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Crizotinib associated with systemic, intracranial disease control in ALK-rearranged NSCLC
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Patients with ALK-rearranged non–small cell lung cancer who had brain metastases demonstrated systemic and intracranial disease control with crizotinib, according to study results.
However, the development of new intracranial lesions — as well as progression of existing intracranial lesions — was common at the time of crizotinib (Xalkori, Pfizer) resistance, results showed.
Daniel B. Costa
“Brain metastases are, unfortunately, common in patients with advanced lung cancer,” researcher Daniel B. Costa, MD, PhD, of the division of hematology/oncology at Beth Israel Deaconess Medical Center, told HemOnc Today. “Patients with brain metastases are underrepresented — and sometimes overtly excluded — in clinical trials of novel anti-cancer compounds. Further, most novel oral anti-cancer drugs approved by the FDA for advanced lung cancer — called kinase inhibitors — have low brain penetration due to the blood–brain barrier, which in non-cancerous conditions tries to minimize toxin exposure to the brain, and their effect in brain metastases is understudied.”
Costa and colleagues sought to evaluate the brain metastases activity of crizotinib — an oral kinase inhibitor approved by the FDA for the treatment of ALK-rearranged NSCLC — using data from two large clinical trials, PROFILE 1005 and PROFILE 1007.
The pooled population included 888 patients. About one-third of these patients (n=275; 31%) had asymptomatic brain metastases; 166 of these patients received radiation therapy for their brain metastases, whereas 109 did not.
The systemic disease control rate at 12 weeks was 63% (95% CI, 54-72) among patients with untreated metastases and 65% (95% CI, 57-72) among patients with treated metastases. The intracranial disease control rate was 56% (95% CI, 46-66) among patients with untreated metastases and 62% (95% CI, 54-70) among patients with treated metastases.
Researchers found 12-week systemic disease control was significantly associated with the occurrence of intracranial disease control in patients with treated and untreated brain metastases (correlation coefficient, 0.76; P˂.001).
The median time to intracranial progression was 7 months (95% CI, 6.7-16.4) in the untreated cohort and 13.2 months (95% CI, 9.9 to not reached) in the treated cohort. Among patients who progressed in the untreated (43%) and treated (37%) cohorts, the central nervous system was the most common site of progression for those with non-target or new lesions (untreated, 70%; treated, 72%).
“Our group was able to determine two important findings,” Costa said. “Crizotinib has initial adequate activity in brain metastases, with most patients with these lesions having them under control within the initial months of therapy. However, eventual progression or development of brain metastases was common in patients, and highlights that brain metastases will continue to be an unmet clinical need in the management of these patients.”
Disease progression occurred in 253 patients who did not have brain metastases at baseline. Twenty percent of these patients (n=51) developed brain metastases with disease progression after a median of 29.9 weeks (range, 2.6-79).
“The findings may change clinical practice by enforcing that oral anti-cancer inhibitors, such as crizotinib, should not be omitted in patients with brain metastases and by ensuring that future clinical trials both enroll and evaluate brain metastases during the development of novel anti-cancer drugs for lung cancer,” Costa said. – by Alexandra Todak
Daniel B. Costa, MD, PhD, can be reached at Beth Israel Deaconess Medical Center, 330 Brookeline Ave., Boston, MA 02215; email: dbcosta@bidmc.harvard.edu.
Disclosure: The study was funded by Pfizer. The researchers report honoraria, research funding and travel expenses from; consultant/advisory, speakers’ bureau and employment roles with; and stock ownership in Ariad Pharmaceuticals, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharmaceutical, Clovis Oncology, Daiichi Sankyo, EnteroMedics, Genentech, Ignyta, Infinity, Janssen, Johnson & Johnson, MedImmune, Mersana, Millennium Pharmaceuticals, Novartis, NxStage Medical, Pfizer, Roche and Zoetis.
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