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Sai-Hong Ignatius Ou
ES18 - Acquired Resistance to TKIs: The Rebiopsy Case and the Future Options (ID 21)
- Event: WCLC 2019
- Type: Educational Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
ES18.04 - New Strategies to Overcome Resistance in ALK Rearranged NSCLC (Now Available) (ID 3255)
11:00 - 12:30 | Presenting Author(s): Sai-Hong Ignatius Ou
Since the discovery of ALK+ NSCLC in 2007, there are now 6 ALK TKI have been approved or in clinical development. These 6 ALK TKI can be generally divided into 3 generations. First-generaion (Crizotinib). Second Generaion (Alectinib, Ceritinib, Brigatinib, Ensartinib). THrid-generation (Lorlatinib). The advantages of the second-generation ALK TKI or beyond is better potentcy an excellent improved CNS penetration. The mode of progression in ALK+ NSCLC are 4 fold and can be single or combination according to individaul patients: developed of acquired second site ALK mutations, CNS progression, bypass activation, and histological transformation.
For second site ALK mutations, sequencing ALK TKIs that will overcome the particular second site mutation(s) or proceed to the most potent ALK TKI is likley be successful.
For CNS progression, lorlatinib has demonstrated CNS activity in CNS progression from second generation ALK TKIs (ceritinib, alectinib). Additionally the use of stereotactic radiation (SRS) or whole brian radiation can contral CNS progression but clinicians should look out for radiation necrosis.
For second bypass activation such as (i.e. RAS, SRC, EGFR, Kit) in vritro pre-clinical modles of combining specific bypass inhibitor and ALK TKI were albe to inhibit growth of these resistance cell lines or patient dervied PDX model, clinical trials are on-going but to date clinical data are lacking. Additional the use of chemotherapy especailyl pemetrexed-based chemotherapy in addition to ALK TKI has showen to be more efficacious than just switching to chemotherapy while discontinuing ALK TKI
For histologic transformation most commonly small cell transformation, the switching to small cell regimen is only viable option at this point. The addition to immunotherapy to chemotherapy (e.g. IMpower133 regimen) or IO + IO combination (e.g. chckmate-032) should be explored in small cell tranformation as mode of progression in ALK+ NSCLC.