Durability of CNS disease control in NSCLC patients with brain metastases treated with immune checkpoint inhibitors plus cranial radiotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have excellent systemic activity and are standard first line treatment in EGFR/ALK wild type metastatic non-small cell lung cancer (NSCLC). However, their role in patients with brain metastases, which affects over 20% of patients and cause significant morbidity, is less clear. METHODS: We reviewed patients with EGFR/ALK wild-type mNSCLC with CNS metastases. Serial MRIs were reviewed to determine the time to intracranial progression (iPFS). Multivariate regression was performed to adjust for the disease-specific graded prognostic score (ds-GPA). RESULTS: We identified 36 ICI- and 33 chemotherapy-treated patients with baseline CNS metastases and available serial MRIs (average frequency:3.5 months). Baseline radiation was given except for 2 chemotherapy-treated patients with asymptomatic solitary metastasis. The CNS burden of disease was higher in the ICI-treated group (ICI:22% vs. chemotherapy:0% had >10 lesions; p = 0.02), but the utilization of WBRT was not (ICI:31% vs. chemotherapy:45%; p = 0.09). At the time of progression, CNS involvement was identified in 30 % of ICI-treated patients compared to 64 % of chemotherapy controls (p = 0.02). ICI-treated patients had superior iPFS (13.5 vs 8.4 months) that remained significant in multivariate analysis (HR 1.9; 95%CI 1.1--3.4). Superior CNS outcomes in ICI-treated patients were driven by the PD-L1 high subgroup where the 12-month cumulative incidence rate of CNS progression was 19% in ICI-treated PD-L1 ≥ 50%, 50% in ICI-treated PD-L1 < 50% and 58% in chemotherapy-treated patients (p = 0.03). CONCLUSIONS: Remarkable CNS disease control is seen with baseline RT plus ICIs in patients with PD-L1 ≥ 50%. Strategies for delaying WBRT should be investigated in this subgroup of patients.

Subtypes of EGFR- and HER2-Mutant Metastatic NSCLC Influence Response to Immune Checkpoint Inhibitors.

INTRODUCTION: The efficacy of immune checkpoint inhibitors (ICIs) is low among EGFR-mutated non-small-cell lung cancer (NSCLC), although prolonged responses have occasionally been reported. We investigated the association between mutation subtypes and ICI outcomes among HER2- and EGFR-mutated NSCLC. PATIENTS AND METHODS: This retrospective single-center study analyzed patients with EGFR- and HER2-mutated advanced NSCLC who received at least 1 cycle of ICI between 2013 and 2019. Patient characteristics, mutation subtype, and ICI outcomes. RESULTS: Among 48 patients with advanced NSCLC, 14 (29%) had HER2 mutations and 34 (71%) had EGFR mutations. EGFR mutations included 16 (47%) exon 19 deletion, 7 (21%) L858R, 5 (15%) uncommon, and 6 (18%) exon 20 insertion. Compared to EGFR-sensitizing mutations (ESMs), HER2 and EGFR exon 20 mutations were associated with a trend toward better response (respectively, ESM, HER2, and EGFR exon 20: 11%, 29%, and 50%; P = .07) and significantly better disease control rates (respectively, 18%, 57%, and 67%; P = .008). Compared to ESM, HER2 mutations (adjusted hazard ratio, 0.35; P = .02) and EGFR exon 20 mutations (adjusted hazard ratio, 0.37; P = .10 trend) were also associated with improved PFS. Programmed death ligand 1 (PD-L1) expression remained an independent predictor of PFS (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.76; P = .004). The 6-month PFS rates were 29% (HER2), 33% (EGFR exon 20), and 4% (ESM). ICIs were generally well tolerated in this population. Importantly, no immune-related toxicity was observed in 10 patients who received a tyrosine kinase inhibitor (TKI) as the immediate next line treatment after ICI. CONCLUSION: HER2 and EGFR exon 20 mutations derive greater benefit from ICIs with comparable PFS to wild-type historical second/third-line unselected cohorts. ICIs remain a treatment option for this genomic subgroup, given the absence of approved targeted therapies for these rare mutations.