SNO summary: Durable responses with Toca 511 + Toca FC

I already posted on this data at the end of October, but here is my long form write-up.

Durable responses observed in IDH1 wildtype and mutant recurrent high grade glioma (rHGG) with Toca 511 & Toca FC treatment

Timothy Cloughesy of UCLA presented updated results for the phase 1 trial of tumor resection followed by injection of Toca 511 into the tumor resection cavity.  This trial (NCT01470794) treated 56 patients with recurrent glioblastoma or anaplastic astrocytoma (WHO grades 3 and 4).  

Pooling results across all three phase 1 dose escalation trials (n=127 patients), Toca 511 was found to be well tolerated, with only 25% of patients experiencing grade 1 or 2 treatment-related adverse events (including fatigue in 11%), and 7% of patients experiencing a grade 3 or higher treatment-related adverse event (including one case of headache, one case of fatigue, and two cases of vasogenic cerebral edema). Administration of the fluorouracil prodrug, Toca FC, was also associated with a low incidence (3.3%) of grade 3 or higher treatment-related adverse events.  Only three out of 122 patients discontinued therapy due to adverse events associated with Toca FC.

In the NCT01470794 trial of resection followed by injection of Toca 511 into the resection cavity, 46/56 (82%) of patients had recurrent glioblastoma, and the remainder had anaplastic (grade 3) or other gliomas.  50% were at first recurrence, 23% were at second recurrence, and 27% were at third or more recurrence.  

This trial included the endpoint of durable response rate, defined as a response lasting at least 24 weeks (5.5 months).  Remarkably, all responders (6 out of 53 patients evaluable for efficacy, 11.3%) are in complete response and still alive, with a median duration of response of at least 35.1 months (nearly 3 years). An additional 18.9% had stable disease as best response, for a clinical benefit rate of 30.2% (response plus stable disease).

In the subset of patients (n=23) treated with higher doses of Toca 511 and meeting the eligibility criteria for the ongoing phase 3 Toca 5 trial (at first or second recurrence, no prior Avastin, and tumor no larger than 5 cm), there were 5 out of 23 patients (21.7%) with durable complete response lasting for a median of 35.7+ months.  An additional 21.7% had stable disease as best response, for a total clinical benefit rate (response + stable disease) of 43.5%.  In this subgroup of 23 patients, three of the complete responders had wild-type IDH1, and two had anaplastic astrocytoma with mutant IDH1. These responses occurred gradually over 6-19 months, consistent with an immunologic mechanism of action.  Median survival from Toca 511 treatment in this subgroup is 14.4 months, which compares favorably with historical benchmarks of 9-10 months for recurrent GBM with standard treatments.

The safety profile, increased median survival relative to historical benchmarks, and relatively high rate of complete durable responses lasting for a median of at least three years is encouraging.  The randomized phase 2/3 Toca 5 trial for recurrent glioblastoma or anaplastic astrocytoma (NCT02414165) recently re-opened in November 2017 to new recruitment and the phase 1 Toca 7 trial for newly diagnosed high grade glioma (NCT02598011) is scheduled to open sometime in 2018.

SNO 2017 Highlights: Intravenous administration of Toca 511

Intravenous delivery of Toca 511 in patients with high grade glioma results in quantifiable expression of cytosine deaminase in tumor tissue

Tobias Walbert of Henry Ford Hospital presented results of this phase 1 trial, which tested administration of the Toca 511 virus by intravenous injection.  Toca 511 is a retroviral replicating vector that transmits a gene to infected tumor cells.  This gene, cytosine deaminase (CD) causes the cell to convert orally administered Toca FC (an extended release version of 5-fluorocytosine) into the active chemotherapy agent 5-fluorouracil.  Following intravenous injection for 1, 3, or 5 days, tumors were resected and additional Toca 511 was injected into the tumor cavity walls.  This pre-resection intravenous administration allowed investigators to analyze tumor tissue for detection of cytosine deaminase (CD) within tumors.

17 patients were included in this trial.  14 of these patients (82%) had diagnoses of GBM and the remaining three had grade 3 gliomas.   47% were at first recurrence while 53% were at second or more recurrence.  

11 of 17 (65%) resected tumors were positive for cytosine deaminase, showing that intravenously administered Toca 511 successfully entered into tumors in the majority of cases. Analysis of resected tumor tissue following intravenous Toca 511 injection found that tumors with high T-cell infiltrate did not limit the ability of Toca 511 to enter tumor cells.  Conversely, the presence of immunosuppressive regulatory T-cells (Tregs) were also not required to allow entry of Toca 511 into tumor cells.  

