Radiographic Response Rate Research Articles

Abstract CT233: Treatment of neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN) with cabozantinib (XL184): A Neurofibromatosis Clinical Trials Consortium Phase II trial

Abstract Background: Cabozantinib, an oral FDA approved multi-receptor tyrosine kinase inhibitor, was tested in our preclinical mouse model of PN. After finding significant reduction of tumor number and size in cabozantinib treated versus control mice, we sought to translate these findings to a phase 2 human study. Here we report the activity of cabozantinib in adolescents and adults with NF1-associated PN. Methods: A multicenter, nonrandomized phase 2 trial (NCT02101736) of cabozantinib in subjects ≥16 years with NF1 and either progressive or clinically significant inoperable PN was performed by the NFCTC (NF-105). The primary study aim was volumetric response of the target PN determined by MRI read centrally. Cabozantinib was administered continuously for up to 24 cycles, each cycle was 28 days. The starting dose was 40 mg once daily with planned escalation to a target dose of 60 mg once daily after 2 cycles. Dose reductions for toxicity were allowed to 20 mg once daily. Partial response (PR) was defined as ≥20% reduction in tumor volume from baseline. Subjects were considered evaluable for response if they completed ≥1 cycle of therapy and had a follow-up MRI. Success was defined as ≥25% of subjects achieving and maintaining a PR after 12 cycles without significant toxicity. Investigation of the impact of cabozantinib on the PN kinome network was performed on murine samples. Results: Twenty-three subjects enrolled; 21 subjects (median age 22 years) were evaluable for toxicity (2 noted to be ineligible before receiving study drug) and 19 subjects (median age 23 years) were evaluable for response (1 subject withdrew during cycle 1 and 1 was found ineligible after starting study drug). Baseline median tumor size was 557 mL (range 57-2954 mL). Among the evaluable patients, 8 (42%) met criteria for PR by cycle 12. Median change in tumor volume was -15.2% (range +2.2% to -36.9%). No subject had PN progression on treatment; maximal tumor response was not achieved until at least 18 cycles in 6/8 responders. A significant portion of patients underwent dose reductions or discontinued cabozantinib due to low grade adverse events (AE) that impaired quality of life; however, 3 responders reduced to 20 mg maintained or improved their response at this dose. The most common AEs (any grade) in ≥10 patients included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia (PPE). Eleven grade 3 AEs occurred in 8 patients, mainly PPE (n=4) and hypertension (n=2); no grade 4 or 5 AEs occurred. Analysis of kinase activity in murine PN treated with cabozantinib showed significantly decreased activity of AXL, MERTK and MET, known cabozantinib targets, but also of DDR1 and DDR2. Conclusions: Cabozantinib demonstrates considerable clinical activity for PN with a radiographic response rate of 42%. Although there were few severe AEs, low grade toxicities impacted the willingness of many subjects to continue treatment. Quantitative kinome analysis revealed that inhibition of DDR1, DDR2, AXL, MERTK and MET might underpin the therapeutic responses seen in these patients. Lower doses of cabozantinib may be optimal for the NF1 population and still lead to therapeutic response. This trial is now enrolling a pediatric cohort of children aged 3 to 15 years. Supported by DOD Award W81XWH-12-1-0155 and Exelixis Citation Format: Chie-Schin Shih, Jaishri Blakeley, D. Wade Clapp, Amy E. Armstrong, Pam Wolters, Eva Dombi, Gary Cutter, Nicole J. Ullrich, Jeffrey Allen, Roger Packer, Stewart Goldman, David H. Gutmann, Scott Plotkin, Tena Rosser, Kent Robertson, Brigitte Widemann, Steven Rhodes, Steven Angus, Gary Johnson, Bruce Korf, Michael J. Fisher. Treatment of neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN) with cabozantinib (XL184): A Neurofibromatosis Clinical Trials Consortium Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT233.

Immune checkpoint inhibitor response in tumors with LRP1B variants.

