Time Of Disease Progression Research Articles

Abstract CT122: BCL2 expression is a potential predictive biomarker of response to venetoclax in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

Abstract The anti-apoptotic proteins BCL-2 and MCL-1 have been shown to promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, and orally bioavailable small-molecule inhibitor of BCL-2. Bortezomib (BTZ) is a proteasome inhibitor that can inhibit MCL-1 activity by increasing the MCL-1 antagonist, NOXA. Results presented herein describe correlative biomarker analyses in the ongoing phase 1b study of VEN in combination with BTZ and dexamethasone in patients with relapsed/refractory (R/R) MM (NCT01794507). As of 19 Aug 2016, 66 patients were enrolled on study. Baseline bone marrow aspirate samples were available from 52 patients, of which 45 were evaluable for BCL-2 family gene expression by droplet digital PCR in CD138-selected tumor cells. Correlation between BCL2 (BCL-2), BCL2L1 (BCL-XL) and MCL1 (MCL-1) mRNA expression (log2-transformed copies/ul normalized to housekeeping gene) and preliminary efficacy [overall response rate (ORR), time to disease progression (TTP) and duration of response (DoR)] were examined by Log-rank and Wilcoxon tests for binary biomarkers, and by risk ratio from Cox proportional hazard model for continuous biomarkers. The ORR was 68% (44/65) for all evaluable patients and 89% (31/35) in patients who had 1-3 prior therapies (31/35). A broad range of BCL2, BCL2L1 and MCL1 expression was observed, however higher BCL2 levels were detected in patients who achieved a partial response (PR) or better (median: 3.01 vs 0.87, p<0.01). Additionally, higher BCL2 levels were observed in patients who had 1-3 prior lines of therapy compared to 4 or more lines of therapy (median: 3.03 vs 0.94, p<0.01). In contrast, no association was observed between BCL2L1 or MCL1 gene expression and response or number of prior therapies. Bootstrapping and aggregating thresholds from trees was used to estimate a threshold value for BCL2 expression that would provide optimum selection of patients likely to have a response. Overall, seventeen of 18 patients with high BCL2 expression (≥3.0) achieved at least a PR (ORR 94%), with 12 patients (66%) achieving VGPR or better. Sixteen of 27 patients with low BCL2 expression achieved at least a PR (ORR 59%), with 6 patients (22%) achieving a VGPR or better. Median TTP (11.6 vs 5.7 months) and DoR (10.2 vs 7 months) were longer for patients with high versus low BCL2 expression. Responses in high BCL2 expressors were independent of cytogenetic status as determined by interphase FISH analysis, including t(11;14), t(4;14), del(13q) and del(17p). Targeting BCL-2 and MCL-1 with the combination of VEN, BTZ and dexamethasone provides a unique approach for MM treatment. Efficacy results in tumors expressing high BCL2 levels, including 94% ORR, provide supportive evidence for the evaluation of this combination regimen in the ongoing phase 3 study (NCT02755597) in R/R MM. Citation Format: Jeremy Ross, Brenda Chyla, Rasna Goswami, Lisa Roberts-Rapp, Yan Sun, Yanwen Jiang, Elizabeth Punnoose, Maria Verdugo, Anahita Bhathena, Paulo Maciag. BCL2 expression is a potential predictive biomarker of response to venetoclax in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT122. doi:10.1158/1538-7445.AM2017-CT122

