Frequency and Outcomes of Brain Metastases in Patients With HER2-Mutant Lung Cancers

Patients with metastatic non-small cell lung cancer (NSCLC) who harbor human epidermal growth factor receptor 2 (HER2) mutations more frequently developed brain metastases during treatment than patients with KRAS mutations or epidermal growth factor receptor (EGFR) mutations, according to a study published in the journal Cancer.¹

The single-institution, retrospective study identified 98 patients with the HER2 mutation, 200 patients with the EGFR mutation, and 200 patients with the KRAS mutation. Twenty-eight percent of patients with HER2-mutant lung cancer experienced brain metastases on treatment, compared with 8% of those with KRAS-mutant disease, and 16% of the EGFR-mutant patients. Median overall survival (OS) rates for those with the HER2-mutant lung cancer (1.6 years;P < .001) was shorter than those with EGFR mutations (3.0 years). Findings from the study provide a strong rationale to develop HER2-targeted therapies with central nervous system activity.

“The high rate of brain metastases in patients with HER2-mutant lung cancers supports our hypothesis that HER2 oncogene activation is associated with an increased propensity for brain metastasis,” the authors wrote. “This finding provides a framework for CNS (central nervous system) surveillance and treatment strategies…and underlines the urgent need for the development of novel HER2-targeted agents with activity in the CNS.”

The median age of all patients in the study was 65 years. Those with HER2 and EGFR mutations were more likely to be younger than the median age, compared with those with KRAS-mutant lung cancer. The authors reported no significant difference in the distribution of sex among all groups. Additionally, those patients with KRAS mutations were more likely to have a history of smoking than either of the patients with the EGFR or HER2 mutations.

Overall, nearly half (47%) of patients with HER2-mutant lung cancer developed brain metastases during the course of their disease, with a median OS of 1.2 years (95% CI, 0.9-1.9) compared to a 2.5-year median OS (95% CI, 1.4-not reached) for those who did not experience metastases.

The investigators noted some limitations to the study. Due to the relative rarity of HER2-mutant lung cancers, a wider range of dates was needed to develop an acceptable sample size of patients in comparison with the more common EGFR- and KRAS-mutant forms of lung cancer. The authors acknowledged that possible changes in standard of care during this time may have introduced a survival bias. Because baseline rates of brain metastases were similar across all mutations, the authors also recognized that differences in treatment regimens and CNS surveillance practices may have influenced the rate of brain metastases or introduced confounding variables.

Still, as there are no currently approved HER2-targeted drugs with validated CNS activity for patients with HER2-mutant NSCLC, these findings give cause for further research into novel therapies.

In an editorial accompanying the article,² Justin F. Gainor, MD, of the department of medicine, Massachusetts General Hospital in Boston, wrote that “Thus far, there are no approved HER2-targeted drugs with validated CNS activity for patients with HER2-mutant NSCLC. The observation that nearly half of the patients with metastatic HER2-mutant NSCLC in this study developed brain metastases at some point during their disease course highlights the importance of developing CNS-penetrant targeted therapies for this oncogenic subset.”

References:
1. Offin, M, Feldman, D, Ni, A et al. Frequency and Outcomes of Brain Metastases in Patients with HER2-Mutant Lung Cancers. Cancer. 2019 Dec 15;125(24):4380-4387.
2. Lin, JJ, Gainor, JF. Time to Tackle the Blood-Brain Barrier in HER2-Mutant Lung Cancer. Cancer. 2019 Dec 15;125(24):4363-4366