Presence Of Brain Metastases Research Articles

Immune checkpoint inhibitors retain effectiveness in older patients with cutaneous metastatic melanoma

IntroductionImmune checkpoint inhibitors (ICIs) have dramatically changed the treatment landscape for advanced melanoma, but their use in older patients remains understudied. An age-related decline in immune function is of concern when treating older patients because host immune factors can influence clinical outcomes with immunotherapy. Therefore, we aimed to evaluate the effectiveness of ICIs in patients 65 years and older. MethodsUsing the SEER-Medicare data, we evaluated survival by first systemic treatment type in a retrospective cohort study of patients aged 65 years and older who were diagnosed with stage IV cutaneous melanoma between 2012 and 2015. Cox proportional hazards regression was used to estimate hazard ratios (HR) and their corresponding 95% confidence intervals. ResultsA total of 541 patients were included in this study. Median survival differed significantly between groups (p < 0.0001) and was longest in patients treated with PD-1 inhibitors (34.0 months), followed by CTLA-4 inhibitors (16.8 months), targeted therapy (9.7 months), chemotherapy (7.1 months), and no systemic therapy (3.6 months). The ICI survival benefit persisted after adjusting for age, sex, comorbidities, M stage, the presence of brain metastases, and evaluation at an NCI-designated cancer center. Hazard ratios comparing ICIs to no systemic therapy were 0.35 (95% CI: 0.24–0.52) for PD-1 inhibitors and 0.48 (95% CI: 0.37–0.63) for CTLA-4 inhibitors. We did not observe a difference in ICI effectiveness by age group (65–74 vs ≥75). ConclusionsIn a nationally representative cohort of patients with advanced melanoma, ICI therapy delivered in a real world setting significantly improved survival in patients aged 65 years and older.

Development of An Individualized Prediction Calculator for the Benefit of Postoperative Radiotherapy in Patients with Surgically Resected De Novo Stage IV Breast Cancer

Locoregional treatment has been increasingly adopted for metastatic breast cancer at presentation. This study aimed to develop an individualized calculator to predict the benefit of postoperative radiotherapy (PORT) for patients with surgically resected de novo stage IV breast cancer. We searched the Surveillance, Epidemiology, and End Results database for patients diagnosed with stage IV breast cancer between 2010 and 2014. After applying exclusion criteria, a total of 4473 patients were included in the analysis. Propensity score matching was used to balance the individual characteristics of the patients. After identifying the significant prognosticators, a nomogram was developed using multivariate regression models and internally validated. A web-based calculator was then constructed using a fitted survival prediction model. With a median follow-up of 34 months, the 3-year overall survival (OS) rates were 54.1% in the surgery alone group and 63.5% in the surgery+PORT group (hazard ratio [HR] 0.80, p < 0.001). The survival benefit of PORT was maintained after propensity score matching (HR 0.79, p < 0.001). Interaction testing of the prognostic variables found significant interactions between PORT and the presence of brain metastasis (p < 0.001), and between PORT and hormonal receptor expression (p = 0.018). After reviewing the performance of various model, a lognormal distributed survival model was adopted, with a C-index of 0.695. A calibration plot verified that the predicted survival rates were strongly correlated with the actual OS rates. A web-based survival calculator was constructed to provide individualized estimates of survival according to PORT, which is available at: http://bit.do/m1_nomogram. PORT significantly improved OS rates, though the individual benefit was affected by a number of factors. We successfully developed a nomogram and web-based calculator that predicted the prognosis according to PORT in patients with surgically resected de novo stage IV breast cancer. These tools are expected to be useful in clinical practice and in the design of related trials.

Circulating Tumor DNA as a Biomarker in Oligometastatic Non-small Cell Lung Cancer

Selected patients with oligometastatic non-small cell lung cancer (NSCLC) benefit from aggressive local consolidative therapy. We explore the clinical utility of liquid biopsy for circulating tumor DNA (ctDNA) as a biomarker for patients with oligometastatic NSCLC. Patients with metastatic lung cancer underwent liquid biopsy with plasma next-generation sequencing of ctDNA at diagnosis or disease progression using a validated ctDNA assay targeting 23 genes. Oligometastatic state was defined < 5 sites of metastatic disease at initial diagnostic imaging or progression of < 5 sites of disease. Driver alterations were defined by the National Comprehensive Cancer Network guidelines to include EGFR, ALK, ROS1, KRAS, BRAF, MET, RET, HER2, or NTRK. ctDNA detection rates were compared based on clinical and treatment characteristics using Fisher’s exact test. Survival was evaluated using Kaplan-Meier analysis from the time of local consolidative radiation therapy. Among 820 patients with advanced NSCLC, 109 patients (13%) had oligometastatic disease and 711 patients (87%) had polymetastatic disease. Among the oligometastatic cohort, 73 patients (67%) were oligometastatic at initial diagnosis whereas 36 patients (33%) were oligoprogressive. Oligometastatic disease was associated with a lower rate of ctDNA detection compared to polymetastatic disease (52/109, 48% vs 478/711, 67%; p < 0.001). The rate of ctDNA detection was higher among oligometastatic patients with extrathoracic metastases compared to patients with disease confined to lungs, pleura, and/or thoracic lymph nodes (43/79, 54% vs 9/30, 30%, p = 0.031). ctDNA detection among oligometastatic patients was not associated with the presence of brain metastases (p = 0.2), liver metastases (p = 0.6), or prior smoking history (p = 0.7). Among patients with oligometastatic disease, 47% (51/109) underwent consolidative radiation therapy including stereotactic body ablative therapy and conventionally fractionated radiation therapy. Detection of a driver alteration in ctDNA was associated with decreased progression-free survival (HR 2.62, 95% CI 1.27 – 5.43, p = 0.009) following consolidative radiation therapy. In the setting of advanced NSCLC cancer, the rate of ctDNA detection varies according to the number of disease sites and anatomic distribution of disease. ctDNA shows potential as a biomarker for identification of oligometastatic NSCLC patients likely to benefit from local consolidative therapy.