The maximum tolerated dose of Toca 511 was not defined and grade 3 or higher adverse events were rare, occurring in only 3 patients (17.6%). 

Stable disease was achieved in 3 of 17 patients (17.6%) and late onset (>12 months after treatment) radiologic responses were seen in two of 17 patients (11.8%), consistent with an immunologic mechanism of action.  The responding patients were an IDH wild-type anaplastic astrocytoma patient at 3rd recurrence, whose response was noted on MRI 9 months after discontinuing Toca FC and was on no other anti-cancer therapy;  and an IDH1-mutant GBM patient at first recurrence who had onset of response 13 months after initiating Toca FC.  Complete response was eventually achieved in this patient, and response has lasted for 16 months and counting. This patient remains on Toca FC and no other anti-cancer therapy.  Median overall survival from trial entry for this group of 17 patients, 53% of whom were at second or more recurrence, is 13.6 months.

This trial is one of three phase 1 trials of Toca 511/ Toca FC for recurrent malignant glioma, which are all now closed to recruitment.  Currently recruiting patients is the Toca 6 trial for recurrent solid tumors, and the randomized phase 2/3 Toca 5 trial for recurrent malignant glioma, which has just reopened as of November 2017.  A phase 1 trial of Toca 511/ Toca FC for newly diagnosed malignant glioma (Toca 7) is scheduled to open in 2018.

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SNO 2017 Highlights, episode 3: Marizomib +/- bevacizumab for recurrent GBM

Full enrollment results from the phase 1/2, multicenter, open-label study of marizomib (MRZ) +/- bevacizumab (BEV) in recurrent WHO grade IV malignant glioma

Daniela Bota of UC Irvine presented these results.  The trial was divided into three parts: Part 1 was a dose escalation and dose expansion trial of the brain penetrant proteasome inhibitor marizomib added to bevacizumab and consisted of 36 patients.  Part 2 was a trial of single-agent marizomib consisting of 30 patients.  Part 3 was an intra-patient dose escalation of marizomib combined with bevacizumab consisting of 35 patients.

In Part 1, 27 out of 36 patients (75%) were treated with 0.8 mg/m2, while 9 patients (25%) were treated at lower doses in the dose escalation phase.  Patients in Part 1 also received standard dose bevacizumab.  The overall response rate for the 36 patients receiving marizomib and bevacizumab was 16/36 or 44.4%.  11/36 or 31% had stable disease.  Response plus stable disease rate is 27/36 or 75%.  Median progression-free survival was 3.9 months and median overall survival was 9.4 months.

In Part 2, 30 patients were treated with marizomib alone.  In this cohort there was only 1 partial response (1/30 or 3%) and 6 with stable disease (6/30 or 20%), for a response plus stable disease rate of 23%.

Patients in Part 1 experiencing central nervous system related adverse events (including ataxia, balance disorder, dizziness, fall, gait disturbance, hallucination) had increased PFS and OS compared to those who did not suffer from these side-effects, and this observation provided a justification for Part 3 of the study, an intra-patient dose escalation of marizomib combined with bevacizumab. In Part 3, 10 out of 35 patients were escalated to 1 mg/m2 of marizomib, but only 1 patient was able to tolerate this dose.  No patient reached 1.2 mg/m2.   The intra-patient dose escalation can therefore be said to have not succeeded, as the next higher dose of 1 mg/m2 was largely not tolerated.

It appears that single agent marizomib has some activity, but only for a minority of patients, while adding bevacizumab to marizomib leads to much higher response rates and increased survival at 12 months, but still leads to an average median overall survival statistic for recurrent glioblastoma.

SNO summary, episode 2: AG-120 phase 1 trial for IDH1-mutant glioma

AG-120, a first-in-class mutant IDH1 inhibitor in patients with recurrent or progressive IDH1 mutant glioma: updated results from the phase 1 non-enhancing glioma population.

Summary by SW who attended the presentation and took photos of the slides.

Ingo Mellinghoff of Memorial Sloan Kettering Cancer Center presented results of a phase 1 trial of AG-120 (ivosidenib), a mutant IDH1 inhibitor, for IDH1-mutant cancers.  The presentation specifically focused on a subset of patients in the phase 1 trial: those with non-enhancing (no contrast enhancement on MRI images) IDH1-mutant gliomas.  This analysis included 11 patients in the dose escalation phase, and an additional 24 patients from the dose expansion phase, a total of 35 patients.  The primary study objective was to evaluate safety and tolerability of AG-120, and determine the maximum-tolerated dose and/or the recommended phase 2 dose.

