Table 4.
Selected completed trials with targeted molecular therapies
| Molecular Target | Signaling Pathway | Therapy | Trial | Trial Concept (examples) | Trial Result |
|---|---|---|---|---|---|
| BRAFV600 mutation | Vemurafenib208 | NCT01524978 | Basket trial with recurrent glioma arm | ORR 25% overall 3/6 GBM had SD as best response | |
| BRAFV600E mutation | Dabrafenib + Trematenib210 | NCT02034110 | Phase II basket trial using novel Bayesian hierarchical statistical design | ORR for GBM 29%; 62% for low grade gliomas | |
| EGFR amplification | Depatuxizumab mafodotin (DM) (ABT414)205 | NCT02573324 (Intellance 1) | Randomized phase III trial in newly diagnosed GBM with EGFR amplification comparing RT + TMZ ± DM | 639 patients randomized Ocular toxicity common DM MS 18.9 (17.4, 20.8) Placebo: 18.7 (17.0, 20.3) HR 1.02 (0.82, 1.26); P = 0.63 | |
| EGFR amplification | Depatuxizumab mafodotin (DM) (ABT414)206 | NCT02343406 (Intellance 2) | Randomized phase II in recurrent GBM comparing DM, DM + TMZ, or TMZ alone | 260 patients 25–30% grade 3 or 4 ocular toxicity Hazard ratio (HR) for the combination arm DM+TMZ compared with the TMZ was 0.71, 95% CI [0.50, 1.02]; P = 0.062 at initial analysis. On long-term follow-up, HR for the comparison of the DM+TMZ compared with control was 0.66 (95% CI = 0.48, 0.93), P = 0.017. Efficacy of DM monotherapy was comparable to that of TMZ (HR = 1.04, 95% CI [0.73, 1.48]; P = 0.83) | |
| Exportin 1 | Important for transport of tumor suppressor proteins and oncoprotein mRNA from nucleus to cytoplasm | Selinexor | NCT01986348 | Multi-arm phase II trial in recurrent GBM | ORR 10% PFS6 19% 6 cycle PFS (24 weeks) 30% |
| FGFR mutations and FGFR-TACC gene fusions | Highly oncogenic FGFR mutations and FGFR-TACC gene fusion that confers sensitivity to FGFR inhibitors | AZD4547 | NCT02824133 | Phase I/II study in patients recurrent glioma positive for FGFR fusion | Not available |
| FGFR mutations and FGFR-TACC gene fusions | Highly oncogenic FGFR mutations and FGFR-TACC gene fusion that confers sensitivity to FGFR inhibitors | Infigratinib (BGJ398)223 | NCT01975701 | Phase II study in recurrent GBM with FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation in FGFR1, 2 or 3 | 26 patients ORR 7.7% 4 patients disease control > 1 year (2 FGFR1 mutations, 1 FGFR3 mutation, 1 FGFR3-TACC3 fusion) PFS6 16% |
| mTOR | Everolimus222 | NCT01062399 | Randomized phase II trial of RT+TMZ ± everolimus in newly diagnosed GBM | 171 patients No difference in PFS (median PFS 8.2 m for everolimus vs 10.2 m for control; P = 0.79) OS for everolimus was inferior to that for control patients (median OS: 16.5 vs 21.2 m, respectively; P = 0.008) | |
| mTOR | Temsirolimus | NCT01019434 | Randomized phase II of RT+TMZ versus RT + temsirolimus in newly diagnosed unmethylated GBM | 111 patients randomized Not difference in 1year survival (72.2% in TMZ arm; 69.6% in the temsirolimus arm. (HR 1.16; P = 0.47]. Phosphorylation of mTORSer2448 in tumor (HR 0.13; P = 0.002), detected in 37.6%, associated with benefit from temsirolimus | |
| Phosphatidylinositol 3-kinase (PI3K) | PIK3CA or PIK3R1 mutation, loss of PTEN activity through PTEN mutation, homozygous deletion or negative PTEN expression (<10% of tumor cells that stained positive), or positive phosphorylated AKTS473 (pAKTS473) | Buparlisib224 | NCT01339052 | Multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence | ORR = 0 PFS6 8% Median PFS 1.7 m |
| VEGF | Bevacizumab171 | NCT0094382 (AVAGlio) | Phase III placebo-controlled trial comparing RT + TMZ ± bevacizumab | 921 patients randomized Median PFS longer in the bevacizumab group than in the placebo group (10.6 months vs 6.2 months;HR 0.64; P < 0.001). OS did not differ between groups (HR, 0.88; P = 0.10). | |
| VEGF | Bevacizumab137 | NCT00884741 (RTOG 0825) | Phase III placebo-controlled trial comparing RT + TMZ ± bevacizumab | 637 patients randomized No difference in OS (bevacizumab median, 15.7 m, control 16.1 m (HR 1.13) PFS was longer in the bevacizumab group (10.7 months vs 7.3 months;HR, 0.79) | |
| VEGF | Bevacizumab148 | NCT01290939 (EORTC 26101) | Phase III trial comparing lomustine to lomustine + bevacizumab in recurrent GBM | 437 patients randomized No survival advantage with addition of bevacizumab Median OS 9.1 m with lomustine compared with 8.6 m in combination group (HR 0.95) PFS 4.2 m with bevacizumab + lomustine compared with 1.5 m with lomustine alone (HR 0.49; P < 0.001) | |
| VEGF receptors 1, 2, and 3 and PDGF receptors | No test yet required | Regorafenib193 | NCT02926222 | Randomized phase II comparing regorafenib with lomustine in patients with relapsed glioblastoma (REGOMA): | 7·4 months (95% CI 5·8–12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank P = 0.0009) |
| VEGFR2, cMET, AXL, RET | No testing required | Cabozantinib225,226 | NCT00704288 | Single arm phase II in recurrent GBM | 220 patients Bevacizumab naïve 14.5–17.6% ORR; PFS6 22.3 to 27.6% Bevacizumab failure 4.3% ORR. |
| CD95/CD95ligand | Lower levels of methylation of the CpG2 in the promoter of the CD95 ligand | Asunercept219 | NCT01071837 NCT03152708 | Re-irradiation ± asunercept in progressive GBM CAN008 biomarker CD95 Ligand and CpG2 methylation in Chinese patients with GBM | PFS6 rates were 3.8% [95% CI, 0.1–19.6] for rRT and 20.7% (95% CI, 11.2–33.4) for rRT+APG101 (P = 0.048). Ongoing |
Abbreviations: CI, Confidence intervals; GBM, glioblastoma; HR, hazard ratio; mTOR; mammalian target of rapamycin; m, months; MS, Median survival; ORR, objective response rate; PFS, progression-free survival; PFS6, Progression-free survival at 6 months; rRT, reirradiation; SD, stable disease; VEGF, vascular endothelial growth factor.