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First-line Alectinib for ALK+ NSCLC
Alectinib: A New Standard of Care for Newly Diagnosed Advanced ALK-Positive NSCLC

Released: July 07, 2017

Expiration: July 06, 2018

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Crizotinib, a first-generation ALK inhibitor, has been the standard of care for patients with newly diagnosed advanced ALK-positive NSCLC. Crizotinib can be very effective in this setting, achieving an ORR of 74% and a median PFS of 10.9 months vs 45% and 7.0 months with platinum/pemetrexed chemotherapy in the first-line PROFILE 1014 trial (P < .001 for both). However, patients invariably relapse on crizotinib, often with brain metastases, highlighting a need for a more effective strategy in the first-line setting.

Alectinib, a second-generation ALK inhibitor, is currently approved for patients with ALK-positive NSCLC who have failed crizotinib based on phase II study results that showed an ORR of approximately 50% and median PFS of 8-9 months with second-line alectinib. Alectinib is known to be more potent than crizotinib and to inhibit many crizotinib-resistant mutations in vitro, as well as to have very potent CNS activity. In a pooled analysis of 2 phase II studies, alectinib achieved a CNS response rate of 64% and a median duration of response of 10.8 months in patients with crizotinib-resistant ALK-positive NSCLC.

Primary results of the global phase III ALEX study presented at ASCO in June 2017 comparing alectinib with crizotinib in the first-line setting have now established alectinib as a new standard of care for newly diagnosed ALK-positive NSCLC, in part due to its effectiveness in treating and preventing brain metastases.

ALEX: Alectinib vs Crizotinib in Newly Diagnosed ALK-Positive NSCLC
The ALEX study randomized 303 patients with newly diagnosed advanced, ALK-positive NSCLC to alectinib (n = 152) or crizotinib (n = 151). Patients with asymptomatic treated or untreated brain metastases were included in this study—approximately 40% of patients in each arm had CNS metastases at baseline, reflecting how common it is for ALK-positive patients to have brain metastases. Furthermore, approximately 60% of these patients had received no previous treatment for their CNS disease. The primary endpoint was PFS based on investigator review. Secondary endpoints included PFS by independent review committee, time to CNS progression by independent review committee, and safety/tolerability. The median duration of follow-up was approximately 18 months in each arm.

ALEX: Improved PFS, CNS Activity, and Safety With Alectinib vs Crizotinib
The results of the ALEX study were strongly positive, showing a median PFS with alectinib more than double that of crizotinib in newly diagnosed ALK-positive NSCLC. The primary endpoint of PFS by investigator review was not reached with alectinib vs 11.1 months with crizotinib (HR for progression: 0.47; 95% CI: 0.34-0.65; P < .0001) (Figure). Similarly, the secondary endpoint of PFS by independent review was 25.7 months with alectinib vs 10.4 months with crizotinib (HR: 0.50; 95% CI: 0.36-0.70; P < .0001). Furthermore, all patient subgroups analyzed, including patients with or without brain metastases at baseline, derived greater benefit from alectinib vs crizotinib.

Figure. Investigator-assessed PFS (primary endpoint).

Alectinib was also shown to be more effective in both the prevention and treatment of CNS disease vs crizotinib. In a competing risk analysis of time to CNS progression, non-CNS progression, and death in the intent-to-treat population, alectinib significantly delayed time to CNS progression vs crizotinib, with an 84% reduction in the risk of having CNS progression as the first event for those patients treated with alectinib compared with crizotinib (P < .0001). Furthermore, alectinib significantly improved CNS response rates and duration of response. Because brain metastases can be very challenging to treat and can have such a negative impact on patient quality of life, the CNS results with alectinib are extremely important for our patients.

Although both drugs were well tolerated overall, alectinib resulted in fewer grade 3-5 AEs and fewer AEs leading to treatment discontinuation, dose reduction, or dose interruption vs crizotinib. The safety profiles for each drug were as expected, including a higher incidence of peripheral edema, dysgeusia, transaminase increases, and gastrointestinal AEs with crizotinib and a higher incidence of myalgia, anemia, bilirubin increases, and weight gain with alectinib. Overall, the ALEX study results are consistent with the previously reported J-ALEX study, a similar, but smaller study comparing alectinib vs crizotinib in a Japanese patient population (N = 207). The results of J-ALEX were also strongly positive, showing a median PFS of not reached with alectinib vs 10.2 months with crizotinib (HR: 0.34; 99.6826% CI: 0.17-0.71; P < .0001) and a favorable safety profile for alectinib.

Sequencing of ALK Inhibitors
Although the magnitude of the PFS improvement with first-line alectinib shown in the ALEX study suggests that patients may benefit from receiving alectinib as initial therapy vs receiving sequential crizotinib followed by alectinib, there currently are no data to inform whether to switch patients who are now receiving first-line crizotinib to alectinib. In my own practice, I would not necessarily switch patients who have been receiving crizotinib for a prolonged period of time (ie, several years) and are tolerating the drug well. These patients have already exceeded the median PFS that we normally see with first-line crizotinib and may continue to do well on crizotinib for some time. However, I would closely monitor the CNS with surveillance brain MRIs every 3-6 months or more frequently in patients with any symptoms. For patients who were just recently started on first-line crizotinib, I would have a conversation about switching to alectinib given the positive results of ALEX and J-ALEX. Of course, for any patients struggling with AEs due to crizotinib, I would immediately switch them to alectinib.

Management of Patients Who Progress on Alectinib
At this time, the mechanisms underlying acquired resistance to first-line alectinib are unclear. In the setting of crizotinib failure followed by alectinib failure, alectinib resistance has been shown to be caused by acquisition of new secondary resistance mutations in ALK in approximately one half of the patients. In many cases, the new resistance mutation can be overcome by another ALK inhibitor, particularly the third-generation ALK inhibitor lorlatinib, which recently received FDA breakthrough therapy designation for previously treated patients and is currently available through an expanded access program. Combination strategies are also being evaluated for overcoming resistance to ALK inhibitors, including resistance to alectinib. Therefore, rebiopsy of a patient who is relapsing on alectinib to assess resistance mechanism will be critical to choose the most effective next therapy. Furthermore, based on several case reports in the literature, ALK-positive tumors in patients relapsing on alectinib can also undergo histologic transformation from NSCLC to small-cell lung cancer, which is another reason to perform a repeat biopsy. Demonstration of a change in histology to small-cell lung cancer would dictate a switch to appropriate chemotherapy for this malignancy.

Please share your thoughts or questions on the care of patients with advanced ALK-positive NSCLC in the comment box below.

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Which of the following treatment options do you currently recommend for your patients with newly diagnosed ALK-positive NSCLC with both lung and bone metastases but no brain metastases?
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