Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

Highlights

• We analyzed failure patterns in EGFR-mutant NSCLC patients treated with erlotinib.

• Main pattern of progression was in initial sites of disease.

• Risk of developing brain metastasis was also substantial.

• This data supports earlier incorporation of local or brain-directed therapy.

Abstract

Objectives

Patients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients.

Materials and methods

We reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing-risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure.

Results

Of 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and ≥4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%.

Conclusion

The main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC.

Introduction

Given the effectiveness of the tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, patients with metastatic non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFRmt) have a remarkably long natural history [1], [2], [3], [4]. Though such patients eventually still experience disease progression, their relatively long survival raises the question of whether local therapy such as radiation might prolong progression-free or even overall survival in some of these patients. A benefit for local therapy seems most likely for patients with oligometastatic disease (often defined as five or fewer total lesions) for whom local therapy to all sites is often feasible, and whose prognosis has been theorized to be better than those with florid metastatic disease.

While interest in local ablative therapy for oligometastatic disease has increased tremendously in recent years, the paucity of randomized evidence underscores the need for caution and for prospective trials, as highlighted in several recent reviews [5], [6], [7]. In the case of oligometastatic NSCLC, multiple studies are underway to evaluate this question in molecularly unselected patients: the SABR-COMET trial will test stereotactic ablative radiotherapy (SABR) in treating oligometastatic recurrence of an otherwise controlled solid primary tumor, though entry criteria are not limited specifically to lung primary tumors; and another phase II study at MD Anderson Cancer Center will assess local consolidative therapy (either surgery or radiotherapy) following chemotherapy for patients with NSCLC with one to three metastases, as well as several other similar studies [8], [9], [10], [11]. Finally, the randomized phase III SARON trial will evaluate the addition of definitive radiotherapy to standard chemotherapy in oligometastatic NSCLC patients limited to 3 metastases [12].

However, such studies of local therapy in oligometastatic disease include a variety of histologies, or do not utilize molecular selection to enhance the underlying probability that patients will have prolonged natural history and a tendency to fail in initially involved sites. Molecularly-selected EGFRmt patients treated with erlotinib represent a particularly promising population for local therapy, but we currently lack a thorough understanding of the pattern of disease progression in these patients. Knowing whether these patients first progress only in their initial sites of disease or in new sites, and identifying predictive factors for either pattern, would not only aid in understanding what sort of surveillance such patients might require, but also in identifying potential subsets that might benefit from early incorporation of local therapy. Though several small reports of oligometastatic progression of oncogene-addicted NSCLC treated with local therapy have shown promising results [13], [14], [15], only two studies to our knowledge have evaluated the pattern of failure in metastatic patients treated with TKIs—one from a group of molecularly unselected patients and one from a relatively small set of EGFRmt patients treated with TKI [16], [17]. In both, half or more of the patients had progression limited to their initial sites of disease. Using a larger cohort of molecularly-selected EGFRmt patients treated with erlotinib, we sought to further characterize the frequency with which such patients progress in their initial sites of disease, and identify potential subsets of patients most likely to exhibit this pattern and therefore, potentially benefit from early local therapy. As disease progression in the CNS (typically, in the brain) is also a common pattern of failure in NSCLC with different clinical and treatment paradigms, we also performed a separate, novel analysis of CNS failure and its predictors.