e14291 Background: Low-density lipoprotein receptor-related protein 1B (LRP1B) is a putative tumor suppressor gene spanning > 500 kb on chromosome 2. A melanoma study previously reported enrichment of LRP1B mutations in responders (34%) to immune checkpoint inhibitors (ICIs) compared with non-responders (3%). Deep deletions in LRP1B are frequently observed in non-small cell lung cancer (NSCLC, 12%), head and neck (11%), cervical (9%), bladder (8%), and prostate cancers (8%). This study examines the clinical response to ICIs in a diverse group of tumor types with LRP1B alterations. Methods: We conducted a single center retrospective study inclusive of all patients (pts) with tumors containing any LRP1B variant who were treated with an ICI between 01/2015 and 11/2018. The primary outcome of the study was to describe the clinical outcomes of patients with LRP1B alterations, with respect to radiographic response to therapy, time on therapy, duration of response, and overall survival. Results: 44 pts with an LRP1B variant were treated with an ICI at Duke between 01/2015 and 11/2018. The most common ICIs were pembrolizumab (29/44, 66%) and nivolumab (12/44, 27%). Tumor types included NSCLC (24/44, 55%), renal cell carcinoma (RCC, 5/44, 11%), and prostate cancer (5/44, 11%). 14 (32%) pts had pathogenic variants (PVs) and 30 pts (68%) had variants of uncertain significance (VUS). Among pts with LRP1b PVs, 36% (95%CI 14%-64%) had radiographic responses (5/14, 2 lung, 1 prostate, 1 RCC, 1 endometrial carcinoma), two of whom were MSI high. As a control, the radiographic response rate among patients with a LRP1b VUS was 10% (95%CI 3%-28%). Of those with PVs, 3 pts had stable disease, one of whom has been on CPI therapy for > 22 months and 5 (36%) remain on therapy, with 2 (14%) pts discontinued due to immune toxicities, and 7 (50%) pts discontinued due to disease progression. The median TMB among responders was 12 (2-150.05 mut/Mb) and the median TMB amongst non-responders was 9.5 (6-18 mut/Mb). Conclusions: In a tumor agnostic population of pts harboring LRP1B PVs, 36% of pts have responses to ICI. The majority of responders were MSS and TMB low, which may suggest that PV in LRP1B may independently predict for response to ICI. Prospective and multicenter validation is now needed.

Outcome of patients with refractory malignant peripheral nerve sheath tumors (MPNST) enrolled on phase 2 trials.

e22534 Background: Multiple phase 2 trials using objective radiographic response rates (ORR) as end point have shown negative results in MPNST. Alternative endpoints such as progression free survival (PFS) may be more appropriate for identifying active agents. PFS from prior trials can provide a historical baseline for future single arm phase 2 trials in this rare disease. Methods: Outcomes of patients with recurrent or unresectable MPNST enrolled on one of five negative phase 2 trials (SARC001, 002, 009, 016, and 023) conducted by the Sarcoma Alliance for Research through Collaboration (SARC) from Nov 2001 – Mar 2016 were retrospectively analyzed to calculate PFS. PFS from SARC006, the phase 2 trial of upfront chemotherapy in newly diagnosed patients with unresectable or metastatic MPNST, was analyzed separately. The impact of neurofibromatosis type 1 (NF1) status, tumor location, metastatic involvement, and prior therapy on PFS was evaluated. Results: Sixty-four patients (29 male, median age 39 years (range 15-81)) with MPNST were enrolled on one of five trials of primarily single agent or combined targeted therapy that were determined to be inactive. Primary endpoint was ORR per RECIST, WHO, or Choi criteria. Patients had received a median of 1 (range 0-5) prior systemic therapies and majority had received prior surgery (77%) and radiation (61%), and had metastatic disease (73%) at enrollment. Median PFS was 1.77 months (95% CI 1.61-3.45), and PFS at 4 months was 16%. Greater number of prior systemic therapies was associated with worse PFS (univariate hazard ratio 1.31, 95% CI 1.03-1.68, p = 0.03). There was no significant difference in PFS based on treatment trial, response criteria, NF1 status, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. PFS at 4 months was 94% in 40 patients enrolled on SARC006 trial, none of whom had received prior systemic or radiation therapy. Conclusions: PFS in patients with recurrent/refractory MPNST enrolled on phase 2 trials is poor and the number of prior regimens may impact PFS. Our data provides a historical baseline PFS that can be used as a comparator in future single arm phase 2 trials in refractory and upfront MPNST patients.

Prognostic and predictive factors for clinical and radiographic responses in patients with painful bone metastasis treated with magnetic resonance-guided focused ultrasound surgery

Background: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an alternative local therapy for patients with painful bone metastasis. However, little is known about the prognostic and predictive factors of MRgFUS in treating bone metastasis.Materials and methods: This retrospective study analyzed the performance status, treated site, pretreatment pain score, pretreatment tumor volume and lesion coverage volume factor (CVF) of 31 patients who underwent MRgFUS. A numerical rating scale for pain was used at the same time to assess the clinical response. Radiographic responses were evaluated using a modified version of The University of Texas MD Anderson Cancer Center criteria and reference to the MR imaging or computed tomography scans obtained 3 months after treatment. Univariate and multivariate logistic regression analyses were conducted to examine the effect of variables on clinical and radiographic responses.Results: The overall clinical response rate was 83.9% and radiographic response rate was 67.7%. Multivariate logistic regression analysis revealed that the better pretreatment Karnofsky performance status (KPS) (odds ratio: 1.220, 95% confidence interval (CI): 1.033–1.440; p = 0.019) was significantly associated with a more positive clinical response, and that the lesion CVF (odds ratio: 1.183, 95% CI: 1.029–1.183; p = 0.0055) was an independent prognostic factor for radiographic responses. The radiographic response of patients with lesion CVF ≥70% and CVF <70% were 91.7% and 52.6%, respectively (p = 0.0235).Conclusion: The pretreatment KPS was an independent prognostic factor for clinical responses, and lesion CVF was an independent prognostic factor for radiographic responses.

