Improvement In Median OS Research Articles

Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Nonmetastatic Pancreatic Adenocarcinoma.

Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. From the 2006-2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p<0.05). SAS (HR 0.79; CI 0.76-0.81; p<0.001) and GRT (HR 0.67; CI 0.65-0.69; p<0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2years vs 1.1 years; p<0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p<0.001). Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.

The impact of ImmunoPrecision in small bowel adenocarcinoma.

e16333 Background: Although approaches to treating adenoCA of the small bowel (SBA) are extrapolated from those of the colon, SBA has distinct pathogenesis, clinical presentation and poorer prognosis. We examine the impact of SBA treatment by ImmunoPrecision, which combines Immunotherapy and Precision genomic targeting. Methods: SBA pts were identified retrospectively from Cedars-Sinai electronic health record (2000 – 2022) on an IRB-approved protocol. Microsatellite status and genomic testing were done in CLIA-certified, CAP-accredited labs. Pt characteristics, pathology, in-depth clinical history and genomics were summarized with descriptive statistics. Endpoint of median OS was estimated by Kaplan-Meier and calculated from pre-treatment imaging to last event. Treatment groups were compared using log-rank test. Results: Between Jan 2003 – Dec 2022, 137 stage 1 – 4 SBA pts (93 duodenal; 44 jejunal/ileal) were identified. Median age was 67 (range 22 – 95). Microsatellite status and genomic testing data were done or known for 72 pts (53%). In 35 pts who had metastases at initial presentation, 15 pts had NGS genomics, which identified actionable targets: 20% Her2amp/mut, 13% FGFR1amp/mut, 7% ALKfusion, 7% KRAS G12C, and 7% ATM R35*. 40% of 10 metastatic pts tested for microsatellite status were MSI/TMB-High, and only 1 pt received immunotherapy. In pts with metastases, median OS was 9.5 mo in duodenal adenoCA (51 pts) vs 13.0 mo in jejunal/ileum adenoCA (23 pts) (p = 0.46). There was a non-significant improvement in median OS to 20.5 mo in metastatic duodenal adenoCA pts who received targeted inhibition of actionable genomics or had MSI/TMB-High status (p = .51). Conclusions: Our real-world cohort of metastatic duodenal adenoCA shows a trend toward improved median OS from ImmunoPrecision targeting of frequent MSI/TMB-High status and actionable genomics. ImmunoPrecision clinical trial investigation is warranted in this rare SBA population. [Table: see text]

Estimation of time cost of anti-cancer drugs approved based on comparisons to best supportive care: A cross sectional analysis

BackgroundFinancial costs from cancer treatment are increasingly recognized, but what has historically been underrecognized is the time cost of therapy. We sought to estimate the time burden of anti-cancer drugs approved based on comparisons to best supportive care (BSC), with the assumption that without this drug, a patient could have been treated with observation, home palliative care or hospice services, with minimal time seeking medical care. MethodsWe searched all FDA approvals (2009 - March 2022) for randomized trials that used BSC as a treatment option for an anti-tumor drug in the metastatic setting and abstracted data on treatment related activities. We then estimated time spent on these activities using previously calculated times. ResultsOf the 13 drugs tested against BSC, nine studies demonstrated an improvement in median OS (median 2.1 months). The median monthly time spent for patients in the intervention arm of BSC trials was 15.8 h. ConclusionTime is a valuable resource for people who have cancer, but especially for patients who may have few to no remaining treatment options, and yet, we found that patients can spend up to 16 h in anti-cancer drug related activities per month. Policy summaryBecause survival outcomes are variable for patients being treated in later lines of therapy, time resources are a valuable consideration in the treatment plan.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Management of Colorectal Cancer with Peritoneal Dissemination: 30 Years of Experience at a Single Institution.

Cytoreductive surgery (CRS) is at the forefront of treatment for colorectal cancer with peritoneal metastasis or "carcinomatosis" (CRC-PC). We report outcomes of the operative management of CRC-PC at a single center. We retrospectively reviewed our database from 1992 through 2021. The Kaplan-Meier method was used to estimate survival. Proportional hazards regression and multivariable models were used for assessments. This study included 345 patients with mean age 53.5 years. Multivariate analysis revealed performance and resection status were associated with overall survival (OS; p < 0.001). Within the R0/R1 group, adverse impact on OS was found with increasing Peritoneal Cancer Index (PCI) score starting at 9 (hazard ratio [HR] = 1.98, CI 1.39-2.82, p = 0.0001) with the most significant hazard noted at PCI >14 (HR = 2.35, CI 1.52-3.63, p = 0.0001). Incomplete resection (R2) had significantly worse OS compared with complete CRS 33.4 (n = 206) vs R2: 12.7 months (n = 139; p < 0.0001. When stratified by PCI for the R0/R1 group, median OS for PCI less than 10, 10 to 15, and greater than 15 was 38.2, 19.7, and 22.2 m, respectively (p = 0.0007 comparing PCI less than 10 and greater than 15). Ten-year increments-1991 through 2000, 2001 through 2010, 2011 through 2020-revealed improvement in median OS (13.4 [n = 66], 19.3 [n = 139], and 29.1 months [n = 140]). However, by resection status, median OS remained stable for R0/R1 (32.3 [n = 23], 31.1 [n = 76], and 34.1 months [n = 107]) and improved for R2 (5.2 [n = 43], 14.4 [n = 63], and 14.6 months [n = 33]). Clavien-Dindo complication rate (greater than or equal to grade III) was 29.4%. CRS improves outcomes for CRC-PC compared with historic outcomes with nonoperative management. This benefit is greatest with complete resection and lower disease burden. Results of CRS (with or without heated intraperitoneal chemotherapy) are improving, and surgery for CRC-PC should be routinely considered.

