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Crizotinib Produces Systemic and Intracranial Disease Control in Patients With Advanced ALK-Rearranged NSCLC and Brain Metastases

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Key Points

  • Crizotinib was associated with high rates of systemic and intracranial disease control in patients with asymptomatic brain metastases at baseline.
  • The central nervous system was the most common site of progression due to nontarget or new lesions in both patients with previous treatment and those with no previous treatment for brain metastases, and brain metastases accounted for 20% of progression in those without metastases at baseline.

In a retrospective analysis reported in the Journal of Clinical Oncology, Costa et al found that crizotinib (Xalkori) treatment resulted in high systemic and intracranial disease control rates in patients with ALK-rearranged non–small cell lung cancer (NSCLC) who had asymptomatic brain metastases at the start of treatment.

Study Details

The study involved data from ALK inhibitor–naive patients receiving crizotinib in the phase II PROFILE 1005 trial and phase III PROFILE 1007 trial. At baseline, 275 (31%) of 888 patients in the pooled population had asymptomatic brain metastases; of these, 109 had received no prior treatment for brain metastases, and 166 had received brain radiotherapy.

Patients With Previously Untreated Metastases

Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate at 12 weeks was 63% (95% confidence interval [CI] = 54%–72%), the intracranial disease control rate was 56% (95% CI = 46%–66%), median intracranial time to progression was 7 months (95% CI = 6.7–16.4 months), and median systemic time to progression was 12.5 months (95% CI = 7.0–14.0 months). Progression during crizotinib treatment occurred in 43% of patients (47 of 109) in this group at the time of data cutoff.

Median progression-free survival overall was 5.9 months (95% CI = 4.2–6.9 months) and for systemic progression was 8.3 months (95% CI = 6.7-14.0 months). Of 43 patients with nontarget or new lesions as progressive disease, the central nervous system (CNS) was the site of progression in 30 (70%).

Previously Treated Metastases

Among patients with previously treated brain metastases, the systemic disease control rate was 65% (95% CI = 57%–72%), the intracranial control rate was 62% (95% CI = 54%–70%), median intracranial time to progression was 13.2 months (95% CI = 9.9 months to not reached), and median systemic time to progression was 14 months (95% CI = 13.5–18.0 months). Progression during crizotinib occurred in 37% of patients (62 of 166) at the time of data cutoff.

Progression-free survival overall was 6.0 months (95% CI = 4.3–9.9 months) and for systemic progression was 13.5 months (95% CI = 6.2–16.5 months). Of 54 patients with nontarget or new lesions as progressive disease, the CNS was the site of progression in 39 (72%).

Patients with systemic disease control were likely to exhibit intracranial disease control at 12 weeks (correlation coefficient = 0.7652, P < .001).

No Baseline Metastases

For patients without evidence of brain metastases at baseline, median overall time to progression was 9.8 months (95% CI = 8.4–11.7 months). Brain metastases developed in 51 (20%) of 253 patients with progressive disease at the time of data cutoff, with a median time to detection of 29.9 weeks (range = 2.6–79 weeks).

Survival

Overall survival data were immature at the data cutoff. Estimates of 6-month survival were 77% (95% CI = 67%–85%) in patients with untreated brain metastases, 74% (95% CI = 66%–80%) in those with previously treated metastases, and 85% (95% CI = 81%–87%) in those with no metastases, and estimates of 1-year survival were 59% (95% CI = 45%–70%), 64% (95% CI = 55%–71%), and 69% (95% CI = 64%–73%).

The investigators concluded: “Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.”

Daniel B. Costa, MD, PhD, of Beth Israel Deaconess Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by the National Cancer Institute, American Society of Clinical Oncology Conquer Cancer Foundation, American Cancer Society, and Pfizer. For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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