study not designed for statistical comparison between arms, but dose selection supported by post hoc comparisons of PFS and OS Stratified by baseline brain metastases and best response to prior crizotinib Locally advanced or metastatic ALK+ NSCLC, ECOG PS ≤ 2, PD on crizotinib, no other ALK-targeted therapy (N = 222) Brigatinib 90 mg QD (n = 112) PD requiring change of therapy, intolerable toxicity, or other reason for discontinuation Brigatinib 180 mg QD* (n = 110) *After 7-day lead-in at 90 mg. DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; IRC, Independent Review Committee; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; RECIST, Response Evaluation Criteria In Solid Tumors. †Lesions with no previous RT or investigator-assessed PD after prior RT. Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007.

ALTA: Baseline Characteristics Brigatinib 90 mg QD (n = 112) Brigatinib 180 mg QD* (n = 110) All Pts (N = 222) Median age, yrs (range) 50.5 (18-82) 56.5 (20-81) 54 (18-82) Female, % 55 58 57 Race, % White Asian Other 64 35 1 69 27 4 67 31 2 ECOG PS 0/1, % 94 92 93 Prior smoker, % 36 43 39 Adenocarcinoma, % 96 98 97 Prior chemotherapy, % 74 Investigator-assessed BL brain mets, % 71 Best response to prior crizotinib, % CR or PR Other response or unknown 63 37 66 34 65 BL, baseline; ECOG, Eastern Cooperative Oncology Group; PS, performance status. *With 7-day lead-in at 90 mg. Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007.

Best Change From Baseline in Target Lesions (%) ALTA: ORR 40 40 90 mg QD 180 mg QD† 20 20 -20 -20 Best Change From Baseline in Target Lesions (%) * -40 * -40 * * -60 -60 ORR: 45% ORR: 54% -80 -80 -100 -100 Progressive disease Stable disease Partial response Complete response CT, chemotherapy. *Unconfirmed response. †After 7-day lead in at 90 mg. One confirmed PR at 180 mg brigatinib in pt with baseline G1202R Confirmed ORR after prior CT: 42% (90 mg) and 54% (180 mg) Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007. Reproduced with permission.

ALTA: PFS Median PFS (95% CI) HR (95% CI)† 100 90 mg QD 180 mg QD* 9.2 months (7.4-15.6) 12.9 months (11.1-not reached) 90 0.55 (0.35-0.86) 80 70 60 PFS (%) 50 40 30 20 10 6 12 18 24 Mos *After 7-day lead in at 90 mg. †Post hoc analysis, not designed to compare arms statistically. Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007.

1-Yr OS Probability, % (95% CI) ALTA: OS 100 90 80 70 60 OS (%) 50 90 mg QD 180 mg QD* 1-Yr OS Probability, % (95% CI) HR (95% CI)† 71 (60-79) 80 (67-88) 0.57 (0.31-1.05) Median OS Not reached 40 30 20 10 6 12 18 24 Mos *After 7-day lead in at 90 mg. †Post hoc analysis, not designed to compare arms statistically. Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007.

ALTA: Intracranial Response IRC-Assessed Efficacy Parameter* Pts With Measurable (≥ 10 mm) Brain Mets Pts With Nonmeasurable Brain Mets Only Brigatinib 90 mg QD (n = 25) Brigatinib 180 mg QD† (n = 18) Brigatinib 90 mg QD (n = 54) Brigatinib 180 mg QD† (n = 54) Confirmed intracranial ORR, % (95% CI) 36 (18-58) 67 (41-87) 6 (1-15) 19 (9-31) Best overall response, % Confirmed intracranial CR Confirmed intracranial PR Intracranial CR awaiting confirmation Intracranial PR awaiting confirmation 8 28 12 67 6 NA 19 2 Intracranial disease control rate, % (95% CI) 88 (69-98) 83 (59-96) 72 (58-84) 87 (75-95) *Intracranial response defined as ≥ 30% decline in measurable lesions or complete disappearance of lesions in pts with only nonmeasurable lesions. †With 7-day lead in at 90 mg. BL, baseline; IRC, Independent Review Committee; NA, not applicable. 70% (151/215) of pts had BL brain metastases IRC-assessed intracranial ORR for pts with measurable, active BL brain metastases was 37% (7/19) for 90-mg brigatinib vs 73% (11/15) for 180-mg brigatinib Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007.

ALTA: Intracranial PFS 100 90 80 70 60 Intracranial PFS (%) 50 90 mg QD 180 mg QD* Median Intracranial PFS (95% CI) HR (95% CI)† 15.6 months (6.5-15.6) Not reached (7.4-not reached) 0.66 (0.32-1.35) 40 30 20 10 6 12 18 Mos *After 7-day lead in at 90 mg. †Post hoc analysis, not designed to compare arms statistically. Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007.

ALTA: Adverse Events TEAE Occurring in ≥ 10% of All Pts, % Brigatinib 90 mg QD* (n = 109) Brigatinib 180 mg QD† (n = 110) Any Grade Grade ≥ 3 Nausea 33 1 40 Diarrhea 19 38 Headache 28 27 Cough 18 34 Fatigue 20 Vomiting 24 2 23 Dyspnea 21 3 Increased blood CPK 11 30 9 Hypertension 6 Rash 7 16 Increased amylase 8 15 Increased AST AE, adverse event; AST, aspartate aminotransferase; CPK, creatine phosphokinase; Gr, grade; TEAE, treatment-emergent adverse event. *Median time on treatment: 7.5 mos. †With 7-day lead in at 90 mg; median time on treatment: 7.8 mos. Select AEs seem dose-related with increased rates mostly in Gr 1/2 events Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007.

ALTA: Dosing Outcomes Select Safety Parameter Brigatinib 90 mg QD (n = 109) Brigatinib 180 mg QD* (n = 110) Dose reduction due to any AE, % 7 20 Dose interruption ≥ 3 days (any reason), % 18 36 Discontinuation, % Due to any AE Due to PD Due to death 3 30 6 8 17 1 Median dose intensity, mg/day 90 174 *With 7-day lead-in at 90 mg *With 7-day lead in at 90 mg. 6% of pts receiving 90-mg brigatinib experienced early onset (Day 1-9) pulmonary AEs (eg, dyspnea, cough, hypoxia, pneumonia, pneumonitis), 3% of which were grade ≥ 3; managed with dose interruption and reintroduction (6/14) or continued treatment (1/14) 7 discontinuations, including 1 pt death after such pulmonary AEs Pathophysiology unknown with trend toward reduced pulmonary AE frequency with ≥ 7-day crizotinib washout (4/110) vs < 7-day (10/109); RR: 2.52 (95% CI: 0.82-7.80) AE, adverse event; PD, progressive disease; RR, relative risk. Slide credit: clinicaloptions.com Kim D-W, et al. ASCO 2016. Abstract 9007.

ALTA: Conclusions Brigatinib at 90 mg or 180 mg is active and tolerable in ALK-positive NSCLC Median PFS over 1 yr at the higher dose Intracranial activity in pts with measurable brain mets Study investigators conclude that brigatinib is a promising, potential option for crizontinib-resistant ALK-positive NSCLC[1] ALTA-1L: ongoing open-label, randomized phase III study of brigatinib 180-mg regimen vs crizotinib in pts with ALK inhibitor-naive ALK-positive NSCLC[2] NSCLC, non-small-cell lung cancer. 1. Kim D-W, et al. ASCO 2016. Abstract 9007. 2. ClinicalTrials.gov. NCT02737501. Slide credit: clinicaloptions.com

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