Do Tumor PD-L1 Expression and Neutrophil to Lymphocyte Ratio Influence the Efficacy of Stereotactic Radiosurgery for Brain Metastases from Non-Small Cell Lung Cancer?

The immune system plays an important role in the pathogenesis and treatment of non-small cell lung cancer (NSCLC). In this study, we explore if immune parameters influence the presentation of limited brain metastases or the efficacy of stereotactic radiosurgery (SRS) for brain metastases from non-small cell lung cancer (NSCLC). We identified patients with NSCLC who were treated with SRS for brain metastases for NSCLC at our institution, underwent post-treatment brain MRI, and had immunohistochemical tumor PD-L1 testing between 2016 and 2017. Responses were quantified using percent change in tumor diameter. Pearson correlation coefficients were used to assess for associations between immune parameters (PD-L1 tumor proportion score and neutrophil-to-lymphocyte ratio[NLR]) and clinical findings. Logarithmic or square root transformations were applied as needed to facilitate parametric testing. Twenty-four patients who underwent 32 courses of stereotactic radiosurgery met eligibility criteria. Median tumor size before treatment was 0.9 cm (range: 0.2 to 3.4 cm). Thirty treatments were delivered in a single fraction (18-24 Gy), and two were delivered in 5 fractions (30-32.5 Gy). Median PD-L1 expression was 10%, and eight patients had high (≥50%) PD-L1 expression. Median NLR before corticosteroid initiation was 3.3. Immunotherapy was delivered prior to SRS in 9 cases. In 8 of those cases, immunotherapy was continued after SRS. In 2 cases immunotherapy was initiated after SRS and before follow-up MRI. One patient who received immunotherapy experienced mild blurry vision, but otherwise no toxicities were noted in the 30 days following SRS. Mean percent change in tumor diameter following SRS was -32% (range: -100% to +140%). PD-L1 expression was inversely associated with metastasis size (p=0.091). Median diameter was 1.3 cm for patients with PD-L1 expression below 10%, compared with 0.7 cm for patients with PD-L1 of at least 10%. NLR was positively associated with metastasis size (p=0.081). PD-L1 expression, NLR, and receipt of immunotherapy before or after SRS were not associated with response to SRS. Tumor and patient immune parameters may influence the presentation of limited brain metastases in NSCLC patients. We did not find that immune parameters or administration of immunotherapy influence radiographic response rates following SRS. Additional studies are required to determine if local management of brain metastases should be altered with the growing role of immunotherapy in the treatment of NSCLC. Moreover, immunotherapy delivered in conjunction with stereotactic radiosurgery appeared to be well tolerated.

Epidermal growth factor receptor mutation predicts favorable outcomes in non-small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery

PurposeThe impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS). Methods and materialsFrom 2008 to 2015, 147 eligible NSCLC patients with 300 lesions were retrospectively analyzed. Patterns of tyrosine kinase inhibitor (TKI) therapy were recorded. Radiographic response was assessed. Brain progression-free survival (BPFS) and overall survival were calculated and outcome prognostic factors were evaluated. ResultsMedian follow-up time was 13.5 months. Of the EGFR-genotyped patients, 79 (65%) were EGFR mutants, and 42 (35%) were wild type. Presence of EGFR mutations was associated with higher radiographic complete response rates (CRR). Median time to develop new BM after SRS was significantly longer for mutant-EGFR patients (17 versus 10.5 months, p = 0.02), predominantly for those with adjuvant TKI therapy (26.3 versus 15 months, p = 0.01). EGFR mutations independently predicted better BPFS (HR = 0.55, p = 0.048) in multivariate analysis. ConclusionsIn patients with NSCLC treated with SRS for BM, the presence of EGFR mutations is associated with a higher CRR, longer time for distant brain control, and better BPFS. The combination of SRS and TKI in selective patient group can be an effective treatment choice for BM with favorable brain control and little neurotoxicity.

Impact of abiraterone on patient-related outcomes in metastatic castration-resistant prostate cancer: current perspectives.

