Faculty Bibliography

OBJECTIVE The incidence of brain metastases is increasing with improved systemic therapies, many of which have a limited impact on intracranial disease. Stereotactic radiosurgery (SRS) is a first-line management option for brain metastases. The purpose of this study was to determine if there is a threshold tumor size below which local control (LC) rates approach 100%, and to relate these findings to the use of routine surveillance brain imaging. METHODS From a prospective registry, 200 patients with 1237 brain metastases were identified who underwent SRS between December 2012 and May 2015. The median imaging follow-up duration was 7.9 months, and the median margin dose was 18 Gy. The maximal diameter and volume of tumors were measured. Histological analysis included 96 patients with non-small cell lung cancers (NSCLCs), 40 with melanoma, 35 with breast cancer, and 29 with other histologies. RESULTS Almost 50% of brain metastases were NSCLCs and commonly measured less than 6 mm in maximal diameter or 70 mm3 in volume. Thirty-three of 1237 tumors had local progression at a median of 8.8 months. The 1- and 2-year actuarial LC rates were 97% and 93%, respectively. LC of 100% was achieved for all intracranial metastases less than 100 mm3 in volume or 6 mm in diameter. Patients whose tumors at first SRS were less than 10 mm maximal diameter or a volume of 250 mm3 had improved overall survival. CONCLUSIONS SRS can achieve LC rates approaching 100% for subcentimeter metastases. The earlier initial detection and prompt treatment of small intracranial metastases may prevent the development of neurological symptoms and the need for resection, and improve overall survival. To identify tumors when they are small, routine surveillance brain imaging should be considered as part of the standard of care for lung, breast, and melanoma metastases. CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort; evidence: Class II.

Background Entinostat is an oral, class I selective histone deacetylase (HDAC) inhibitor that has been shown in pre-clinical models to enhance anti- PD-1 activity through inhibition of immune suppressor cells in the tumor microenvironment. ENCORE 601 is a Phase 1b/2 study evaluating safety and efficacy of ENT plus PEMBRO in NSCLC, melanoma and colorectal cancer patients. We previously reported the results of Phase 1b, which identified ENT 5 mg PO weekly plus PEMBRO 200 mg IV every 3 weeks as the dose to be further explored. Methods Efficacy of ENT 5 mg PO weekly plus PEMBRO 200 mg IV q3wks is being assessed in a Simon 2-stage Phase 2 study involving two cohorts of patients with advanced NSCLC: anti-PD-(L)1-naive (Cohort 1), and progressed on anti-PD-(L)1 (Cohort 2). The primary endpoint is objective response rate. Based on investigator feedback to incorporate Phase 1b patients dosed at entinostat 5 mg into the Stage 2 go/no go assessment, revised criteria for advancement were >=4 responses observed out of 17 evaluable patients in Cohort 1 and >=3 out of 31 in Cohort 2. Tumor biopsies and blood samples for immune correlates were taken pre- and post-treatment. Results Enrollment has been completed for Stage 1 of both cohorts. In Cohort 1, 4 of 17 (24%, 95% CI: 7-50) evaluable patients achieved a partial response (PR; 2 confirmed, 2 unconfirmed). In Cohort 2, 3 of 31 (10%, 95% CI: 2-26) evaluable patients achieved a PR (2 confirmed, 1 unconfirmed). As of the data cutoff, the longest duration of response was 24 weeks (and ongoing). Baseline PD-L1 expression for responders was <1% (1 patient), 1-49% (2 patients) and not available (1 patient) for Cohort 1, and <1% (2 patients) and not available (1 patient) for Cohort 2. 31% of patients experienced a Grade 3/4 event deemed related to study drug. The most common of these events included hypophosphatemia and neutropenia in Cohort 1, and fatigue, anemia, and pneumonitis in Cohort 2. 13% of patients discontinued therapy due to an adverse event. Circulating myeloid derived suppressor cells were reduced in both cohorts at Cycle2/Day1 compared to pretreatment. Gene expression analysis of tumor biopsies and association with responses is in progress. Conclusions ENT plus PEMBRO demonstrates anti-tumor activity and acceptable safety in patients with NSCLC who are both naive to and have progressed on prior PD-(L)1 blockade. Based on the responses seen, Cohort 2 has advanced to Stage 2 and is currently enrolling

