Treatment landscape of advanced ALK-positive NSCLC

ALK-positive non-small cell lung cancer (NSCLC) consists of 3-5% of patients with NSCLC. ALK tyrosine kinase inhibitor (ALK-TKI) therapy is the standard of care for advanced ALK-positive NSCLC. As of November 2021, there are 5 ALK-TKIs therapy approved by the United States Food and Drug Administration (FDA).

Crizotinib was first approved in 2011 based on two single-arm trials demonstrating objective response rates ranging 50-61% and median durations of response of 42-48 weeks². Crizotinib was compared with platinum-doublet chemotherapy in patients with untreated advanced ALK-positive NSCLC in PROFILE 1014 where progression-free survival and objective response rate were significantly improved with crizotinib³. Progression in the central nervous system (CNS) is common with crizotinib, limiting its efficacy⁴. Next-generation ALK-TKIs were approved subsequently, further improving treatment outcomes in ALK-positive NSCLC.

Ceritinib is a second-generation ALK-TKI that has shown to improve progression-free survival (PFS), compared with chemotherapy, in both the first-line and second-line settings^5,6. One of the notable side effects of ceritinib was gastrointestinal toxicity such as nausea, vomiting, and diarrhea. Ceritinib 450 mg once daily taken with food is associated with a more favorable GI safety profile than the original dosage, 750 mg once daily fasted⁷.

Alectinib is another second-generation ALK-TKI that showed significantly prolonged PFS and lower toxicity compared with crizotinib in treatment-naive ALK-positive NSCLC⁸. While overall survival (OS) data remain immature, the 5-year OS rate was 62.5% with alectinib and 57.4% with crizotinib with median OS not reached in the alectinib group vs. 57.4 months with crizotinib⁹. Time to CNS progression was significantly improved with alectinib versus crizotinib and the CNS objective response rate (ORR) with alectinib was 78.6% versus 40.0% with crizotinib in those who had not received brain radiotherapy¹⁰. Similar to alectinib, brigatinib, a second-generation ALK-TKI, significantly improved PFS compared with crizotinib¹¹.

Brigatinib was associated with an intracranial ORR of 78% vs. 29% with crizotinib. Of note, early-onset pulmonary events (interstitial lung disease and pneumonitis) were rarely observed with brigatinib, but not with crizotinib. Management strategies for early-onset pulmonary events associated with brigatinib has been published elsewhere¹².

Lastly, lorlatinib is a third-generation ALK-TKI that is approved for both first- and second-line use. In untreated ALK-positive NSCLC, patients who received lorlatinib had significantly longer PFS and a higher frequency of intracranial ORR than those who received crizotinib¹³. Lorlatinib has shown activity against major ALK resistance mutations including G1202R that can mediate resistance to second-line ALK-TKIs¹⁴ and is a viable option for patients whose disease progressed on other ALK-TKI. Of note, the presence of ALK resistance mutations may serve as biomarkers of lorlatinib response and therefore, tumor- or plasma-based genotyping for ALK mutations could be useful to identify those who are more likely to derive benefit from lorlatinib¹⁵.

When ALK-TKI based treatment options are no longer available, pemetrexed-based chemotherapy could be used as the next-line of treatment in the absence of clinical trial options¹⁶. Anti-PD-1/PD-L1 antibody monotherapy has a limited role due to the low ORRs in ALK-positive NSCLC¹⁷.

Table 1 shows the First-line treatment options for metastatic ALK fusion positive NSCLC