Efficacy of Pembrolizumab Monotherapy in Patients With or Without Brain Metastases From Advanced Non-Small Cell Lung Cancer With a PD-L1 Expression ≥50%.

The authors conducted a multicenter retrospective study on the outcome of programmed death-ligand 1 tumor proportion score≥50% advanced non-small cell lung cancer patients treated with first-line pembrolizumab according to the presence/absence of brain metastases. A total of 282 patients were included, of whom 56 had brain metastases that were treated with upfront local radiation therapy in 80.3% of cases. The overall response rate was 39.2% and 44.4% in patients with and without brain metastases (P=0.48), respectively, while intracranial response rate and intracranial disease control rate were 67.5% and 85.0%, respectively. The median time-to-treatment failure (TTF) and overall survival (OS) were 4.2 and 9.9 months versus 10.8 and 26.5 months for patients with and without brain metastases (P=0.06 and 0.05, respectively). Drug discontinuation rate due to treatment-related adverse events was 10.7% and 10.2% in patients with and without brain metastases, respectively. Multivariate analysis showed that baseline steroids was an independent predictor for a worse OS (P<0.001), while performance status (PS)≥2 was an independent predictor for a poorer TTF (P<0.001) and OS (P<0.001). In patients with brain metastases, only PS ≥2 was predicted for a worse TTF (P=0.02) and OS (P=0.03). Pembrolizumab has activity against brain metastases from non-small cell lung cancers with programmed death-ligand 1≥50%. Presence of brain metastases per se does not appear to be prognostic, and PS ≥2 seems to be the only factor associated with a worse outcome in patients with brain metastases.

Expanding the Definition of Oligometastatic in Lung Adenocarcinoma

The term oligometastatic is defined as having up to 3 metastatic lesions at the time of diagnosis. More recent studies have incorporated up to 5 metastatic sites, though patients with >3 metastatic areas were highly under-represented in these trials. Current ongoing trials are looking to expand the definition of oligometastatic to 10 sites or less, however presently there is limited data in the modern setting to suggest patients with more than 5 metastatic sites have similar oncologic outcomes to those with 5 or less sites of disease. The purpose of this study is to evaluate oncologic outcomes based on the number of metastatic sites at the time of diagnosis in patients with lung adenocarcinoma. A retrospective analysis of metastatic lung adenocarcinoma patients with known Epidermal Growth Factor Receptor (EGFR) status who underwent treatment from 2009 to 2018 at our institution was performed. All patients included underwent upfront staging with body positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) brain imaging; number of metastatic sites was counted individually. Overall survival (OS) was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing OS. Additional variables included in the analysis were age, gender, race, smoking history, presence of brain metastases, pleural disease, and number of oligometastatic sites. Among the 429 adenocarcinoma patients included, the breakdown of total number of upfront metastases were as follows: 1-3 (40.8%), 4-5 (13.3%), 6-10 (17.2%), 11-20 (11.0%), >20 (17.7%). Median OS was as follows: 1-3 (34 mo; 95% confidence interval [CI], 22-46 mo), 4-5 (22 mo; 95% CI, 16.9-27.1), 6-10 (23 mo; 95% CI, 13.7-32.3), 11-20 (33 mo; 95% CI, 23.6-42.4), >20 (22 mo; 95% CI, 12.9-31.1) (log-rank p=0.055). Under multivariate analysis including all patients, presence of >20 metastatic sites (hazard ratio [HR] 1.84; 95% CI, 1.24-2.72; p=0.002) was associated with worse OS, with no differences in OS seen in patients with 4-5 (HR 1.26; p=0.301), 6-10 (HR 1.43; p=0.067), and 11-20 sites (HR 1.15; p=0.562) (reference 1-3 sites). On subset multivariate analysis of EGFR mutation-positive patients, having >20 metastatic sites (HR 2.55; 95% CI, 1.50-4.33; p=0.001) was again associated with worse OS, with no differences seen in patients with 4-5 (HR 1.02; p=0.955), 6-10 (HR 1.51; p=0.179), and 11-20 sites (1.02; p=0.964) (reference 1-3 sites). The definition of oligometastatic disease will continue to evolve with future studies in the era of better systemic therapies and more refined radiation techniques. In our patient population, specifically those with EGFR mutation-positive disease, there appears to be relatively similar survival differences in patients with up to 20 metastatic sites, suggesting the potential benefit for more aggressive local therapies in these individuals. For patients with >20 metastatic sites, outcomes continue to be poor.

