Table 1. Summary of phase II/III trials of targeted therapies aimed at other targets for rGBMs.
| References | No. | Phase | Therapeutic target | Therapy | Protocol | Results | Beneficial
subgroup |
Adverse effects | Conclusions | ||||
| PFS
(month) |
OS
(month) |
6-month
PFS (%) |
ORR
(%) |
All
grade |
≥grade
3 |
||||||||
| PFS, progression-free survival; OS, overall survival; ORR, objective response rate; HDAC, human class I and class II histone deacetylases; EGFR, epidermal growth factor receptor; TGF, transforming growth factor; HGF, hematopoietic growth factor; PDGFR, platelet-derived growth factor receptor; CA9, carbonic anhydrase 9; HIF-1α, hypoxia inducible factor 1 alpha; CSF1R, colony stimulating factor 1 receptor; PARP, poly (ADP-ribose) polymerase; MET, mesenchymal-epithelial transition factor; ANG, angiopoietin; FGFR, fibroblast growth factor receptor; NA, not available. | |||||||||||||
| Reardon DA,
et al., 2008 (56) |
81 | II | Integrin receptor | Cilengitide | 500 mg cilengitide | 2.0 (1.9−3.9) | 6.5 (5.2−9.3) | 10 | NA | KPS=90/100 | 34 | 5 | Cilengitide is well tolerated and exhibits modest antitumor activity |
| 2,000 mg cilengitide | 2.0 (1.4−3.8) | 9.9 (6.4−15.7) | 15 | NA | 29 | 3 | |||||||
| Galanis E,
et al., 2009 (57) |
66 | II | HDAC | Vorinostat | 200 mg vorinostat | 1.9 (0.3−28) | 5.7 (0.7−28) | 15.6 | 3 | NA | NA | 17 | Vorinostat is well tolerated and has modest single-agent activity |
| van den Bent, MJ.,
et al., 2009 (58) |
110 | II | EGFR | Erlotinib | Erlotinib | 1.8 | 7.7 | 11.4 | 3.7 | Low pAkt expression | NA | 13 | Erlotinib has insufficient single-agent activity in unselected rGBM |
| BCNU/
temozolomide |
2.4 | 7.3 | 24.1 | 9.6 | NA | 17 | |||||||
| Sepúlveda-Sánchez JM,
et al., 2017 (59) |
59 | II | EGFR | Dacomitinib | Patients without EGFRvIII mutation | 2.7 (2.3−3.2) | 7.8 (5.6−10.1) | 13.3 | 6.6 | NA | 47 | 20 | Dacomitinib has limited single-agent activity in rGBM with EGFR amplification |
| Patients with EGFRvIII mutation | 2.6 (1.8−3.4) | 6.7 (4.3−9.1) | 5.9 | 5.3 | |||||||||
| de Groot JF,
et al., 2011 (60) |
42 | II | VEGF | Aflibercept | 4 mg/kg aflibercept | 3.0 (2.0−4.0) | 9.8 | 7.7 | 18 | CA9, HIF-1α, SMAD2 | NA | NA | Aflibercept has moderate toxicity and minimal single-agent activity |
| Bogdahn U,
et al., 2011 (61) |
103 | II | TGF-b2 | Trabedersen (AP 12009) | 10 μM trabedersen | NA | 7.3 (5.0−12.0) | 14 | 0 | Age ≤55 years, KPS>80 | 40 | 32 | Superior efficacy and safety for 10 mM trabedersen over 80 mM trabedersen and chemotherapy. |
| 80 μM trabedersen | NA | 10.9 (5.6−13.9) | 15 | 3 | 48 | 37 | |||||||
| PCV/temozolomide | NA | 10.0 (7.0−13.0) | 15 | 0 | 44 | 18 | |||||||
| Brandes AA,
et al., 2016 (62) |
