1. Entrectinib in ROS1-Positive NSCLC: Pooled Analysis of 3 Early-Phase Studies Supported by educational grants from AbbVie, AstraZeneca, Genentech, and Takeda Oncology. Building a Bridge Between Science and Practice: CCO Independent Conference Highlights* from the 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada *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.

2. Entrectinib in ROS1+ NSCLC: Background  Entrectinib: oral, potent, selective ROS1/NTRK/ALK TKI with CNS activity [1] ‒More potent ROS1 inhibitor than crizotinib in preclinical studies ‒Demonstrated pan-TRK inhibition in clinical trials across multiple tumor types ‒Inhibition of MAPK-PI3K/AKT downstream pathways inhibits tumor growth and cell proliferation, spurs cell cycle arrest and apoptosis, and inhibits TRK phosphorylation ‒Can cross blood–brain barrier and remain within CNS ‒Demonstrated activity in primary brain tumors, secondary CNS metastases  Current analysis pools efficacy and safety data from 3 early studies of entrectinib in ROS1+ NSCLC: STARTRK-2, STARTRK-1, and ALKA-372-001 [2] 1. Rolfo C, et al. Expert Opin Investig Drugs. 2015;24:1493-1500. 2. Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.comclinicaloptions.com

3. Treatment of Brain Metastases: An Unmet Need in ROS1+ NSCLC  ROS1 fusions are oncogenic driver mutations occurring in 1% to 2% of patients with NSCLC [1,2]  Brain metastases are common in treatment-naive patients with stage IV ROS1+ NSCLC (36%) [3]  Current standard of care for ROS1+ NSCLC is crizotinib, although outcomes vary based on presence/absence of CNS disease and baseline ECOG PS ─PROFILE 1001 (N = 50) [4] : 72% ORR; median PFS 19.2 mos; median DoR 17.6 mos ─CNS a common first site of progression in patients on crizotinib for ROS1+ NSCLC (52%) [3]  Patients with ROS1+ tumors may benefit from first-line treatment with a CNS- penetrant ROS1 inhibitor 1. Bergethon K, et al. J Clin Oncol. 2012;30:863-870. 2. Dugay F, et al. Oncotarget. 2017;8:53336-53351. 3. Bowles DW, et al. WCLC 2018. Abstract P1.01-78. 4. Shaw AT, et al. N Engl J Med. 2014;371:1963-1971. Slide credit: clinicaloptions.comclinicaloptions.com

4. Entrectinib in ROS1+ NSCLC: Integrated Analysis Doebele RC, et al. WCLC 2018. Abstract OA02.01. ClinicalTrials.gov. NCT02568267. Drilon A, et al. Cancer Discov. 2017;7:400-409. Slide credit: clinicaloptions.comclinicaloptions.com  Primary endpoints: ORR, DoR  Secondary endpoints: PFS, OS, intracranial ORR and DoR, safety/tolerability Efficacy population: ROS1+ NSCLC with no prior ROS1 inhibitor (n = 53) Safety population: Entrectinib-treated ROS1+, all tumor types and gene rearrangements (n = 355) STARTRK-2 Multicenter, global basket phase II study; 600 mg QD, 28-day cycle (n = 37 with NSCLC) ALKA-372-001 Phase I dose escalation (n = 9 with NSCLC) STARTRK-1 Phase I dose escalation (n = 7 with NSCLC)

5. Entrectinib in ROS1+ NSCLC: Baseline Characteristics Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.comclinicaloptions.com OutcomeROS1+ NSCLC (N = 53) Median age, yrs (range)53 (27-73) Female, %64.2 Asian, %35.8 White, %58.5 ECOG PS 0-1, %87.79 ECOG PS 2, %11.3 Never smoker, %58.5 Current/former smoker, %41.5 Adenocarcinoma histology, %76.1 0 prior lines of systemic therapy, %13.2 1-2 prior lines of systemic therapy, %39.7 ≥ 3 prior lines of systemic therapy, %47.1 CNS disease at baseline, n (%)23 (43.4)