RET/PTC3 translocation in a rare hemorrhagic brain metastasis of papillary thyroid cancer post Chernobyl radiation affects vessels ultrastructure

BackgroundSlow progression and good prognosis are the usual characteristics of papillary thyroid carcinoma (PTC). The presence of brain metastases (0.4–1.2%) is suggestive of a worse prognosis. RET/PTC rearrangements were particularly prevalent in PTCs developed after Chernobyl nuclear accident. Case descriptionA 50-year-old woman born in Slovakia, exposed to radiation resulting from the accident at the Chernobyl nuclear power plant, affected since 2017 by papillary thyroid cancer and in therapy at our hospital, experimented cerebral hemorrhagic metastasis. Biopsy analyses revealed a RET/PTC3 rearrangement, so our aim was to find possible morphological relation between hemorrhagic metastasis and RET/PTC3 translocation. ResultsImmunohistochemical analysis showed diffuse and intense positivity for VEGF in endothelial cells of the neoplasm’ vascular network. Transmission electron microscopy images showed vessels with unorganized pattern and uneven diameters. In particular, metastasis endothelial cells (MECs) showed irregular shape and size, thickened cytoplasm and swelling of endoplasmic reticulum. MECs organized in irregular monolayers or multiple layers, surrounded by a thickened but unstructured extracellular matrix. Absence of strong junctional complexes among MECs resulted in a further weakened vessels wall. ConclusionRET/PTC3 translocation causes VEGF overexpression via STAT3 signaling cascade and the increased amount of VEGF adds to the greater amount of VEGFRs expressed by MECs. Our ultrastructural investigation show that this condition creates a massive growth of altered vessels prone to bleeding. The clinical significance of our study consists in alert oncologist and surgeons on possible arising of hemorrhagic brain metastases in patients with PTC and RET/PTC3 translocation exposed to ionizing radiation as people living in areas caught up in Chernobyl or Fukushima disasters.

TERT Promoter Mutation as an Independent Prognostic Marker for Poor Prognosis MAPK Inhibitors-Treated Melanoma.

Although the development of mitogen-activated protein kinase (MAPK) inhibitors has greatly improved the prognosis of BRAFV600 cutaneous melanomas, the identification of molecular indicators for mutated patients at risk of early progression remains a major issue. Using an amplicon-based next-generation-sequencing (NGS) assay that targets cancer-related genes, we investigated co-occurring alterations in 89 melanoma samples. We analyzed both their association with clinicopathological variables and clinical significance in terms of progression-free survival (PFS) and overall survival (OS) according to BRAF genotyping. Among co-occurring mutations, TERT promoter was the most frequently mutated gene. Although no significant difference in PFS was observed in the presence or absence of co-occurring alterations to BRAFV600, there was a trend of longer PFS for patients harboring TERT c.-124C>T mutation. Of most interest, this mutation is an independent marker of good prognosis in subgroups of patients with poor prognosis (presence of brain metastasis and elevated level of lactate dehydrogenase, LDH). Moreover, combination of elevated LDH level, presence of brain metastasis, and TERT c.-124C>T mutation was identified as the best fit model for predicting clinical outcome. Our work revealed the potential interest of c.-124C>T status determination in order to refine the prognosis of BRAFV600 melanoma under mitogen-activated protein kinase (MAPK) inhibitors.

Development of an Individualized Prediction Calculator for the Benefit of Postoperative Radiotherapy in Patients with Surgically Resected De Novo Stage IV Breast Cancer

Purpose: Locoregional treatment has been increasingly adopted for metastatic breast cancer at presentation. This study aims to develop an individualized calculator to predict the benefit of postoperative radiotherapy (PORT) for patients with surgically resected de novo stage IV breast cancer. Methods and Materials: We searched the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with stage IV breast cancer between 2010 and 2014. After applying exclusion criteria, a total of 4473 patients were included in the analysis. Propensity score matching was used to balance the individual characteristics of the patients. After identifying the significant prognosticators, a nomogram was developed using multivariate regression models and internally validated. A web-based calculator was then constructed using a fitted survival prediction model. Results: With a median follow-up of 34 months, the three-year overall survival (OS) rates were 54.1% in the surgery alone group and 63.5% in the surgery + PORT group (p < 0.001). The survival benefit of PORT was maintained after propensity score matching (p < 0.001). Interaction testing of the prognostic variables found significant interactions between PORT and the presence of brain metastasis (p = 0.001), and between PORT and hormonal receptor expression (p = 0.018). After reviewing the performance of various models, a log-normal distributed survival model was adopted, with a C-index of 0.695. A calibration plot verified that the predicted survival rates were strongly correlated with the actual OS rates. A web-based survival calculator was constructed to provide individualized estimates of survival according to PORT. Conclusion: PORT significantly improved OS rates, though the individual benefit was affected by a number of factors. We successfully developed a nomogram and web-based calculator that predicted the prognosis according to PORT in patients with surgically resected de novo stage IV breast cancer. These tools are expected to be useful in clinical practice and in the design of related trials.