Abiraterone acetate has established a major role in the treatment paradigm of metastatic castration-resistant prostate cancer ever since pivotal trials, COU-AA-301 and COU-AA-302, have shown benefit in both the second-line and first-line (post- and pre-chemotherapy) setting, respectively, with improvement in overall survival as well as secondary end points such as prostate-specific antigen (PSA) and radiographic response rates, time to PSA progression, and progression-free survival. There has been a lot of interest and emphasis in the evaluation of patient-related outcomes (PROs) as it relates to quality of life, pain, adverse events, fatigue, and among others, in the use of different agents that have been shown to improve survival. This review examines the companion PROs in conjunction with abiraterone acetate use. This is particularly relevant since PROs are increasingly viewed as a key metric for drug label claims in granting approval across regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency.

Reirradiation of the spine with stereotactic radiosurgery: Efficacy and toxicity

PurposeTo determine the potential benefits and adverse effects associated with reirradiating the spinal cord when at least 1 course of radiation therapy (RT) is stereotactic radiosurgery (SRS). Methods and materialsThis institutional review board–approved retrospective review included 162 patients (237 reirradiated spine lesions). All patients received SRS at our institution between 2001 and 2013. Electronic medical records were reviewed for clinical exams and radiologic tests (computed tomography/magnetic resonance imaging). Primary endpoints were pain, neurological, radiographic responses, and the development of adverse effects. ResultsA total of 120 patients (74.1%) were deceased with a median survival of 13 months. Time between courses of RT was a median of 10.2 months. Median SRS dose was 16 Gy in 1 fraction, whereas the median conventional external beam radiation therapy (cEBRT) dose was 30 Gy in 10 fractions. The median tumor equivalent dose in 2-Gy fractions (EQD2) for SRS doses was 34.7 Gy, whereas the median tumor EQD2 for cEBRT was 32.5 Gy, providing a median total tumor EQD2 of 69.3 Gy (22-145.6 Gy). The median critical nervous tissue EQD2 for SRS and cEBRT was 56 Gy and 37.5 Gy, respectively, resulting in a median total critical nervous tissue EQD2 of 93.5 Gy. Overall pain, neurological, and radiographic response rates were 81%, 82%, and 71%, respectively. Adverse effects occurred in 11 (6.8%) patients. Seventy-seven vertebral compression fractures were observed, 22 (9.3%) of which may be attributed to RT. ConclusionsOur results demonstrate that reirradiation achieves favorable response rates with minimal toxicity if recommended dose constraints to the spinal cord with SRS are carefully observed. To the best of our knowledge, this is the largest reported single-institution experience analyzing the efficacy and toxicity of reirradiation of the spine when at least 1 course of RT is stereotactic radiosurgery.

Gefitinib in combination with pemetrexed in patients with advanced non-small cell lung cancer harboring EGFR mutations: is there any difference in acquired resistance mechanism between gefitinib monotherapy and the combination treatment?

Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are the most reliable predictors of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). In randomized phase III trials, EGFR-TKIs in patients with advanced EGFR mutant NSCLC were associated with longer progression-free survival (PFS) and higher radiographic response rates than the standard first-line platinum-based chemotherapy (1-7). Based on these results, three types of EGFR-TKIs, gefitinib, erlotinib and afatinib have been approved for treatment of advanced EGFR-mutant NSCLC as a first-line setting. Despite an initially marked response, almost all patients treated with EGFR-TKIs eventually acquire resistance to these drugs, with an average PFS of around 1 year. To improve these results, several combinations of EGFR-TKIs and other drugs, such as targeted drugs and chemotherapy, have been developed.

A pilot study of palbociclib in patients with HER2-positive breast cancer with brain metastasis.

TPS1110 Background: HER2+ breast cancers have the propensity to metastasize to the CNS. Most systemic therapy does not cross the blood-brain barrier (BBB) effectively, limiting treatment options. Palbociclib is a small molecule inhibitor of cyclin dependent kinases (CDK) 4 and 6, which has been studied in hormone positive breast cancers and found to have significant anti-tumor activity. Preclinical models demonstrate HER2+ tumors require cyclin D1 and CDK4 for progression and maintenance, and palbociclib has been found to have single agent activity in transgenic HER2+ models. Preclinical studies have also found that palbociclib crosses the BBB and exerts anti-cancer effects; indeed, clinical trials investigating its activity in primary brain tumors are ongoing. The summary of these data provide rationale for investigation of palbociclib in patients with HER2+ breast cancer and brain metastasis. Methods: A single arm study of palbociclib in patients with metastatic HER2+ breast cancer with brain metastasis was designed. The primary objective is to determine overall radiographic response rate in the CNS using modified RANO-BM criteria. Secondary objectives include PFS, OS, systemic response rates, safety, and tolerability. Exploratory objectives include assessment of mutational profiles in tissue and ctDNA, and quality of life endpoints using FACT-Cog and FACT-Br. Eligible patients must have metastatic HER2+ breast cancer with measurable brain metastasis (at least 1 lesion &gt; = 5mm). Patients with rapidly progressive symptoms or with leptomeningeal disease are excluded. Concurrent therapy with trastuzumab is allowed. Eligible patients are treated with palbociclib 125mg PO (21 days on, 7 days off) until progressive disease or unacceptable toxicity. Available archival tissue will be obtained, ctDNA/FACT-Cog/Br will be assessed at baseline, 2, and 4 months. A total of 20 patients will be enrolled. To detect a radiographic response rates increase from 23% to 40%, a Bayesian posterior probability will be calculated after the response status in 20 patients has been assessed. The goal is that there is at least an 80% probability that the response rate exceeds 40%. Clinical trial information: NCT02774681.

