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HER2-mutant NSCLC confers high brain metastases risk

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Anti-HER2 therapies with CNS penetration needed

The report by Offin et al. adds to the growing body of literature supporting the potential value of surveillance brain imaging in a subset of patients with lung cancer. The optimal frequency of surveillance brain imaging in patients with non–small cell lung cancer (NSCLC) after the initial diagnosis of metastatic disease has not been established, and practices vary widely. For example, in our own practice, we routinely perform surveillance brain imaging for patients with ALK fusion–positive lung cancer even in the absence of new neurologic symptoms or signs because of a relatively high cumulative incidence of brain metastases within this subgroup in retrospective studies. Whether a similar approach should be taken for HER2-mutant patients awaits further data. Ultimately, in this era of rapidly evolving therapies for advanced NSCLC, early detection of relatively small, asymptomatic brain metastases could translate into the ability to avoid potentially morbid local CNS-directed therapies (such as surgical resection or whole-brain radiotherapy) while allowing the prompt initiation of CNS-active systemic therapies. At the same time, surveillance strategies will need to be data driven and balanced against health utilization considerations and patient preferences.

Overall, the study by Offin et al. offers important new insights into the incidence of brain metastases in HER2-mutant NSCLC. The finding of a relatively high cumulative incidence of brain metastases in this patient population and the shorter survival resulting therein underscore the urgency of developing better HER2-targeted therapeutics with CNS efficacy. Finally, further investigation will be needed to continue to elucidate potential differences in the CNS tropism of distinct oncogenic drivers in NSCLC and to understand the biological mechanisms underlying these differences.

Remarks by Jessica J. Lin, MD, and Justin F. Gainor, MD, from the Massachusetts General Hospital Cancer Center in Boston are adapted and condensed from an editorial accompanying the study by Offin et al. published online in Cancer. No funding source was reported. Dr. Lin reported serving as a compensated consultant for or receiving honoraria from Chugai and Boehringer Ingelheim, and receiving institutional research funding from Loxo Oncology and Novartis. Dr. Gainor has served as a compensated consultant for or received honoraria or research support from numerous pharmaceutical companies and has an immediate family member who is an employee of Ironwood Pharmaceuticals.



Although only a small percentage of non–small cell lung cancers are positive for HER2 mutations, HER2-mutant lung cancers are associated with a high incidence of brain metastases, investigators have found.

Among 98 consecutive patients with HER2-mutant non–small cell lung cancer (NSCLC), the incidence of brain metastases at initial diagnosis was comparable with or slightly lower than that seen with other, more common mutations, but the incidence during treatment was significantly higher than in patients with KRAS-mutant NSCLC, and trended higher than the incidence rate of brain metastases in patients with epidermal growth factor receptor (EGFR)–mutated NSCLC, reported Michael Offin, MD, and colleagues from Memorial Sloan Kettering Cancer in New York.

“This finding provides a framework for CNS surveillance and treatment strategies, including radiotherapy, for patients with HER2-mutant lung cancers and underlines the urgent need for the development of novel HER2-targeted agents with activity in the CNS,” they wrote in Cancer.

NSCLC with oncogenic driver mutations in HER2 account for 2% of adenocarcinomas of the lung, but relatively little is known about the risk for brain metastases in patients HER2-mutant lung cancer, the authors wrote.

“Because HER2-amplified breast cancers are more likely to develop brain metastases through constitutive HER2 signaling, we hypothesize that HER2-mutant lung cancers are also more apt to develop brain metastases in comparison with lung cancers driven by other oncogenes,” they wrote.

To explore this hypothesis, they conducted a retrospective record review of 98 patients treated at their center with metastatic HER2-mutant NSCLC, and compared them with 200 patients with metastatic KRAS-mutant NSCLC, and 200 with metastatic, sensitizing EGFR-mutant NSCLC.

They found that at the initial diagnosis of metastatic disease, the percentage of patients with brain metastases was similar between patients with HER2 mutations and those with KRAS mutations (19% vs. 24%; odds ratio for HER2 vs. KRAS, 0.7; P = .33). However significantly more patients with EGFR-mutant tumors had brain metastases at diagnosis, compared with patients HER2 mutations (31% vs. 19%; OR, 0.5; P = .03).

Interestingly, significantly more patients with HER2-mutant tumors developed brain metastases on treatment than patients with KRAS-mutant tumors (28% vs. 8%; hazard ratio, 5.2; P less than .001). There was also a trend toward more on-treatment brain metastases among patients with HER2 mutations, compared with patients with EGFR mutation (28% vs .16%; HR, 1.7), but this difference was not statistically significant.

The risk for on-treatment brain metastases was even higher among patients with a HER2 mutation characterized by a 12 base–pair, in-frame insertion in exon 20 (HER2 YVMA). In these patients, the OR for brain metastases developing during treatment versus patients with KRAS mutations was 5.9 (P less than .001).

The median overall survival was worse for patients with KRAS-mutant NSCLC (1.1 years) and HER2-mutant cancers (1.6 years) versus 3 years for patients with EFGR-mutant cancers (P less than .001 for KRAS; P = .002 for HER2 vs. EGFR).

The use of HER2-targeted therapies did not have an effect on either the development of brain metastases or survival, and overall survival was slightly but significantly worse for patients with HER2-mutant tumors who had radiotherapy of the brain.

The study was supported by the National Institutes of Health through a National Cancer Institute Cancer Center support grant and by the Eloise Briskin Foundation. Dr. Offin reported honoraria from Bristol-Myers Squibb, Merck, PharmaMar, Novartis, and Targeted Oncology. Multiple coauthors had similar disclosures.

SOURCE: Offin M et al. Cancer. 2019 Aug 30. doi: 10.1002/cncr.32461.

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