Phase I/II Study of Lorlatinib in Advanced ALK+ or ROS1+ 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.

Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Background ALK+ and ROS1+ NSCLC pts frequently develop resistance to TKIs through secondary mutations[1,2] Lorlatinib: novel, broad spectrum, potent ALK and ROS1 inhibitor Active against multiple mutations conferring resistance to other ALK and ROS1 TKIs, including crizotinib, ceritinib, alectinib[3] Current report on dose escalation component of ongoing phase I/II study of lorlatinib in advanced ALK+ or ROS1+ NSCLC[4] NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor. 1. Johnson TW, et al. J Med Chem. 2014;57:4720-4744. 2. Zou HY, et al. Proc Natl Acad Sci U S A. 2015;112:3493-3498. 3. Zou HY, et al. AACR-NCI 2013. Abstract A277. 4. Solomon BJ, et al. ASCO 2016. Abstract 9009. Slide credit: clinicaloptions.com

Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Study Design Open-label phase I/II trial Primary objective: safety/tolerability at increasing dose levels to establish RP2D Secondary objectives: antitumor activity, PK, pt-reported outcomes, correlative studies ALK+ or ROS1+ NSCLC; treatment-naive or PD after ≥ 1 prior ALK/ROS1 TKI; ≥ 1 measurable extracranial lesion (N = 54) Dose Escalation Lorlatinib 10, 25, 50, 75, 100*, 150, or 200† mg QD Q3W 35, 75, or 100 mg BID Q3W Tx until PD or unacceptable toxicity *Chosen as RP2D, n = 17. †One DLT observed. DLT, dose-limiting toxicity; NSCLC, non-small-cell lung cancer; PD, progressive disease; PK, pharmacokinetics; RP2D, recommended phase II dose; TKI, tyrosine kinase inhibitor; Tx, treatment. Slide credit: clinicaloptions.com Solomon BJ, et al. ASCO 2016. Abstract 9009.

Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Baseline Characteristics All Pts (N = 54) Mean age, yrs (SD) 51.9 (12.8) Female, % 59 Race, % White/black/Asian/other 78/7/13/2 Brain metastases present, % 72 ALK/ROS1 status, % ALK+ ROS1+ Not confirmed 76 22 2 Prior no. ALK/ROS1 TKIs, % 1 ≥ 2 13 37 50 NSCLC, non-small-cell lung cancer; SD, standard deviation; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Solomon BJ, et al. ASCO 2016. Abstract 9009.

Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Safety Treatment-Related AE, % All LOR Doses (N = 54) LOR 100 mg QD (n = 17) Any Gr 3/4 93 30 94 29 Causing dose delay 33 20 24* 18* Causing dose reduction 24 9 Hypercholesterolemia 69 11 82 12 Peripheral edema 37 53 Hypertriglyceridemia 6 41 Peripheral neuropathy 22 NR Fatigue 15 Slow speech 18 AE, adverse event; Gr, grade; LOR, lorlatinib; NR, not reported; NSCLC, non-small-cell lung cancer. *Most frequently because of hypercholesterolemia. Slide credit: clinicaloptions.com Solomon BJ, et al. ASCO 2016. Abstract 9009.

Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Efficacy I Response 1 Prior ALK TKI (n = 14) ≥ 2 Prior ALK TKIs (n = 26) Total ALK+ (n = 41) ORR, % (95% CI) 57 (29-82) 42 (23-63) 46 (31-63) Best overall response, % CR PR Unconfirmed PR SD PD Indeterminate 7 50 21 14 8 35 4 19 27 39 2 20 24 Median PFS, mos (95% CI) 13.5 (1.6-NR) 9.2 (1.5-NR) 11.4 (3.4-16.6) 12-mo PFS, % (95% CI) 41.0 (23.2-58.0) 18-mo PFS, % (95% CI) 23.4 (6.0-47.3) NR, not reached; NSCLC, non-small-cell lung cancer; PD, progressive disease; SD, stable disease; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Solomon BJ, et al. ASCO 2016. Abstract 9009.

Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Efficacy II Lorlatinib RP2D of 100 mg QD achieved plasma concentrations sufficient to inhibit WT ALK and ROS1 fusions and in range to inhibit common secondary mutations Demonstrated good CSF penetration and clinically significant intracranial responses 39% ORR in ALK+ pts with intracranial target lesions Majority of ALK+, ROS1+ pts showed reduction in target lesion size with durable responses 20 of 41 ALK+ patients remain on treatment including 9 pts for longer than 1 yr CSF, cerebrospinal fluid; NSCLC, non-small-cell lung cancer; RP2D, recommended phase II dose. Slide credit: clinicaloptions.com Solomon BJ, et al. ASCO 2016. Abstract 9009.

Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Conclusions Lorlatinib well tolerated at RP2D of 100 mg QD with manageable toxicity profile Hypercholesterolemia observed most frequently Lorlatinib shows promising antitumor activity, including intracranial activity, in ALK+ and ROS1+ NSCLC pts pretreated with 1 or more approved ALK TKIs Phase II portion of this trial currently under way NSCLC, non-small-cell lung cancer; RP2D, recommended phase II dose; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Solomon BJ, et al. ASCO 2016. Abstract 9009.

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