Selective Arterial Embolization for the Treatment of Sacral and Pelvic Giant Cell Tumor: A Systematic Review.

Giant cell tumor of the bone (GCTB) is a locally aggressive tumor with a certain distant metastatic rate. For sacral GCT (SGCT) and pelvic GCT (PGCT), surgery has its limitations, especially for unresectable or recurrent tumors. Selective arterial embolization (SAE) is reported to be an option for treatment in several cases, but there are few systematic reviews on the effects of SAE on SGCT and/or PGCT. Medline and Embase databases were searched for eligible English articles. Inclusion and exclusion criteria were conducted before searching. All the clinical factors were measured by SPSS software, with P-values ≤0.05 considered statistically significant. A total of 9 articles were retrieved, including 44 patients receiving SAE ranging from 1 to 10 times. During the mean follow-up period of 85.8 months, the radiographic response rate was 81.8%, with a local control and overall survival rate of 75% and 81.8%, respectively. No bowel, bladder, or sexual dysfunction was observed. Three patients developed distant metastases and finally died. Patients with primary tumors tended to have better prognosis than those with recurrence (P = 0.039). The favorable outcomes of SAE suggest that it may be an alternative treatment for SGCT and PGCT patients for whom surgery is not appropriate.

Does radiologic response correlate to pathologic response in patients undergoing neoadjuvant therapy for borderline resectable pancreatic malignancy?

In patients with borderline resectable pancreas cancers, clinicians frequently consider radiographic response as the primary driver of whether patients should be offered surgical intervention following neoadjuvant therapy (NT). We sought to determine any correlation between radiographic and pathologic response rates following NT. Between 2005 and 2015, 38 patients at a tertiary care referral center underwent NT followed by pancreaticoduodenectomy for borderline resectable pancreas cancer. Radiographic response after the completion of NT and pathologic response after surgery were graded according to RECIST and Evans' criteria, respectively. Preoperatively, 50% of patients underwent chemotherapy alone and 50% underwent chemotherapy and chemoradiation. Radiographically, one patient demonstrated a complete radiologic response, 68.4% (n = 26) of patients had stable disease (SD), 26.3% (n = 10) demonstrated a partial response, and one patient had progressive. Among patients without radiographic response, 77.7% (n = 21) achieved a R0 resection. Of patients with SD on imaging, 26.9% (n = 7) had Evans grade IIB or greater pathologic response. Our data indicate that approximately one-fourth of patients who did not have a radiologic response had a grade IIB or greater pathologic response. In the absence of metastatic progression, lack of radiographic down-staging following NT should not preclude surgery.

Induction chemoradiotherapy for unresectable thymic tumors

Curative treatment of locally advanced thymic neoplasms is challenging where optimal multi-modality therapy is not well defined. Thymic tumors that are deemed unresectable at presentation should always be re-considered for resection by a multi-disciplinary team after attempting an induction treatment strategy. Induction strategies have been evaluated in small single institution retrospective and some multi-institution prospective series with no superiority of chemoradiotherapy compared to chemotherapy alone. Despite less robust radiographic response rates compared to induction chemotherapy alone (often around 70%), combination chemotherapy + concurrent radiation therapy appears to increase the rate of complete resection (around 80%), but at the cost of increased perioperative morbidity and mortality. This review outlines the limited published literature addressing the role of induction chemoradiotherapy for “unresectable” thymic neoplasms and provides some insight into interpreting the data.

PUB122 Effects of Whole Brain Radiotherapy for Brain Metastases from Lung Adenocarcinoma with or without EGFR Mutations