Abstract SP085: Metastatic TNBC - What’s new on the horizon?

Abstract Until very recently, the treatment for locally advanced or metastatic breast cancer revolved solely around sequential chemotherapies, alone or in combination. With the increasing recognition that triple negative breast cancers are a very heterogeneous group of tumors, exciting new strategies have emerged. Here we review some of the recent advances to standard chemotherapy now in clinical use as well discuss new strategies in development. Immunotherapy: There is currently an indication for nab-paclitaxel and atezolizumab for patients with locally advanced or metastatic triple negative breast cancer with PD-L1 positive tumor-infiltrating immune cells. The Impassion130 study first presented a median PFS of 7.2 months with nab-paclitaxel and atezolizumab vs. 5.5 months of nab-paclitaxel and placebo (HR 0.80; 95% confidence interval (CI) 0.69-0.92). Further analyses showed no benefit in the PD-L1 negative group.1 An exploratory overall survival analysis in the PD-L1+ subset showed an increase in the atezolizumab group of 25 months vs 18 in the control group.2 Immunotherapy for metastatic breast cancer will be presented in greater detail in another talk in this session. Sacituzumab govitecan: Sacituzumab govitecan is an antibody-drug conjugate (ADC) targeting Trop-2 and linked with SN-38, the active metabolite of irinotecan and a potent DNA- damaging agent. Trop-2 has been estimated to be expressed in up to 90% of TNBC, making it an attractive target for an ADC. Sacituzumab govitecan was conditionally approved for use after the Phase I/II trial demonstrated and objective response rate of 33.3% and a median overall survival of 13.0 months.3 The recently presented phase III ASCENT trial evaluated patients with metastatic TNBC who had at least 2 previous lines of therapy in the metastatic setting. There was an improvement in median PFS from 1.7 to 5.6 months for patients who received sacituzumab vs. physician’s choice of therapy. The HR for PFS was 0.41; 95% CI: 0.32-0.52) Additionally, there was an improvement in median OS of 6.7 to 12.1 months (HR 0.48; 95%CI:0.38-0.59).4PARP Inhibitors: There are now 2 PARP inhibitors that have FDA approval for use for patients with metastatic breast cancer and a germline BRCA pathogenic variant.5,6 Both Olaparib and Talazoparib demonstrated improvements in PFS which led to FDA approval. While neither the OlympiAD (olaparib) nor the EMBRACA (talazoparib) trial showed statistically significant improvement in OS, both trials showed a significant improvement in quality of life measures. Future Directions: Ongoing trials evaluating further ADCs, targeted therapies and drugs targeting DNA Damage Repair pathways for both germline and somatic pathogenic variants will be discussed 1.Schmid P, Adams S, Rugo HS, et al: Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. NEJM 379:2108-2121, 20182.Schmid P, Rugo HS, Adams S, et al: Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer The Lancet Oncology 21:44-59, 20203.Bardia A, Mayer IA, Diamond JR, et al: Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer. J Clin Oncol 35:2141-2148, 20174.Bardia A, Tolaney S, Loirat D, et al: ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Annals of Oncology 31:S1142-S1215. 10.1016/annonc/annonc325, 20205.Robson M, Im S-A, Senkus E, et al: Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. NEJM 377:523-533, 20176.Litton JK, Rugo HS, Ettl J, et al: Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. NEJM 379:753-763, 2018 Citation Format: J Litton. Metastatic TNBC - What’s new on the horizon? [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP085.

Alliance/CALGB 80802: Impact of hepatitis C (HCV) on doxorubicin (DO) + sorafenib (S) versus S in patients (pts) with advanced hepatocellular carcinoma (aHCC).

