ASCO 2015 Abstracts

The following are a selection of abstracts presented at the 2015 meeting of the American Society of Clinical Oncology (ASCO). The abstracts were published on May 13 in advance of the conference taking place May 29 through June 2 in Chicago.

Phase 3 trials

Tumor treating fields (TTFields): A novel treatment modality added to standard chemo- and radiotherapy in newly diagnosed glioblastoma—First report of the full dataset of the EF14 randomized phase III trial. This is the first public data on all 700 patients treated in the phase 3 EF14 trial for newly diagnosed glioblastoma. As of November 2014, the TTFields device is called Optune. Results are similar to those seen in the preliminary analysis presented at the 2014 SNO conference in Miami. Progression free survival was 7.1 months from randomization (post-radiochemotherapy) in the TMZ+TTF arm and 4.2 months for TMZ alone, a significant difference (p=0.001). Median overall survival from randomization was 19.4 months in the TMZ+TTF arm versus 16.6 months for TMZ alone, also significant (p=0.02). 2-year survival rates from randomization are 43% versus 29%.
Abstract

Radiotherapy in relation to temozolomide: Subgroup analysis of molecular markers of the randomized phase III study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033) in patients with a high risk low-grade glioma.Subgroup analysis suggests that PFS is longer in patients with IDHmut/non-codel tumors when treated in first-line with RT compared to treatment with TMZ. With still only a few events no such difference is visible in 1p/19q co-deleted tumors. However, maturation of survival data is needed to derive more firm conclusions.
Abstract

Phase 2 trials

Continuous low dose temozolomide with or without VT-122 in glioblastoma. VT-122 refers to the combination of the FDA-approved non-cancer drugs propranolol and etodolac. This was a trial testing the addition of these two drugs to metronomic low-dose temozolomide for recurrent glioblastoma. All 41 patients took 20 mg TMZ twice daily every day. 21 of these patients also took propranolol and etodolac (VT-122). In the TMZ+VT-122 group, response rate was 57% versus 35% in the control group. 1-year survival rate in the TMZ+VT-122 group was 67% versus 30% in the control group. Median overall survival (I assume from the start of the trial) was 17.6 months in the TMZ+VT-122 group versus 9.2 months in the TMZ alone group. These results seem exceptionally positive, though the abstract provides no indication of how the patients were stratified, or whether the two groups were well balanced for prognostic variables such as age, extent of resection, KPS, or MGMT status. Nevertheless, the results are intriguing and it is hoped that this trial will be published in full detail in the near future.
Abstract

A phase 2 study on efficacy, safety and intratumoral pharmacokinetics of oral selinexor (KPT-330) in patients with recurrent glioblastoma (GBM). All 12 patients in arm B (selinexor alone until progression) were evaluable for response. There were two partial responses (17%), four with stable disease (33%) and six progressive disease (50%). Main toxicities were fatigue and anorexia.
Abstract

A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma.In patients with one recurrence (n = 24 and 23, respectively), there was a trend towards statistical significance in longer median PFS time in the BEV + CCNU arm (4.96 months) compared to the BEV alone arm (3.22 months, p = 0.08). Median OS in patients with 1 recurrence on BEV + CCNU was longer (13.05 months) than those treated with BEV alone (8.79 months, p = 0.77) but this did not reach statistical significance…The study was not designed to test only at first recurrence, but in that subgroup there was a strong trend towards the combination supporting the findings of the recently published BELOB trial. With a larger sample size, a statistically significant difference in median PFS between treatments arms would likely have been observed.”
Abstract

Continuing or ceasing bevacizumab at disease progression: Results from the CABARET study, a prospective randomized phase II trial in patients with recurrent glioblastoma. “Continuing Bev after progression of rGBM did not improve PFS or OS in this prospective study.
Abstract

Does extent of resection matter in recurrent glioblastoma? Lessons from the DIRECTOR trial. The DIRECTOR trial was a randomized phase 2 trial testing two different temozolomide rechallenge schedules (7 days on/7 days off versus 21 days on/7 days off) for recurrent glioblastoma. “Complete resection of gadolinium-enhancing tumor (N = 39) versus residual detection of gadolinium enhancement (N = 20) was associated with improved OS (11.5 months vs. 6.7 months, P = 0.006)… Conclusions: Surgery at first recurrence of glioblastoma may improve outcome if complete resection of Gadolinium-enhancing tumor is feasible.
Abstract