Our purpose was to analyze the association between WBRT efficacy and EGFR status of BM patients from lung adenocarcinoma. The data of NSCLC were retrospectively reviewed from August 2010 to May 2015, 1391 NSCLC patients with EGFR mutations status referred to Shanxi Cancer Hospital. 304 patients were diagnosed with BM. Among them, 89 patients who received WBRT were eligible for this study. Eighty -nine lung adenocarcinoma patients with BM received WBRT. The standard regimen was 30 Gy in 10 fractions or 40 Gy in 20 fractions. The radiographic response rate (RR) in BM after WBRT, intracranial progression-free survival (IFS) and overall survival (OS) were analyzed. The log-rank test and Cox regression tests were used to confirm the influence of different variables on IPFS and OS. Among all the patients, the total RR was 61.8% (17 with CR and 38 with PR). In uni-variate testing, patients with mutant EGFR had a better RR than those with wild type (86.4% vs 53.7%，P = 0.011). By multivariate analysis, the following were significantly associated with higher radiotherapy RRs : EGFR mutations (OR = 4.262, 95% CI = 1.105-16.435; P = 0.035) and KPS at BM (OR = 8.344, 95% CI =1.688-41.252; P = 0.009). At the end of the 6-month follow-up, there were 63 patients still alive. The median survival time was 12 months (95% CI 9.535-14.465). By the log-rank test, the following were associated with a much longer IPFS: EGFR mutation (P = 0.007), KPS at BM (P<0.001), and control of primary tumor (P = 0.008). Multivariate analysis further revealed that EGFR mutation and KPS scores at BM were independent effectors (Table 3, Figure 1). The univariate analysis revealed that being female (P = 0.066), control of primary tumor (P =0.002), and higher KPS scores (P <0.001) were associated with longer OS. Consistently, by the multivariate analysis, the independent prognostic factors were KPS (P<0.001), and control of primary tumor (P = 0.031). our results suggest that EGFR mutations in BM from lung adenocarcinoma were significantly associated with a better treatment response and a longer IPFS after WBRT, relative to patients without EGFR mutations. However, an influence on OS was not observed. Prospective clinical randomized testing with more patients is needed.

Abstract IA06: Co-Targeting cell cycle and androgen signaling to personalize therapy for hormone dependent prostate cancer

Abstract Prostate cancer (PC) is an androgen driven and dependent disease and androgen deprivation therapy (ADT) is the standard for patients with metastatic hormone sensitive disease. Despite a high response rate, most patients will progress to castration resistance. The expanding molecular knowledge highlights the biologic heterogeneity and adaptive capacity of PC, and provides the rationale for a preemptive multi-targeted therapeutic strategy. Compelling support for the latter strategy is provided by recent data from two randomized trials demonstrating an unprecedented impact on survival with the addition of docetaxel to ADT. Androgens drive proliferation of PC cells via upregulation of cyclin D which complexes with the cyclin-dependent protein kinases 4/6 (CDK4/6) resulting in phosphorylation of retinoblastoma (Rb) tumor suppressor protein and G1/S progression. Alterations in this pathway contribute to progression to castration-resistance. Palbociclib is a novel specific CDK4/ 6 inhibitor which was recently approved in combination with letrozole for postmenopausal women with ER +, HER2 negative advanced breast cancer. In preclinical prostate cancer models, palbociclib inhibited proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner. Current data indicate that wild-type Rb expression is present in in 95% vs 75% of patients with newly diagnosed vs metastatic castration resistant PC respectively. We estimate that 80-90% of early metastatic hormone-sensitive PC will harbor intact Rb. Based on the biologic and preclinical data, we developed a multicenter randomized phase II clinical trial (NCT02059213) to test the hypothesis that adding palbociclib to ADT in patients with newly metastatic Rb-positive PC will significantly increase the efficacy of ADT. Patients (n = 60) with new metastatic hormone sensitive PC and Rb intact tumors based on metastatic biopsy are stratified by disease extent and randomized (1:2) to ADT or ADT+ palbociclib. Primary endpoint is confirmed prostate specific antigen (PSA) response (&amp;lt; 4 ng/mL) after 28 weeks of therapy. With 20 patients randomized to ADT and 40 randomized to ADT plus palbociclib there will be a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher's exact test. Secondary endpoints: safety and tolerability of ADT + palbociclib, rate of undetectable PSA (&amp;lt; 0.2ng/mL), biochemical and clinical progression-free survival, overall PSA and radiographic response rates, assessment of biomarkers which predict therapy response (circulating DNA and tumor cells, tumor protein and transcriptome analysis) and to establish a repository of metastatic hormone sensitive prostate tumor samples. To date 39 patients have been registered and underwent tumor metastatic disease biopsy (soft tissue 26, bone 13). 2 patients were Rb negative and 5 had inadequate tissue. 32 patients have been randomized to ADT (11 patients) or ADT + palbociclib (21 patients). The study is in progress. Support: Movember-PCF Challenge Award, Pfizer. Citation Format: Maha Hussain, Phillip L. Palmbos1, Scott A. Tomlins1, Stephanie Daignault-Newton, Neeraj Agarwal, Przemyslaw Twardowski, Alicia K. Morgans, Emmanuel S. Antonarakis, Karen E. Knudsen, Felix Y. Feng. Co-Targeting cell cycle and androgen signaling to personalize therapy for hormone dependent prostate cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA06.

Impact of IDH1 mutation status on outcome in clinical trials for recurrent glioblastoma.