325 Background: Alliance/CALGB 80802 randomized phase III trial evaluated DO+S vs. S in pts with aHCC, and showed no improvement in median OS. Multi-drug resistant pathway mitigation by the Ras/Raf/MEK/ERK pathway and bFGF-mediated activation of Raf-1 promotes the formation of antiapoptotic Raf-1 and ASK1 complex, induced by anthracyclines. S efficiently blocks NS5A-recruited c-Raf mediated HCV replication and viral gene expression. Once inhibited by S, VEGF expression of HepG2 may limit HCV cellular entry. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via S putatively differ in the presence or absence of DO. We hypothesize treatment with S reduces HCV titer levels (TL) and influence pts’ outcome. Methods: In 80802 HCV pts, TL were evaluated in both arms at baseline and post-baseline at Day 1 of Cycles 2, 3, and every 2 cycles and at progression or discontinuation of therapy. HCV undetectable (HCV-UN) levels were defined as &lt; 50 copies/mL. TL were evaluated in relation to OS and PFS. HCV RNA levels were measured by TaqMan PCR and by genotype. Results: Of 356 pts, 83 were HCV+ with more Black/African American (25/50 = 50%) vs. White (54/239 = 23%) or other race groups (4/67 = 6%) (p &lt; 0.0001). HCV titer data were available on 54 pts (S: 28, DO+S: 26). At baseline, 12 pts (S: 7, DO+S: 5) were HCV-UN, and post-baseline HCV TL did not significantly differ between treatment arms; one patient in each arm went from detectable (HCV-D) to HCV-UN. Post-baseline, 40 pts were HCV-D vs. 14 who were HCV-UN (S+DO: 8, S: 6 pts). Except for the two pts who became HCV-UN, baseline HCV-D vs. HCV-UN titers was similar to that status post-baseline. PFS and OS between HCV-D and HCV-UN both at baseline and post-baseline are delineated in the table. Conclusions: We observed that S did not influence HCV TL. Pts treated with DO+S vs. S had worse PFS if they had HCV-UN, and further that higher levels of HCV titers at baseline were associated with significantly improved PFS. Given the small sample size, these findings warrant further prospective evaluation. Support: U10CA180821, U10CA180882, U24CA196171; Bayer, Bristol-Myers-Squibb, and Sanofi. https://acknowledgments.alliancefound.org . Clinical trial information: NCT01015833. [Table: see text]

Accrual Barriers and Detection of Early Toxicity Signal in Older Less-Fit Patients Treated with Azacitidine and Nivolumab for Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS) in the SWOG 1612 Platform Randomized Phase II/III Clinical Trial

Accrual Barriers and Detection of Early Toxicity Signal in Older Less-Fit Patients Treated with Azacitidine and Nivolumab for Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS) in the SWOG 1612 Platform Randomized Phase II/III Clinical Trial

A Double-Blind, Placebo-Controlled, Phase 3 Registration Trial to Evaluate the Efficacy of Uproleselan (GMI-1271) with Standard Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia

A Double-Blind, Placebo-Controlled, Phase 3 Registration Trial to Evaluate the Efficacy of Uproleselan (GMI-1271) with Standard Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia

ACTR-60. A PHASE 2, HISTORICALLY CONTROLLED STUDY TESTING THE EFFICACY OF TTFIELDS WITH ADJUVANT TEMOZOLOMIDE IN HIGH-RISK WHO GRADE II AND III ASTROCYTOMAS (FORWARD)

Abstract BACKGROUND A long-standing observation in neuro-oncology concerns a group of patients with WHO Grade II and III gliomas expressing isolated hTERT promoter mutations, which exhibit indolent histological features but are highly aggressive and resistant to standard chemoradiation therapy. These patients show an overall survival rate similar to glioblastoma WHO Grade IV, necessitating new treatment options. This represents the first study of its kind testing novel treatment for this rare subgroup of lower grade gliomas with high-risk cytogenetics. METHODS This Phase 2, single arm, multicenter open label study [NCT03906448] will enroll 100 adult patients with newly diagnosed WHO grade II and III astrocytoma without IDH mutations and 1p/19q codeletions and with isolated hTERT promoter mutations who have completed standard radiotherapy with concurrent temozolomide, followed by adjuvant temozolomide for 12 cycles in combination with 24 months of TTFields therapy. The primary endpoint is overall survival compared to historical controls. Secondary endpoints are safety, quality of life, and progression free survival. Correlative studies will examine the effect of TTFields on intratumoral immune microenvironment and the role of electric field distribution on disease control and outcomes. Sample size was based on improvement in median OS versus historical controls (N=59; median survival 22 months). Improvements in median overall survival was based on a one-sided Wald test of the Weibull regression coefficient (H0: beta=0, alpha=0.05). A consortium of 15 institutions across the US will participate, with the first enrollment May 2019. Total accrual of 100 is planned over 36 months. The survival results and the correlative studies are designed to provide new insights for future therapeutic development for these patients.

The Impact of Adjuvant Chemotherapy on Survival in Pancreatic Cancer after Neoadjuvant Treatment

The benefit of adjuvant chemotherapy after neoadjuvant chemotherapy and surgery in patients with non-metastatic pancreas cancer is unknown. We analyzed patients with non-metastatic pancreatic cancer using the National Cancer Database (NCDB) for patients diagnosed between 2006 and 2014. All patients received neoadjuvant chemotherapy (NAC) followed by pancreatectomy. Patients were analyzed according to whether or not they received neoadjuvant chemotherapy (NAC) only or neoadjuvant chemotherapy plus adjuvant chemotherapy (NAC + AC). The primary endpoint was OS from the time of diagnosis. Propensity-score matching was used to account for differences in baseline characteristics. Kaplan-Meier and Cox proportional hazard modeling were used to analyze OS. A total of 2,517 patients were included for analysis; 1,820 in the NAC group, and 697 in the NAC + AC group. Neoadjuvant radiation was received by 51% of patients. After propensity score matching, well-balanced groups of 267 patients were analyzed. After median follow-up of 21.1 months in the NAC group, and 23.9 months in the NAC + AC group, there was a statistically significant improvement in median OS for those treated with NAC + AC (31.1 months, 95% CI: 26.1 – 37.9 months), compared to those who received NAC only (25.6 months, 95% CI: 22.1 – 29.1 months, p=0.014). The 1-year, 3-year, and 5-year OS rates for the NAC + AC group were 90.3%, 45.9%, and 18.9%, respectively. For the NAC group, the 1, 3, and 5-year OS rates were 82.5%, 34.5%, and 15.7%, respectively. After shared frailty Cox UVA, the addition of AC to NAC was found to decrease the risk of death (HR 0.74, p=0.01). On subgroup analysis, patients with ypN+ had improved OS with the addition of AC (HR 0.71, p=0.024), while those with ypN0 did not (HR 0.78, p=0.17). In patients with non-metastatic pancreatic cancer treated with neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy (NAC + AC), there was a statistically significant improvement in OS compared to those treated with neoadjuvant chemotherapy and surgery alone (NAC). This improvement in OS was only seen in ypN+ patients on subgroup analysis.