Abstract LB-058: ABIraterone (ABI) and ENZalutamide (ENZ) induce changes in immunologic profile of patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: ABIraterone (ABI) is a CYP17-lyase inhibitor, while ENZalutimide (ENZ) is an androgen receptor (AR) antagonist that inhibits nuclear translocation. Changes in serum cytokines have been noted in patients (pts) receiving docetaxel for metastatic castration-resistant prostate cancer (mCPRC) therapy (Mahon KL et al Br J Cancer 2015). We postulate that ABI and ENZ may also have a complex effect on cytokine profile. Methods: In a prospective trial in mCPRC pts, ABI or ENZ was given according to physician preference. Blood was drawn at baseline, 4 weeks, 8 weeks, 12 weeks and at the time of progressive disease (PD). Plasma was separated from patients’ blood using Vacutainer CPT tubes (BD) within 2 hours after collection by centrifuging at 1800×g for 20 min at room temperature and stored in -80°c. Plasma samples were analyzed for 30 human cytokines and chemokines using Luminex FLEXMAP 3D system. Trends in serum cytokine profile were analyzed by supervised clustering, with segregation based on radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3 (PCWG3) criteria. Results: From May 2013 to June 2016, 33 pts were enrolled with a median age of 67. 13 and 20 pts received ABI and ENZ, respectively. Of these, 13 pts had received prior treatment with the opposing agent (e.g., ABI→ENZ, or ENZ→ABI). Prior docetaxel was rendered in 4 pts. 16 pts had rPFS < 6 mos, while 17 pts had rPFS ≥ 6 mos. Using supervised clustering, higher levels of GM-CSF (P=0.008) and IL-10 (P=0.008) were noted at 8 weeks in pts with rPFS ≥ 6 mos, while lower levels of IL-17 (P=0.008) and VEGF (P=0.001) were observed in this cohort. Across the entire cohort, a trend was noted with sequential decline in HGF from baseline to 4 and 8 weeks, but a pronounced rise was observed at the time of progression (P<0.05 for comparison of progression to baseline and 4 weeks). Conclusions: Our study suggests HGF as a mediator of ABI/ENZ resistance, supporting the well-established role of the HGF/MET signaling axis in prostate cancer pathogenesis. After initiation of therapy, lower levels of proinflammatory and proangiogenic mediators such as IL-17 and VEGF, respectively, are associated with protracted response to ABI and ENZ. These results may inform combination trials in mCRPC incorporating checkpoint inhibitors or other immune modulators. Note: This abstract was not presented at the meeting. Citation Format: Meghan Salgia, Marc L. Perez, Jeremy Jones, Hae Jung Won, Valeriy Poroyko, Przemyslaw Twardowski, Marcin Kortylewski, Sumanta K. Pal. ABIraterone (ABI) and ENZalutamide (ENZ) induce changes in immunologic profile of patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-058. doi:10.1158/1538-7445.AM2017-LB-058

Impact of Ki67 re-assessment at time of disease progression in patients with pancreatic neuroendocrine neoplasms.

BackgroundAlthough re-assessment of proliferative activity by K67 evaluation during the course of neuroendocrine neoplasms (NENs) is recommended in selected patients, its impact on patients’ management is not clear due to the lack of data supporting this practice.AimTo investigate Ki67 change at time of progressive disease (PD) in entero-pancreatic NENs (EP-NENs).Patients and methodsRetrospective analysis of sporadic EP-NENs which received histological re-assessment after PD once radiologically documented.ResultsForty-three patients were evaluated, including 24 pancreatic NENs (PNENs), and 19 small intestine NENs (SI-NENs). At time of initial histological evaluation, 19 patients had grade 1 (G1) NETs (44.2%), and 24 grade 2 (G2) NETs (55.8%), overall median Ki67 being 3% (range 1%-20%). At time of PD, 13 patients had G1 NETs (30.2%), 26 G2 NETs (60.5%), and 4 had grade 3 (G3) NECs (9.3%), thus resulting in a significant median Ki67 increase (8%, range 1%-70%; p = 0.0006), and a G upgrading in 12 patients (27.9%). A statistically significant Ki67 increase and G grading change at time of PD was observed in PNENs (p = 0.0005 and p = 0.028, respectively). Conversely, no statistically significant change occurred in non-PNENs.ConclusionsIn PNENs with documented PD, Ki67 increase occurs in a significant proportion of patients, providing useful information necessary to choose appropriate therapeutic options.

Radiogenomics of High-Grade Serous Ovarian Cancer: Multireader Multi-Institutional Study from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group.

