Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer

Abstract

Background The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC). Patients and methods This study included all epidermal growth factor receptor-mutated (EGFR + , n = 108) and anaplastic lymphoma kinase-rearranged (ALK + , n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed ( n = 34; 24%) or no LT ( n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases. Results Median overall survival (OS) was 49.1 months for ALK + and 19.5 months for EGFR + patients ( P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM ( P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and ‘short’ EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR + and ALK + subsets. Conclusions Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR + /ALK + NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR / ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.

Efficacy of different therapies for brain metastases of non-small cell lung cancer: a systematic review and meta-analysis

“…In our study, we did not observe a significant difference in icORR or iPFS between the WBRT and SRS subgroups, which might be related to data volume limitations. Similar results were obtained in a retrospective study that included 179 driver gene mutation-positive NSCLC patients with BM who received TKIs combined with RT; that is, WBRT did not offer better intracranial control than SRS, and this was probably related to the better systematic tumor control with TKI and ICI compared with pure chemotherapy ( 60 ). Another possible reason is the impact of the number of BMs.…”

Optimal Initial Time Point of Local Radiotherapy for Unresectable Lung Adenocarcinoma: A Retrospective Analysis on Overall Arrangement of Local Radiotherapy in Advanced Lung Adenocarcinoma

“…Ni et al found that upfront brain radiotherapy before crizotinib for patients with advanced ALK-positive NSCLC postpones disease progression (30). Analogically, Shafie et al observed a better intracranial progression-free survival in TKI-treated EGFR/ALK mutant NSCLC treated with early local therapy, regardless of the radiotherapy technique (31). A retrospective analysis observed that the mPFS was 36 months in the LCT plus TKI group and 14 months in the TKI-only group in metastatic NSCLC (32).…”

Real-world efficacy and safety of mobocertinib in EGFR exon 20 insertion-mutated lung cancer

“…platinum-based chemotherapy and EGFR inhibitors ( 21 ), therefore brain involvement appears to be an adverse prognostic factor for this patient group under several different therapies. Thus, use of mobocertinib in patients with brain metastases will require complementary use of radiotherapy in order to extend the intracranial PFS, as is also standard for patients with other oncogene-driven NSCLC beyond the first line ( 22 ). At the same time the ORR under mobocertinib was clearly superior to that of current alternatives, such as monochemotherapy and EGFR inhibitors, which both showed ORR of 0-10% in real-world studies of pretreated patients with EGFR exon20ins ( 21 ).…”