Leptomeningeal disease (LMD) is well described in patients with brain metastases, presenting symptomatically in approximately 5% of patients. Conventionally, the presence of LMD is an indication for whole brain radiation therapy (WBRT) and not suitable for stereotactic radiosurgery (SRS). The purpose of the study was to evaluate the local control and overall survival of patients who underwent SRS to focal LMD. We reviewed our prospective registry and identified 32 brain metastases patients with LMD, from a total of 465 patients who underwent SRS between 2013 and 2015. Focal LMD was targeted with SRS in 16 patients. The median imaging follow-up time was 7 months. The median volume of LMD was 372 mm3 and the median margin dose was 16 Gy. Five patients underwent prior WBRT. Histology included non-small cell lung (8), breast (5), melanoma (1), gastrointestinal (1) and ovarian cancer (1). Follow-up MR imaging was available for 14 patients. LMD was stable in 5 and partially regressed in 8 patients at follow-up. One patient had progression of LMD with hemorrhage 5 months after SRS. Seven patients developed distant LMD at a median time of 7 months. The median actuarial overall survival from SRS for LMD was 10.0 months. The 6-month and 1-year actuarial overall survival was 60% and 26% respectively. Six patients underwent WBRT after SRS for focal LMD at a median time of 6 months. Overall, focal LMD may be may be treated successfully with radiosurgery, potentially delaying WBRT in some patients.

INTRODUCTION: We examined the effect of access to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on survival for Asian female (AF) EGFR mutation-enriched patients with advanced lung adenocarcinoma. MATERIALS AND METHODS: We used the Surveillance Epidemiology and End Results database to study patients with stage IV lung adenocarcinoma diagnosed from 1998 to 2012. We compared survival (lung cancer-specific survival [LCSS] and overall survival) between AFs and non-Asian males (NAMs), an EGFR mutation-enriched and EGFR mutation-unenriched population, respectively, with a diagnosis in the pre-EGFR TKI (1998-2004) and EGFR TKI (2005-2012) eras. We used Cox proportional hazards models to examine the interaction of access to TKI treatment and EGFR enrichment status. RESULTS: Among 3029 AF and 35,352 NAM patients, we found that LCSS was best for AFs with a diagnosis in the TKI era (median, 14 months), followed by AFs with a diagnosis in the pre-TKI era (median, 8 months), NAMs with a diagnosis in the TKI era (median, 5 months), and NAMs with a diagnosis in the pre-TKI era (median, 4 months; log-rank P < .0001). In a multivariable model, the effect of a diagnosis in the TKI era on survival was greater for AFs than for NAMs (LCSS, P = .0020; overall survival, P = .0007). A lung cancer diagnosis in the TKI era was associated with an overall mortality decrease of 26% for AFs (hazard ratio, 0.740; 95% confidence interval, 0.682-0.80) and 15.9% for NAMs (hazard ratio, 0.841; 95% confidence interval, 0.822-0.860). CONCLUSIONS: We found increased survival for lung adenocarcinoma diagnoses made after widespread access to EGFR TKIs, with the greatest increase among AF patients enriched for EGFR mutations. The present analysis eliminated the effect of crossover, which has complicated assessments of the survival advantage in EGFR TKI randomized trials.

PURPOSE: Prognostic models for pleural mesothelioma (MPM) are needed to prevent potentially futile outcomes. We combined MPM plasma biomarkers with validated clinical prognostic indices to determine whether stratification of risk for death in 194 MPM patients improved. PATIENTS AND METHODS: Individuals were recruited from three different centers: a discovery cohort (83 MPM) created by combining patients from two US centers and a separate, independent cohort from Canada (111 MPM). Univariable/multivariable analyses were performed on the initial discovery and independent cohorts separately. In multivariable analyses, prognostic factors were adjusted for the Mesothelioma EORTC Prognostic Index (PI). The prognostic significance of adding plasma biomarker data to the PI was determined using the likelihood ratio test, comparing models with and without the addition of biomarker to the clinical PI. The predictive ability of the biomarker was then assessed formally using Harrell's c-index by applying the fitted model variables of the discovery cohort to the second, independent cohort, including and not including the biomarker with the PI. RESULTS: Higher levels of osteopontin and mesothelin were individually associated with worse prognosis after adjusting for the PI. In the independent cohort, incorporating either plasma osteopontin or mesothelin into the baseline predictive PI model substantively and statistically significantly improved Harrell's c-statistic. In the final prognostic model, log-osteopontin, EORTC CPI, and hemoglobin remained as independently significant predictors, and the entire prognostic model improved the optimism-corrected Harrell's c-index significantly from 0.718 (0.67-0.77) to 0.801 (0.77-0.84). CONCLUSION: These data suggest a possible role for preoperative plasma biomarkers to improve prognostic capability of the MPM EORTC PI.

We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7 %, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.

Reactivation of Mycobacterium tuberculosis can occur in patients with latent tuberculosis (TB) with risk factors including chronic disease (i.e., malignancy). We herein describe the case of an immigrant from Hong Kong with lung cancer and no known TB disease who presents with reactivation of TB in the setting of chemotherapy and radiation therapy.