Purpose To evaluate interradiologist agreement on assessments of computed tomography (CT) imaging features of high-grade serous ovarian cancer (HGSOC), to assess their associations with time-to-disease progression (TTP) and HGSOC transcriptomic profiles (Classification of Ovarian Cancer [CLOVAR]), and to develop an imaging-based risk score system to predict TTP and CLOVAR profiles. Materials and Methods This study was a multireader, multi-institutional, institutional review board-approved, HIPAA-compliant retrospective analysis of 92 patients with HGSOC (median age, 61 years) with abdominopelvic CT before primary cytoreductive surgery available through the Cancer Imaging Archive. Eight radiologists from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group developed and independently recorded the following CT features: characteristics of primary ovarian mass(es), presence of definable mesenteric implants and infiltration, presence of other implants, presence and distribution of peritoneal spread, presence and size of pleural effusions and ascites, lymphadenopathy, and distant metastases. Interobserver agreement for CT features was assessed, as were univariate and multivariate associations with TTP and CLOVAR mesenchymal profile (worst prognosis). Results Interobserver agreement for some features was strong (eg, α = .78 for pleural effusion and ascites) but was lower for others (eg, α = .08 for intraparenchymal splenic metastases). Presence of peritoneal disease in the right upper quadrant (P = .0003), supradiaphragmatic lymphadenopathy (P = .0004), more peritoneal disease sites (P = .0006), and nonvisualization of a discrete ovarian mass (P = .0037) were associated with shorter TTP. More peritoneal disease sites (P = .0025) and presence of pouch of Douglas implants (P = .0045) were associated with CLOVAR mesenchymal profile. Combinations of imaging features contained predictive signal for TTP (concordance index = 0.658; P = .0006) and CLOVAR profile (mean squared deviation = 1.776; P = .0043). Conclusion These results provide some evidence of the clinical and biologic validity of these image features. Interobserver agreement is strong for some features, but could be improved for others. © RSNA, 2017 Online supplemental material is available for this article.

Efficacy and safety of anti-VEGF therapy in metastatic unresectable hepatocellular carcinoma: A meta-analysis.

e15632 Background:Conventional chemotherapy has limited role in metastatic unresectable hepatocellular carcinoma (HCC). Sorafenib is currently approved for metastatic unresectable HCC. We wanted to assess the efficacy and safety of other tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor (VEGF) receptor such as brivanib, linifanib and regorafenib in metastatic HCC. Methods: We have searched electronic databases Pubmed, Google scholar to identify published trials using brivanib, linifanib and regorafenib in HCC. The outcomes evaluated were overall survival, time to disease progression (TTDP) and adverse effects. Hazard ratios (HR) with their respective 95% confidence intervals (CI) were then computed using the appropriate model for categorical variables. We used STATA 13.0 and Comprehensive Meta Analysis 2.0 software for all analyses. Results: We included seven randomized control studies. A combined analysis of these seven randomised control trials showed improved overall survival (OS) in VEGF-TKI group when compared to placebo HR - 0.79; (95% CI 0.62-1.00). However, there was no significant survival benefit of the newer VEGF receptor inhibitors when compared to sorafenib (HR - 1.05; 95% CI 0.95-1.17). The time to disease progression (TTDP) was significantly better in VEGF-TKI group as compared to placebo (HR - 0.61; 95% CI 0.39-0.97). However, there was no significant difference in TTDP between VEGF-TKI group and Sorafenib (HR - 0.88; 95% CI 0.66-1.16). Adverse effects were noted to be higher in VEGF-TKI group when compared to placebo (HR- 1.07; 95% CI 1.01-1.13). Conclusions: Treatment with TKI targeting VEGF receptor is associated with a significant improvement in OS and TTDP with tolerable side effect profile. Inhibiting the VEGF receptor pathway could lead to improved outcomes in HCC.

Phase II trial of capecitabine +/- erlotinib in advanced colorectal cancer, with retrospective KRAS and primary tumor site analysis.