Abstract OT3-06-01: SHERBOC: A double-blind, placebo-controlled, phase 2 trial of seribantumab (MM-121) plus fulvestrant in postmenopausal women with hormone receptor-positive, heregulin positive, HER2 negative metastatic breast cancer whose disease progressed after prior systemic therapy

Abstract Background: The receptor tyrosine kinase, HER3 and its ligand, heregulin (HRG), have been implicated in the initiation and progression of multiple cancer types including: breast, lung, and head &amp; neck cancers. Seribantumab is a fully human, monoclonal IgG2 antibody that binds to the ligand-binding domain of HER3 and inhibits HRG-mediated signaling. Previously, seribantumab was tested in combination with exemestane in a placebo-controlled, Phase 2 study in post-menopausal women with ER/PR+, HER2 negative metastatic breast cancer (mBC). Although the trial failed to meet its primary efficacy objective of a 50% reduction in hazard ratio in the seribantumab/exemestane treatment vs. the placebo/exemestane control group, a positive trend in PFS and a statistically significant improvement in median OS was observed in patients in the seribantumab/exemestane treatment group. Seribantumab has also been tested in three randomized Phase 2 studies adding to standard of care (SOC) in non-small cell lung, ER/PR+ mBC, and platinum resistant/refractory ovarian cancer. These studies were retrospectively analyzed to determine correlation between HRG mRNA levels in tumor tissue and PFS. In each of these studies, the presence of tumor cell HRG mRNA was prognostic for shortened PFS with SOC treatment. Further, the addition of seribantumab to SOC therapy improved PFS for patients with HRG+ tumors. These data support the hypothesis that HRG expression may define a drug tolerant cancer cell phenotype characterized by poor response to multiple classes of cytotoxic and targeted therapies, including aromatase inhibitors and SERDs. Additionally, blockade of HRG-induced HER3 signaling by seribantumab may counter such protective effects of HRG on cancer cells, with the potential for improved outcomes in HRG+ patients. It is estimated that ˜45% of hormone-receptor positive, HER2 negative advanced breast cancers are HRG+ and that HRG expression may contribute to accelerated clinical progression observed in this subset of patients. Trial design: In the upcoming randomized, double-blinded, multi-center, Phase 2 study, ER/PR receptor-positive, HER2 negative mBC patients with HRG+ tumors will be prospectively selected using a HRG RNA in situ hybridization assay. Approximately 200 women will be screened to enroll 80 HRG+ subjects. Eligible subjects will be randomized in a 1:1 ratio to receive seribantumab/fulvestrant or placebo/fulvestrant until investigator-assessed disease progression or unacceptable toxicity, whichever comes first. Subjects will have progressed on one or two prior hormonal therapies, one of which must have been a CDKi-containing regimen. The goal of this study is to determine if the combination of seribantumab + fulvestrant is more effective than placebo + fulvestrant based on PFS (primary end point) in HRG positive subjects. Secondary endpoints include OS, objective response rate, and time to progression. Safety will also be assessed. Enrollment is expected to begin in 2017 at approximately 80 sites globally. Citation Format: Kaufman PA, Pipas M, Finn GJ, Mathews SE, Zhang H, Richards J, Kudla AJ, Bloom T, Zalutskaya AA, Llorin-Sangalang J, Pinto AC, Ettl J. SHERBOC: A double-blind, placebo-controlled, phase 2 trial of seribantumab (MM-121) plus fulvestrant in postmenopausal women with hormone receptor-positive, heregulin positive, HER2 negative metastatic breast cancer whose disease progressed after prior systemic therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-01.

Gemcitabine (G) + nab-paclitaxel (nab-P) versus G in patients (pts) with advanced pancreatic cancer (PDAC) after FOLFIRINOX: A single center, retrospective review.

