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Second-line Tx in NSCLC
How I Choose Second-line Treatment After Crizotinib Failure in Advanced NSCLC

Released: June 20, 2016

Expiration: June 19, 2017

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For patients with non-small-cell lung cancer (NSCLC), initial diagnosis should include an assessment for ALK translocations, which result in an oncogenic ALK fusion protein. In May 2016, the current standard first-line therapy for ALK-positive NSCLC is the ALK tyrosine kinase inhibitor (TKI) crizotinib. In the phase III PROFILE 1014 study, the median PFS with crizotinib was approximately 11 months, less than a year. Thus, a key question is how to best manage patients with NSCLC and an ALK translocation who progress on first-line crizotinib.

Defining Resistance
First, how should we define drug resistance to crizotinib? Drug resistance is typically defined by RECIST criteria. However, this is not always clinically applicable because for patients receiving a TKI such as crizotinib, the tumor can shrink to 1 or 2 cm, making it challenging to measure an increase by 30% that defines progression by RECIST criteria. As a result, some patients are treated with crizotinib beyond disease progression. In an analysis of 2 single-arm studies of crizotinib in advanced ALK-positive NSCLC, patients who were treated beyond progression appeared to have longer survival (caveat: retrospective study). Of importance, disease progression varies based on symptomatic vs asymptomatic, rapid vs slow progression, and CNS metastases vs no CNS metastases.

Finding the Cause of Resistance
Causes for resistance to crizotinib include the emergence of KRAS and EGFR mutations, as well as so-called gatekeeper mutations at sites on the ALK kinase such as L1196M or G1269A, and a more-resistant mutation at G1202R. Obtaining a biopsy upon progression to determine which mutation is the cause of the resistance helps guide subsequent treatment decisions. For patients who cannot have a second biopsy, next‑generation sequencing of plasma DNA may provide insight.

Second-Generation, Second-line ALK Inhibitors
Once progression on crizotinib beyond RECIST criteria occurs and a gatekeeper mutation is identified, a second-generation TKI against ALK can be selected. The most important new second-generation TKIs for progressive ALK-positive NSCLC are ceritinib, alectinib, and brigatinib. Other TKIs in earlier development for this population include ensartinib and CEP-37440.

Ceritinib
Ceritinib was FDA approved in 2014 for ALK-positive, metastatic NSCLC with progression on or intolerance to crizotinib and effectively inhibits ALK harboring L1196M, G1269A, and other mutations. The approval was based on the single-arm ASCEND-1 study (N = 255), which included 163 patients with previous exposure to crizotinib. In this population, the response rate was 56%. The efficacy of ceritinib in this setting was further supported by the phase II ASCEND-2 study (N = 140), in which the response rate was 39% and the median PFS was 7.2 months. These data show reasonable efficacy. However, there was some selective toxicity of note: In both studies, there was a moderate increase in gastrointestinal toxicity, including nausea and vomiting (grade 3/4 in approximately 5% of patients), and diarrhea.

Alectinib
Alectinib was approved in 2015 by the FDA for ALK-positive NSCLC after progression on crizotinib and is also available in Japan. Alectinib inhibits most ALK resistance mutations. Approval was based on a phase II study by Ou and colleagues in which the response rate was 48% and the median PFS was 8.1 months. The phase III J-ALEX study (N = 207), which is comparing alectinib with crizotinib as a first-line treatment in ALK-positive NSCLC, was recently reported at the ASCO annual meeting. This study reported a 66% decrease in risk of disease progression or death with alectinib compared with crizotinib in this disease setting. Median PFS was not reached and 10.2 months (P < .0001), respectively.

Brigatinib
Brigatinib is an investigational TKI with activity against the ALK fusion protein, specifically including the G1202R crizotinib resistance mutation, among others. In the recent phase II ALTA study of second-line brigatinib in advanced ALK-positive NSCLC with progression on crizotinib (N = 222), the response rate was 45% with 90 mg once daily and 54% for those who received 180 mg starting on Day 8. Median PFS was 9.2 and 12.9 months, respectively. Of importance, the phase III ALTA-1L trial is comparing first-line brigatinib vs crizotinib in patients with ALK-positive advanced NSCLC (planned N = 270).

CNS Penetration
All 3 of these second-generation ALK inhibitors have improved CNS penetration and response compared with crizotinib, which has poor CNS penetration. The intracranial response rate to ceritinib was 36% vs 57% for alectinib in patients with CNS-measurable disease at baseline and 67% for brigatinib, although it is important to note that the patient numbers in all cases were small.

Toxicity
Regarding toxicity concerns with these different ALK-targeted TKIs, the gastrointestinal effects of ceritinib are controllable by reducing the dose, administering an antiemetic, and suggesting the medicine be taken with food. Alectinib has less gastrointestinal toxicity, although it does confer a small risk of hepatic toxicity that clinicians should be aware of. Overall, it appears to be more manageable than ceritinib. The most common treatment-related adverse events associated with brigatinib are nausea, diarrhea, fatigue, cough, and headache.

Conclusions
Overall, there’s no doubt that second-generation TKIs are effective following crizotinib in ALK-positive NSCLC, with high response rates and relatively long PFS. Following failure of first-line crizotinib, it is important to determine which resistance mutation is responsible, whether by biopsy or identifying a gatekeeper mutation via next-generation sequencing of plasma DNA. Then, an appropriate second-generation TKI can be selected which, hopefully, will optimize the duration of control of both systemic and CNS metastases.

However, which drug to use depends not only on resistance mutations but also on availability. Alectinib was recently approved in the United States, but elsewhere (eg, Asia), access is limited to clinical trials, and ceritinib would be the primary option. Brigatinib is promising but not yet approved.

Have you used any of these new agents in your clinical practice? Let me know in the comments how they have benefited your patients.

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