Results of Ivosidenib (inhibitor of mutant IDH1) for nonenhancing IDH1 mutant gliomas

Just published in the Journal of Clinical Oncology

Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma
https://sci-hub.tw/10.1200/JCO.19.03327

• out of 35 patients with nonenhancing glioma, objective response rate was 2.9% with one partial response
• of these same patients, 30/35 (85.7%) had stabilization of their disease.
• for these same 35 patients, median progression-free survival was 13.6 months.
• the drug was well-tolerated with no dose-limiting toxicities reported.

As seen here, many of the patients with non-enhancing glioma have had disease stabilization for three years or more.  Not bad for a drug that is so well tolerated and with no dose-limited toxicities.

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.

new paper on IDH305, mutant IDH1 inhibitor

abstract on pubmed here

sci-hub download here

New study from the Costello lab (UCSF) on IDH1 mutant low grade glioma

The study is called Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1.  View abstract here.  I've also uploaded this to the Brain Tumor Library, Pathology folder, IDH-mutant glioma subfolder.  This data was presented at the SNO conference in Phoenix last year.  I'll be following up with comments, and perhaps an Astrocytoma Options update on this.

PCV vs Temodar in IDH1 mutated unmethylated astrocytoma

There must be a lot of people who have already dealt with this issue but I didn't see any discussions on it.

I'm 47 years old with a recurrent grade 2 Astrocytoma previously treated with surgeries. Just over 12 years ago it was also treated with radiation, but not with chemotherapy. It's IDH1 mutated, unmethylated and 1p/19q are intact. I'm deciding between radiation followed by PCV or radiation with Temodar and adjuvant Temodar.

The results of RTOG 9802 make PCV appear to be a reasonable option, but RTOG 0424  Temodar results are just as good. My doctor's say Temodar will be as effective as PCV and more tolerable. The advantages of PCV are: the RTOG 9802 survival plot for IDH1 mutations looks good, it's a multi-agent treatment, the methylation status isn't a factor, and there seems to be less risk of hypermutation.

Has anyone with similar tumor characteristics chosen PCV over Temodar, if so what influenced your decision and how did it work out?

Hi,

I'm updating this discussion for anyone in the future who might be interested.

I've had the 3 opinions below.

UCSF:

They didn't give me any new information about hypermutation. Results of trials will be released in 3 or 4 years.

They confirmed my diagnosis and recommended SOC with 6 cycles. They said there was no information more cycles or a different dose schedule provided any benefit. I wasn't eligible for the Everolimus or the other 2 trials for low-grade tumors.

UCLA:

This is where the recurrence was initially diagnosed.

They recommended SOC. With the following expected response rates for patients similar to me

50% without radiation.

75% response rate with radiation.

I didn't get a definition of response, but I think it means either shrinkage or cessation of growth.

Said there's no data to indicate the ketogenic diet helps, but it won't hurt

UCSD:

Confirmed diagnosis.

Said preliminary study results indicate Temodar works about as well as PCV.

10 or 15 % experience hypermutation.

12 cycles recommended.

Most tumors cease growing and about 15% of patients see a reduction in tumor size.

MGMT is less important in low-grade tumors than high-grade tumors.

IDH1 mutated tumors are more chemosensitive.

Treatment: I decided to go with proton radiation + Temodar. I can always change my mind after radiation if new information indicates switching chemo is best. I'm also taking various supplements and started the ketogenic diet.

I had my first proton and Temodar yesterday and woke up surprised by how much it affected me. Symptoms included: fatigue, headache, and I threw up after only 3 sips of coffee. An extra Ondanestron cleared up the nausea after about 1/2 hour.