Biologic subtypes as a predictor of local control in patients with brain metastases from breast cancer after stereotactic radiosurgery

Biological subtypes have been strongly correlated with loco-regional recurrence after definitive treatment for localized breast cancer. Brain metastases (BM) occur in 15% of patient diagnosed with breast cancer (BC). Therefore, we sought to determine whether biologic subtype is predictive of local control (LC) in BC patients with BM treated with stereotactic radiosurgery (SRS). This is a single-center retrospective study conducted with Institutional Review Board approval for the period January 1, 2004–December 31, 2018. Eligibility criteria included (1) histopathologic proven BC with documented biologic subtype, (2) presence of BM treated with SRS (single fraction), (3) follow-up MRIs, and (4) clinical follow-up. Patients were subdivided into three biologic subtypes: ER+/HER2- (“luminal”), HER2+, and ER-/PR-/HER2 (TN). All patients were treated with LINAC-based SRS with dose according to published guidelines. Cox proportional hazard model and Kaplan-Meier were used for statistical analysis of LC and overall survival (OS). With a median follow-up of 11.1 months, 17 BC BM in 50 consecutive patients were included in this study. The median disease-specific GPA was 2.0, and all patients received systemic chemotherapy and/or hormonal therapy. The 12-month LC rates for the entire cohort were 85%, 87%, and 49% for luminal, HER2+, and TN, respectively, with a significantly shorter time to local failure for the TN subtype (p = 0.014). The 12-month OS rates were 83%, 88%, and 80% for luminal, HER2+, and TN, respectively, with a trend toward shorter OS in the TN group. This study shows that in BC patients with BM treated with SRS, biologic subtype affects LC. Consideration of radiation treatment intensification or altered fractionation to improve LC may be indicated for the TN subtype. Further multicenter studies are necessary to corroborate our results.

Clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine tumors: A population-based analysis.

e21575 Background: The clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine (NE) tumors is unknown; we therefore conducted a population based analysis to evaluate the implications of brain metastases in these patients. Methods: The NCDB database was queried to identify patients with stage IV bronchopulmonary NE tumors treated between the years of 2004-2012. Patients were split into two groups based on the presence of brain metastases at diagnosis and survival probabilities with multivariate models were performed. Results: A total of 7,725 patients with Stage IV bronchopulmonary NE tumors were identified. The histological subtypes studied in this cohort were NE carcinoma (65.4%), large cell NE carcinoma (30.5%), typical carcinoid (2.8%) and atypical carcinoid (1.3%) . The patients included in this study were mainly white (86.4%) men (56.8%) with a median age of 67 years who had liver (9.5%), bone (6.2%) and brain (5.9%) metastases at diagnosis. The median overall survival (OS) of the cohort was 5.59 (95% CI: 5.4-5.8) months, but when OS was stratified by histological subtype it was significantly better in patients with typical carcinoid (table). In the whole cohort, the median OS did not differ between patients with and without brain metastases (5.55 vs. 5.68; p = 0.24). However, a sensitivity analysis by histology showed that the presence of brain metastases worsen the median OS of patients with typical carcinoid only (15.1 vs 4.6, p = 0.04). An adjusted multivariate analysis restricted to patients with brain metastases showed that administration of systemic chemotherapy (HR:0.5; 95% CI:0.35-0.72, p &lt; 0.001) and resection of distant metastases (HR:0.5; 95% CI:0.29-0.88, p = 0.017) were the two most powerful independent prognostic factors. Conclusions: The presence of brain metastases negatively impact survival of patients with typical carcinoids but not in those with the other histological subtypes included in this study. Staging MRI should be strongly considered at diagnosis in patients with bronchopulmonary NE tumors, due to the sizable proportion of these patients presenting with brain metastases and also due to its prognostic value in a subset of this population. [Table: see text]

Outcomes in patients with metastatic non-small cell lung cancer (mNSCLC) with brain metastases treated with pembrolizumab-based therapy.