IDH1 mutated glioblastoma (GB) has a better prognosis than IDH1 wildtype GB. However, it remains unknown whether patients (pts) with IDH1 mutated GB have a higher 6-month progression free survival (PFS6) or radiographic response (RR) rate on clinical trials for recurrence. Retrospective review of GB pts at MDACC between 2006 and 2012 identified 330 patients in recurrent GB trials. 93 patients (28 %) had either PFS6 or a complete/partial RR per RANO criteria. 49/93 (53 %) patients with PFS6 or a complete/partial RR had tumor tissue for IDH1 testing. A matched cohort of 49 patients on recurrent GB clinical trials that failed to achieve PFS6 or RR (also with tissue for IDH1 testing) was identified for comparison. IDH1 status was obtained in 92/98 (94 %) patients of which 17 (18 %) had an IDH1 mutation. PFS6 was seen in 26/49 (53 %) patients. IDH status was unknown in two of these patients. 5/24 (21 %) were IDH1 mutated compared to 5/24 (21 %) of their matched cohort without PFS6. RR was found in 47/49 (94 %) patients. IDH status was unknown in four of these patients. IDH1 mutation was present in 7/43 (16 %) patients with RR compared to 10/43 (23 %) in the matched cohort without RR (p = 0.48). Median OS for trials at first recurrence was 9.8months for IDH1 wildtype GB vs. 19.32months for IDH1 mutated GB (p = 0.14). IDH1 mutation status was not predictive of PFS6 or RR in recurrent GB trials for this data set. However, further examination in larger randomized prospective studies is needed.

Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience.

Rituximab (RTX) improves the outcome in patients with systemic diffuse large B-cell lymphoma (DLBCL), but its benefit in primary central nervous system lymphoma (PCNSL) is unclear. In the present study, a single-institution retrospective analysis was performed for 12 patients with newly diagnosed PCNSL treated with combined high-dose methotrexate (HD-MTX) and RTX. MTX was administered biweekly at 8 g/m2/dose until a complete response (CR) was achieved or for a maximum of eight doses. RTX was provided for a total of eight weekly doses at 375 mg/m2/dose. Following a median of 11 cycles of MTX, the radiographic overall response rate was 91% and the CR rate was 58%. A CR was achieved after a median 6 cycles of MTX. The median progression-free survival time was 22 months and the median overall survival time has not yet been attained. These results compare favorably to single-agent HD-MTX and suggest a role for immunochemotherapy in the treatment of PCNSL.

Abstract IA11: Perfusion MRI: A potential biomarker of tumor response in clinical trials

Abstract This presentation will show an overview of perfusion MRI for in vivo imaging of solid cancers and emerging evidence supporting the use of this technique to monitor response to anticancer therapy is discussed. The noninvasive nature and high image resolution of Magnetic Resonance Imaging (MRI) makes it the preferred modality for in vivo imaging and disease monitoring of most solid cancers. While conventional MRI provides important anatomic information on the tumor and surrounding tissue, it reveals fewer insights on the metabolic and hemodynamic status and function of the tumor. With the advent of antiangiogenic agents that are not directly cytotoxic, there is an urgent need for clinical trials to incorporate advanced imaging analyses that goes beyond traditional and formalized imaging-based response criteria – usually by assessing tumor load after contrast agent administration. Blockade of vascular endothelial growth factors (VEGF) results in decreased vascular permeability and reduced tumor contrast enhancement on conventional MRI, artificially boosting radiographic response rates. Unfortunately, the high response rates do not always translate into prolonged survival [1]. The negative results of several recent late-phase trials suggest that first-line administration of antiangiogenic therapies in unselected patient groups is probably not the best approach, owing to diversity in cancer biology and natural history. Identification of a subset of cancer patients most likely to benefit from therapy and understanding the underlying mechanisms that separate these responding patients from non-responders are of high priority. According to the National Cancer Institute imaging response criteria [2], developing and validating clinical trial-acceptable advanced imaging methods can lead to smaller clinical trials with fewer patients by earlier and more-focused response assessments; faster regulatory approvals, and by this, earlier use of new drugs in clinical care. Dynamic contrast-enhanced MRI, or perfusion MRI, may help address the limitations of conventional imaging methods in antiangiogenic trials and complement these imaging exams with information on vascular permeability, blood flow and blood volume, among others. A large number of retrospective human studies show consistent reductions in abnormal vascular permeability after antiangiogenic therapy in a range of cancer types [3]. Small studies of brain tumor patients treated with VEGFR inhibitors also show a transient normalization of inefficient blood flow in a selected group of patients and suggest that vascular normalization may be a mechanism for improved delivery of adjuvant therapy and prolonged survival [4]. Similar data on changes in relative blood volume also show a sensitive, yet more complex response to VEGFR inhibition [5]. These efforts are followed by the recent introduction of MRI-based measurements of tumor vessel caliber and relative tissue oxygen saturation in clinical trial data [6]. These measurements are made possible using MR images sensitive to the vessel-size-related scale of magnetic field inhomogeneities created by blood and contrast agents flowing through the vessels. Most, if not all major manufacturers of MRI apparatus now provide these dedicated image protocols. Collectively, perfusion MRI may provide the clinical decision maker with a battery of complementary parameters capable of identifying the initial response, duration and end of the vascular remodeling period following antiangiogenic therapy and thereby enable early identification of patients most likely to benefit from targeted therapies.