Newly diagnosed glioblastoma patients treated with an autologous heat shock protein peptide vaccine: PD-L1 expression and response to therapy.The median overall survival for patients with high PD-L1 expression (above the median, 54.5% of monocytes) was 18.0 months as compared to 44.7 months for low PD-L1 expressors (hazard ratio for death 3.35; p = 0.003). A multivariate proportional hazards model revealed MGMT methylation status and PD-L1 expression as the greatest independent predictors of survival.” In other words, immunotherapy vaccines should probably be administered together with FDA-approved inhibitors of PD-1 signaling such as nivolumab (Opdivo) or pembrolizumab (Keytruda) to maximize benefit.
Abstract

Phase II multicenter study of gene mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. This trial tested a virally-delivered “suicide gene” therapy, similar in concept to the Toca511/TocaFC system. In this case the viral vector is AdV-tk and the prodrug used is valacyclovir. Outcomes in this single arm trial were compared with “concurrent matched control group meeting protocol criteria and SOC at an institution not active in the treatment trial”. “The improvement was mostly in patients that underwent gross total resection: median OS increased from 16.9 to 25 months (p = 0.0492).” The abstract does not tell us the relative distribution of grade 3 gliomas and glioblastomas in the trial group.
Abstract

ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma.These near-final data show that rindopepimut induces potent EGFRvIII-specific immune response and tumor regression, and appears to significantly prolong survival when administered with BV, in pts with relapsed GB.
Abstract

The failure of targeted inhibitors approved or designed for non-central nervous system cancers

NCCTG N0872 (Alliance): A randomized placebo-controlled phase II trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma (GBM).The combination of the Src kinase inhibitor dasatinib with Bev did not improve the outcome of recurrent GBM pts as compared to single agent Bev.
Abstract

Randomized, placebo-controlled, phase II study of dasatinib with standard chemo-radiotherapy for newly diagnosed glioblastoma (GBM), NCCTG N0877 (Alliance).The combination of the Src kinase inhibitor dasatinib with standard RT/TMZ did not improve the outcome of newly diagnosed GBM patients as compared to standard therapy alone.” In this trial, progression-free survival and overall survival was actually more favorable in the placebo arm. A recent editorial in Neuro-Oncology by David Schiff and Jann Sarkaria stated “the results of randomized phase II trials adding dasatinib to radiation plus temozolomide (Alliance N0877, NCT00869401) in newly diagnosed disease and to bevacizumab in recurrent disease (Alliance N0872, NCT00892177) are anticipated shortly. If these studies prove negative as well, they will likely represent the death knell of dasatinib in glioblastoma.” As seen in this abstract and the preceding one, it unfortunately looks like this has come to pass.

Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. “Tivozanib was well tolerated but most patients progressed rapidly…suggesting that this anti-angiogenic agent had limited impact on brain tumor vasculature.”
Abstract

Phase II trial of dovitinib in recurrent glioblastoma.Dovitinib is an oral, small-molecule tyrosine kinase inhibitor of FGFR 1-3, PDGFR β, and VEGFR 1-3. Accrual in arm A was stopped after the first stage due to futility. Dovitinib is not active in recurrent GBM, regardless of prior anti-angiogenic therapy.
Abstract

A phase II study of galunisertib monotherapy or galunisertib plus lomustine compared to lomustine monotherapy in recurrent glioblastoma. Galunisertib is a TGF-βR1 kinase inhibitor. “The observed efficacy outcomes including OS and PFS were similar in all 3 treatment arms suggesting no efficacy improvement when adding galunisertib to lomustine
Abstract

Brain Tumor Trials Collaborative Bayesian Adaptive Randomized Phase II trial of bevacizumab plus vorinostat versus bevacizumab alone in adults with recurrent glioblastoma (BTTC-1102).In this trial, Bev+Vor did not yield an improved PFS or OS or clinical benefit in terms of reduced symptom burden compared with Bev alone in patients with recurrent GB and does not warrant further investigation.
Abstract

Phase II study of bevacizumab and vorinostat for recurrent glioblastoma.VOR and BEV combination therapy was well-tolerated in recurrent GBM, although it did not improve 6-month PFS when compared to BEV monotherapy.
Abstract

Phase 1 trials

Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. Ten patients were treated in each arm. Nivolumab alone was tolerated far better than the combination of nivo plus ipi. All adverse events in the nivo arm were grade 1 or 2. Eight patients (80%) in the nivo plus ipi arm had grade 3 or 4 adverse events. Five patients (50%) in this arm also discontinued therapy due to adverse events, including colitis, cholecystitis, diabetic ketoacidosis, confusion, and increased lipase. Survival at 6-months was reported, though the 12-month overall survival rate will be more meaningful. Progression-free survival and response rate are still being evaluated.
Abstract