9599 Background: Patients (pts) with mNSCLC with active brain metastases (BM) are often excluded from clinical trials; data on efficacy and safety of immunotherapy in this population are limited. We compared outcomes of pts with mNSCLC with and without BM who received pembrolizumab-based therapy. Methods: We conducted a retrospective single-center study of pts with mNSCLC treated with pembrolizumab (P) with or without chemotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier methodology and compared using multivariable Cox regression and log rank testing. Results: We identified 587 consecutive pts with mNSCLC who began P-based therapy between 8/2013 and 12/2018: 306 (52%) female, median age 67 years (range 32-98), 437 (74%) adenocarcinoma, and 508 (87%) former/current smokers. 388 (66%) patients received P in first line therapy, and 334 (57%) received single-agent P. 131 pts (22%) had detectable BM at baseline (start of P-based therapy). Pts with BM were younger (median 65 y vs 68 y, p &lt; 0.01) and more likely to have adenocarcinoma (86% vs. 71%, p &lt; 0.01) and baseline steroid use (22% vs 1%, p &lt; 0.01). Presence of BM did not differ by race, sex, line of therapy, treatment regimen, or PD-L1 status. Of the 131 patients with detectable BM on pre-treatment brain MRI, 55 (42%) had stable BM as a result of prior local therapy, while 76 (58%) had active (new or growing) BM on pre-treatment imaging. Most patients with active BM underwent radiation therapy (RT) in either the 30 days before (n = 46) or 30 days after (n = 17) P start; of the remaining 13 treated with P-based therapy alone, intracranial responses included 2 CR, 2 PR, 3 SD, and 4 PD. As of 1/1/2020, with 15-month median follow up, there was no difference in mPFS (9.2 vs 7.3 months, p = 0.41) or mOS (18.3 vs 18.0 mo, p = 0.67) between pts with and without BM in our P-treated cohort. On multivariable analysis, female sex, ECOG 0-1, adenocarcinoma histology, and P as first line therapy were associated with improved PFS and OS. Presence of BM, baseline steroid use, and timing of local RT (before vs. after P) were not associated with inferior survival. Conclusions: In our single-center experience of pts with mNSCLC treated with P, pts with and without BM had similar PFS and OS. We observed several intracranial responses to P-based therapy alone, but most pts with active BM underwent local RT. mNSCLC pts with BM should be considered for P-based therapy; BM may be treated with RT immediately before or even after P with similar survival outcomes.

Gemcitabine with carboplatin in metastatic breast cancer: Characterizing outcomes in a modern, real-world population.

e13085 Background: The specifics of the salvage regimen gemcitabine/carboplatin (G/C) in metastatic breast cancer (MBC) are not well-characterized and are limited to the clinical trial setting, which often excludes heavily pretreated patients with high disease burden and velocity. The primary objective of this study is to assess real-world outcomes in patients with MBC treated with G/C. Methods: A retrospective chart review was conducted on adults with MBC who received &gt;1 dose of G/C at Emory Healthcare / Winship Cancer Institute from December 1, 2005 to April 30, 2019 (n = 109). Patients were stratified by receptor status (hormone receptor (HR), triple-negative (TN), and human epidermal growth factor receptor-2 (HER2)). Results: Patients were heavily pretreated (median 2 lines, range 0-11) and had extensive metastatic disease (median 3 sites, range 1-6). The median starting doses were carboplatin AUC 2 (range: 1.5-5) and gemcitabine 1000 mg/m2 (range 400-1100). The median cycle length was 21 days (range 14-28). The median progression-free survival (mPFS) was 3.7 months and median overall survival (mOS) was 7.7 months. OS at 24 months was 23.1%. Previous immunotherapy, radiation for palliation, or historical receipt of neoadjuvant/adjuvant cytotoxic therapy was significantly associated with improved survival outcomes, while possessing lung, liver, or bone metastases was significantly associated with worse survival outcomes. The presence of brain metastases did not correlate with outcomes. Side effect/intolerance led to dosing and scheduling adjustments in 38.5% and 49.5% of patients, respectively, and resulted in treatment discontinuation in 21% of patients. Hospitalization occurred in 51.4% of patients on treatment. Conclusions: G/C is a safe and effective regimen in real-world MBC patients regardless of receptor subtype. Even low doses of G/C may provide some CNS penetration and control. Improved survival outcomes associated with previous immunotherapy and radiation for palliation may be due to disease control or carry over effect and warrant further study. [Table: see text]

A phase III, open-label, randomized study of atezolizumab in combination with carboplatin + paclitaxel + bevacizumab compared with pemetrexed + cisplatin or carboplatin with stage IV non-squamous non-small cell lung cancer (NSCLC) with activating EGFR mutation or ALK translocation (ATLAS Trial).

TPS9636 Background: In patients with activating EGFR mutations and ALK fusion, target specific tyrosine kinase inhibitor (TKI) showed significant survival improvement compared to the cytotoxic chemotherapy. However, the questions remain which combination strategy will be the best option for the patients who have failed from TKI. Especially, the role of an immune checkpoint inhibitor (ICI) in this population is still unclear. This study is designed and conducted based on the recent subgroup analyses from the IMpower 150 study which showed the positive clinical outcomes of atezolizumab combined with VEGF inhibitor and conventional cytotoxic chemotherapy in EGFR mutation and ALK translocation. Methods: This study is the phase III, open-label, multicenter study of atezolizumab in combination with bevacizumab + carboplatin + paclitaxel (ABCP, Arm A) compared with pemetrexed + cisplatin or carboplatin (Arm B). The study population will be randomized to either Arm A (n = 152) or Arm B (n = 72) based on two stratification factors, EGFR vs. ALK and presence of brain metastases. In Arm A, patients will be treated with 4 or 6 cycles of ABCP followed by maintenance atezolizumab and bevacizumab every three weeks. In Arm B, pemetrexed maintenance therapy will be applied every three weeks after 4 or 6 cycles of pemetrexed + cisplatin or carboplatin. As key inclusion criteria, the patients must be diagnosed with stage IV non-squamous non-small cell lung cancer with either activating EGFR mutation or ALK translocation. All the patients need to be cytotoxic chemotherapy naïve and must have experienced disease progression to treatment with at least one EGFR or ALK TKI. If the patients have T790M mutation after 1st or 2nd generation EGFR TKI, second line 3rd generation EGFR TKI treatment is mandatory. The number of T790M positive patients is restricted to under 30% of the entire study population. The primary endpoint is progression-free survival and the major secondary endpoints are overall survival, objective response rate and duration of response. A total of 228 subjects will be enrolled to detect a hazard ratio of 0.67. The first subject received treatment in Aug. 2019 and 19 patients receive the treatment. This study is opened in 3 sites and expected to be opened at 18 sites in South Korea. The time point for the primary analyses is Q3. 2022. Clinical trial information: NCT03991403 .

