Small Steps Forward in Brain Tumor Therapy


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Jeffrey J. Olson, MD

Jeffrey J. Olson, MD

SOME RECENT ADVANCES in the treatment of brain tumors are promising, but others are less so, according to Jeffrey J. Olson, MD, Professor of Neurosurgery at Emory University, Atlanta. At the 2017 Debates and Didactics in Hematology and Oncology Conference, held in Sea Island, Georgia, and sponsored by Emory, Dr. Olson offered his opinion on approaches that have recently emerged in his field. 

Aminolevulinic Acid Aids Surgeons 

ACCORDING TO Dr. Olson, one truly positive step has come in the form of an optical imaging agent, aminolevulinic acid (Gleolan). The compound has been used in Europe since the 1990s but was only recently approved by the U.S. Food and Drug Administration (FDA). 

Aminolevulinic acid is an adjunct for the visualization of malignant brain tumor tissue during surgery. “Portions of a malignant glioma do not look much different from the surrounding brain, but with this agent, which turns malignant brain tumor tissue a brilliant orange, they stand out considerably,” Dr. Olson noted. 

The compound is administered to the patient 3 hours prior to anesthesia. Surgeons use a standard surgical operating microscope adapted with a blue light-emitting source and ancillary filters to visualize fluorescence on malignant tissue. Studies have shown that resection performed under the guidance of aminolevulinic acid results in improved overall survival, presumably because it allows for a greater extent of resection. 

Tumor-Treating Fields Possibly Helpful but Studies Flawed 

THE ACTUAL BENEFIT of tumor-treating fields using an FDA-approved, patient-operated medical device (Optune) is less clear, according to Dr. Olson. Once applied, the device resembles a swimmer’s cap with insulated electrodes lining the interior. Transducer arrays are applied to the shaved scalp and connected to a battery. Tumor-treating fields therapy delivers low-intensity, intermediate-frequency alternating electrical fields to the brain that are toxic to proliferating cells. 

The novel treatment was approved for newly diagnosed glioblastoma based on the prospective, multicenter EF-14 trial. The study randomized 700 newly diagnosed glioblastoma patients, after surgery, radiotherapy, and temozolomide therapy, to continued treatment with temozolomide or the same plus 18 hours a day of tumor-treating fields therapy.1 Median overall survival was 20.9 months for the tumor-treating fields/temozolomide group and 16 months for temozolomide alone (hazard ratio [HR] = 0.63; P = .00006). Median progression-free survival was 6.7 vs 4 months (P = .00005). The 2-year overall survival rate was 43.1% and 30.7%, respectively. 

“With the proper statistical analysis, the results look pretty good,” he noted. “However, the study itself has been subject to skepticism.” Dr. Olson was referring to an editorial by the German neuro-oncologist Wolfgang Wick, MD, who rendered the following criticisms2

  • The study was initiated based on a negative trial for patients with progressive glioblastoma. 
  •  The mechanism of action is unknown. 
  • The study was not sham-controlled. 
  • Since patients receiving tumor-treating fields were seen weekly by their oncologists, the level of their care was “indisputably higher.” 
  • Treatment with tumor-treating fields was allowed after the primary endpoint of progression was reached; the relevance of this is unknown. 
  • The patient population was unusual in the following ways: (1) Implantation of carmustine wafers (Gliadel) was allowed, which can create artifacts on magnetic resonance imaging, and (2) patients had already experienced a favorable disease course, as the median interval between diagnosis and randomization was 3.8 months. (In an earlier trial of radiation therapy by the same investigators, progression-free survival was measured from randomization but at a time closer to diagnosis, and by 3.5 months, 30% of patients had disease progression.3

“It appears the investigators cherry-picked their patients. I can think of about a dozen different ways this study was biased,” he said. “However, the FDA likes it, patients like it, and it doesn’t hurt anyone.” 

Vaccination Therapy for Brain Tumors 

DR. OLSON SAID he remains optimistic about the use of vaccine therapies in cancer, including brain tumors, but so far, the efforts have not borne much fruit. For example, Alliance A071101 evaluated heat shock protein-peptide complex-96 (HSPCC-96) vaccine plus bevacizumab (Avastin) vs vaccine and bevacizumab at progression vs bevacizumab alone in surgically resected recurrent glioblastoma patients. The vaccine was generated from autologous tumors removed during surgery. 

RECENT ADVANCES IN BRAIN TUMOR MANAGEMENT

  • Aminolevulinic acid imaging
  • Tumor-treating fields therapy
  • Vaccine therapy
  • Checkpoint inhibitors
  • IDH/2HG–directed therapy

The study was powered to show a 36% improvement in overall survival, but after 90 patients, the interim analysis showed futility. In fact, median overall survival for patients receiving HSPCC-96 plus bevacizumab was 7.5 months, less than the 10.7 months for those on bevacizumab alone (HR = 2.06; P = .008). The study was terminated early. 

