Leveraging molecular datasets for biomarker-based clinical trial design in glioblastoma

BackgroundThe debate surrounding the acceptance of progression-free survival (PFS) as an intermediate endpoint to overall survival (OS) has grown in recent years, due to the challenges in demonstrating an OS benefit within clinical trials today. PFS is generally a good predictor of OS for cases where survival post-progression (SPP) is short, and less so when SPP is long. SPP depends on multiple factors, including residual effect from experimental treatment and effect from crossover or other subsequent therapies, posing unique challenges into the translation of PFS benefit into OS.MethodsThe objective of this analysis was to conduct simulations investigating how increasing SPP impacts PFS translation to OS, utilizing data from the AXIS (axitinib versus sorafenib in advanced metastatic renal cell carcinoma) trial. The underlying assumption was a treatment benefit in PFS (the PFS distribution parameters were chosen to be equal to median PFS in the AXIS trial) but no treatment effect on SPP, implying that PFS improvement is directly reflected in OS improvement.ResultsThe probability of a statistically significant difference between arms for OS decreased from 54.7% to 6.1% when median SPP was increased from one to 20 months. The probability of the hazard ratio of OS being ≥0.9 was similarly increased from 24.3% to 72.6%, even though the hazard ratio for PFS was 0.69.ConclusionThe present study shows that when simulated SPP is added to trial PFS data, the existing PFS benefit is diluted. Knowing that the AXIS treatment arms are well balanced with respect to post-trial treatments, we conclude that the PFS to OS benefit translation is primarily obscured by random variability largely unrelated to the true outcomes. The implications for drug development are not insignificant, as there would be a need to include more patients in studies or utilize a longer follow-up time to overcome the SPP variability issue.

Cancer medicine continues to evolve into a more molecularly based discipline with many new treatments being developed aimed at specific cancer-related pathways and genetic alterations. In order to meet the challenges of the evolving science, new clinical trial designs and approaches for treatment trials are needed to evaluate the promise of these potential therapies. The National Cancer Institute (NCI) with the national NCI Clinical Trials Network (NCTN) Groups will launch two clinical research initiatives in lung cancer in 2014 that demonstrate innovative approaches to the design and conduct of clinical trials. The first initiative is the ALCHEMIST trial (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) which is aimed at patients with lung adenocarcinoma that has been entirely removed by surgery. In this study, samples of tumor tissue from thousands of patients will be tested for two specific genetic alterations, one in the EGFR gene, and the other in the ALK gene. These alterations are not common; about 10% of the lung cancer patient population in the US will have tumors with alterations in the EGFR gene and 5% will have alterations in the ALK gene. Rather than conduct a single trial for each alteration, the screening component of the ALCHEMIST trial will screen patients for both alterations at the same time. The ALCHEMIST is connected to 2 specific NCI-supported NCTN Group clinical treatment trials that are each testing a targeted agent specific for one of the alterations in conjunction with adjuvant therapy. Patients found to have tumors containing one of the alterations will be offered enrollment onto the appropriate clinical treatment trial. Every patient in the ALCHEMIST trial, including those without an EGFR or ALK alteration, will also be studied for cancer risk characteristics and their tumor tissue will be analyzed in a research genomics initiative conducted by the NCI Center for Cancer Genomics (CCG). This effort will employ next-generation sequencing technology to capitalize on the foundation of the CCG's earlier effort, the Cancer Genome Atlas. The second initiative, the Advanced Squamous Cell Carcinoma Lung Master Protocol, is a public-private effort made possible through collaboration with stakeholders including the NCI, NCTN Groups, FDA, NIH Foundation, the Friends of Cancer patient advocacy group, and the pharmaceutical industry. By pooling resources to screen tumor samples from about a thousand patients per year with advanced squamous cell carcinoma for multiple genetic alterations, this master protocol will enable several, randomized, phase II clinical trials with promising new agents to take place in parallel within a single study management framework. Agents will be evaluated rapidly and either be further evaluated in a phase III clinical trial or replaced by other new agents for phase II evaluation, without having to develop individual trials de novo each time. Compared with the usual process of developing clinical trials, these two new design approaches will hopefully allow more patients to be enrolled in trials with agents targeted for important molecular characteristics specific for their tumors and the trials will yield clinically useful results more rapidly. Citation Format: Margaret M. Mooney, Jack Welch, Jeffrey S. Abrams. Clinical trial design and master protocols in NCI clinical treatment trials. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA08.

