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Page 4 of 9 Malapelle et al. J Transl Genet Genom 2019;3:3. I https://doi.org/10.20517/jtgg.2018.29

ALK + NSCLC TREATMENT: ALK TKI
Being able to incorporate genomic information into the diagnostic and clinical pathways, shaping
personalized precision cancer therapies, has been one of the biggest shift in modern day oncology, and ALK
+ NSCLC treatment is a perfect example. In fact, according to the most recent American Society of Clinical
Oncology and the European Society for Medical Oncology guidelines, ALK-TKIs presently represent the
standard of care in the treatment of this subgroup of patients, granting results far beyond chemotherapy;
more specifically, three ALK-TKIs (alectinib, ceritinib and crizotinib) are FDA and European Medicines
Agency approved for the clinical practice, while another TKI (brigatinib) is only FDA-approved for the
clinical practice [19-21] . Furthermore, all of the ALK-TKIs share the same mechanism of action: specifically and
competitively binding the ATP binding pocket they manage to block phosphorylation, thus inhibiting TKI
[22]
signal transduction pathways and ultimately cell survival and proliferation .
However, when compared to first-generation ALK-TKIs (crizotinib), second generation ones (ceritinib,
alectinib and brigatinib) manage to grant superior clinical performances thanks to the improved chemical
structure, specifically designed in order to be more selective and potent (and thus associated with lower
IC50) and to be able to easily cross the blood-brain barrier, due to the high rates of brain metastases in ALK
+ NSCLCs [23,24] .

First-line ALK-TKI
Crizotinib
Crizotinib was the first FDA-approved ALK-TKI, receiving accelerated approval in 2011 and regular approval
in 2013 for ALK + NSCLC affected patients, based on the findings from the A8081007 study, a randomized
(1:1) trial in which 347 ALK + NSCLC affected patients that had already received a previous platinum-
based treatment were randomized to receive either crizotinib or standard of care chemotherapy (docetaxel/
pemetrexed). Results favored crizotinib over chemotherapy: progression free survival (PFS): 7.7 months vs.
[25]
3.0 months, respectively, plus a 46% absolute increase in objective response rate (ORR) .

These promising results were then confirmed in a first line setting by the PROFILE 1,014 study, in
which 343 naive ALK + NSCLC affected patients were randomized to receive crizotinib or standard of
care chemotherapy (cisplatin/carboplatin + pemetrexed). In fact, results were completely in favor of the
crizotinib arm: PFS: 10.9 months (crizotinib) vs. 7.0 months (chemotherapy), ORR: 64% (crizotinib) vs.
45% (chemotherapy), OS: not reached (NR) (crizotinib) (95% CI, 45.8 months to NR) vs. 47.5 months
(chemotherapy), survival probability at 4 years: 56.6% (crizotinib) vs. 49.1% (chemotherapy) [26,27] .

Ceritinib
Ceritinib was the second ALK-TKI to receive FDA approval for the treatment of naive ALK + NSCLC
patients in 2017, thanks to the results coming from the ASCEND 4 study, a phase III trial randomizing
376 patients (1:1) to receive first line ceritinib or standard of care chemotherapy (cisplatin/carboplatin +
pemetrexed). The ceritinib regimen performed significantly better than the platinum-based one according
to every endpoint: PFS: 16.6 months (ceritinib) vs. 8.1 months (chemotherapy), ORR: 73% (ceritinib) vs.
27% (chemotherapy); moreover, unlike crizotinib, ceritinib performed greatly also with respect to central
nervous system (CNS) lesions, with an overall intracranial response rate of 57% vs. 22% (chemotherapy), and
[28]
a median CNS response duration of 16.6 months .
Alectinib
Alectinib was the third FDA-approved ALK-TKI (2017) for the treatment of naive NSCLC harboring ALK
rearrangements in the first line setting and is currently considered the best upfront treatment available, due
to the findings coming from the ALEX trial.