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Malapelle et al. J Transl Genet Genom 2019;3:3. I https://doi.org/10.20517/jtgg.2018.29 Page 5 of 9

In this phase III trial, 303 naive ALK + NSCLC patients were randomized (1:1) to receive upfront alectinib
or crizotinib and the alectinib arm achieved consistently better results: ORR: 82.9% (alectinib) vs. 75.5%
(crizotinib), duration of response (DOR): 33.3 months (alectinib) vs. 11.1 months (crizotinib), PFS: 34.8
[29]
months (alectinib) vs. 10.9 months (crizotinib) .
Second-line ALK-TKI
To date, ceritinib, alectinib and brigatinib are FDA-approved for the second-line treatment of ALK + NSCLC
patients, after intolerance to or failure of a first line crizotinib treatment.

Ceritinib
In 2014, ceritinib was the first ALK-TKI to be granted FDA approval for the treatment of ALK + NSCLC
patients who had progressed on or were intolerant to crizotinib treatment, thanks to a single-arm trial (163
[30]
patients) that showed an ORR of 44% and a DOR of 7.1 months .
Alectinib
In 2015, alectinib was granted FDA-approval for the treatment of ALK + NSCLC patients, after intolerance
to or failure of a first line crizotinib treatment, based on the findings from two different single-arm trials,
that respectively showed an ORR of 38% and 44%, a DOR of 7.5 months and 11.2 months, alongside with a
[31]
CNS ORR of 61% and a CNS DOR of 9.1 months .
Brigatinib
In 2017, brigatinib was granted FDA approval for the treatment of ALK + NSCLC patients who had
progressed on or were intolerant to crizotinib treatment, based on the results from the ALTA trial, a
randomized phase II trial, evaluating two regimens of brigatinib 90 mg vs. 180 mg.

Two hundred and twenty-two patients were randomized (1:1) and the results showed: ORR: 48% vs. 53%,
CNS ORR: 42% vs. 63%, respectively, plus a DOR of 13.8 months and a CNS DOR of 5.6 months (180 mg
[32]
regimen) .

ACQUIRED RESISTANCE
Regarding ALK-TKI treatment, the main hurdle to overcome is represented by the cancer cells acquired
mechanisms of resistance to therapy, that ultimately lead to the progression of disease; even though these
mechanisms can consistently vary according to the administered ALK-TKI, clinical and pre-clinical models
indicate that resistance can develop through 3 main mechanisms: activation of other oncogenic signals that
allow the tumor to bypass the ALK signaling pathway, TKIs pharmacokinetic liabilities or secondary mutations
that affect the kinase domain of ALK; nevertheless, secondary resistance mutations appear to be the major
resistance mechanisms adopted by cancer cells and most importantly the only presently targetable one [33,34] .

Secondary resistance mutations
Considering one of the largest and most extensive systematic analysis addressing ALK inhibitors resistance
[33]
published by Gainor et al. in 2016, assessing 83 repeat biopsies - from as many ALK-positive patients -
performed from 2009 to 2016 following disease progression on first (crizotinib) and/or second (ceritinib,
alectinib, brigatinib) generation ALK-TKIs (n = 51 patients received crizotinib, n = 24 patients received
ceritinib, n = 17 patients received alectinib and n = 6 patients received brigatinib), ALK secondary resistance
mutations were observed in just 20% of ALK + NSCLC affected patients progressing on crizotinib. On the
other hand, the same mutations were detected in 56% of ALK-rearranged patients progressing on a second-
generation ALK inhibitor (54% of patients progressing on ceritinib; 53% of patients progressing on alectinib
[33]
and 71% of patients progressing on brigatinib). G1202R mutation was the most frequent one .