ALK Mutation Extends Survival in NSCLC Patients With Brain Metastases

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A rare genetic mutation appears to extend survival among a subset of patients diagnosed with non-small cell lung cancer (NSCLC) brain metastases, and represents a promising biomarker that can help guide radiotherapy planning, according to authors of a new multi-institutional study published online in the Journal of Clinical Oncology.¹ The findings were also presented on Monday, October 19, 2015, at the 2015 Annual Meeting of the American Society for Radiation Oncology.

"This study is among the first to show that genetic information about tumors can guide decision making for the treatment of brain metastases," said lead study author Kimberly L. Johung, MD, PhD, of the Yale University School of Medicine in New Haven, Conn., 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.^"2

These patients are likely to benefit from first-line stereotactic radiosurgery (SRS) rather than whole-brain radiotherapy (WBRT), the authors reported.

The study team identified 90 patients with brain metastases from ALK-rearranged NSCLC at six cancer centers. Of these patients, 84 had received brain radiotherapy and 86 had been administered tyrosine kinase inhibitor (TKI) therapy.

"Median OS [overall survival] after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached),” the coauthors reported.¹ "Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common."

Improved OS was associated with an absence of extracranial metastases (P = .003), Karnofsky performance scores of 90 or higher (P < .001), and no history of TKIs before brain metastases had developed (P < .001), the coauthors reported.¹

Neither presence of a single brain metastasis, nor initial radiotherapy modality correlated with patient survival, however.¹ "Since WBRT is associated with significant cognitive effects and the use of additional radiation therapy for progression is common in this population, patients with ALK mutation may benefit."

Multivariate analysis was used to identify prognostic groups representing 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively, the coauthors reported.¹

"Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs had prolonged survival, suggesting that the interventions to control intracranial disease are critical," they reported. "The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS [central nervous system] observation, and treatment of emergent CNS disease."

NSCLC accounts for 85% of all lung cancers, and up to half of patients will develop metastatic NSCLC tumors in the brain. Prognosis is poor for these patients, with most surviving less than 7 months. Only approximately 5%  of patients harbor tumors with the ALK rearrangement, but these patients survive an average of 4 years, with the disease controlled in the brain nearly a year after their initial treatment, said Dr. Johung.  

Because whole-brain radiation is associated with significant cognitive effects and additional radiation therapy following disease progression, the authors argue that patients with the ALK mutation would benefit from undergoing radiosurgery focused on individual metastases, instead of WBRT.

"Since patients are living longer with systemic disease controlled, there is likely a benefit to intensifying treatment of their brain lesions," Dr. Johung explained. "This is a significant change in strategy for this population."

References:

• Johung KL, Yeh N, Desai NB, et al. (2015). Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastasis. Journal of Clinical Oncology, doi: 10.1200/JCO.2015.62.0138.
• Agnew V. (2015).  Rare mutation may extend survival in lung cancer patients with brain metastases. Yale News.