348 Background: The MPACT study showed that G + nab-P improved OS and PFS over G as first line therapy for metastatic PDAC. However, there is limited data studying this combination after FOLFIRINOX. Here, we compared G + nab-P to G in pts with advanced PDAC previously treated with FOLFIRINOX. Methods: From 3/2010 to 5/2014, we identified all pts treated with FOLFIRINOX for PDAC who later received G +/- nab-P at the MGH. PFS and OS were calculated from the start of G +/- nab-P and analyzed using Kaplan-Meier and Cox-regression analyses. Results: 40 pts received G + nab-P and 36 pts received G. 29 of 36 pts in the G arm started G prior to the FDA approval of nab-P. Baseline characteristics were similar except 7 pts in the G + nab-P arm had locally advanced PDAC at start of G + nab-P while all other pts in both arms had metastatic PDAC. The median OS was 4.8 months (m) for G + nab-P vs 4.2m with G (HR 0.69, 95% CI 0.42 – 1.13). The median PFS was 2.4m for G + nab-P vs 1.8m for G (HR 0.70, 95% CI 0.44-1.12). The median OS did not change when the analysis was restricted to pts with metastatic PDAC – 4.8m vs 4.2m (HR 0.68, 95% CI 0.41-1.14). The median PFS for pts with metastatic PDAC was also similar – 2.7m for G + nab-P vs 1.8m with G (HR 0.69, 95% CI 0.42-1.12). Pts treated with G + nab-P received a median of 4m of treatment vs 2m for pts with G alone. The median relative dose of G was 50% of the maximum anticipated dose over the first 8 weeks for G + nab-P vs 66% with G. The median relative dose for nab-P was 50% of the maximum anticipated dose over the first 8 weeks. The most common reasons for discontinuing therapy were progression (62.5% vs 69%), patient decision (5% vs 11%), and infection (12.5% vs 0%). Conclusions: Although retrospective and limited by a small sample size, our data suggests that G + nab-P could be considered over G for advanced PDAC after FOLFIRINOX. However, G + nab-P affords marginal improvement in median OS and PFS, thus calling for the need to explore other agents in the second-line setting. Moreover, our experience suggests that the addition of nab-P led to a reduction in the achievable dose of G – raising the question of tolerability in combining further agents to G + nab-P in this setting.

Persistent Disparities Among Patients With T-Cell Non-Hodgkin Lymphomas and B-Cell Diffuse Large Cell Lymphomas Over 40 Years: A SEER Database Review.

As of 2013, more than 550,000 people are living with non-Hodgkin lymphoma (NHL). We undertook a large Surveillance Epidemiology and End Results (SEER) based analysis to describe outcome disparities in different subgroups of aggressive T-cell and B-cell NHL patients, with a focus on various ethnicities. The final analysis included 7662 patients with T-cell and 84,910 with B-cell NHL. Survival analysis revealed that male sex and increasing age were independent predictors of worse overall survival (OS; P < .001). For aggressive T-cell NHL, there was no significant improvement in median OS between 1973 and 2011 (P = .081), and ethnic minorities (Asians, Hispanics, and African Americans) had significantly worse OS than whites (P < .001). There were similar trends for age, sex, and race for diffuse large B-cell NHL, but a significant improvement in median OS was seen over time (P < .001). These results are the first to elicit outcomes in a broad classification of ethnic minorities and underscore the urgency for development of novel therapeutics, especially in T-cell NHL. In addition, in-depth studies of disease biology and health care utilization are required for better triage of health care resources, especially for ethnic minorities.

Outcome Disparities in T-Cell Non-Hodgkin Lymphoma and the Lack of Significant Improvement over the Years: A SEER Database Review

Background: As of 2013, approximately 558,340 people are living with non-Hodgkin lymphoma (NHL). Outcome disparities have been reported in lymphoid malignancies but a comprehensive analysis, especially with expanding ethnic minorities is necessary. We undertook a large Surveillance Epidemiology and End Results (SEER) based analysis to describe outcome disparities in different subgroups of T-cell and B-cell NHL patients (pts), with a focus on various ethnicities.Methods: The SEER 18 Registry data (1973-2011) was utilized for pts with a confirmed diagnosis of T-cell or B-cell NHL. Cases that received a diagnosis at death certificate or autopsy, no follow-up records, no documented age at diagnosis, sex, or race/ethnicity were excluded. Cox proportional hazards models, adjusted for gender, age, race, year (yr) of diagnosis, and stratified by SEER registries were used to evaluate association between pt characteristics and survival. All statistical tests were two-sided and utilized the SAS software (v9.4) with a two-sided significance level of 0.05.Results: The final analysis included 7,662 pts with T-cell NHL and 84,910 pts with B-cell NHL. The pt demographics are shown in Table 1. Pts were stratified based on yr of diagnosis to study the impact of therapeutic developments on pt outcomes (Table 1). Pts were also divided by T-cell NHL subtype: mature T-cell (9702/3) 51%, angioimmunoblastic T-cell (9705/3) 16%, anaplastic large cell (ALCL) (9714/3) 32%, and hepatosplenic gamma-delta cell (HSϒd) (9716/3) 0.8%. Median age at diagnosis was youngest for AA pts (54 yrs) and oldest for Asian pts (65 yrs) (Figure 1 A). Survival analysis revealed that females had a better median OS than males (3.3 yrs vs. 2.3 yrs, HR 0.876; 95% CI 0.824, 0.932; p<0.001). Increasing age was an independent predictor of worse overall survival, with pts age 18-44 having a median OS 9.4 yrs (HR 0.345; 95% CI 0.312, 0.382) and pts age ≥75 having a median OS of 1.0 yr (p<0.001). There was no statistically significant difference seen in median OS for pts with respect to yr of diagnosis (p=0.081). Among the different T-cell NHL subtypes, pts with ALCL had the best (3.8 yrs, HR 0.766; 95% CI 0.714, 0.822) and pts with HSϒd had the worst median OS (0.7 yrs HR 1.959; 95% CI 1.424, 2.695) (p<0.001). AA pts (1.7 yrs, HR 1.292; 95% CI 1.176, 1.419) and Hispanic pts (1.9 yrs, HR 1.215; 95% CI 1.087, 1.357) had significantly worse OS compared to White pts who had the longest median OS (3.1 yrs) (p<0.001) (Figure 1 B). To compare and contrast with aggressive B-cell NHL, similar analyses were performed using diffuse large B-cell (DLBCL) NHL (9680/3). DLBCL showed similar trends regarding sex, age and race. Ethnic minorities had significantly worse median OS including Hispanic (2.8 yrs, HR 1.154; 95% CI 1.111, 1.198) and AA pts (3.3 yrs, HR 1.261; 95% CI 1.212, 1.312) compared to White pts with a median OS of 5.8 yrs (p<0.001). B-cell NHL pts had a significant improvement in median OS over time with pts diagnosed in 2007-2011 having more than 3 times the median OS of pts diagnosed in 1973-1991 (7 yrs vs. 2.4 yrs; p<0.001).Conclusions: Studies of outcome disparities are important for evaluating disease characteristics and their relationship to specific pt populations over time. We have performed the largest population-based analysis for T-cell and B-cell NHL including various ethnicities in the novel therapeutic agent era. We observed that males, older pts and ethnic minorities had worse median OS for both T-cell and B-cell NHL. Despite novel therapeutics targeting T cells there has been no statistically significant improvement in OS over time. In contrast, significant improvement in B-cell NHL OS has been noted, presumably due to the advent of monoclonal antibodies. These results underline the urgency for the development of novel therapeutics as well as aggressive studies of disease biology and healthcare utilization for better triage of healthcare resources, especially for ethnic minorities. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract A28: Immune responses to mutated Ras - development of a yeast-based immunotherapeutic