781 Background: Palliative capecitabine (X) monotherapy for advanced colorectal colorectal cancer (aCRC) is generally well tolerated by elderly or frail pts. Epidermal growth factor receptor (EGFR) monoclonal antibodies improve efficacy when added to combination chemotherapy for mCRC. Erlotinib (E), an oral EGFR tyrosine kinase inhibitor (TKI) may add benefit when added to X. We conducted a randomized phase II trial to investigate the novel “all-oral” combination of X and E in aCRC. Methods: Pts with untreated aCRC who were either deemed unfit for, or chose against, combination chemotherapy were randomized to X (1000 mg/m2 PO BID x 14 days) alone or in combination with E (150 mg PO OD) on a 3-week schedule. Primary endpoint was time to disease progression (TTP); secondary endpoints included: objective response rate (ORR), overall survival (OS), and safety. Tumours were designated as left-sided if there were distal to the transverse colon. KRAS status was retrospectively analyzed for 72 of 82 pts. Results: From 2004 to 2008, 82 pts were randomized to X alone (40 pts) or XE (42 pts). TTP was not different between X and XE (7.9 m vs. 9.2 m; p = 0.890), however, KRAS subgroup analysis revealed pts with KRAS mutations did significantly worse when treated with XE compared to X alone (1.9m vs 7.4m; HR = 2.63; P = 0.038). Pts with KRAS wild-type (WT) treated with XE had an improved TTP compared to those treated with X (11.7m vs. 8.4m, HR = 0.73; Wilcoxon P = 0.061). KRAS-WT pts treated with XE with left-sided disease had an improved OS compared to pts with right-sided disease (16m vs. 12.1m, not significant). KRAS-WT pts with left-sided primaries treated with XE had a non-significant improvement in TTP compared to pts treated with X alone (11.7m vs 8.4m). XE was well tolerated but had significantly higher rates of diarrhea and acneform skin rash. Conclusions: The addition of E to X is generally well tolerated but associated with additional toxicities. E may benefit pts with KRAS-wild-type CRC, specifically those with left-sided primary tumours, and likely harms those with KRAS-mutated CRC. Further study of oral EGFR-TKIs in left-sided KRAS-wild-type aCRC is warranted.

A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study

PurposeThe PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).MethodsThis randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).Results210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).ConclusionBoth PLD and capecitabine are effective first-line agents for MBC.

Outcomes of patients with relapsed and refractory chronic lymphocytic leukemia (CLL) who discontinue idelalisib treatment.

7531Background: Idelalisib (IDELA) is effective in the treatment of patients (pts) with relapsed/refractory (R/R) CLL. Nonetheless, pts may discontinue (D/C) IDELA due to progressive disease (PD) o...

Prognostic Significance of Lymph Node Ratio in Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck.

The prognostic variables in patients with metastatic cutaneous nodal squamous cell carcinoma (SCC) are well documented; however, the relationship between lymph node ratio (LNR) and outcome is not well researched. LNR represents the ratio of positive lymph nodes to total excised lymph nodes. We analyzed the correlation between LNR and outcome in patients who have undergone surgery for metastatic cutaneous nodal SCC of the head and neck. Analysis was performed on retrospectively collected data, identifying patients who underwent surgery at Westmead Hospital, Sydney. Pathology reports were reviewed to ascertain LNR. A log-rank test identified a specific LNR value to compare time to disease progression (TTDP) and overall survival (OS). Multivariate proportional hazard regression models were used to review outcome. In total, 193 males and 45 females with a median of age 68years were identified, with a mean recorded LNR of 0.15. On multivariate analysis, an LNR cutpoint of 0.21 was a significant predictor of decreased TTDP [hazard ratio (HR) 2.34, 95% confidence interval (CI) 4.40-0.49; p=0.009] and OS (HR 2.75, 95% CI 1.57-4.82; p<0.001). Forty-nine of 238 patients (21%) developed recurrence, with most recurrences being regional (29 of 49; 59%). A total of 17% of patients with an LNR ≤0.21 recurred compared with 40% for patients with an LNR >0.21. LNR is potentially an independent predictor of outcome in patients with metastatic cutaneous nodal SCC. The clinical relevance of this finding requires further validation.

