ALK Rearrangements Are Associated With Improved Outcomes in Patients With Non‒Small Cell Lung Cancer and Brain Metastases

Key Points

  • The median overall survival was 13.6 months for patients in the EGFR subgroup, 26.3 months for patients in the ALK subgroup, 5.7 months for patients in the KRAS subgroup, and 5.5 months for patients in the wild-type subgroup.
  • ALK rearrangement status alone was significantly associated with improved overall survival, whereas EGFR mutation status and KRAS mutation status were not.
  • Receipt of targeted therapy after cranial radiotherapy was associated with improved overall survival.

Compared with mutations in EGFR, KRAS, or with patients with no known mutations, ALK rearrangements were independently associated with improved survival outcomes in patients with non–small cell lung cancer (NSCLC) who received radiotherapy for brain metastases, according to the results of a study reported by Mak et al in Neuro-Oncology. In addition, targeted tyrosine kinase inhibitor therapy against ALK or EGFR after cranial radiotherapy was associated with further survival benefit.

Brain metastases occur in 20% to 40% of patients with NSCLC and are associated with a poor median survival. Although cranial radiotherapy and stereotactic radiosurgery have been the primary options in patients with brain metastases, newer targeted therapies such as tyrosine kinase inhibitors have led to improved outcomes for patients with EGFR mutations or ALK rearrangements.

In previous studies, agents such as afatinib (Gilotrif), erlotinib (Tarceva), and gefitinib (Iressa) have shown to be of benefit in improving progression-free survival in patients with EGFR- and ALK-associated brain metastases compared with chemotherapy. However, there currently are no such targeted therapies for patients with KRAS- or wild-type–associated brain metastases.   

For clinicians, there is still much to uncover about the relationship between patients with brain metastases and EGFR, ALK, and KRAS genetic alterations. Thus, Mak and colleagues evaluated the impact of EGFR, ALK, and, KRAS on outcomes after radiotherapy for brain metastases.

Study Details

The investigators analyzed the medical records of 525 patients with NSCLC who were treated with radiotherapy for brain metastases from 2005 to 2012. Of these patients, 172 (33%) underwent genotyping: 54 (31%) had EGFR mutations, 12 (7%) had ALK rearrangements, 38 (22%) had KRAS mutations, and 68 (40%) had no known driver mutation. The median follow-up was 8.6 months for all patients (range, 0.2–131.3 months) and 9.5 months for surviving patients (range, 1.3–29.4 months).

Of note, there were higher rates of smokers in the KRAS and wild-type subgroups than in the EGFR and ALK subgroups (P < .0001). However, there were no significant differences among the four subgroups with respect to age, sex, race, or performance status.

Results

The median overall survival was 13.6 months for patients in the EGFR subgroup, 26.3 months for patients in the ALK subgroup, 5.7 months for patients in the KRAS subgroup, and 5.5 months for patients in the wild-type subgroup. ALK rearrangement status alone was significantly associated with improved overall survival, whereas EGFR mutation status and KRAS mutation status were not.

Receipt of targeted therapy after cranial radiotherapy was strongly associated with improved overall survival (hazard ratio = 0.30, 95% confidence interval [CI] = 0.17–0.54, P < .001). This finding was independent of genetic alteration status. The use of chemotherapy after radiotherapy was also associated with improved overall survival.

Patients with an EGFR mutation (33%) or an ALK rearrangement (17%) who were taking a tyrosine kinase inhibitor prior to the diagnosis of brain metastases had significantly worse outcomes than patients with these genetic alterations who were not on targeted therapy. The median overall survival was 9.0 vs 19.6 months (P < .001).

Closing Thoughts

The investigators suggested that after allowing for the administration of targeted therapy, the receipt of chemotherapy, the number of brain metastases, the presence of extracranial metastases, age, and performance status, ALK rearrangements were associated with improved survival. In addition, the use of targeted therapy after cranial irradiation was also associated with improved survival. Although EGFR mutations were significantly associated with improved overall survival on univariate analysis, this was no longer the case once targeted therapies were administered.

ALK rearrangements are independently associated with improved survival outcomes in non–small cell lung cancer patients who receive radiotherapy for brain metastases compared with mutations in EGFR or KRAS or a wild-type genetic profile,” concluded the investigators. “Targeted therapy against ALK or EGFR after cranial radiotherapy is associated with additional survival benefit.”

Helen A. Shih, MD, of the Department of Radiation Oncology, Massachusetts General Hospital, Boston, is the corresponding author of the article in Neuro-Oncology.

The study was supported by institutional funding. Justin F. Gainor, MD, is a consultant for Boehringer-Ingelheim; Lecia V. Sequist, MD, MPH, is an uncompensated consultant for Clovis, Boehringer-Ingelheim, AstraZeneca, and Merrimack Pharmaceuticals; Alice T. Shaw, MD, PhD, is a consultant for Pfizer, Novartis, Ariad, Chugai, and Daiichi-Sankyo; and Dr. Shih is a consultant for Novartis. The other study authors reported no potential conflicts of interest.

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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