Abstract Background: While mutations in the ras gene and corresponding product are known to be etiologic in a number of human cancers, efforts to block the mutated protein have been largely unsuccessful leading to its characterization as “undruggable.” We have taken an alternative approach involving generation of T cell responses to the mutated protein. GI-4000 is a series of proprietary immunotherapeutics designed to target cells with activating ras mutations using heat-killed Saccharomyces cerevisiae yeast (named Tarmogens: Targeted Molecular Immunogens) genetically engineered to express Ras G12 and Q61 mutations. Tarmogens activate antigen-specific T cell-mediated immune responses that kill target cells expressing a number of cancer antigens including mutated Ras. Activating mutations in ras occur in &amp;gt; 90% of pancreas cancer cases and &amp;gt;20% cases of NSCLC. GI-4000 has been evaluated in phase 2 trials in both these indications. GI-4000 has demonstrated: i) protection in a murine model of lung cancer (1), ii) in the pancreas trial, improvements in median RFS and OS vs placebo in subjects with a favorable proteomic signature (2), iii) also in the pancreas trial, 3 month improvement in median OS (p=NS) in R1 subjects, with 5 month improvement for immune responders (2), iv) improved OS in subjects with NSCLC treated with GI-4000 compared to case matched controls: HR=0.577, p=NS. In addition, Tarmogens specific for other oncologic targets decreased human regulatory T cells (Tregs) in vitro with a reciprocal increase in effector T cells (3). Here we discuss immunologic outcomes in R0 subjects enrolled in the pancreas cancer trial. Methods: In the pancreas cancer study 176 subjects with Ras mutant+ adenocarcinoma of the pancreas post resection were randomized 1:1 to GI-4000/gemcitabine or placebo/gemcitabine (stratified by resection status: R0/R1). Three weekly injections of GI-4000 or placebo were followed by 6 cycles of gemcitabine 1000 mg/m2 iv (day 1, 8, 15, then every 28 days). Monthly GI-4000 or placebo were administered on gemcitabine off-weeks and continued monthly until disease recurrence, intolerable toxicity or death. R0 subjects (n=102) with adequate blood samples available from timepoints throughout the study were assayed for immune response by interferon-γ (IFNγ) ELISpot assay using Ras peptide pools containing the G12 mutation present in the subject's tumor and a mismatched peptide set identical to the mutation-specific set except at G12. Frequencies of Tregs at baseline and pre-gemcitabine were measured by flow cytometry (n=76). Results: In contrast to the R1 group, there was no increase in Ras mutation-specific IFNγ responses in the R0 GI-4000 group compared to placebo: 16/52 (30.8%) vs 22/50 (44.0%) based on pre-specified criteria. However, naive Tregs (CD4+/CD45RA+/Foxp3low) in the GI-4000 treated group were significantly decreased compared to placebo: 11/42 (26.2%) vs 3/34 (8.8%) subjects had a &amp;gt;2-fold decrease in this fraction (p=0.048 Fisher's exact test). IFNγ responses and OS were strikingly influenced by G12 mutation and associations of specific Ras mutations with outcome will be discussed. Conclusions: GI-4000 decreases frequencies of Tregs, which could be an important attribute for an immunotherapeutic in the treatment of cancer. GI-4000 also generates mutation-specific immune responses and appears to have clinical activity in pancreas cancer and NSCLC. Immune targeting of the activating mutation may be a promising approach to Ras mutated cancers.

