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.