Intracranial Efficacy of Crizotinib for Patients with ALK-Positive Lung Cancer

Summary and Comment |
April 11, 2016

Intracranial Efficacy of Crizotinib for Patients with ALK-Positive Lung Cancer

  1. Anne S. Tsao, MD

Intracranial disease control was better with crizotinib than with chemotherapy.

  1. Anne S. Tsao, MD

Up to half of patients with ALK-rearranged non–small-cell lung cancer (NSCLC) will develop brain metastases within 2 years of diagnosis. To evaluate the use of crizotinib in this setting, investigators conducted an industry-supported, single-arm, phase III trial (PROFILE 1014), in which 343 ALK-rearranged NSCLC patients received frontline treatment with oral crizotinib or intravenous platinum-pemetrexed chemotherapy. Patients with stable treated brain metastases were eligible. Intracranial efficacy was assessed with brain imaging every 6 weeks in the 23% of patients with stable treated brain metastases at baseline or every 12 weeks in those without known brain metastases.

Results were as follows:

  • A trend toward improvement in intracranial time to progression was seen with crizotinib versus chemotherapy in the intent-to-treat (ITT) population (hazard ratio, 0.60; P=0.069), in those with treated brain metastases at baseline (HR, 0.45; P=0.063).

  • Patients with treated brain metastases at baseline had improved intracranial disease control with crizotinib versus chemotherapy at 12 weeks (85% vs. 45%; P<0.001) and at 24 weeks (56% vs. 25%; P=0.006).

  • Rates of intracranial disease progression were 27% in patients with treated brain metastases at baseline and 11% in those without treated brain metastases at baseline.

  • Extracranial disease was more common than intracranial disease, and it occurred more often in patients receiving chemotherapy than in those receiving crizotinib.

  • Disease progression solely in the brain was more common with crizotinib than with chemotherapy in the ITT population (24% vs. 10%), in those with treated brain metastases at baseline (38% vs. 23%), and in those without brain metastases at baseline (19% vs. 6%).

Comment

This study supports the use of crizotinib over chemotherapy as a frontline agent in patients with ALK-rearranged NSCLC. However, crizotinib is not known to have substantial penetrance into the central nervous system. Therefore, the treatment paradigm may shift again following frontline trials of other ALK-targeted therapies with better blood–brain barrier penetrance, such as ceritinib, alectinib, brigatinib, and lorlatinib. These newer-generation agents are already shifting the clinical paradigm in the salvage setting by potentially deferring brain radiation, thus sparing patients cognitive compromise. It remains to be seen whether frontline use of the newer-generation ALK inhibitors will be superior to crizotinib in preventing or delaying the occurrence of brain metastases.

Editor Disclosures at Time of Publication

  • Disclosures for Anne S. Tsao, MD at time of publication Consultant / Advisory board Genentech; Boehringer Ingelheim; ARIAD Pharmaceuticals, Inc. Speaker’s bureau Genentech; Roche; Medimmune; Novartis; Astellas; Boehringer Ingelheim; Eli Lilly Grant / Research support Department of Defense; SWOG; Merck & Co.; Medimmune; NIH/National Cancer Institute; Radiation Therapy Oncology Group; Hope Foundation; Eli Lilly and Company; Millennium; American Cancer Society; Genentech Leadership positions in professional societies American Medical Association (Member); American Association for Cancer Research (Member); AACR–Women in Cancer Research (Member); American Society of Clinical Oncology (Member); International Mesothelioma Interest Group (Member); SWOG (Member); International Association for the Study of Lung Cancer (Communications Committee Chair); American Radium Society (Chair); Radiation Therapy Oncology Group (Member); Mesothelioma Applied Research Foundation (Member); National Cancer Institute–Thoracic Malignancy Steering Committee (Member)

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