Sunitinib scheduling in metastatic renal cell cancer: A single-center experience.

554 Background: Sunitinib is a receptor tyrosine kinase inhibitor that has proven activity as first line treatment for metastatic renal cell carcinoma (mRCC). The recommended dose is 50mg once daily in a 4 week on 2 week off schedule. However this regimen has a significant side effect profile and alternative schedules have been used to minimize dose reductions and maintain dose intensity. We sought to identify the incidence of dose modifications and assess toxicity in patients treated with two sunitinib schedules in a National Cancer Center. Methods: Patients with mRCC who had sunitinib as first line treatment were identified retrospectively and patient data reviewed. Two patient groups were identified: those who received sunitinib 50mg day 1-28 in 6 week cycles (cohort 1) and those who received sunitinib 50mg day 1-14 in 3 week cycles (cohort 2). Primary end point was incidence of dose modification. Secondary end points included incidence of common sunitinib-related side effects. Known prognostic variables, including prior nephrectomy, body mass index (BMI) and use of angiotensin system inhibitors (ASI) were correlated with time to disease progression (TTP). Results: Between 2009 and 2014, 28 patients were identified. Of those, 23 (83%) patients were treated in cohort 1, and 5 (17%) patients in cohort 2. Dose modifications were required in 13 (56.5%) patients in cohort 1, but only 2 (40%) patients in cohort 2. Common sunitinib-related side effects in cohort 1 included hypertension in 19 (79%), weight loss in 10 (41.6%), fatigue in 9 (37.5%) and nausea in 8 (33.3%) patients respectively. Overall, the use of ASIs correlated significantly with longer median TTP (10.5 months) compared to non-users (4 months) (p = 0.04). BMI ≥ 25 (TTP 9 vs. 3 months, p = 0.008) demonstrated a similar correlation. However, no difference in median TTP was noted between patients who had prior nephrectomy compared to those who had not (5 vs. 4 months) (p = 0.18). Conclusions: In this small retrospective study, standard sunitinib scheduling was associated with a high incidence of dose modifications and side-effects. Consistent with previous studies, we identified known prognostic variables. The use of sunitinib 50mg day 1-14 in 3 week cycles may be more tolerable for patients.

Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer.

BackgroundRegorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear.MethodsTumor attenuation as measured by Hounsfield units (HU) in contrast-enhanced computed tomography (CT) and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80) treated with regorafenib in a prospective study.Results141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%–20.7%). Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson’s r = 0.37, p = 0.002). Among 53 patients with lung metastases, 17 (32.1%) developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD) according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50) and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13).ConclusionRegorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies.

Abstract A2: Clinical implications of anti-angiogenic effect of regorafenib in metastatic colorectal cancer