756O - Chemohormonal Therapy Versus Hormonal Therapy for Hormone Naïve High Volume Newly Metastatic Prostate Cancer (Prca): Ecog Led Phase III Randomized Trial

ABSTRACT Aim: Androgen deprivation therapy (ADT) is standard therapy for metastatic PrCa and although most respond, many develop castration resistant prostate cancer (CRPC). Patients with high volume disease have poorer outcomes compared with low volume patients. Docetaxel (D) prolongs the overall survival of men with CRPC and we aimed to see if D improves overall survival when given at time of starting ADT. Methods: 1:1 randomization to ADT alone or ADT + D at 75mg/m2 every 3 weeks for 6 cycles within 4 mos of ADT. Stratification factors: high volume (HV) vs. low volume (LV) disease (HV: visceral metastases and/or 4 or more bone metastases with at least one outside of the vertebral column and pelvis); Anti-androgen use beyond 30 days; Age ≥70 vs. 12 vs. ≤ 12 mos (mos); FDA approved drug for delaying skeletal related events. Key eligibility criteria: suitable organ and neurological function for D; adjuvant ADT ≤ 24 mos and no progression within 12 mos of adjuvant ADT. Overall survival was the primary endpoint with an improvement in median OS of 33.3% (80% power and 1-sided alpha = 2.5%). Projected median OS for ADT alone: HV-33 mos; LV - 67 mos. Results: 790 men were accrued from 7/28/06 to 11/21/2012: ADT n = 393; ADT + D: 397; balanced for demographic, stratification and disease factors. Median age: 63 years (range: 36 to 91); 99% ECOG PS 0 or 1; 89% Caucasian; 24% prior prostatectomy; HV 64% on ADT and 67% on ADT + D. ADT + D: Gde 3/4 Neutropenic fever: 4/2%; Gde 3 neuropathy: 1% sensory, 1% motor; 1 death due to treatment was in the LV subset (no death on ADT alone). Efficacy data for high volume subset of pts in table 1. Conclusions: ADT + D improves disease control and OS over ADT alone in men with HV disease. NCT00309985 Disclosure: C. Sweeney: Consultant with compensation: Sanofi; M. Carducci: Compensated consultant; M. Eisenberger: Compensated consultant. All other authors have declared no conflicts of interest. Intent to treat Analysis High Volume Pts ADT N = 253 ADT + D N = 265 p-value Hazard Ratio (95%CI * ) PSA 6.3% 15.5% 0.0011 N with PSA or clinical PD 137 113 Time to PSA or clinical PD 8.8 mos 15.0 mos 0.55(0.42-0.71) N with clinical PD 112 70 Time to clinical PD 14.1 mos 29.5 mos 0.43 (0.32-0.59) N with docetaxel for CRPC 98 38 Median OS 32.2 mos 49.2 mos 0.0013 0.62 (0.46, 0.83) * CI: confidence intervals; #PD: progressive disease in months; N = number of patients

Randomised Study of Axitinib (Axi) Plus Best Supportive Care (Bsc) Versus Placebo (Pbo) Plus Bsc in Patients with Advanced Hepatocellular Carcinoma (Hcc) Following Prior Antiangiogenic Therapy

ABSTRACT Aim: The efficacy and safety of Axi, a potent and selective inhibitor of VEGF receptors 1-3, was evaluated in a global, randomised, double-blind phase II clinical trial in patients (pts) with locally advanced or metastatic HCC. Methods: Eligible pts progressed on or were intolerant to 1 prior antiangiogenic therapy and had ECOG performance status 0 or 1. Pts were randomised 2:1 to receive Axi + BSC or Pbo + BSC at a starting dose of 5 mg twice daily and stratified by tumour invasion (presence vs absence of extrahepatic spread and/or vascular invasion) and geographic region (Asia vs non-Asia). Primary end point was OS and secondary end points included ORR, PFS and safety. The study had 80% power to detect an improvement in median OS (mOS) from 5.0 to 8.3 mo with Axi + BSC, corresponding to a HR 0.60 (1-sided a = 0.025). Results: Two hundred two pts (134 Axi vs 68 Pbo), predominantly of Asian origin (63 vs 62%), were randomised. Baseline pt characteristics and stratification factors were well balanced between the Axi vs Pbo arms. All pts were in Child-Pugh A category and 76% of pts in both arms had tumour invasion. mOS with Axi was 12.7 mo (95% CI: 10.2, 14.9) vs 9.7 mo (95% CI: 5.9, 11.8) with Pbo and was not statistically significant (HR 0.870; 95% CI: 0.620, 1.222; 1-sided stratified P = 0.211). Investigator-assessed median PFS (mPFS) with Axi was 3.6 mo vs 1.9 mo with Pbo and was statistically significant (HR 0.618; 95% CI: 0.438, 0.871; P = 0.004). ORR was 9.7% with Axi vs 2.9% with Pbo (P = 0.083). More pts discontinued due to AE with Axi vs Pbo (23 vs 13%). Most common all causality AEs (Axi vs Pbo, % of pts) were diarrhoea (54 vs 12%), hypertension (54 vs 13%), decreased appetite (47 vs 21%), fatigue (35 vs 26%), abdominal pain (34 vs 21%), hand-foot syndrome (34 vs 6%), weight decrease (27 vs 3%), nausea (26 vs 10%), dysphonia and hypothyroidism (25 vs 0% each). Conclusions: Axi + BSC did not demonstrate statistically significant improvement in mOS but improved mPFS compared to Pbo + BSC in pts with advanced HCC who received prior antiangiogenic therapy. Safety profile with Axi was consistent with earlier clinical trials and no new safety signal was detected. Disclosure: Y. Kang: I have been a consultant for Pfizer Inc and Bayer Healthcare Pharmaceuticals; J. Park: I am (was) a member of Consultancy/Advisory Board of Taiho Pharmaceutical, Bayer Healthcare Pharmaceuticals, and Roche, and received honorarium from Taiho Pharmaceutical and research funding from Bayer Healthcare Pharmaceuticals; S.L. Chan: I received research funding from Pfizer Inc.; J. Tang and O. Valota: I am employed by and own stock in Pfizer; D. Chakrabarti: is an employee of and owns stock in Pfizer.All other authors have declared no conflicts of interest.