28 out of 35 patients (80%) of patients in this analysis were treated with 500 mg of AG-120 daily.  The majority (24/35, or 69%) of patients in this non-enhancing glioma cohort were WHO grade 2 gliomas.  An additional 23% were WHO grade 3.  Only one grade IV glioma (3%) was included.

Most patients in this analysis had been previously treated with either radiation (57%) or chemotherapy (69%) and the median number of prior systemic therapies was 2.

AG-120 was well tolerated, and the maximum tolerated dose was not reached. The majority of adverse events were low grade, and only 20% of patients experienced a grade 3 or higher adverse event. 

Pharmacodynamic analysis of tumor tissue in two patients revealed that AG-120 treatment strongly suppressed 2-hydroxyglutarate levels in the tumors.  2-hydroxyglutarate is the oncometabolite produced by the mutant IDH1 enzyme.

By far the most common response to AG-120 treatment in this cohort was stable disease, which was achieved in 83% of patients. Only two patients (5.7%) achieved a minor response, including one grade 2 and one grade 3 glioma. Only four out of the 35 patients (11%) had progressive disease with neither stabilization or response.  

More important is the duration of stable disease without progression.  Median duration of AG-120 treatment for all 35 patients is 16 months. For the grade 2 gliomas, representing nearly 70% of the population of this study, median progression-free survival has not yet been reached, and looks to be at least 19 months at the time of the analysis (data cutoff May 12 2017).

When volumetric growth rates pre- and post AG-120 treatment were calculated by imaging studies for the 24 patients in the dose expansion group, the mean percentage change in tumor volume per six months was found to be 24% prior to treatment, and 11% after AG-120 treatment.  In the 1p/19q intact (that is, the astrocytoma) subgroup of 15 patients, before and after AG-120 growth rates per six months were 38% and 14%.  This confirms that the primary effect of AG-120 in this group of non-enhancing (mostly) lower grade gliomas is to significantly slow tumor progression, which was deemed to be a disease stabilization in the majority of cases.

A different drug by Agios Pharmaceuticals, called AG-881, is a dual inhibitor of mutant IDH1 and IDH2, is more brain penetrant than AG-120, and is also being studied in clinical trials for IDH mutant gliomas.

SNO summary, episode 1: CeTeG trial (CCNU + TMZ versus TMZ alone)

Phase III trial of CCNU/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMT-methylated glioblastoma patients: the CeTeG/NOA-09 trial presented by Ulrich Herrlinger for the Neurooncology Working Group (NOA) of the German Cancer Society.

The summary below written by SW, who was in attendance at the presentation by Ulrich Herrlinger and took photos of the slides presented.

The CeTeG trial (also known as NOA-09) is a randomized phase 3 trial for newly diagnosed glioblastoma with methylated MGMT promoter, testing CCNU (lomustine) combined with temozolomide (TMZ) versus TMZ alone. This trial was conducted at 17 centers in Germany and was a follow-up to a non-randomized phase 2 trial which had results published in 2006 and 2009. The CeTeG trial was relatively small for a phase 3 trial, with a sample size calculation of 128 patients total, and this sample size was based on expectations of a significant increase in survival rate at 2 years as seen in the phase 2 trial compared to historical controls. 

Patients in this trial had relatively good prognosis, with high rates of complete resection and high average KPS.  Overall the arms were well balanced, with the only significant imbalance between the two arms being gender, which was not prognostically relevant.

In the combination arm receiving CCNU + TMZ, cycles were 6 weeks in length, with 100 mg/m2 oral CCNU given on day 1 of each cycle and TMZ on days 2-6 of each cycle, with a starting TMZ dose of 100 mg/m2 and possible escalation up to 200 mg/m2 in later cycles. Cycle 1 starts at the same time as radiation.

In the control arm of TMZ alone, cycles were 4 weeks in length, and used the standard TMZ schedule (daily at a dose of 75 mg/m2 during radiation, and 150 mg/m2 on days 1-5 of the first adjuvant cycle and possible escalation up to 200 mg/m2 in later cycles.

Importantly, this trial achieved its primary endpoint of increased overall survival. Survival in the CCNU + TMZ arm was statistically superior to TMZ alone, with a p value of 0.049.  Hazard ratio for death from any cause was 0.6 in the CCNU + TMZ arm.