Phase I study of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly diagnosed glioblastoma multiforme (GBM).Our pilot group of 7 pts that received DC CMV vaccine with one dose of anti-CD25 antibody (basiliximab) had median progression free survival (PFS) and overall survival (OS) of 23.5 months and 30.3 months respectively. There were no adverse events associated with the vaccine or anti-CD25 Ab therapy.
Abstract

A phase 1b/2 study of the combination of the IDO pathway inhibitor indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors: Safety analysis and preliminary efficacy of the phase 1b component. In this phase 1/2 trial, the maximum tolerated dose of indoximod was established as 1200 mg twice daily. One out of 12 (8%) TMZ-refractory patients has experienced a partial response to indoximod plus standard dose TMZ.
Abstract

Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioma. Dianhydrogalactitol is better known as VAL-083, an alkylating agent that is not subject to MGMT-mediated repair. Though the phase 1 portion of this trial was only a dose-finding study, it is somewhat disappointing that of the 25 patients enrolled into 8 different dose cohorts, only three patients (12%) had stable disease or partial response on this therapy.
Abstract

Use of a novel radio-sensitizer for treatment of GBM. In this phase 1/2 trial, newly diagnosed glioblastoma patients are given standard of care radiochemotherapy combined with trans sodium crocetinate as a radiosensitizer. “TSC may promote radio-sensitization since there was a large incidence of pseudo-progression, with complete tumor regression in about 10% of patients.
Abstract

Retrospective Studies

Metronomic chemotherapy with daily low-dose temozolomide and celecoxib in elderly patients with newly diagnosed glioblastoma multiforme. In this retrospective study, the addition of chemotherapy (either standard dose or low dose combined with celecoxib) to radiation for patients 65 and older more than doubled median survival. Low dose temozolomide plus celecoxib was better tolerated than standard dose temozolomide.
Abstract

Survival benefit of tumor treating fields plus stereotactic radiosurgery for recurrent malignant gliomas.Compared to those who did not receive SRS (stereotactic radiosurgery using Cyberknife), patients who were treated with SRS in addition showed an increase in median overall survival.
Abstract

The role of salvage radiation in recurrent glioblastoma after bevacizumab failure.
The group that received subsequent RT had a statistically significant increase in both OS (8.8 vs 5.4 mos; p = 0.05) and PFS (4.1 vs 2.3 mos; p = 0.006) when compared to the group that did not receive RT. In both univariate and multivariate analyses, only RT use after bevacizumab failure was predictive of OS. Conclusions: In this small cohort, use of salvage RT after bevacizumab failure in recurrent GBM was associated with improved survival.
Abstract

Preclinical studies

Targeting dopamine receptor 2 (DRD2) signaling in combination with temozolomide chemotherapy as a novel therapeutic concept in glioblastomas.The combination of TMZ and Thioridazine significantly decreased intracranial glioblastoma growth, and improved survival of tumor-bearing mice compared to treatment with TMZ alone.
Abstract

Pathology

Mutational analysis of matched initial and recurrent TP53 WT primary GBM.As distinct from recent reports of recurrent lower grade glioma very few patients showed a “hypermutable” signature that is characterized by numerous temozolomide (TMZ) associated specific mutations after treatment. In total, only 2/29 samples (7%) appeared to be hypermutated at relapse, with 55.6% of these mutations being attributable to TMZ-associated mutagenesis in the first patient and 44.3% in the second… In contrast to previous studies we found evidence of hypermutation associated with TMZ treatment in the minority of patients. We propose that this may be related to the wild-type TP53 status in these patient’s tumours.” According to this hypothesis, the TMZ-induced hypermutation phenomenon may be particularly problematic in patients with p53-mutant tumors. p53 mutation is found in the large majority of lower grade IDH1-mutant astrocytomas, and in approximately one-third of primary glioblastomas.
Abstract

Tumor profiling on 1245 gliomas and paired tumor study on 19 high grade gliomas.PD-L1 expression on tumor cells was seen in 27% and was more common in tumors without MGMT Methylation (36% vs. 18%, p = 0.01). PD-1 expression on tumor-infiltrating lymphocytes was seen in 48% and was higher in GBM than grade II-III (54% vs. 30%, p = 0.005).” As described in another abstract, presence of PD-L1 may play a large role in determining the efficacy of immunotherapy vaccines.
Abstract