581 Final analysis of 2-THE-TOP: a phase 2 study of TTFields (Optune) plus pembrolizumab plus maintenance temozolomide (TMZ) in patients with newly diagnosed glioblastoma

Background

TTFields induce anti-tumor immunity via simultaneous activation of type-1 interferon (T1IFN) pathways of the STING and AIM2 inflammasomes and immunogenic cell death.¹ Thus, TTFields-treated GBM cells may provide a complete in situ vaccination platform and synergize with immune checkpoint inhibitors to prolong survival in GBM patients.

Methods

We enrolled 26 newly diagnosed GBM patients in a pilot phase 2 study combining TTFields, pembrolizumab and maintenance temozolomide (TMZ). To distinguish immune effects of TTFields from those of pembrolizumab, TTFields was started at cycle 1 of TMZ while pembrolizumab (200 mg IV every 3 weeks) at cycle 2 of TMZ. Primary endpoints were progression-free survival (PFS) versus case-matched controls treated with TTFields plus TMZ only in the EF-14 study.² Secondary endpoints included overall survival (OS), toxicity, signature and mechanism of response by multiomics analyses of PBMCs and tumors.

Results

The median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. Median PFS was 12.0 months versus 5.8 months in a case-matched control cohort of 26 patients (HR = 0.377; 95% CI: 0.217–0.653; P = 0.0026). Median OS was 24.8 months versus 14.6 months in controls (HR = 0.522; 95% CI: 0.301–0.905; P = 0.047). Importantly, residual tumor size positively correlated with the objective response and survival. Six of 15 (40%) patients with measurable disease achieved partial to complete response. The most common serious adverse events were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (7.7%) patients, respectively. Molecular analyses prior to the addition of pembrolizumab confirmed robust T cell activation by TTFields via the T1IFN trajectory, as evidenced by a high correlation between TCRab clonal expansion and T1IFN responsive plasmacytoid dendritic cells (Spearman coefficient = -0.8; P = 0.014) and defined a T cell-based gene signature of TTFields effects. Subsequently, the ability of the top expanded TCRab clones to adapt to the everchanging tumor microenvironment through successful clonal switching by 2 months after the addition of pembrolizumab strongly predicted response to the triple combination in a Cox HR fit model for OS with a concordance rate of 0.876, P = 0.031.

Conclusions

The triple combination was well tolerated and demonstrated promising efficacy in ndGBM. Bulky residual disease was associated with better outcomes, consistent with the in-situ immunizing properties of TTFields, which synergize with pembrolizumab. Additional molecular analysis will be updated.

References

Chen D, Le SB, Hutchinson TE, et al. Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma. J Clin Invest 2022;132 Stupp, R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA, 201; 318(23): 2306−2316.

Ethics Approval

The study was approved by USC’s and UF’s IRBs, approval numbers USC#HS-23–00020 and UF#IRB201702270, respectively.