Radiation Plus PCV Shows Potential In Glioma Subgroup

Ranee Mehra, MD

Erica Bell, MD

Pembrolizumab (Keytruda), when studied in 2 clinical trials for the treatment of patients with pretreated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), showed an objective response rate (ORR) of 18%, according to findings presented at the 2016 ASCO Annual Meeting.

Patients with high-risk, low-grade glioma may soon benefit from radiation plus procarbazine, CCNU, and vincristine (PCV), according to Erica Bell, MD.

In an interview with Targeted Oncology, Bell, assistant professor, Ohio University, discusses the RTOG 9802 trial, which compared radiation versus PCV or radiation-alone in patients with high-risk, low-grade glioma. Bell also stresses that while the treatment may be useful, finding the correct subgroup through molecular testing is vital.

TARGETED ONCOLOGY:Can you tell us a little bit about RTOG 9802?  

Bell:

We've had follow-up data to the primary report of RTOG 9802, which was a phase III study looking at radiation versus radiation plus PCV in high-risk, low-grade glioma population. It was a positive study, so the addition of adjuvant PCV for high-risk, low-grade glioma is now the new standard of care for this population. We did look at one molecular factor, which was the IDH mutations, the R132H mutation specifically, which showed a very large benefit for that subpopulation. So patients with that particular IDH mutation responded very well to radiation plus PCV.

That led us to question if all subgroups of grade 2 glioma respond in a similar manner. It's a continuation of that work, what we're doing now. Not only did we look at that IDH mutation, we looked at IDH1, IDH1, ATRX, CIC, FUBP1 mutations, as well as promoter mutations. All of these are known players in the field of gliomas. Work from the TCG and other groups have shown their value in diagnosis and prognosis, but what still remains to be determined is kind of the predictive status, and that's what we're still looking at. Because this is a retrospective study on a prospective trial, tissue was not mediated to look at the molecular markers. Hindsight is always 20/20 when it comes to that.

Of course when these trials were initiated in 1998, tissue was not mandated. Now we do prospectively collect tissue, which helps us do molecular studies. We were able to receive about 50% of tissues from this study, and we're trying to increase that a little bit to look at the predictive status. So I will say that predictive status is ongoing, but we are reporting on the prognostic statuses. By looking at IDH a little further, we increased our numbers and determined that about 75% of the patients had an IDH mutation on this particular population. We we did confirm validity that it's an independent prognostic factor that was significant upon progression free survival and overall survival, independent of all other clinical variables. We also found that CIC and TERT promoter mutations were significantly associated with overall survival in this population. However, this can be associated with one 1P19Q status, which we did not look at for this particular study, but it is ongoing and we are happy to report that we are going to be presenting that work later this year at the Society of Neuro-Oncology.

TARGETED ONCOLOGY:What do you hope community oncologists take away from this study?  

Bell:

Bell: You need to molecularly subtype these patients, and I think that's kind of implied in the new WHO classifications. Especially for IDH mutations and 1P19Q. That's very important, and if there's not a certified lab at their institute then they need to send their specimens to a lab that can do this, because it really means a lot when it comes time for prognosis and likely treatment for this patient population.

TARGETED ONCOLOGY:Where would you say this field is right now with biomarker development? 

Bell:

We are heavily engaged in this research. We have the tissue samples, the long-term follow-up data, but we need very long-term follow-up data for these patients. Some patients do very well. We measure their survival in decades, and that makes it a little bit hard to study because we need to go back that long ago to get the patient samples. Some of the patient samples are old, they weren't collected well, they've been degraded, ect. So that's making this research a little bit hard, but with the technology now and the molecular studies, we can use that tissue if it is available going back to 20 years ago.

This is what we're doing a lot of times now. Looking at all the different next-gen sequencing panels and profiling these tumors, and correlating it with the survival data. Many groups are doing this, not only in the United States but also Europe, and we're also doing this in clinical trials. The clinical trial I speak to right now is RTOG 9802. We're not just looking at the known players. We're looking globally, trying to understand the biology more.

One issue with studying lower-grade gliomas, which is grade 2 and 3, is the models. We don't have great in vitro animals and they don't tend to grow well in culture, so validating these findings is hard, and with second tissue cohorts, if we're looking at them in a phase III study, there may not be another phase III study for us to validate it in. So that's kind of where it's a little hard to do.

If we want to do a clinical trial now, we have to wait 10 to 15 years to follow up the data. We are starting to do more prospective studies, and we are going to do them in a biomarker-driven manner. They're going to be stratified based on molecular biomarkers. The biomarker field in the low-grade gliomas has flourished in the past few years and will continue to be very productive. I think that's exactly where the field is going, and the new WHO classification validates that.

TARGETED ONCOLOGY:What do you see coming in this field in the future? 

Bell:

Bell: The biomarker-driven trials are going to be the future. That's where we're going, and we need to split patients into different subpopulations. For the patients that do well, the question becomes if you can de-escalate that treatment a little bit or not give them as much toxic radiation therapy, and do they still see great survival benefits? You want to really give them enough to make their survival outcomes good, but less toxicities. So it's quality of life issues, and that's really where I think the big question is going to come — what combination of radiation and chemotherapy do we give these patients with good toxicities and long-term outcomes. Even if they're going to live for decades, we want them to live with a good quality of life.

The patients that resemble more glioblastoma, we need to escalate their treatment. If the treatments that we have now aren't working, then we need novel therapies and we probably need better therapies for all these subgroups. One of the drugs out there right now is one that targets the IDH mutation, and I think a lot of trials are going to be ongoing with that. The question then becomes if you can combine it with standard of care without increases toxicities.