Phase III trial of sitravatinib plus nivolumab vs. docetaxel for treatment of NSCLC after platinum-based chemotherapy and immunotherapy (SAPPHIRE).

TPS9635 Background: Sitravatinib is an oral spectrum-selective tyrosine kinase inhibitor that targets the TAM (TYRO3/AXL/MERTK) and split (VEGFR2/KIT) family receptor tyrosine kinases (RTKs), as well as MET. Inhibition of TAM RTKs may promote the depletion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) and repolarize tumor associated macrophages towards the pro-inflammatory M1 phenotype. Inhibition of the split RTKs may reduce immunosuppressive regulatory T cells in addition to MDSCs within the TME. Given these pleiotropic immune-stimulating effects, sitravatinib may reverse resistance to checkpoint inhibitor therapy (CIT) and augment the antitumor immune response of nivolumab in patients (pts) with non-small cell lung cancer (NSCLC). An ongoing Phase 2 study (MRTX-500) demonstrates clinical activity of this combination in pts with metastatic non-squamous NSCLC after progression on or after CIT. Methods: Global, randomized, open-label, Phase 3 study of sitravatinib in combination with nivolumab vs docetaxel in pts with advanced non-squamous NSCLC who have progressed on or after CIT. Pts must have also received platinum-based chemotherapy either in combination with CIT or prior to CIT. Pts are randomized (1:1) to receive oral sitravatinib 120 mg once daily in continuous 28-day cycles combined with nivolumab IV 240 mg every 2 weeks or 480 mg every 4 weeks vs treatment with docetaxel 75 mg/m2 IV every 3 weeks. Patients are stratified based on number of prior treatment regimens in the advanced setting, ECOG performance status, and presence of brain metastases. Key eligibility criteria include duration of treatment of CIT of at least 4 months, discontinuation of prior treatment with CIT &lt; 90 days prior to the date of randomization, and absence of symptomatic or uncontrolled brain metastases. The primary endpoint is overall survival (OS). Key secondary endpoints include safety and tolerability, ORR, PFS, PROs, and PK. OS will be analyzed using Kaplan-Meier methods and the stratified log-rank test to estimate and compare the median OS between the two treatment arms with 95% CI. An IDMC will review safety at regular intervals and efficacy at a planned interim analysis based on OS. Enrollment is ongoing. Clinical trial information: NCT03906071 .

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for PD-L1 Testing in Non-small Cell Lung Cancer

Programmed death-ligand 1 (PD-L1) expression on cancer cells is a clinically important biomarker to select patients with non-small cell lung cancer (NSCLC) for treatment with programmed death-1/PD-L1 inhibitors. Clinical trials of immunotherapy in patients with NSCLC have required histologic evidence for PD-L1 testing; in clinical practice, cytologic samples commonly are acquired in patients with advanced disease. This study aims to investigate whether endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples are adequate for PD-L1 testing in NSCLC. This study investigates the sampling adequacy of EBUS-TBNA for PD-L1 testing when compared with other methods. Furthermore, the relationship between clinicopathologic characteristics and PD-L1 expression in the study population have been examined. Five hundred seventy-seven NSCLC specimens were analyzed from consecutive patients with NSCLC across six centers in the United Kingdom and one center in the United States between January 2015 and December2016. In the EBUS-TBNA group (189 specimens), the overall percentage of patients with successful PD-L1 testing was 94.7%. There was no significant difference in sampling adequacy with other methods of tissue acquisition. Older patients had higher failure rates of PD-L1 testing (OR, 1.06; P= .008). In multivariate analysis, advanced N-stage (P= .048) and presence of brain metastasis (P< .001) were associated with high PD-L1 expression. This large multicenter study shows that EBUS-TBNA provides samples adequate for PD-L1 testing and that advanced N stage and the presence of brain metastasis are associated with high PD-L1 expression.

Clinical and Cancer-Related Predictors for Venous Thromboembolism in Cancer Patients Presenting to the Emergency Department.