Abstract Introduction: Regorafenib is an oral multikinase inhibitor, which has anti-angiogenic and anti-tumor activity by inhibition of a number of angiogenic and oncogenic kinases. It induces distinct radiological changes in metastatic colorectal cancer (mCRC), which are decrease in tumor attenuation and cavitation of lung metastasis. These changes may be a result of anti-angiogenic activity, but the clinical implications of the changes are unclear. This study was designed to analyze the radiological changes in association with treatment outcome in mCRC patients treated with regorafenib. Methods: All patients were a part of a main study entitled Identification of Predictive Biomarker of Regorafenib in Refractory Colorectal Cancer: A Prospective Explorative Study (NCT01996969). Tumor attenuation measured by Hounsfield units (HU) of contrast-enhanced computed tomography (CT) scan and cavitary changes of lung metastases were evaluated in mCRC patients (N = 80) treated with regorafenib (160mg orally once daily, on days 1-21 of a 28-day cycle). Maximum standardized uptake values (mSUV) of tumor lesions at baseline and after 2 cycles of treatment were analyzed in patients whose 18-fluoro-deoxyglucose positron emission tomography (PET)-CT images were available for analysis. Treatment outcome was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The association between radiological changes and treatment outcome was analyzed. Results: A total of 141 lesions in 72 patients were analyzed with HU measurement. After 2 cycles of regorafenib treatment, 87.5% of patients had a decrease in tumor attenuation. Median change in tumor attenuation was -23.9% (range -61.5% to 20.7%). Lesional attenuation changes were modestly associated with changes in mSUV in PET-CT scans (Pearson's r = 0.38, p&amp;lt;0.001). Among 53 patients with lung metastases, 17 patients (32.1%) developed cavitary changes after treatment. New cavitation was observed in 15 patients and 6 had increases in pre-existing cavity size. Neither of the radiological changes was associated with disease control rate, progression-free survival, or overall survival. At the time of progressive disease (PD) according to RECIST 1.1, tumor attenuation was lower than baseline in 86.0% (43/50) of patients and cavitary change of lung metastases persisted without refilling in 88.2% (15/17) of patients. Conclusions: Regorafenib showed prominent anti-angiogenic activity in mCRC represented by the radiological changes. Although the changes were not associated with treatment outcome, it was persistently observed at the time of PD by RECIST 1.1. The results suggest the possibility of inadequacy of current conventional response evaluation paradigm in treating mCRC patients with regorafenib. We may need to develop alternative evaluation and treatment strategies considering the anti-angiogenic activity. Citation Format: Yoojoo Lim, Sae-Won Han, Jeong Hee Yoon, Jeong Min Lee, Jung Min Lee, Jin Chul Paeng, Jae-Kyung Won, Gyeong Hoon Kang, Seung-Yong Jeong, Kyu Joo Park, Kyung-Hun Lee, Jee Hyun Kim, Tae-You Kim. Clinical implications of anti-angiogenic effect of regorafenib in metastatic colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A2.

A single centre retrospective analysis of the addition of clarithromycin (biaxin) to lenalidomide and dexamethasone (len-dex) during time of progressive disease in patients with multiple myeloma (MM)

A single centre retrospective analysis of the addition of clarithromycin (biaxin) to lenalidomide and dexamethasone (len-dex) during time of progressive disease in patients with multiple myeloma (MM)

A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer

BackgroundBicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). MethodsProstate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18months.Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline’s RandAll System. Subjects who completed 18months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blinded.Primary end-point was time to disease progression (TDP) up to 42months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication). FindingsThere was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n=62) compared with bicalutamide/placebo (n=65) (hazard ratio (HR)=0.94 [95% confidence interval (CI) 0.61, 1.46]; p=0.79). The estimated median TDP was 425days (95% CI 302, 858) in the bicalutamide/placebo group and 623days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non-White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups. InterpretationIn men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting.

Effects of pazopanib therapy on mean corpuscular volume in patients enrolled in MC1112: Analysis of correlation with time to disease progression in solid tumors.

