ALK Translocations
Nearly 5% of NSCLC patients are found to have overexpression of ALK
protein caused by translocations of ALK. The first target drug that was
associated with improved ORR and median PFS in these patients was
crizotinib, which is an inhibitor of dual receptor tyrosine kinases
including ALK and MET. In two randomized phase III trials involving
patients with NSCLC and ALK alterations, crizotinib had superior
efficacy as compared with chemotherapy in previously treated patients
(median PFS, 7.7 vs. 3.0 months) [50], as well as in previously
untreated patients in the PROFILE 1014 trial (median PFS, 10.9 vs. 7.0
months) [51]. ALK-TKIs became the standard of care as initial
therapy based on the above phase III trials. This also highlighted the
importance of doing next generation sequencing in all patients at the
time of diagnosis of metastatic NSCLC. In the four-year follow up of the
final OS analysis of PROFILE 1014 trial in 2018, median OS for
crizotinibwas NR (95% CI, 45.8 months - NR) versus 47.5 months with
chemotherapy (95% CI, 32.2-NR) [52] showing superior efficacy of
crizotinib over chemotherapy.
Soon it became evident that patients with ALK translocations treated
with crizotinib became resistant to the treatment and further analysis
showed several complex escape mechanisms and secondary mutations as
mechanisms of resistance [53]. This led to clinical trials with
newer second generation ALK-TKIs (alectinib, ceritinib and brigatinib)
that were more potent and effective in overcoming resistance to
crizotinib as evidenced by radiographic responses among patients with
ALK mutations who progressed on crizotinib[54-56].Response rates of
38%-56% have been reported with a median PFS of 5.7-8.0 months when
second-generation ALK tyrosine kinase inhibitors such as ceritinib or
alectinib were given to patients with ALK translocations after the
failure of crizotinib therapy. Furthermore, these drugs show efficacy in
patients with brain metastases (brain response rate, 33-57%), which is
of clinical importance for this group of patients.
In untreated patients with ALK alterations, ceritinib proved superior to
chemotherapy in the ASCEND-4 trial (median PFS, 16.6 vs. 8.1 months; HR
for progression or death, 0.55; 95% CI, 0.42-0.73; p<0.001)
[57]. Alectinibwas superior to crizotinib in the Japanese J-ALEX
trial (PFSNR vs. 10.2 months; HR for progression or death, 0.34; 95%
CI, 0.17-0.70; p<0.001) [58] and in the ALEX trial (PFSNR
vs. 11.1 months; HR for progression or death, 0.47; 95% CI, 0.34-0.65;
p<0.001) [59]. Another randomized study showed increased
ORR and median PFS for alectinib compared to crizotinib in patients with
previously untreated ALK-positive NSCLC, establishing alectinib as a
first-line treatment option. Significantly higher median PFS was
reported with alectinib compared to crizotinib (34.8 months versus 10.9
months, respectively) in an updated data on the ALEX trialin 2019
[60]. Alectinibwas found to have much better toxicity profile
compared tocrizotinibdespite longer treatment duration with
alectinib[60].In ALTA-1L study brigatinibshowed improved efficacy
compared tocrizotinib (N = 275; 12-month Kaplan-Meier PFS rate, 67%
versus 43%; P < .001), with fewer episodes of
progressive disease in the CNS [61]. Updated data after more than 2
years of follow-up fromALTA-1L showed that the risk of disease
progression or death was reduced by brigatinib by 76% (HR, 0.24; 95%
CI, 0.12–0.45), in newly diagnosed patients who had CNS involvement at
the time of enrollment. Brigatinibwas also associated with 57%
reduction in the risk of disease progression or death in all patients
[61].Alectinib was FDA approved on Nov 6, 2017 and brigatinibon May
22, as initial therapy for patients with ALK-positive NSCLC.
The emergence of drug resistance was unfortunately seen with second
generation TKIs, alectinib and brigatinib as well despite a prolonged
median disease-free period of 2 years. This led to further trials
looking into third generation ALK inhibitor, loratinib for treatment of
ALK-positive NSCLC patients who had progressed on two prior ALK-TKI.
Loratinib finally got FDA approval on 2nd November 2018 for second- or
third-line treatment of ALK-positive metastatic NSCLC based on a
multiple-cohort phase 2 trial.[62]
This has led to median survival of nearly 5 years among patients with
ALK-positive NSCLC treated with crizotinib followed by a second or third
generation TKI.