“We’ve had many vaccines developed in neuro-oncology. The first was given the year I was born,” Dr. Olson said. “The science behind vaccine therapies is good, and we’ve learned a lot from the studies, but not one patient has been treated curatively with vaccine therapy alone. We at Emory continue to participate in these trials, however. Hope springs eternal.” 

He is optimistic that vaccines that harness the immune system will prove more effective, and he noted that at least a dozen trials are now evaluating peptide vaccines, viral-based vaccines, and dendritic cell therapies.4 He encouraged attendees to enroll patients on these trials and singled out a Duke University study of an IDH1 peptide vaccine for recurrent grade II gliomas (ClincalTrials.gov identifier NCT02193347). 

Checkpoint Inhibitors and More 

MORE THAN A DOZEN other trials are currently evaluating checkpoint inhibitors, T-cell therapies, and combinations of immunotherapies,4 which have not yet shown much efficacy in recurrent glioblastoma. For example, while phase II studies were encouraging, CheckMate 143, the first randomized phase III trial of a checkpoint inhibitor in recurrent glioblastoma, found no benefit for nivolumab (Opdivo).5 

“But stay tuned,” he said. “There are studies underway that are preliminarily promising.” 

One of them is KEYNOTE-028, which is evaluating pembrolizumab (Keytruda) in bevacizumab-naive patients at second or third recurrence.6 At 6 months, the progression-free survival rate was 45%, compared to the historical rate of 40% with bevacizumab. 

“The programmed cell death protein 1 (PD-1)/PD-L1 inhibitors will probably find a small niche, such as in mismatch repair–deficient tumors [for which pembrolizumab is approved].”
— Jeffrey J. Olson, MD

Some patients remained progression-free for more than 80 weeks. 

Interim results for durvalumab (Imfinzi), a programmed cell death ligand 1 (PD-L1) inhibitor, also look promising in bevacizumab-naive patients with recurrent glioblastoma. At 6 months, 20% of durvalumab recipients were progression-free, which is double the 10% seen with chemotherapy; 44% were alive at 1 year.7 

“There may be some value in these agents,” Dr. Olson predicted. “The programmed cell death protein 1 (PD-1)/PD-L1 inhibitors will probably find a small niche, such as in mismatch repair–deficient tumors [for which pembrolizumab is approved].” In a small study, robust clinical and radiologic responses were observed in nivolumab-treated patients with glioblastoma resulting from germline biallelic mismatch repair deficiency.8 Nine clinical trials are currently evaluating PD-1/PD-L1 inhibitors in primary and recurrent malignant brain tumors. 

IDH/2HG–Directed Therapy 

THERE ARE ALSO NEW DEVELOPMENTS in targeting the IDH1 mutation, which is seen in 20% of adult gliomas. IDH1 mutations result in 100-fold elevation of the metabolite 2-hydroxyglutarate (2HG), which is involved in tumor development. 

Although the depletion of 2HG alone is not enough to kill tumor cells, depletion of the coenzyme nicotinamide adenine dinucleotide (NAD+, a cofactor in cellular energy processes) may be. Mutant IDH1 reduces the expression of an enzyme that maintains NAD+ levels, rendering IDH1-mutant tumor cells highly sensitive to direct NAD+ depletion. Several drugs that inhibit the synthesis of NAD+ are in clinical trials. ■

DISCLOSURE: Dr. Olson reported no conflicts of interest. 

REFERENCES 

1. Stupp R, Taillibert S, Kanner AA, et al: Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: A randomized clinical trial. JAMA 314:2535-2543, 2015

2. Wick W: TTFields: Where does all the skepticism come from? Neuro Oncol 18:303-305, 2016

3. Stupp R, Mason WP, van den Bent MI, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987- 996, 2005

4. Puduvalli VK, Chaudhary R, McClugage SG, et al: Beyond alkylating agents for gliomas: Quo vadimus? ASCO Educational Book 37:175-186, 2017. 

5. Omuro A, Vlahovic G, Baehring J, et al: Nivolumab in combination with radiotherapy with or without temozolomide in patients with newly diagnosed glioblastoma: Updated results from CheckMate 143. Neuro Oncol 19(suppl 3):Abstract OS07.3, 2017. 

6. Reardon DA, Kim T-M, Frenel J-S, et al: Results of the phase IB KEYNOTE-028 multicohort trial of pembrolizumab monotherapy in patients with recurrent PD-L1-positive glioblastoma multiforme. Neuro Oncol 18(suppl 6):Abstract ATIM-35, 2016. 

7. Reardon D, Kaley T, Dietrich J, et al: Phase 2 study to evaluate the clinical efficacy and safety of Medi4736 (durvalumab) in patients with glioblastoma: Results for cohort B (durvalumab monotherapy), bevacizumab-naive patients with recurrent GBM. Neuro-Oncol 18(suppl 6):Abstract ATIM-04, 2016. 

8. Bouffet E, Larouche V, Campbell BB, et al: Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 34:2206-2211, 2016.



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