TTFields use in special GBM populations and potential combination with immunotherapy

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour with a very poor prognosis. Tumour-treating fields (TTFields) are a relatively new, noninvasive treatment for GBM, which delivers low-intensity alternating electric fields that disrupt cancer cell division. At a recent scientific meeting organized by the Hong Kong Neurosurgical Society, Dr Alexander Grote of the Department of Neurosurgery, University Hospital of Marburg, Germany, and Professor Michael Lim of the Department of Neurosurgery, Stanford University, US, discussed the evolving role of TTFields in managing patients with GBM.

TTFields: An established SoC for GBM
TTFields are a treatment for adult patients (≥18 years of age) with newly diagnosed or recurrent GBM. In newly diagnosed GBM, TTFields are given together with maintenance temozolomide (TMZ) and may be continued after TMZ is stopped. [Hong Kong Commercial Optune Physician Instructions for Use] In the US National Comprehensive Cancer Network (NCCN) guidelines, use of TTFields in newly diagnosed GBM patients is given a category 1 recommendation, while use in recurrent disease is supported by a category 2B recommendation. [NCCN Guidelines for Central Nervous System Cancers, version 2.2022]

The recommendation for first-line use of TTFields is based on the randomized phase III EF-14 trial (n=695), where the addition of TTFields to maintenance TMZ significantly improved survival outcomes in patients with newly diagnosed GBM vs TMZ alone (median progression-free survival [PFS], 6.7 months vs 4.0 months; hazard ratio [HR], 0.63; 95 percent confidence interval [CI], 0.52–0.76; p<0.001) (median overall survival [OS], 20.9 months vs 16.0 months; HR, 0.63; 95 percent CI, 0.53–0.76; p<0.001). [JAMA 2017;318:2306-2316]

An earlier randomized phase III trial (n=237) compared TTFields monotherapy vs treating physicians’ best choice of salvage chemotherapy in patients with recurrent glioblastoma who had failed several lines of prior therapy. Although no survival difference was observed, TTFields achieved a higher response rate (14.0 percent vs 9.6 percent), with favourable toxicity and quality of life findings, vs salvage chemotherapy. [Eur J Cancer 2012;48:2192-2202]

“Notably, in EF-14, a strong dose-response relationship was demonstrated between TTFields usage time and survival,” pointed out Grote. “The subgroup of patients [n=43] who wore the TTFields device for >20 hours a day [ie, >90 percent compliance] had an increase of nearly 9 months in median OS vs the TMZ alone group [24.9 months vs 16.0 months; p=0.0007).” [J Neurooncol 2019;141:467-473]

TTFields in elderly patients
The median age at diagnosis for GBM is 65 years. In patients 65–74 years and 75–84 years of age, GBM occurs at a rate of 13.0 and 15.3 cases per 100,000, respectively, representing a more than 4-fold increase in incidence compared with the overall population (3.23 cases per 100,000). [Neuro Oncol 2020;22(12 Suppl 2):iv1-iv96]

A post hoc analysis of 134 elderly patients (≥65 years of age) from the EF-14 trial has demonstrated significant improvements in PFS and OS with TTFields plus TMZ vs TMZ alone (median PFS, 6.5 months vs 3.9 months; p=0.0236) (median OS, 17.4 months vs 13.7 months; p=0.0204). [Front Oncol 2021;11:671972]

Consistent with the dose-response relationship observed in the overall EF-14 population, there was a significant increase in OS in the elderly cohort with an average daily TTFields usage of ≥75 percent (≥18 hours/day) vs those with daily usage of <75 percent (median OS, 21.7 months vs 12.5 months). (Figure 1) [Front Oncol 2021;11:671972]

“A majority [57 percent] of elderly patients used TTFields for an average of ≥18 hours/day, which shows that they were able to comply with usage recommendations,” remarked Grote.“TTFields therapy is therefore feasible in this patient population.” [Front Oncol 2021;11:671972]

TTFields in patients with VP shunts
“Up to 10 percent of GBM patients may develop hydrocephalus,” shared Grote. [J Neurooncol 2022;158:453-461] “The decision of whether or not to implant a ventriculoperitoneal [VP] shunt in these patients is a crucial one. In particular, older individuals who may have also received multiple treatments are at high risk of developing complications from implanting such a device. In addition, some neurooncologists are uncertain about the safety of TTFields use in the presence of VP shunts in adult GBM patients.”

