Radiotherapy, TKIs improve survival for patients with ALK-rearranged NSCLC, brain metastases

Patients with ALK-rearranged non–small cell lung cancer and brain metastases have prolonged survival when treated with radiotherapy and a tyrosine kinase inhibitor, according to findings from a multi-institutional study presented at the ASTRO Annual Meeting and simultaneously published in Journal of Clinical Oncology.

These data show interventions to control intracranial disease are crucial to extend survival in this patient population, according to researchers.

“This study is among the first to show that genetic information about tumors can guide decision-making for the treatment of brain metastases,” Kimberly Johung, MD, assistant professor of therapeutic radiology at Yale Cancer Center, said in a press release. “Patients with the ALK mutation respond so well to targeted systemic treatments that the brain lesions actually become the driving prognostic factor in their treatment plan.”

Median survival among patients with NSCLC and brain metastases ranges from 3 to 14.8 months, according to the researchers. Approximately 5% of NSCLCs harbor an ALK rearrangement, and patients with this genetic mutation often achieve prolonged PFS with the TKI crizotinib (Xalkori, Pfizer).

However, disease progression in the brain appears common in this subgroup because crizotinib does not penetrate the central nervous system wall. Researchers, thus, have focused on local control of disease at sites of progression — such as with stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), or surgical resection — to improve outcomes.

Johung and colleagues sought to identify prognostic factors and analyze outcomes for patients with ALK-rearranged NSCLC and brain metastases.

The analysis included data from 90 patients (median age, 52 years; range, 23-80) diagnosed at one of six academic institutions between 2007 and 2014. Most were non-smokers (67%) and had stage IV NSCLC (74%).

Thirty percent of patients had brain metastases at the time of diagnosis. The other patients developed brain metastases after a median of 27 months (range, 2-174 months) from their initial NSCLC diagnosis.

Overall, 84 patients underwent radiotherapy to the brain and 86 patients received TKI therapy (crizotinib, n = 84; second-generation ALK inhibitor, n = 41). Patients underwent 188 brain procedures, which included 119 SRS treatments in 64 patients, 48 courses of WBRT in 45 patients and 21 neurosurgical procedures in 16 patients.

Forty-three patients underwent repeat radiotherapy procedures and 21 underwent three or more radiotherapy procedures.

Median OS after the development of brain metastases was 49.5 months (95% CI, 29-not reached) and the median intracranial PFS was 11.9 months (95% CI, 10.1-18.2).

Forty-five percent of patients with follow-up had brain metastases at death and 33% had symptomatic brain metastases.

Researchers observed improved survival among patients without extracranial metastases (P = .003), patients with a Karnofsky performance score (KPS) of 90 or higher (P < .001) and patients without a history of TKIs prior to the development of brain metastases (P < .001).

However, having a single brain metastasis or undergoing initial treatment with SRS vs. WBRT did not appear associated with improved survival.

Results of a multivariable analysis showed a KPS score of at least 90, absence of extracranial metastasis and no prior ALK-targeted TKI were independent predictors of OS. The estimated rate of 2-year survival for patients with all three factors was 100% compared with 33% among patients with no factors. Researchers estimated 2-year OS rates of 76% among patients with three of the factors and 59% among patients with two of the factors (P ˂ .001 for all).

“Since patients are living longer with systemic disease controlled, there is likely a benefit to intensifying treatment of their brain lesions,” Johung said. “This is a significant change in strategy for this population.” – by Anthony SanFilippo

References:

Johung KL, et al. Extended survival and prognostic factors for patients with ALK rearranged NSCLC and brain metastasis. Presented at: ASTRO Annual Meeting; Oct. 18-21, 2015; San Antonio, Texas.

Johung KL, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.62.0138.