ASCO 2024, and the slow progress in low grade glioma research

I haven't personally attended ASCO since the pre-pandemic are, but I've been keeping a keen eye on the news coming out of the conference, analysing it through both a professional lens, as well as a personal one.

Just as ASCO was about to kick off, my sister had a consultation with her neurologist and oncologist following the mid-point of her chemotherapy, having completed 3 out of a planned 6 cycles of PCV chemo. She's currently at a cross-roads, and has an important decision to make: continue putting up with the side-effects that are having a significant impact on her QoL, or terminate the treatment midway and risking a sub-optimal impact from the chemo. On the latter, the neurologist made the fair point that all these treatment protocols, including the recommended number of cycles, are based on a consensus derived from limited data, thereby making it almost impossible to say what the added advantage of another 3 cycles would be. The oncologist, however, felt that as long as she could (blood tests staying within acceptable range), the rational thing to do would be for my sister to continue the chemotherapy. But, at the end of the day, it's the patient's decision.

Limited data: this is one of the most frustrating aspects of the current treatment paradigm for low grade gliomas (LGG). Somewhat understandably, the majority of research to date for gliomas has focused on glioblastoma (GBM), the most aggressive form of the disease. That's not to say that researchers have shied away completely from studying LGG; however, it is a really challenging disease type to study, due to the slow-growing nature of these tumours. As patients (thankfully) often survive with stable disease for 10 years or more, this means that studies with very long follow-up periods (multiple decades) are required to observe any significant differences in the impact of treatment interventions, such as systemic therapies.

While less aggressive than their high-grade counterparts, LGGs can still have a very significant impact on patients' QoL, and the uncertainty surrounding the prognosis can be especially debilitating. Given that almost all LGGs eventually do transform into a higher grade, patients and their families want to focus on doing what they can to postpone that transformation for as long as possible. This includes aiming for resecting as much of the tumour as possible, often followed up with radiotherapy, chemotherapy, or a combination of both. While the timing and choice of these modalities is potentially key in extending overall survival, there is - as noted above - a lack of very clear data surrounding the choice of chemotherapy regimens (most arguments focusing on PCV vs temozolomide), or the impact of early treatment termination (given that many patients do tend to stop chemo early, particularly in the case of PCV).

While in the case of most cancers it becomes clear fairly quickly during systemic drug therapy whether the tumour is responding to the treatment, this is far less obvious with LGGs. The aim here is typically not to show a significant immediate reduction in tumour volume - in many cases, as in my sister's, all that remains after surgery is a thin layer of residual cells along the edge of the resection, which may not even be visible - but to slow down future growth by an indeterminate amount. The rationale, in other words, is: if we administer this treatment now, it should (hopefully) result in the tumour coming back by X number of months (or years). And while the studies (mostly) show an average increase in PFS and OS for treatments like PCV [1], it is impossible to retrospectively state for any given individual if the tumour would have recurred/transformed any earlier if chemo hadn't been administered when it was. Similarly, it is impossible to state whether the administration of systemic chemo will in fact result in a prolonged PFS or OS for that individual X number of years down the line. As my sister's neurologist put it "your residual tumour is stable on the MRI, but it's impossible to state whether that's because of the radiation or chemo, or if it would have been stable anyway".

This can be very hard to cope with mentally. As my sister told me "I had mentally already decided to stop early due to the many side-effects, which make it very difficult to enjoy the time I have left. On the other hand, if I stopped now, I will probably regret it when my tumour does transform and I end up paralysed and fully disabled".

Low grade glioma research at ASCO 2024

Given the above, I was curious to see how many of the abstracts and presentations accepted at ASCO 2024 specifically covered the topic of low grade gliomas. The number is somewhat depressing. There are 117 abstracts/posters that are related to CNS tumours, but a large proportion of those are about brain metastases. Most of the ones pertaining to primary brain tumours are, of course, about GBM. Using the search term "low grade gliomas" returns just 3 results, though searching for "oligodendrioglioma" brings up another one, and there were a few additional abstracts concerning IDH-mutant gliomas (which are often low grade) that caught my eye.

