A New Standard in Non-Small Cell Lung Cancer? Alectinib vs. Crizotinib

Bhargav Patel, Mercer University College of Pharmacy

Non-small cell lung cancer (NSCLC) is characterized by symptoms such as hoarseness, weight loss, loss of appetite, shortness of breath, and a prolonged cough. It may account for up to 85% of all lung cancer cases and is thought to be insensitive to treatment with chemotherapy. [1] Several treatment options, such as surgery, radiation therapy, and chemotherapy, are available. Crizotinib acts to inhibit anaplastic lymphoma kinase (ALK) and is the standard of therapy to manage ALK-positive disease. Alectinib attempts to block ALK tyrosine kinase and could be a new treatment option due to its possible activity against the ALK mutations that confer resistance against crizotinib. [2]

Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer [3]
Design Phase 3, multicenter, open-label, randomized, head-to-head; N= 303
Objective To compare the efficacy of alectinib and crizotinib
Study Groups Alectinib (n= 152); crizotinib (n= 151)
Methods Patients with confirmed ALK-positive NSCLC, who were 18 years or order with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (on a 5-point scale, with higher numbers reflecting greater disability), and no previous systemic treatment for advanced NSCLC were included.

Patients either received oral alectinib 600 mg two times a day with food or crizotinib 250 mg two times a day. They underwent tumor imaging at baseline, including scans of the brain. Subsequent tumor evaluation, including systematic brain imaging in all patients, was performed every 8 weeks until disease progression. Treatment was continued until disease progression, unacceptable toxic effects, withdrawal of consent, or death.

Duration 30 months (recruitment, treatment and follow-up)
Primary Outcome Measure Progression-free survival time and rate
Secondary Outcome Measure Response rate, survival rate, central nervous system (CNS) complete response, and duration of CNS response
Baseline Characteristics
Alectinib Crizotinib
Mean age, years (SD) 56.3 (12) 53.8 (13.5)
Male, % 45 42
ECOG performance status, %
  0 or 1 93 93
  2 7 7
Current stage of disease, %
  3B 3 4
  4 97 96
CNS metastases, % 42 38
Results
Alectinib Crizotinib Hazard ratio p value
12 month progression-free survival rate, % (95% CI) 68.4 (61-75.9) 48.7 (40.4-56.9) 0.47 (0.34-0.65) <0.001
Progression free survival, months (95% CI) 25.7 (19.9-not estimable) 10.4 (7.7-14.6) 0.5 (0.36-0.7) <0.001
Intention-to-treat population
Response rate, % (95% CI) 82.9 (76-88.5) 75.5 (67.8-82.1) 0.09
12 month survival rate, % (95% CI) 84.3 (78.4-90.2) 82.5 (76.1-88.9) 0.76 (0.48-1.2)
CNS response rate, % 81 (58-95) 50 (28-72)
CNS complete response, % 38 5
Median duration of CNS response, months (95% CI) 17.3 (14.8-not estimable) 5.5 (2.1-17.3)
Adverse Events Common Adverse Events (alectinib vs. crizotinib): nausea (14% vs. 48%), vomiting (7% vs. 38%), diarrhea (12% vs. 45%), photosensitivity reaction (5% vs. 0%)
Serious Adverse Events (alectinib vs. crizotinib): anemia (20% vs. 5%) and myalgia (16% vs. 2%)
Percentage that Discontinued due to Adverse Events (alectinib vs. crizotinib): 11% vs. 13%
Study Author Conclusions Alectinib improved progression free survival in a statistically significant manner versus crizotinib in patients with ALK-positive NSCLC.

Alectinib had greater CNS penetration and improvement over crizotinib, which may lead to its establishment as the new standard of therapy in ALK-positive NSCLC, especially for patients affected by CNS metastases. The small sample size might be a limiting factor but it has set the groundwork for future trials. Adding an extra layer of patient diversity through a global study design makes the clinical impact more relevant. Alectinib’s long term impact on practice remains uncertain due to high rates of ALK gene mutations, but the question of what to do after crizotinib’s efficacy wanes is closer to being addressed.

References:

[1] About Non-Small Cell Lung Cancer. American Cancer Society. 2017. Accessed at June 15, 2017. https://www.cancer.org/cancer/non-small-cell-lung-cancer.html.

[2] Toyokawa G, Seto T. ALK inhibitors: what is the best way to treat patients with ALK+ non-small-cell lung cancer?. Clin Lung Cancer. 2014;15(5):313-9.

[3] Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017.

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