Outcome of Patients with Non–Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors

IntroductionAlthough frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.MethodsData from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.ResultsA total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0–1, 58.5% with a score of 1.5–2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5–2.1) and 2.1 (95% CI: 1.9–2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8–12.0) with BM and 11.4 months (95% CI: 8.6–13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48–0.52) were associated with improved OS.ConclusionIn multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis.     

Brain Metastases in Non–Small-Cell Lung Cancer

Up to 50% of patients with advanced non-small-cell lung cancer will develop brain metastases at some point during their illness. These metastases cause a substantial burden in morbidity and mortality, which has motivated research and technological innovation over the past 2 decades. Surgery, radiotherapy, and systemic therapies have each played a role in management, with the greatest changes associated with the popularization of stereotactic radiosurgery. In this review, the evidence behind each modality used in the management of brain metastases for non–small-cell lung cancer patients is examined, and recommendations regarding the current standards of care and areas of future research focus are provided.     

Combined Immunotherapy and Stereotactic Radiotherapy Improves Neurologic Outcomes in Patients with Non–small-cell Lung Cancer Brain Metastases

BackgroundThe purpose of this study was to compare the outcomes of patients with non-small cell lung cancer (NSCLC) brain metastases treated with stereotactic radiotherapy (SRT) alone versus SRT and immune checkpoint inhibitors (ICIs).Patients and MethodsPatients treated for their first diagnosis of intracranial metastases with SRT or SRT plus ICI were retrospectively identified. Overall survival (OS), local control (LC), distant brain failure (DBF), neurologic death, and rates of radiation necrosis were calculated. Univariate (UVA) and multivariable (MVA) analyses with competing risk analysis were performed.ResultsSeventy-seven patients with 132 lesions were analyzed, including 44 patients with 68 lesions in the SRT group and 33 patients with 64 lesions in the SRT plus ICI group. There were no differences in baseline factors between groups. Use of ICI predicted for decreased DBF (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.84; P = .01), decreased rates of neurologic death (HR, 0.29; 95% CI, 0.10-0.85; P = .02), and better OS (HR, 0.46; 95% CI, 0.23-0.91; P = .03). Two-year LC was 97% for the SRT + ICI group, and 86% for the SRT-alone group (P = .046). Actuarial 2-year DBF was 39% for the SRT + ICI group and 66% for the SRT alone group (P = .016). On MVA, ICI use persisted in predicting lower incidence of neurologic death (HR, 0.25; 95% CI, 0.09-0.72; P = .01) and DBF (HR, 0.47; 95% CI, 0.25-0.85; P = .01) when adjusted for competing risk of death.ConclusionIn this cohort of patients with NSCLC brain metastases, ICI use combined with SRT predicted for improved LC and OS and decreased DBF and risk of neurologic death.     

Clinical Outcomes and Predictors of Lung Toxicity After Multiple Courses of Lung Stereotactic Body Radiotherapy for Early-Stage Non–Small Cell Lung Cancer

BackgroundThe clinical outcomes of multicourse lung stereotactic body radiotherapy (SBRT) have yet to be validated in a prospective study, and there are a lack of data on allowable composite dosimetry.Patients and MethodsForty-four patients underwent multicourse lung SBRT for recurrent or metachronous NSCLC. The median biologically effective dose (BED₁₀) for the first course and subsequent courses were 132 and 100 Gy, respectively. Patient and treatment characteristics were evaluated to determine the correlation with the development of radiation pneumonitis (RP).ResultsThe local control rate was 91%. A total of 13.6% developed a grade 2+ RP, and 4.5% developed a grade 3+ RP, including one grade 5. On univariable analysis, multiple composite dosimetric factors (V₅ [proportion of lung structure receiving at least 5 Gy], V₁₀, V₂₀, V₄₀, and mean lung dose) were correlated with the development of RP. When comprised of the first and second course of SBRT, a composite lung V₅ of < 30% and > 50% was associated with a 0 and 75% incidence of grade 2+ RP, respectively. We identified no significant correlation on multivariable analysis but observed a strong trend between composite lung V₅ and the development of grade 2+ RP (hazard ratio, 1.157; P = .058). Evaluation of multiple clinical factors also identified a significant correlation between the timing of repeat lung SBRT and the development of grade 2+ RP after the second course (P = .0028).ConclusionSubsequent courses of lung SBRT, prescribed to a median BED₁₀ of 100 Gy, can provide a high rate of local control with a 4.5% incidence of grade 3+ toxicity. Composite lung V₅ and the timing of the second course of lung SBRT may be correlated to the development of RP.     

EGFR Exon 20 Insertion Mutations: Clinicopathological Characteristics and Treatment Outcomes in Advanced Non–Small Cell Lung Cancer

BackgroundEpidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non–small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database.Patients and MethodsPatients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics.ResultsAmong 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62).ConclusionAlthough phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective.     

Ablative Therapy for Oligometastatic Non–Small Cell Lung Cancer

The oligometastatic state represents a distinct entity among those with metastatic disease and consists of patients with metastases limited in number and location, representing an intermediate state between locally confined and widely metastatic cancer. Although similar, “oligorecurrence” (limited number of metachronous metastases under conditions of a controlled primary lesion) and “oligoprogressive” (disease progression at a limited number of sites with disease controlled at other disease sites) states are distinct entities. In non–small cell lung cancer (NSCLC), the oligometastatic state is relatively common, with 20% to 50% of patients having oligometastatic disease at diagnosis. This subgroup of patients when receiving ablative therapy, such as surgery or stereotactic body radiation radiotherapy, can obtain markedly long progression-free and overall survival. The role of radical treatment for intracranial oligometastases is well established. Fewer data exist regarding radical treatment of extracranial metastases in lung cancer; however, retrospective series using surgery or stereotactic body radiotherapy for extracranial oligometastatic disease in NSCLC have shown excellent local control, with a suggestion of improvement in progression-free survival. In the present report, we have reviewed the data on the treatment of brain metastases in oligometastatic NSCLC and the results of ablative treatment of extracranial sites. Recently, the first randomized trial comparing ablative treatment versus control in oligometastatic disease was reported, and those data are reviewed in the context of smaller series. Finally, areas of controversy are discussed and a therapeutic approach for patients with oligometastatic disease is proposed.     

Outcomes in Patients With Non–small-cell Lung Cancer With Brain Metastases Treated With Pembrolizumab-based Therapy

BackgroundPatients with metastatic non–small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited.Patients and MethodsWe conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation.ResultsBetween Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy.ConclusionsPatients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy.     

Pembrolizumab-Associated Cutaneous and Pulmonary Sarcoidosis in Non–Small Cell Lung Cancer Treatment

Immune checkpoint inhibitor (ICI) therapy has reshaped the treatment landscape in many cancers including non–small cell lung cancer (NSCLC). ICI-therapy can lead to a diverse array of immune-related adverse effects (irAEs), and prompt recognition and management are key to successful treatment. With wide-spread use of ICI therapy in clinical practice, rare irAEs are being increasingly recognized. This report documents a patient with advanced NSCLC who developed pembrolizumab-associated sarcoidosis with multiorgan involvement. Multidisciplinary management led to timely diagnosis and treatment, leading to improvement in symptoms. This case raises awareness of sarcoidosis as a rare side effect of pembrolizumab.