The accurate detection of cancer-associated venous thromboembolism (VTE) can avoid unnecessary diagnostic imaging or laboratory tests. We sought to determine clinical and cancer-related risk factors of VTE that can be used as predictors for oncology patients presenting to the emergency department (ED) with suspected VTE. We retrospectively analyzed all consecutive patients who presented with suspicion of VTE to The University of Texas MD Anderson Cancer Center ED between January 1, 2009, and January 1, 2013. Logistic regression models were used to identify risk factors that were associated with VTE. The ability of these factors to predict VTE was externally validated using a second cohort of patients who presented to King Hussein Cancer Center ED between January 1, 2009, and January 1,2016. Cancer-related covariates associated with the occurrence of VTE were high-risk cancer type (odds ratio [OR] 3.64 [95% confidence interval {CI} 2.37-5.60], p<0.001), presentation within 6months of the cancer diagnosis (OR 1.92 [95% CI 1.62-2.28], p<0.001), active cancer (OR 1.35 [95% CI 1.10-1.65], p=0.003), advanced stage (OR 1.40 [95% CI 1.01-1.94], p=0.044), and the presence of brain metastasis (OR 1.73 [95% CI 1.32-2.27], p<0.001). When combined, these factors along with other clinical factors showed high prediction performance for VTE in the external validation cohort. Cancer risk group, presentation within 6months of cancer diagnosis, active and advanced cancer, and the presence of brain metastases along with other related clinical factors can be used to predict VTE in patients with cancer presenting to the ED.

Brain metastases from germ cell tumor: time to reconsider radiotherapy?

The presence of brain metastases (BMs) from germ cell tumor (GCT) remains a rare situation. BMs predominantly occur among patients with testis primary tumor site, and are almost exclusively associated with non-seminomatous (NS) histologies. Two situations must be distinguished, which differ in terms of clinical presentation, overall prognostic and management. At diagnosis, BMs are almost systematically associated with extra-cerebral metastases and the cornerstone of treatment is chemotherapy, while the role of local treatment remains controversial. In the metachronous setting, BMs more frequently constitute an isolated site of relapse, the outcome is poorer, and the role of local treatment is more consensual. However, all these data widely come from old reports, with outdated radiation techniques. The recent advances in radiation oncology, especially the rising use of stereotactic radiotherapy, could lead to the reconsideration of ancient dogmas regarding the "radiosensitivity" of (NS)GCT and the role of radiotherapy among patients with BMs.

No Changes in T1 Relaxometry After a Mean of 11 Administrations of Gadobutrol.

Quantitative T1 relaxometry is the benchmark in imaging potential gadolinium deposition and known to be superior to semiquantitative signal intensity ratio analyses. However, T1 relaxometry studies are rare, commonly limited to a few target structures, and reported results are inconsistent.We systematically investigated quantitative T1 relaxation times (qT1) of a variety of brain nuclei after serial application of gadobutrol. Retrospectively, qT1 measurements were performed in a patient cohort with a mean number of 11 gadobutrol applications (n = 46) and compared with a control group with no prior gadolinium-based contrast agent administration (n = 48). The following target structures were evaluated: dentate nucleus, globus pallidus, thalamus, hippocampus, putamen, caudate, amygdala, and different white matter areas. Subsequently, multivariate regression analysis with adjustment for age, presence of brain metastases and previous cerebral radiotherapy was performed. No assessed site revealed a significant correlation between qT1 and number of gadobutrol administrations in multivariate regression analysis. However, a significant negative correlation between qT1 and age was found for the globus pallidus as well as anterior and lateral thalamus (P < 0.05 each). No T1 relaxation time shortening due to gadobutrol injection was found in any of the assessed brain structures after serial administration of 11 doses of gadobutrol.

Does presence of bone metastases portend worsened prognosis in metastatic renal cell carcinoma? Analysis of the REMARCC (Registry of MetAstatic RCC) database.

655 Background: The presence of brain metastases and bone metastases are generally understood to herald worsened prognosis following nephrectomy in patients with renal cell carcinoma (RCC). However, we sought to determine the effect of bone metastases on outcomes when already present at the time of cytoreductive radical nephrectomy (RN). Methods: Multicenter retrospective analysis of mRCC patients from the REgistry of MetAstatic RCC) REMARCC. Demographics, clinical variables, and outcomes were collected. Patients were stratified into low, medium, and high-risk groups based on Motzer Criteria, and analysis of impact of bone metastases was conducted within each group utilizing Kaplan-Meier analysis (KMA). Multivariable analysis (MVA) was utilized to identify predictors for outcomes. Primary outcome was progression-free survival (PFS) and secondary outcome was overall survival (OS). Results: A total of 447 patients (low- n=30, intermediate- n=208, and high-risk mRCC n=123, median follow-up 14.3 months) were included in the analysis. 124 patients had bone metastases and 323 had mRCC but no bone metastases. No significant demographic differences were noted between groups. KMA (Figure) showed no difference in median PFS for bone metastases vs. non bone metastases groups (6.1 vs. 6.4 months, p=0.973). KMA showed no difference in median OS (25.5 vs. 26.5 months, p=0.958). Similarly, stratification of patients into different Motzer risk categories did not demonstrate difference between bone vs. none bone mRCC for PFS and OS. MVA for PFS demonstrated increasing Motzer risk category (low risk referent vs. intermediate OR 1.89, p=0.006, high risk OR 3.24, p&lt;0.001) as independent predictors. MVA for OS revealed increasing Motzer risk category (low ref, vs. intermediate OR 1.88, p=0.033, high risk 5.17, p&lt;0.001) as being predictive. In neither analysis was presence of bone metastases significant (PFS p=0.690, OS p=0.268). Conclusions: Presence of bone metastases does not independently predict survival or oncologic outcomes in mRCC. While further validation is needed, the prognostic significance of bone metastases may be less than previously thought.