e13596 Background: Pazopanib is a multi-targeted kinase inhibitor approved for use in renal cell carcinoma and soft tissue sarcoma and has also shown benefit in other cancers. Macrocytosis has been reported consequent to therapy with some kinase inhibitors (e.g. sunitinib, imatinib) but not previously with pazopanib. Interestingly, macrocytosis has been correlated with tumor response in some reports. We assessed both changes in Mean Corpuscular Volume (MCV) and its potential association with time to disease progression (TTP) observed in conjunction with a phase I pharmacokinetic (PK)-guided dose-individualized pazopanib clinical trial in solid tumors (MC1112, clinicaltrials.gov identifier: NCT01552356). Methods: We collected and analyzed MCV data on patients who received pazopanib as part of MC1112 from April 2012 to December 2014 (N = 35). Patients who discontinued therapy (N = 4) due to toxicity were censored for analysis of TTP. Logrank test was used to assess whether TTP differed with respect to MCV changes. Results: Changes in MCV associated with pazopanib therapy varied temporally: an initial drop in MCV was observed in 27/35 (77%) patients after 4 weeks of therapy [median: -1.41% (range: -4.77 to +4.83%)]; MCV increased progressively thereafter, and subsequently plateaued around cycle 6. Median change in MCV after 2, 3, 6 and 12 cycles were +1.8% (N = 32), +5.9% (N = 18), +13.3% (N = 12) and +11 % (N = 6) respectively. There was a trend towards increased TTP in patients with > 2% increase in MCV from baseline after 8 weeks of pazopanib therapy (p = 0.021). Conclusions: Pazopanib therapy is associated with initial drop in MCV after 4 weeks of therapy, followed by a progressive rise in MCV, reaching a plateau around cycle 6. MCV changes may be a biomarker of pazopanib antitumor effects; however, these findings need further validation in larger studies and across distinct tumor types. Supported by: UL1 TR000135 and CA186686 (NIH/NCI). Clinical trial information: NCT01552356.

Updated analysis of CALGB/ECOG/BMT CTN 100104: Lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma (MM).

8523 Background: CALGB 100104 studied Len vs. PBO maintenance following ASCT for newly diagnosed MM patients (pts), demonstrating improved time to progression (TTP), overall survival (OS) and increase in second primary malignancies (SPM) for Len at 34 months (mos) median follow-up. This is an updated intent-to-treat analysis of TTP, OS, and SPM at 65 mos median follow-up for OS. Methods: 460 pts age < 70 years with stable disease or better 100 days post ASCT were randomly assigned to Len (n = 231) vs. PBO (n = 229). Starting dose was 10 mg daily and was escalated to 15 mg daily after 3 mos. Primary endpoint was TTP (time of progressive disease (PD) or death from any cause). After several interim analyses, the study was unblinded at 18 mos median follow-up and 86/128 PBO pts without PD chose to cross over to Len. Results: SPMs diagnosed after randomization but before PD included 14 hematologic and 11 solid tumor SPMs in the Len arm vs. 3 hematologic and 7 solid tumor SPMs in the PBO arm (Table 1). Estimate...

Clinical effect of TKI dose-escalation after disease progression in patients with metastatic renal cell carcinoma.

4562 Background: Given the variability in drug levels with tyrosine kinase inhibitors (TKI) in patients (pts) with metastatic renal cell carcinoma (mRCC), escalation of dose at the time of progressive disease (PD) may have anti-tumor effect. Methods: Pts with mRCC who were treated at Cleveland Clinic with TKIs and were dose-escalated following PD per RECIST 1.1 were retrospectively reviewed. Patient and disease-related data were collected and summarized as frequency counts and percentages, or medians and ranges. The Kaplan-Meier method was used to summarize treatment duration on escalated doses. Results: Nineteen patients were identified. The majority of patients (84%) were male; median age was 58 (range, 40-71). The most common histology was clear cell (79%), 78% of pts were intermediate risk by IMDC criteria, and all but one patient had prior nephrectomy. Axitinib was the most frequently escalated agent following disease progression (89%); starting at 5mg BID and generally escalating by 1-2mg BID as tol...

Paclitaxel liposome combined with cisplatin chemotherapy in non-small cell lung cancer with brain metastasis