Efficacy of Idelalisib and Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Treated Outside of Clinical Trial. a Report of the Gimema Group

Postprogression Survival in Patients With Advanced Non–Small-Cell Lung Cancer Who Receive Second-Line or Third-Line Chemotherapy

e21570 Background: Small molecule inhibitors of epidermal growth factor receptor kinase (EGFR) are approved for EGFR-positive non-small cell lung cancer (NSCLC). Targeted therapies include agents that block tumor-specific molecular targets and thereby interfere with tumor growth and metastasis. This study focuses on a meta-analysis of therapeutic outcomes from phase II and III clinical trials for anti-EGFR monotherapy compared to anti-EGFR therapy in combination with targeted agents. Methods: A literature search was conducted using EMBASE, Pubmed, Scifinder Scholar, clinicaltrials.gov and the Cochrane library for the following terms: “epidermal growth factor receptor kinase”, “combination therapy”, “non-small cell lung cancer”. Eligible studies included patients of advanced stage IV NSCLC and any mutation status that met the predefined inclusion criteria. Data was extracted on trial demographics and therapeutic outcomes including progression-free survival (PFS), survival post progression (SPP), overall survival (OS) and adverse events (AE). Sub-group analysis based on patient mutation status of wild-type (wt) EGFR, mutant EGFR, wt KRAS and mutant KRAS and a correlation analysis between OS, PFS and SPP was conducted. Results: A total of 34 studies were identified that fit the inclusion criteria from 2009-2019. The pooled OS hazard ratio (HR) was 0.94 (95% Confidence Interval (CI): 0.87-1.01); the pooled PFS HR was 0.8 (95% CI: 0.74-0.87). Median OS correlated more closely with median SPP (r2 = 0.97 for monotherapy; r2 = 0.88 for combination therapy) than to median PFS (r2 = 0.90 for monotherapy; r2 = 0.82 for combination therapy), although the linear association between log-HR OS and log-HR PFS had a positive slope (β = 0.31± 0.19). A greater incidence of rash and diarrhea was observed in the combination arm compared to monotherapy. A significant improvement was observed for PFS in wt EGFR patients for combination therapy, pooled PFS HR 0.8 (95% CI: 0.67-0.95). Conclusions: A statistically significant improvement in PFS was observed for anti-EGFR combination regimens compared to anti-EGFR monotherapy. The improvement in OS was not statistically significant for anti-EGFR combination regimens compared to monotherapy.

e15674 Background: Several factors including pro-angiogenic cytokines have been reported as predictive markers for the treatment effect of sorafenib in patients with HCC; however, many of them were determined based on the results of retrospective studies. Methods: In this prospective cohort study (UMIN000009771), we recruited advanced HCC patients who were treated with sorafenib, and periodically measured serum levels of eight pro-angiogenic cytokines, which were risk factors for the prognosis reported by us and others. The effect of the cytokine expressions before and at 2 (4) weeks after starting sorafenib and at PD, on progression free survival (PFS), overall survival (OS), and post progression survival (PPS) were evaluated. The effect of early appearance of adverse events within 30 days, which were reported as other risk factors, was also evaluated. Results: Eighty patients were enrolled. Median PFS and OS were 3.1 and 11.7 months, respectively. There was no statistically significant variable that could predict PFS, which included patients’ characteristics, cytokines before the therapy, and early onset of adverse events. However, PFS of the patients who showed the decrease of platelet-derived growth factor after 2 weeks (HR2.78, 95%CI 1.35-6.21, P=0.005) or vascular endothelial growth factor after 4 weeks (HR3.31, 95%CI 1.59-6.83, P=0.001) compared to the values before sorafenib treatment was short. OS was short in patients with poor performance status, large tumor size (>30mm), large tumor number (>5), high des-gamma-carboxyprothrombin (DCP, >100mAU/mL), high hepatocyte growth factor, and high angiopoietin-2 (Ang-2) before therapy, in addition to no hand foot syndrome within 30 days. Multivariate analysis with these factors revealed that high Ang-2 (HR2.25, 95%CI 1.08-4.86, p=0.029) and high DCP (HR3.55, 95%CI 1.25-12.7, p=0.014) were the independent risk factors for OS. High Ang-2 at PD could also be a marker of short PPS. Conclusions: The prediction of PFS, OS and PPS is possible by measuring serum pro-angiogenic cytokines at appropriate timing. Ang-2 is a key cytokine for predicting the prognosis of HCC patients treated with sorafenib.