6. Entrectinib in ROS1+ NSCLC: ORR (BICR Assessment) Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.comclinicaloptions.com Response Total (N = 53) CNS Disease at Baseline (n = 23) No CNS Disease at Baseline (n = 30) ORR, n (%)41 (77.4) (95% CI: 63.8-87.7) 17 (73.9) (95% CI: 51.6-89.8) 24 (80.0) (95% CI: 61.4-92.3) CR, n (%)3 (5.7)03 (10.0) PR, n (%)38 (71.7)17 (73.9)21 (70.0) SD, n (%)1 (1.9)01 (3.3) PD, n (%)4 (7.5)4 (17.4)0 Non-CR/non-PD, n (%)3 (5.7)03 (10.0) Missing or unevaluable, n (%)4 (7.5)2 (8.7)2 (6.7) Clinical benefit rate (CR/PR/SD for ≥ 6 mos), n (%)41 (77.4) (95% CI: 63.8-87.7) Median DoR, mos24.6 (95% CI: 11.4-34.8) 12.6 (95% CI: 6.5-NE) 24.6 (95% CI: 11.4-34.8)  12-mo probability of EFS  Median follow-up from first response: 16.6 mos

7. Entrectinib in ROS1+ NSCLC: Survival Outcomes  Median follow-up: 15.5 mos Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.comclinicaloptions.com Total (N = 53) CNS Disease at Baseline (n = 23) No CNS Disease at Baseline (n = 30) Median PFS by BICR, mos19.0 (95% CI: 12.2-36.6) 13.6 (95% CI: 4.5-NE) 26.3 (95% CI: 15.7-36.6) Patients with PFS event, n (%)25 (47.2)11 (47.8)14 (46.7)  PD, n  Death, n 20 5 8383 12 2  12-mo probability of PFS: 65%  12-mo probability of OS: 85%

8. Entrectinib in ROS1+ NSCLC: Intracranial ORR and DoR (BICR Assessment) Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.comclinicaloptions.com ResponsePatients With CNS Metastases at Baseline (n = 20) Intracranial ORR, n (%)11 (55) (95% CI: 31.53-76.94)  CR4 (20)  PR7 (35)  SD0  PD3 (15) Non-CR/non-PD and nonevaluable6 (30) Median intracranial DoR, mos12.9 (95% CI: 5.6-NE) Patients with event, n (%)5 (45.5)  Disease progression, n3  Death, n2 Patients at risk at 6 mos, n7 6-mo event-free probability, %71

9. Entrectinib in ROS1+ NSCLC: Safety Summary Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.comclinicaloptions.com Treatment-Related AE in ≥ 10% of Patients, n (%) Safety-Evaluable Population (N = 355) All GradesGrade 3/4 Dysgeusia147 (41.4)1 (0.3) Fatigue99 (27.9)10 (2.8) Dizziness90 (25.4)2 (0.6) Constipation84 (23.7)1 (0.3) Nausea74 (20.8)0 Diarrhea81 (22.8)5 (1.4) Weight increased69 (19.4)18 (5.1) Paresthesia67 (18.9)0 Blood creatinine increased54 (15.2)2 (0.6) Myalgia54 (15.2)2 (0.6) Peripheral edema50 (14.1)1 (0.3) Vomiting48 (13.5)0 Anemia43 (12.1)16 (4.5) Arthralgia44 (12.4)2 (0.6) AST increased39 (11.0)4 (1.1)  N = 355 patients in 3 clinical trials  Most AEs grade 1/2, reversible  Treatment-related AEs ─Leading to treatment discontinuation: 3.9% ─Leading to dose reduction: 27.3% ─Leading to dose interruption: 25.4% ─Serious AEs: 8.5% ─No deaths due to treatment-related AEs

10. Entrectinib in ROS1+ NSCLC: Conclusions  Entrectinib demonstrated activity with durable responses in ROS1+ NSCLC with and without CNS metastases ‒ORR: 77.4%; median DoR: 24.6 mos ‒Median PFS: 26.3 mos (no CNS metastases) and 13.6 mos (CNS metastases)  Durable intracranial activity reported in patients with baseline CNS disease ‒Intracranial ORR: 55% ‒Median intracranial DoR: 12.9 mos  Entrectinib was tolerable with a manageable safety profile ‒Most AEs were low grade and managed with dose interruption or reduction ‒Few patients discontinued entrectinib due to treatment-related toxicity Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.comclinicaloptions.com

11. clinicaloptions.com/oncology Go Online for More CCO Coverage of WCLC 2018! Capsule Summaries of all the key data Additional CME-certified analysis with expert faculty commentary on all the key studies