Abstract P1-18-13: Impact of prior (neo)adjuvant trastuzumab exposure on the efficacy of HER2 targeted therapy for metastatic breast cancer

Abstract Background: HER2 targeted therapies, such as trastuzumab, pertuzumab and trastuzumab-emtansine (TDM-1), have improved survival of patients (pts) with HER2+ metastatic breast cancer (MBC). In the pivotal phase III study of pertuzumab/trastuzumab/docetaxel in MBC (NCT00567190), only 10% of pts received prior trastuzumab, whereas in modern practice the majority of recurrent HER2+ MBC pts have received neo(adjuvant) trastuzumab [NAT]. Survival outcomes in the real world setting have not been well described. Methods: Pts were part of a prospective national registry collecting clinicopathologic, treatment and outcome data for HER2+ MBC pts diagnosed between 10/2006 and 1/2019. Survival was estimated by the Kaplan-Meier method and compared among groups by log-rank test. A multivariable analysis was used to assess the impact of prior trastuzumab-use on survival. Analysis was stratified by estrogen receptor (ER) status to exclude the impact of concurrent endocrine therapy in the ER positive (ER+) subgroup. The TABITHA registry is sponsored by BioGrid Australia with financial support from Roche Products Pty Limited. Results: Of 254 HER2+ MBC pts in the registry, 225 received HER2 directed therapy in the first-line advanced disease setting and were included for analysis. Median age was 58 years, 100 (44%) had de novo metastatic disease, 131 (58%) had ER+ disease and 24 (11%) had brain metastases. Of the 125 (56%) pts with recurrent disease, 89 (71%) pts received NAT. First-line HER2 therapy was pertuzumab plus trastuzumab in 176 (78%), trastuzumab in 38 (17%), TDM-1 in 9 (4%), and lapatinib or pertuzumab alone in single pts (&amp;lt;1%). Concurrent chemotherapy was given in 205 (91%) pts, all but one case was taxane-based. The response rate to anti-HER2 therapy among all MBC pts evaluable for response was 42% in pts who received NAT, and 53% in pts who did not (p=0.20). Median progression free survival (PFS) was 16.4 months and 22.6 months, in pts who were trastuzumab-treated and trastuzumab-naïve, respectively (HR 1.44 [95%CI 0.99 - 2.10], p=0.05). The median overall survival (OS) from first-line HER2-directed therapy for MBC was 41.2 months in pts who had prior NAT, and 52.0 months in trastuzumab-naïve pts (HR 1.73 [95%CI 1.04 - 2.86], p=0.03). On multivariable analysis, prior trastuzumab-exposure was no longer significantly associated with survival. Factors significantly associated with PFS were ER status (HR 0.63, p=0.02) and age (HR 1.02, p=0.04), while only age was significantly associated with OS (see table). Among the subset of 93 ER negative (ER-) pts, prior NAT was significantly associated with inferior PFS (HR 1.97 [95%CI 1.11 - 3.52], p=0.02) and OS (HR 2.13 [95% CI 1.00 - 4.57], p=0.046). Multivariable analysis found only age and presence of brain metastases to be significantly associated with OS in the ER- subgroup. NAT exposure did not impact on PFS (HR 1.15, [95% CI 0.70 - 1.90], p=0.58) or OS (HR 1.37, [95% CI 0.68 - 2.73], p=0.37) in ER+ pts. Conclusions: In pts with HER2+ MBC, receipt of NAT was associated with inferior survival when HER2 targeted therapy was used in the metastatic setting on univariate analysis, but this finding was not seen in a multivariable analysis. Furthermore, the impact of NAT was only observed in the subset of pts with ER- tumors, raising the possibility that the disease-course in ER+ subgroup is not entirely HER2 driven. Survival rates of these HER2+ MBC pts treated in the community are comparable to that reported in clinical trials. Cox proportional hazard models for OS in MBC on HER2-targeted therapyUnivariableMultivariableHR95% CIPHR95% CIPAdjuvant trastuzumab Y vs N1.731.04 – 2.850.031.370.64 – 2.940.42De novo metastatic disease Y vs N0.610.37 – 1.020.060.810.38 – 1.730.59Estrogen receptor positive vs negative0.880.53 – 1.440.600.690.41 – 1.180.18Brain metastases Y vs N1.800.88 – 3.670.111.960.90 – 4.260.09Age (years)1.021.00 – 1.040.051.031.01 – 1.060.003 Citation Format: Yada Kanjanapan, Dan Tran, Sheau Wen Lok, Peter Gibbs, Richard De Boer, Belinda Yeo, Sally Greenberg, Frances Barnett, Louise Knott, Gary Richardson, Rachel Wong, Michelle Nottage, Ian Collins, Javier Torres, Janine Lombard, Julie Johns, Michael Harold, Laeeq Malik. Impact of prior (neo)adjuvant trastuzumab exposure on the efficacy of HER2 targeted therapy for metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-13.