David Reardon, MD
Findings from separate trials exploring the PD-1 inhibitor pembrolizumab (Keytruda) and the PD-L1 inhibitor durvalumab (MEDI4736) point to a role for checkpoint inhibitors in the treatment of glioblastoma multiforme (GBM), based on encouraging efficacy signals and safety data with the two agents reported by David Reardon, MD, at the 21st Society for Neuro-Oncology (SNO) Annual Scientific Meeting.
Reardon said that these results mark important firsts in the field: “There has been a lot of anticipation regarding the role of checkpoint inhibitors for glioblastoma and whether we’ll see results in any way similar to the exciting results that have been observed in other cancer indications with this new class of cancer therapeutics.”OncLive
spoke with Reardon, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, while at the SNO 2016 Annual Meeting to discuss these two trials, next steps, and what these advancements mean for the field of neuro-oncology.
OncLive: Let’s start with the KEYNOTE-028 trial.
: The KEYNOTE-028 trial was a “basket” clinical trial looking at the PD-1 inhibitor pembrolizumab across a number of solid tumor types, including recurrent GBM. All of the patients treated on this study received single-agent pembrolizumab. The GBM basket included patients with any recurrence: about one-third of the patients were enrolled at second or higher recurrence, and about two-thirds were treated following their first recurrence. These were bevacizumab-naive patients who had progressed after standard of care therapy. All of the patients received pembrolizumab on a standard dosing schedule of 10 mg/kg every 2 weeks.
What were the results of this trial?
This was a single-arm study, so there's no control population, but there are well-established historical control data for recurrent GBM to judge our outcomes. The study revealed that these agents were quite well-tolerated for the glioblastoma population—there were really no unusual or unexpected side effects observed which is always reassuring in the brain cancer setting.
What we observed from an efficacy point of view was also encouraging, but the results do have to be understood in the context of a single-arm, fairly small study—nonetheless, they are encouraging. We saw a rate of progression-free survival (PFS) at 6 months of 45%. The historical benchmarks for recurrent glioblastoma with salvage therapies are in the order of about 10%. Bevacizumab (Avastin), which is FDA-approved on an accelerated basis in the United States for recurrent GBM, has a PFS–6-month rate of about 40%. So what we saw with this checkpoint-inhibitor data is comparable with data on bevacizumab, in terms of PFS at 6 months.
What was really exciting, though, was not only were patients maintaining PFS rate at 6 months, but a subset of these patients maintained their durability well beyond that and have remained progression-free for up to 80 weeks. This suggests there may be a very exciting tail of the curve for glioblastoma patients in a way that's analogous to what's been observed in other cancer indications, such as melanoma treated with a PD-1 or CTLA-4 checkpoint inhibitor.
We also saw an encouraging overall survival rate on this study, although the follow-up and maturation of the data are ongoing.
What are the next steps for this trial?
These are very encouraging results for pembrolizumab, and we certainly are moving forward with other clinical trials, utilizing this particular PD-1 checkpoint inhibitor. We have completed a larger, randomized, phase II study of recurrent glioblastoma patients who were randomized to receive pembrolizumab monotherapy versus pembrolizumab plus bevacizumab in the recurrent setting. That trial randomized about 80 patients between the 2 arms. We expect a read out probably early next year. Hopefully, that will build on this smaller, single-arm study experience.
There are also a number of other investigator-initiated trials going forward with pembrolizumab, particularly in promising combinatorial regimens for glioblastoma patients.
We don't have results from this yet, but also ongoing is an evaluation of some of the immuno-correlative biomarkers. The patients on this study were required to have tumors that were positive for PD-L1 expression, which we know has been an important predictor in other cancers of patients who are more likely to benefit from checkpoint blockade. We are looking at that, and the data are forthcoming, not only PD-L1 as a potential biomarker, but other immuno-correlative biomarkers that were collected and are currently being analyzed and will be reported subsequently as well.