A systematic review evaluating the relationship between progression free survival and post progression survival in advanced ovarian cancer

Drug resistance, an impenetrable barrier in the treatment of ovarian cancer (OC), is often associated with poor outcomes. Hence, it is urgent to discover new factors controlling drug resistance and survival. The association between neurocalcin delta (NCALD) and cancer drug resistance is poorly understood. Here, we reveal that NCALD messenger RNA expression, probably regulated by DNA methylation and microRNAs, was significantly downregulated in at least three independent microarrays covering 633 ovarian carcinomas and 16 normal controls, which includes the Cancer Genome Atlas (TCGA) ovarian cohort. In the sub-groups of the TCGA cohort, NCALD was suppressed in 90 platinum-resistant tissues vs in 197 sensitive tissues. It is consistent with the quantitative reverse transcription polymerase chain reaction results revealing gene downregulation in carboplatin-resistant SKOV3 and HeyA8 OC cells as compared with that in controls. Low expression of NCALD predicted poor overall survival (OS) in sub-groups of 1656 patients, progression-free survival (PFS) in 1435 patients, and post-progression survival (PPS) in 782 patients according to Kaplan-Meier plotter covering 1815 OC patients. Comprehensive bioinformatic analyses strongly implicated NCALD in the regulation of drug resistance, probably via competing for endogenous RNA (ceRNA) interactions with CX3CL1 and tumor immune-microenvironment. NCALD acted as a ceRNA for CX3CL1 in 21 different cancers includes OC according to Starbase. These two genes negatively correlated with tumor purity and positively correlated with infiltration levels of neutrophils and dendritic cells in OC. The combined low expression of NCALD and CX3CL1 showed better prognosis potential for OS, PFS, and PPS in the 1815 OC patients than any of the individually tested genes. In summary, NCALD acts as a ceRNA for CX3CL1, and its downregulation may affect drug resistance and prognosis in OC. Thus, NCALD could be a new therapeutic target for anticancer therapy and a new biomarker for survival prediction in OC.

Chapter 11 - Clinical Trial Design in Immuno-Oncology

406 Background: Despite anatomical and biological differences, upper and lower tract UC (UTUC; LTUC) are usually managed similarly. Modern era clinical trial data comparing their outcomes with ICI are conflicting. We hypothesized that response and outcomes would be similar in patients (pts) with advanced UTUC and LTUC. Methods: We performed a retrospective cohort study collecting demographic, clinicopathologic, treatment, and outcome data for pts with advanced UC receiving ICI (2013-2020) across 24 centers (US; Europe). We compared objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between pts with UTUC and LTUC. Uni- / multi- variable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Stratified subgroup analyses were performed according to histology (pure, mixed) and line of treatment (first-line, subsequent). Results: A total of 984 pts were identified, and 707, 717, and 738 were included in ORR, OS, and PFS analyses, respectively. After exclusions, the UTUC group comprised of 130 pts (vs. 616 in LTUC) with median age 71 (40-92) (vs. 70 [32-93]), 62% men (vs. 76%), 41% never smokers (vs. 29%), 62% with history of prior radical surgery for primary tumor (vs. 52%), and 29% with liver metastases (vs. 18%). Table shows results of ORR, OS, and PFS analyses. In the overall population, pts with UTUC and LTUC receiving ICI had comparable ORR, OS, and PFS. Pts with mixed-histology UTUC had significantly lower ORR (adjusted OR 0.20, 95%CI 0.05-0.91) and shorter PFS (adjusted HR 1.66, 95%CI: 1.06-2.59) vs. mixed-histology LTUC. Conclusions: Pts with advanced UTUC and LTUC receiving ICI have similar response and outcomes, except for pts with mixed-histology UTUC vs LTUC. Subset analysis of primary tumor location in ongoing clinical trials can validate our data, while biomarker work is ongoing. [Table: see text]

The benefits of second-line chemotherapy on the overall survival (OS) of small-cell lung cancer (SCLC) patients might be confounded by subsequent therapies. In this study, we aimed to determine the influence of progression-free survival (PFS) and postprogression survival (PPS) on OS after second-line chemotherapy in patients with refractory SCLC treated with amrubicin monotherapy. We analyzed the data of 35 patients with refractory SCLC who were treated with amrubicin monotherapy as second-line chemotherapy between July 2005 and December 2015. The correlations of PFS and PPS with OS were statistically analyzed at the individual level using Spearman's rank correlation and linear regression analyses. The correlation between PPS and OS was strong (r = 0.88, P < 0.05, R2 = 0.87), while that between PFS and OS was weak (r = 0.60, P < 0.05, R2 = 0.15). The number of regimens administered after disease progression postsecond-line chemotherapy was significantly associated with PPS (P = 0.003). OS is more strongly linked to PPS than to PFS in refractory SCLC patients who undergo amrubicin monotherapy as a second-line treatment. These results suggest that treatments administered after second-line chemotherapy affect the OS of refractory SCLC patients treated with amrubicin monotherapy.