MNGO-04PHASE II TRIAL OF BEVACIZUMAB IN PATIENTS WITH SURGERY AND RADIATION REFRACTORY PROGRESSIVE MENINGIOMA

BACKGROUND: Systemic treatment options are limited for meningioma that progress following surgery and radiotherapy. VEGF is associated with neovascularization, tumor growth, and edema in meningioma. This prospective phase II study was undertaken to determine the efficacy of bevacizumab (BEV), a VEGF ligand binding monoclonal antibody in patients with progressive benign (BM), atypical (AM), and malignant meningioma (MM) as measured by 6-month progression free survival (PFS-6). Secondary endpoints included median progression free survival (mPFS), median overall survival (mOS), and radiographic response rate (RR). METHODS: Patients with histologically confirmed BM, AM, or MM with radiographic progression were eligible. There was no limit on prior therapies. BEV was administered 10 mg/kg intravenously every two weeks. After 6 months of therapy, stable patients were eligible to switch to an every 3-week schedule of BEV (15 mg/kg). Clinical examination and imaging were performed every 4 and 8 weeks respectively for the first 6 months then every 6-12 weeks. Responses were graded using the Macdonald criteria. RESULTS: 40 patients were treated: 15 BM, 22 AM, and 13 MM. Median KPS was 80. Median age was 54 (23-81) years. Median number of BEV infusions was 16 (2-62). Best responses were stable disease (BM: 100%; AM: 86%; MM: 82%); partial response (BM: 0%; AM: 5%; MM: 0%), progressive disease (BM: 0%; AM: 5%; MM:18%). PFS-6, mPFS, and mOS were 87%, 22.5 months, 35.6 months for BM; 77%, 15.3 months, not reached for AM, and 46%, 3.7 months, 12.4 months for MM. CONCLUSIONS: Treatment of progressive meningioma with BEV commonly leads to disease stabilization. The results are promising compared to a contemporary meta-analysis, in which PFS6 was 29% and 27% for BM and AM/MM respectively, but require confirmation. Toxicity was minimal and expected for BEV notwithstanding prolonged drug exposure.

ATCT-32A PHASE II STUDY OF TEMOZOLOMIDE IN THE TREATMENT OF ADULT PATIENTS WITH SUPRATENTORIAL LOW-GRADE GLIOMA

INTRODUCTION: Optimal adjuvant management of low-grade gliomas (LGGs) remains controversial. Radiotherapy has been shown to improve progression-free survival compared to observation, but carries the potential for substantial late toxicity. In an effort to delay or obviate the need for radiotherapy, there has been increasing interest in the use of adjuvant chemotherapy in LGGs. However, there is a dearth of prospective studies with long-term follow-up evaluating the efficacy of adjuvant chemotherapy without radiation in patients with newly diagnosed LGGs. METHODS: Patients over the age of 18 with histologically proven supratentorial LGG (WHO grade II) who underwent subtotal resection or biopsy were eligible for enrollment. All patients received monthly cycles of oral Temozolomide (TMZ) for 12 months or until disease progression. Patients were assessed for radiographic response and progression with MRIs every two months during and after treatment. The primary outcome was objective radiographic response rate; secondary outcomes included progression-free and overall survival. RESULTS: 120 patients were enrolled in the trial (57 oligodendrogliomas, 20 oligoastrocytomas, 43 astrocytomas), with a median follow-up of 6.9 years. Objective responses were seen in 7 patients (6%), and 86% demonstrated stable or improved disease during treatment with TMZ. Median progression-free survival was 4.2 years, and median overall survival was 9.7 years. Partitioning analysis demonstrated favorable results in patients with disease confined to one hemisphere undergoing subtotal resection. Treatment was well tolerated with minimal toxicity. CONCLUSIONS: In this high-risk cohort of newly diagnosed LGGs undergoing subtotal resection or biopsy, adjuvant TMZ alone achieved progression-free survival comparable to that seen in similar cohorts treated with adjuvant radiation. TMZ was very well tolerated, and could be considered as adjuvant therapy in appropriately selected patients. Work is ongoing to determine the demographic, pathologic and molecular characteristics of patients who are optimal candidates for adjuvant TMZ.