Median reported survival was 46.9 months for CCNU + TMZ versus 30.4 months for TMZ alone, a difference of 16.5 months.  As seen in the Kaplan-Meier survival estimates, the curves did not separate until after the 2 year mark.  1, 2, 3, 4, and 5 year survival rate was 88.8, 71.4, 57.4, 48.8 and 34% in the CCNU + TMZ arm versus 84.4, 65.4, 42.3, 31.4 and 27.7% in the TMZ arm.  Differences in the survival rate between the two arms were greatest at the 3 and 4 year mark, with 15% more patients surviving to 3 years and 17.4% more patients surviving to 4 years in the combination arm versus the TMZ alone arm.

Given the significant overall survival differences, it's surprising to note that progression-free survival was not significantly different between the two arms (p=0.41), although the progression-free survival curves separated somewhat at about 2 years (a phenomenon also seen in the overall survival curves), after which time CCNU + TMZ shows a slight superiority over TMZ alone. Some potential explanations given by the authors for the lack of a strong PFS signal included: "problems with PFS assessment according to RANO?" including potential undetected pseudoprogressions; and "long-term effects of CCNU?", noting that in studies of low grade gliomas treated with CCNU, responses were sometimes seen months or years after the end of therapy.

  

The percentage of patients receiving further lines of therapy after progression was similar in both arms (59.1% in the CCNU + TMZ arm, 63.5% in the TMZ arm).  More patients underwent re-resection in the CCNU + TMZ arm (31.8% versus 22.2%), and more patients received re-irradiation in the TMZ alone arm (23.8% versus 18.2%). More patients in the TMZ alone arm received further chemo or targeted agent therapy (60.3% versus 48.5%).  The percentage of patients receiving bevacizumab after progression was similar in both arms (27% in the TMZ alone arm, 30.3 % in the TMZ + CCNU arm).  The authors concluded that differences in treatment after progression are not an explanation for the superior survival in the TMZ + CCNU arm.

Combination therapy with TMZ + CCNU approximately doubled the rate of low-grade (but not high-grade) hematoxicity (including neutropenia and thrombocytopenia) and nausea.  However no deaths due to treatment toxicity were observed, and no severe infections, liver failure, or lung fibrosis. More brain edema was observed in the combination arm, and more low-grade alopecia (patchy hair loss).

The authors concluded by noting that acute toxicity of the combination treatment was rare, and importantly, "the primary aim of CeTeG/NOA-09 was achieved: the OS superiority of CCNU/TMZ for MGMT promoter methylated newly diagnosed GBM could be demonstrated".

This may well be the most significant trial outcome reported at the 2017 SNO conference. Since TMZ was approved for newly diagnosed glioblastoma in 2005, it has been exceedingly rare for a phase 3 trial in the newly diagnosed GBM setting to achieve statistically significant prolongation of survival with a novel regimen.  More work needs to be done to explain why progression-free survival benefit was more modest than overall survival benefit in this trial. A potential hypothesis for the improved survival results for the combination therapy is a possible synergistic interaction between TMZ and CCNU, whereby cells escaping sensitivity to TMZ through mismatch repair defects are thereby rendered more sensitive to the CCNU treatment (Stritzelberger et al. 2017). Now that the results of CeTeG have been reported to the international neuro-oncology community, the mechanisms behind the improved outcomes with the combination chemotherapy will likely become the subject of more intense investigation.

SNO conference, San Francisco and Optune compliance

Myself and a friend who also frequents this blog are at this year's SNO conference in San Francisco. I will be reporting on the conference very soon.

To get us started, here is a report from Novocure showing increased survival in the EF-14 trial for patients who achieved 90% or more compliance with Optune (that is to say, wore the Optune device for an average of 90% of the time each day).

Median survival (from randomization, which was 3.8 months after diagnosis), was 21.7 months with 70-80% compliance and 24.9 months with 90% or more compliance.  5-year survival rate in the 90% compliance group was 29.3%.

This dose-response effect is a powerful argument against those who would argue that the positive results in favor of Optune seen in this trial could be a result of a lack of a placebo control, or the result of increased supportive care in the Optune arm.

https://www.novocure.com/patients-who-used-optune-more-than-90-percent-of-the-time-had-the-greatest-chance-of-survival-in-novocures-ef-14-trial-a-median-survival-of-24-9-months-from-randomization-and-a-five-ye/