Abstract B295: A Phase Ib study of bavituximab plus carboplatin and pemetrexed in chemotherapy-naïve incurable stage IIIb/IV non-squamous non-small cell lung cancer.

Abstract Background: Bavituximab (B) is a phosphatidylserine (PS) targeting monoclonal antibody that modulates the tumor microenvironment from a primarily immunosuppressive state to an immune activating state. PS exposure in the tumor microenvironment is immunosuppressive, and increases in response to chemotherapy, radiotherapy and oxidative stress. B has been shown to overcome immune suppression and stimulate antitumor immunity in preclinical models. A randomized phase II study of B in combination with docetaxel showed a 60% improvement in median OS in second line NSCLC, and a phase III trial is planned. We report on B in combination with pemetrexed (P) and carboplatin (C), in treatment naïve locally advanced or metastatic non-squamous NSCLC. Methods: We conducted an open-label, single arm phase Ib study (standard 3+3 design) of B (0.3mg/kg, 1mg/kg, and 3mg/kg) with fixed dose with C (AUC 6) plus P (500mg/m2) q3wks x maximum 6 cycles, with optional maintenance B until disease progression. Primary objectives are to characterize the safety, determine dose limiting toxicities (DLT), and establish the recommended phase 2 dose (RP2D). Secondary objectives include determining ORR and PFS. At the MTD, up to 16 patients (pts) are enrolled to further characterize safety and preliminary evidence of efficacy, incorporating an early stopping rule based on an excessive proportion of DLTs observed. DCE-MRI at baseline and end of cycle 1 was explored as a potential pharmacodynamic biomarker. Results: Currently 21 of 25 pts have received at least one dose of CPB (48% female, 90% white), median age of 53 (range 43-73y). Most commonly reported drug-related AEs (&amp;gt;10%), include (all %; G3/4%): anemia (62; 10), fatigue (48; 10), nausea (48; 5), thrombocytopenia (43; 29), neutropenia (38; 19), vomiting (38; 19), ALT and AST increase each (29; 0), anorexia (24; 5), thromboembolic event (19; 19), diarrhea (19; 0), rash (19; 0), leukopenia (14; 10), hyponatremia (14; 5), edema (14; 0), insomnia (14; 0), skin disorder (14; 0). No DLTs have been reported. 16 SAEs have been reported in 7 pts, of which 3 were considered related to study. As of 8/8/13, 14 completed planned 4 cycles CPB therapy; 5 came off study prior to completion due to SAEs (2 venous and 2 arterial thromboembolism, 1 hematologic toxicity), 1 due to PD, and 1 withdrew consent. 2 completed &amp;gt;10 cycles with maintenance B. Best unconfirmed response includes 35% PR, 50% SD, 10%PD, 1 pt not available. 3 pts have completed the optional DCE-MRI biomarker imaging. Conclusions: CPB is relatively well tolerated, with most toxicities attributable to CP. No unexpected adverse events were identified. A DLT was not identified and the RP2D is yet to be determined. Response rates reported to date are encouraging, although conclusions are limited due to the small number. Data are not sufficiently mature to report PFS and OS. Results including DCE-MRI imaging will be updated. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B295. Citation Format: Juneko E. Grilley-Olson, Liza C. Villaruz, Thomas E. Stinchcombe, Jared Weiss, Joseph Shan, Anshu Vashishtha, Anastasia Ivanova, Mark A. Socinski. A Phase Ib study of bavituximab plus carboplatin and pemetrexed in chemotherapy-naïve incurable stage IIIb/IV non-squamous non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B295.

Newer Agents in Colon Cancer: What’s Next?

Colorectal cancer (CRC) was the third leading cause of cancer deaths in the United States in 2012, and most patients eventually develop metastatic disease. The use of cytotoxic chemotherapy, the antiangiogenesis drug bevacizumab, and the anti-EGFR monoclonal antibodies cetuximab and panitumumab have led to an improvement in median OS for metastatic CRC. Despite this improvement in survival, few agents have activity against CRC. Between 2006 and 2012, the FDA approved no new agents for patients with metastatic CRC (mCRC). Recently, the FDA has approved aflibercept and regorafenib for use in the treatment of patients with mCRC, and several new agents are currently in development. This paper reviews the use of new agents and new uses for established agents in mCRC.

C-MET: an exciting new target for anticancer therapy

c-MET: an exciting new target for anticancer therapy