Objective To evaluate the clinical efficacy and toxicity of paclitaxel liposome combined with cisplatin chemotherapy in NSCLC with brain metastasis. Methods Twenty-eight patients were newly diagnosed NSCLC with brain metastasis (confirmed by pathology or cytology). The patients were treated with paclitaxel liposome (135 mg/m2) on day 1 intravenous drip for 3 hours, cisplatin, 25 mg/m2 on day 1-3. The course of treatment was 21 days. The patients accepted the anti-allergy treatment before chemotherapy. Results Twenty-eight patients could be evaluated, and 101 treatment cycles were completed (3.6 cycles per patient). General lesion assessment presented that no patient got complete remission (CR), 13 patients (46.43%) got a partial response (PR), 11 (39.28%) had a stable disease(SD) and 4 (14.29%) had a progressive disease (PD). The objective response rate (RR) was 46.43%, and the disease control rate (DCR) was 85.71%. Local cerebral response assessment showed that no patient got CR, 6 patients (21.43%) got a PR, 15 (53.58%) had a SD and 4 (14.29%) had a PD. The RR was 21.43%, and the DCR was 85.71%. There was a significant difference in the RR (χ2=3.90, P=0.03) but not in the DCR (χ2=0.15, P=0.3) between the local cerebral disease and the general lesion. The median time to disease progression (TTP) for general lesion and local cerebral were 7.2 months and 6.2 months, respectively (χ2=6.43, P<0.05). The adverse reactions included bone marrow suppression, gastrointestinal reactions, elevated transaminases, alopecia, neurotoxicity, etc. All of these could be well controlled. Conclusion Paclitaxel liposome combined with cisplatin regimen demonstrates a higher efficacy and well tolerable against main metastasis of NSCLC, and the adverse effects are minor. Key words: Lung neoplasms; Neoplasm metastasis; Cisplatin; Paclitaxel liposome

Pulmonary Metastasectomy Could Prolong Overall Survival in Select Cases of Metastatic Urinary Tract Cancer

BackgroundThe purpose of the study was to evaluate the efficacy of metastasectomy for urinary tract carcinoma (UTC) and to determine prognostic factors that affect survival. Patients and MethodsData from a total of 30 patients with metastatic UTC who underwent a metastasectomy between February 2000 and July 2014 were analyzed retrospectively. Time to disease progression (TTP) and overall survival (OS) from metastasectomy, and potential prognostic factors were evaluated. ResultsThe lung was the most frequent site of metastasectomy (n = 24) followed by the liver (n = 3) and lymph nodes (n = 3). With a median follow-up duration of 54.2 months, the median TTP was 15.2 months and the median OS was 30.0 months (95% confidence interval, 15.1-42.9) with a 3-year survival rate of 41%. In multivariate analysis, initial stage IV disease (P = .047), pure urothelial pathology (P = .034), and nonpulmonary metastasectomy (P = .040) were independent prognostic factors for a shorter TTP. Nonpulmonary metastasectomy was an independent factor affecting OS (P = .001). ConclusionA metastasectomy has the potential to contribute to better oncologic outcome in select patients with metastatic UTC, especially those with a single rather than multiple and pulmonary rather than nonpulmonary metastases due to recurrent rather than initially metastatic urinary tract cancer.

Efficacy and adverse events of transcatheter arterial chemoembolization in combination with sorafenib in the treatment of unresectable hepatocellular carcinoma.

The aim of the present study was to assess the association between the efficacy and adverse events (AEs) of transcatheter arterial chemoembolization (TACE) combined with sorafenib in patients with unresectable hepatocellular carcinoma (HCC). Between July 2008 and May 2011, 50 patients with unresectable HCC were enrolled and assigned to receive TACE combined with sorafenib in the present study. The primary outcomes were considered as time to disease progression (TTP) and sorafenib-related AEs. In the present study, 34 of 50 patients had disease progression with a median TTP (mTTP) of 210 days. The most common AEs included hand-foot skin reaction (HFSR), fatigue, diarrhea and hypertension. The mTTP of patients with HFSR extended 140 days compared to that of the patients without HFSR. Kaplan-Meier analysis was used for mTTP between the two groups of patients. This difference was statistically significant when analyzed by the univariate COX proportional hazards regression model. In conclusion, TACE in combination with sorafenib had an acceptable safety profile in the treatment of unresectable HCC. Additionally, it also revealed that HFSR served as a good prognostic predictor in using combination therapy. Therefore, discontinuation of sorafenib treatment should be prevented to avoid disease progression.