A global, retrospective, postmarketing surveillance study has provided real-world safety data for the use of TTFields in the presence of VP shunts in adult patients with GBM (n=156). The analysis showed that the overall adverse event (AE) profile in patients with VP shunts was consistent with the known safety profile of TTFields in patients without VP shunts. [J Neurooncol 2022;158:453-461]

“The incidence of AEs was comparable between patients on TTFields with or without VP shunts [77 percent vs 70 percent],” remarked Grote. “The most common AE was skin reaction. Side effects such as headache and fatigue could be attributed to other concomitant treatments and/ or the tumour itself.” [J Neurooncol 2022;158:453-461] Nonserious cases of pain or discomfort due to placement of the array at the shunt site (3 percent) and shunt malfunction (3 percent) were considered unrelated to TTFields therapy. [J Neurooncol 2022;158:453-461]

“VP shunts and TTFields work independently,” recapped Grote. “TTFields therapy is a feasible and well-tolerated treatment for GBM patients with programmable and nonprogrammable VP shunts.”

Future direction of TTFields plus immunotherapy
Given the advances in immunotherapy across multiple cancer types, immune-based therapeutic approaches have been investigated in GBM.

“In the preclinical setting, improved survival was demonstrated when combining nivolumab, an anti–PD-1 monoclonal antibody, with RT vs either modality alone,” said Lim. “Unfortunately, in subsequent phase III clinical trials, the addition of nivolumab did not confer survival benefits in newly diagnosed GBM patients with methylatated [CheckMate 548] or unmethylated [CheckMate 498] MGMT promoter.” [Int J Radiat Oncol Biol Phys 2013;86:343-349; Neuro Oncol 2022;24:1935-1949; Neuro Oncol 2022:noac099]

“GBM has adaptive and intrinsic resistance mechanisms to the immune system,” explained Lim. “One of these mechanisms is ‘T-cell exhaustion’, where chronically stimulated T cells have permanently lost their effector functions.” [Nat Immunol 2019;20:1100-1109; Clin Cancer Res 2018;24;4175-4186]

A multimodal approach is needed to reverse T-cell exhaustion. For example, focused RT has been shown to increase activation of T cells and was found to work synergistically with PD-1 blockade to generate a strong antitumour response. [Clin Cancer Res 2016;22:1161-1172; Int J Radiat Oncol Biol Phys 2013;86:343-349]

“The combined use of TTFields and immunotherapy in patients with GBM is currently under investigation,” said Lim. The phase II single-arm 2-THE-TOP trial evaluated the safety and preliminary efficacy of TTFields in combination with pembrolizumab and TMZ in 24 patients with newly diagnosed GBM. Of 22 patients with follow-up ≥9 months, median PFS was ≥11.1 months with TTFields plus pembrolizumab and TMZ vs 6.7 months in the matched control patients from the EF-14 trial. Moreover, 23 percent of patients had partial to complete objective response. [WFNOS 2022, abstract F-1182]

It is hypothesized that TTFields create an immunogenic environment by inducing micronuclei clusters to recruit and activate two major DNA sensors – cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2). This in turn activates their cognate inflammasomes – STING and AIM2 – and promotes the production of immune-stimulating proinflammatory and interferon type 1 cytokines in tumour cells, thereby activating the immune system. [J Clin Invest 2022;132:e149258]

Summary
TTFields therapy is a feasible and safe treatment for elderly GBM patients and those with programmable and nonprogrammable VP shunts. Patients who use TTFields ≥18 hours/day derive the greatest survival benefit. Emerging data suggest that some of the benefit of TTFields may be due to immune stimulation through inflammasome signalling pathways. TTFields can potentially work synergistically with immunotherapy to further enhance the antitumour response in GBM.