This presentation summarizes a study examining the potent ALK inhibitor brigatinib (AP26613) and its ability to overcome resistance to first- and second-generation ALK inhibitors in preclinical models. The study found that brigatinib more effectively inhibited tumor growth in mouse xenograft models of ALK-positive cancers compared to other ALK inhibitors like crizotinib, ceritinib, and alectinib. Specifically, brigatinib led to dose-dependent inhibition and even regression of tumors derived from Karpas-299 and H2228 cell lines implanted in mice. It also more strongly inhibited ALK signaling compared to crizotinib at equivalent doses. The results suggest brigatin

1. WELCOME TO MY
PRESENTATION
Presented By: Md. Tanvir Hossain Bhuiyan.
Masters of Pharmacology and Clinical Pharmacy
North South University

2. The Potent ALK Inhibitor Brigtanib
(AP26613) Overcomes Mechanisms of
Resistance First-and Second-
Generation ALK Inhibitors in
Preclinical Studies

3. Bibiliography
Sen Zhang,Rana Anjum, Rachel Squillace, Sara Nadworny, Tianjun Zhou, Jeff
Keats, Yaoyu Ning, ScottD. Wardwell, David Miller, Youngchul Song, Lindsey E
ichinger, Lauren Moran, WeiSheng Huang, Shuangying Liu, Dong Zou, Yihan
Wang, Qurish Mohemmad, HyunGyung Jang, Emily Ye, Narayana Narasimhan,
Frank Wang, Juan Miret, Xiaotian Zhu, Tim Clackson, David Dalgarno, Willia
m C. Shakespeare and Victor M. Rivera
 Clinical Cancer Research volume22 issue 22, page 5527-5536(25th October
2016)

4. Main Goal
Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements
(ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase
(ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary
resistance mutations in ALK or disease progression in the brain.
Mutations that confer resistance to second-generation ALK TKIs ceritinib and
alectinib have also been identified.

5. Main in vivo Findings
Brigatinib is a highly potent and selective ALK
inhibitor. It works better than crizotinib and ceritinb and
alectinb in inhbiting ALK and ALK+. It is better at inhibiting
tumor growth in vivo mice model and brain tumor model

6. Materials
Brigatinib (AP26113) & Crizotinib
Karpas 299,H2228 or engineered
Ba/F3 cell
CB-17 SCID or SCID beige
female mice

7. In vivo tumor models
Institutional Animal Care and Use Committee (IACUC). Tumors were established by
subcutaneous injection of Karpas-299, H2228, or engineered Ba/F3 cells into the
right flank of about 8-week-old CB-17/SCID or SCID beige female mice (Charles
River Laboratory).
Subcutaneous injection of Karpas-299, H2228, or engineered Ba/F3 cells into the right
flank of about 8-week-old CB-17/SCID or SCID beige female mice (Charles River
Laboratory). When the average tumor volume reached about 200 mm3 (Karpas-299 and
Ba/F3 models) or 300 mm3 (H2228 model), mice were randomized to the various treatment
groups and administered vehicle or TKI once daily by oral gavage.

8. Result
Xenograft mouse models, with oral administration of brigatinib (10,25,or 50mg/kg once daily)
leading to a dose dependent inhibiton of tumor growth.
Xenografting tumor cells into mice has advanced
pre-clinical cancer research significantly

9. Result
In the Karpas-299 model, induced near complete tumor regression that
was maintained for at last 13 days after treatment.
A 100 mg/kg daily dose of crizotinib inhibited tumor growth (by
90%) and ALK signaling to a similar degree as 25mg/kg brigtinib.
H2228-derived tumors,possibly because of their slower growth rate, were even more
sensitive to ALK inhibition that karpas-299 derived tumors, with 10, 25, or 50 mg/kg
brigatinb inducing substantial tumor regression that was maintained for more than 28
days after treatment.

10. Figure

11. Figure: 2 C, efficacy of brigtanib and crizotinib in ALK+ tumor models in vivo, SCID beige
mice were implanted subcutaneously with either Karpas-299 (ALC) or H2228 (NSCLC) cells
and dosed orally with brigatanib (10,25,or 50 mg/kg) once daily) for 14 days (Karpas-299) or
21 days (H2228). Mean tumor volumes shown for each treatment group (n=10 mice/group).
Error base, SE

12. THANK YOU