The road we travel

The article by Omuro et al. on the results of a randomized phase 3 trial of radiotherapy with nivolumab versus temozolomide in newly diagnosed glioblastoma with unmethylated MGMT promoter is an important report of a negative study.¹ The struggle to advance therapy considerations for all glioblastoma and specifically the unmethylated MGMT population has proven and re-proven to be difficult. Are there observations from this study to inform researchers on potential ways forward? I believe there are at least 3 points to consider.

First, we may look at the design and performance of the clinical trial. CHECKMATE 498 was a well-done study specifically structure to compare nivolumab to temozolomide in the newly diagnosed unMGMT glioblastoma population. The design was appropriate and even innovative by dropping TMZ in the experimental arm for nivolumab. It was supported statistically and well-balance between the arms. The accrued population is reflective of the disease. It enrolled 560 patients at 124 sites across 19 countries in a short period of time between March 2016 and October 2018. The sponsor collected adverse events and clearly reported. However, in the end the reported results failed to improve outcome for newly diagnosed unmethylated MGMT glioblastoma patients. The experimental arm with a novel PD-1 inhibitor actually faired a bit worse in terms of overall survival. How do we analyze such as investment in time, energy, and financial support. The trial is well designed, executed, and analyzed. I believe we can feel confident the experimental agent received a proper evaluation in newly diagnosed unMGMT population with our current standard therapy. The authors note challenges to the immunosuppressive environment of glioma within the central nervous system, the need for predictive biomarkers and genomic characterization, and role of as well as the incorporation of standard of care therapy. Let’s consider these points a bit deeper.

Second, we should consider the use of immune modulatory therapy in glioblastoma. When we analyze the immune-related adverse events in CHECKMATE 498, any grade but especially the serious adverse effects grade 3 and 4 which were 11.2%, we see similar percentages as seen in immune checkpoint trials utilizing PD-1 inhibitors where significant and meaningful clinical benefit occurs.^2,3 This suggest the therapy was functioning as it should systemically but without a CNS anti-glioma effect. Clinicians have long recognized the immunosuppressive nature of glioblastoma. In addition, we increasingly recognize the detrimental impact of prolonged dexamethasone use which was kept to a minimum in this study. We now have increasing laboratory evidence pointing to a significant myeloid contribution and interaction with tumor cells in creation and diversification of a CNS constrained tumor microenvironment.^4,5 These study results and laboratory efforts suggest advances may require better understanding of the innate immune response, the myeloid compartment, and strategies to enhance T-cell function within the CNS. We must strongly consider if our study designs are allowing the best opportunity for immune based therapies to work.

Third, as suggested by the authors, are we truly critically considering the design for our trials in newly diagnosed glioblastoma? Are the modalities for treatment available to us in the form of surgery, radiation therapy, and chemotherapy (or biological) being deployed in the most creative fashion to generate potential durable responses or in the fashion of tradition? We have always done it like this or we are comfortable with this way. In John Gunther’s small text of his son’s fight with glioblastoma, Death Be Not Proud, the treatment was largely similar to treatment today. The book was published in 1949.⁶ The young man’s fight for life sent him to the pioneers of neurosurgery, early use of cranial irradiation, and an attempt at personalized therapy with the foundational elements of alkylating chemotherapy. He was 17 years old at diagnosis and survived 18 months. Seventy-five years later, we need to be doing better. Despite the availability of AI (artificial intelligence), machine learning, the EMR, and layers of rules and regulations, are we as a field confident in our approach through which we wish to advance the outcomes for patients. Do we believe small incremental “statistically significant” changes in overall survival are truly meaningful in glioblastoma? Are we able to preserve neurological function with this approach so patients can maintain their station in life? Should we be so comfortable in accepting our current path? The recent headline creating ASCO abstract on results from a small investigator-initiated study of patients with advanced rectal cancer where all participants had a complete response was not so incredible because the therapy worked, it was incredible because it was biomarker driven and the standard-of-care (which is successful in this disease) was delayed. Actually, never used, as at the time of the report, none of the enrolled patients had required surgery, radiation, or chemotherapy.⁷

As we travel along the road of clinical investigation in glioblastoma, we should consider the path proposed by Nassim Taleb, master of probability in “Skin in the Game.”⁸ As the title implies, are we willing to be failed risk takers, are we willing to commit to advancing care as much as our patients are committed to us, are we willing to have skin in the game? I would encourage the field to reconsider our dependency and requirement for incorporating the standard of care in newly diagnosed glioblastoma clinical trials. In the blossoming field of biological understanding and biology driven therapeutics, we should engage in increasingly selected populations for biological targeted therapies in a window of opportunity before the use of standard radiation and chemotherapy.

Declaration

The text is the sole product of the author and no third party had input or gave support for its writing.