PCN9 VALIDITY OF PROPORTIONAL HAZARDS (PH) WEIBULL MODELS FOR ANALYZING PROGRESSION FREE SURVIVAL (PFS) AND OVERALL SURVIVAL (OS) IN PATIENTS WITH TRASTUZUMAB (TZ)-REFRACTORY ERBB2+ (HER2+) METASTATIC BREAST CANCER (MBC) RECEIVING LAPATINIB PLUS CAPECITABINE (L+C) VERSUS CAPECITABINE ONLY (C-ONLY)

BACKGROUND: The recent identification of isocitrate dehydrogenase (IDH) mutations in gliomas and several other cancers suggests that this pathway is involved in oncogenesis; however effector functions are complex and yet incompletely understood. To study the regulatory effects of IDH on hypoxia-inducible-factor 1-alpha (HIF1A), a driving force in hypoxia-initiated angiogenesis, we performed mRNA-expression and functional, as well as genotype/imaging phenotype correlation analysis. METHODS: We studied differential mRNA-expression profiles from 288 samples with low-grade and anaplastic gliomas from The Cancer Genome Atlas (TCGA) of HIF1A and related downstream signaling on a single-gene and pathway level, as well as upstream biological causes and probable downstream effects between mutant and wild-type IDH tumors. Genotype/imaging phenotype correlation analysis was performed in a separate (local) dataset with relative cerebral blood volume (rCBV) MRI - an estimate of tumor angiogenesis - in 73 treatment-naive patients with low-grade and anaplastic gliomas. RESULTS: We show decreased expression of HIF1A-target genes on a single-gene and pathway level, strong inhibition of upstream regulators such as HIF1A and downstream biological functions such as angio- and vasculogenesis in IDH-mutant tumors. Our radiogenomic imaging approach revealed increased levels of rCBV in IDH wild-type tumors, where a one-unit increase in rCBV corresponded to a two-third decrease in the odds for an IDH-mutation and correctly predicted IDH mutation status in 88% of patients. CONCLUSION: Together, these findings show that IDH-mutation status is associated with a distinct angiogenesis transcriptome signature which is non-invasively predictable with rCBV-imaging.

Objective: To analyze the prognosis factors of cerebrospinal fluid (CSF) spread after surgery in glioblastoma (GBM) patients when tumors progressed and the effect factors on prognosis. Methods: A retrospective study was conducted on 124 patients who were pathologically diagnosed as glioblastoma after surgery, and found tumor progressed during regularly follow-up at Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University between January 2009 and August 2017.There were 82 males and 42 females, aged 47.9 years(range: 19 to 75 years) .Patients were divided into local recurrence group(96 cases) and CSF spread group (28 cases) .Clinical data were recorded in detail and compared by independent sample t test or χ(2) test.Kaplan-Meier survival curves was used to demonstrated the distribution of progression free survival (PFS) overall survival (OS) and post progression survival (PPS), and differences between local recurrence and CSF spread groups were assessed by Log-rank test.Cox proportion hazard regression analysis was used to identify independent prognostic factors. Results: Logistics regression analysis showed ventricle entry was the only prognosis factor of CSF spread (OR=2.667, 95% CI: 1.128 to 6.304, P=0.025).No significant distinction was observed in PFS between CSF spread group and local recurrence group(7.0 months vs.9.3 months, P=0.066).However, OS and PPS were substantially shortened in CSF spread group (13.0 months vs.23.0 months, P=0.011; 6.0 months vs.11.0 months, P=0.022, respectively).Mutations of isocitrate dehydrogenase gene, distant spread, gross-total resection, Ki-67 index>30% were independent prognostic factors of GBM patients. Conclusions: Ventricle entry is a prognosis factor for CSF spread, after which the median OS and PPS are markedly diminished.However, ventricle entry is not independent prognosis factor shortening survival.

Understanding the Prognostic Value of Primary Tumor Location and KRAS in Metastatic Colorectal Cancer: A Post Hoc Analysis of the OPTIMOX3 DREAM Phase III Study