Notable abstracts/presentations that I could find through my search include:

• Survival outcomes associated with first-line PCV or temozolomide in combination with radiotherapy in IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma [2]

• Retrospective study of ivosidenib for patients with recurrent IDH mutant gliomas [3]

• A phase II, open label, single arm study of nivolumab for recurrent or progressive IDH mutant gliomas with prior exposure to alkylating agents [4]

• Health state utility assessment for low-grade glioma [5]

Let's start with the last one. While research into novel treatments is of course crucial in the fight against cancer (and particularly in this setting, where we're still literally stuck with drugs from the 1960s), it is always nice to see studies that focus on quantifying the - very real but often poorly understood - impact on quality of life slow-growing malignancies such as LGGs have. As the authors rightly state:

Though resection and adjuvant therapies have significantly improved survival, there are increased risks of long-term neurological decline and treatment-related side effects. As a result, not only quantity but also quality of life (QoL) must be considered when appraising therapeutic paradigms.

One of the data points that stood out to me in the results was the following:

Radiation negatively impacted UVs [Utility Values], as UVs of Stable LGG with Chemoradiation [...] were significantly lower than UVs of Stable LGG with Chemotherapy alone

UVs here on a scale from 0 (death) to 1 (perfect health). While the fact that radiation is often seen as a trade-off between added efficacy and (potential for) added toxicity is not a novel concept, it is valuable to see this impact on QoL quantified using the rigorous approach the authors used in this paper.

Jumping to the first paper, this one particularly spoke to me, given that this choice - between PCV and temozolomide - was a major challenge for my sister prior to eventually settling for PCV. While the study focuses on grade 3 (and not grade 2) oligodendrogliomas, it is reassuring to see that this analysis (based on the French national cohort study POLA) too points in the direction of PCV being the superior choice:

In patients with newly-diagnosed O3IDHmt/Codel from the POLA cohort, first line PCV/RT was associated with better OS outcomes compared to TMZ/RT. Our data suggest that the improved safety profile associated with TMZ comes at the cost of inferior efficacy in this population

The other two abstracts, looking into investigational therapies in IDH mutant gliomas (across grades), are a mixed bag. The ivosidenib retrospective analysis focuses on a small (n=33) group of mostly heavily pre-treated (and mostly grade 2) IDH-mutated gliomas, a subset of patients that tends to not have many options left for treatment. It is therefore reassuring to see at least a "manageable safety profile", and also "in a subset of patients, there was disease stabilization in heavily pre-treated recurrent IDH mutant gliomas", despite somewhat depressing median PFS and OS data.

The nivolumab study, meanwhile, showed an ORR of just 9% across 33 patients. Not exactly stellar numbers. That said, the three patients that did show a response were all grade 3, and still showed CR or PR after the 24 months of planned treatment, which is encouraging for at least this (small) subset of patients that saw a benefit. As the authors concluded:

This study provides data on single-agent PD-1 inhibition, which will serve as baseline efficacy data for ongoing and future combination immunotherapy trials with PD-1 inhibitors in recurrent IDH-mutant gliomas

In summary, while progress continues to feel frustratingly slow for those of us with loved ones that are literally racing against the clock, it would be unfair to state that this is a forgotten disease. Important research continues to be carried out, and it is my hope that these stepwise advances will culminate in treatments that are able to either significantly improve QoL for an extended period of time, or completely eliminate these insidious tumours.

References:

1. Buckner JC, Shaw EG, Pugh SL et al.. Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. N Engl J Med. 2016;374(14):1344–1355.

2. Salah Eddine O. Kacimi et al., Survival outcomes associated with first-line PCV or temozolomide in combination with radiotherapy in IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma.. JCO 42, 2004-2004(2024).

3. Joseph El-Ghoubaira et al., Retrospective study of ivosidenib for patients with recurrent IDH mutant gliomas.. JCO 42, 2040-2040(2024).

4. Eunji Yim et al., A phase II, open label, single arm study of nivolumab for recurrent or progressive IDH mutant gliomas with prior exposure to alkylating agents.. JCO 42, 2056-2056(2024).

5. Debarati Bhanja et al., Health state utility assessment for low-grade glioma.. JCO 42, e14039-e14039(2024).