158 | II | TGF-b | Galunisertib | Galunisertib + CCNU | 1.8 (1.7−1.8) | 6.7 (5.3−8.5) | 6 | 1.3 | ECOG PS=0, receiving bevacizumab post discontinuation therapy, small baseline tumor burden and high baseline macrophage-derived chemokine | 71 | 46 | Failed to demonstrate improved OS |
| Galunisertib | 1.8 (1.6−3.0) | 8.0 (5.7−11.7) | 15 | 5.1 | 37 | 23 | |||||||
| CCNU | 1.9 (1.7−1.9) | 7.5 (5.6−10.3) | 6 | 0 | 35 | 26 | |||||||
| Wen PY,
et al., 2011 (63) |
61 | II | HGF | AMG 102 (rilotumumab) | 10 mg/kg AMG 102 | 1.0 (1.0−1.0) | 6.5 (4.1−9.8) | 12.5 | 0 | No prognostic biomarkers found | 23 | 4 | AMG 102 at doses up to 20 mg/kg had no significant antitumor activity |
| 20 mg/kg AMG 102 | 1.1 (1.0−2.0) | 5.4 (3.4−11.4) | 10 | 0 | 8 | 1 | |||||||
| Friday BB,
et al., 2012 (64) |
37 | II | HDAC | Vorinostat +
bortezomib |
400 mg vorinostat + 1.3 mg/m2 bortezomib | 1.5 (0.5−5.6) | 3.2 (0.7−24.8) | 0 | 3 | Having received prior bevacizumab therapy | NA | 14 | Vorinostat-bortezomib combination showed no antitumor activity |
| Wen PY,
et al., 2014 (65) |
43 | I/II | EGFR/mTOR | Erlotinib +
temsirolimus |
150 mg erlotinib + 50 mg temsirolimus | 2.0 (2.0−2.5) | NA | 0 | 13 | Retained PTEN protein expression | 36 | 2 | Minimal antitumor activity and increased toxicity |
| Lassman AB,
et al., 2015 (66) |
50 | II | SRC, KIT, PDGFR, EPHA2, and BCR-ABL fusion | Dasatinib | Dose-escalation dasatinib | 1.7 (1.3−1.9) | 7.9 (5.6−10.2) | 6 | 0 | NA | 48 | 20 | Dasatinib was ineffective in rGBM |
| Butowski N,
et al., 2015 (67) |
37 | II | CSF1R | PLX3397 | 1,000 mg | NA | 9.4 (6.7−NA) | 8.8 | 0 | No prognostic biomarkers found | 35 | 18 | Well tolerated and but showed no efficacy. |
| Reardon DA,
et al., 2015 (68) |
119 | I/II | ErbB | Afatinib | Afatinib + temozolomide | 1.53 | 8.0 | 10 | 7.7 | Highly positive EGFRvIII expression | 36 | 14 | Manageable safety profile but limited single-agent activity |
| Afatinib | 0.99 | 9.8 | 3 | 2.4 | 34 | 9 | |||||||
| Temozolomide | 1.87 | 10.6 | 23 | 10.3 | 22 | 8 | |||||||
| Robins HI,
et al., 2016 (69) |
212 | I/II | PARP | ABT-888 (velparib) | Temozolomide + ABT-888 (BEV naive) | 2.1 (1.9−2.3) | 10.3 (8.4−12) | 17 | 3.8 | NA | NA | NA | The combination of TMZ and ABT-888 did not significantly improve PFS6 for both groups |
| Temozolomide + ABT-888 (BEV failure) | 1.9 (1.8−2.1) | 4.7 (3.5−5.6) | 4.5 | 5.3 | NA | NA | |||||||
| Duerinck J,
et al., 2016 (70) |
44 | II | VEGFR | Axitinib | Axitinib | 3.3 (2.3−3.5) | 7.3 (4.3−10.0) | 34 | 27 | MGMT promoter methylation | NA | 8 | Single-agent activity and manageable toxicity |
| Bevacizumab/CCNU | 2.5 (0.8−4.0) | 4.3 (0.3−8.5) | 28 | 23 | NA | 10 | |||||||
| Cloughesy T,
et al., 2017 (71) |
129 | II | MET | Onartuzumab | Onartuzumab + bevacizumab | 3.9 | 8.8 | 33.9 | 22.2 | High expression of HGF or unmethylated MGMT | NA | 25 | No evidence of further clinical benefit |
| Bevacizumab | 2.9 | 12.6 | 29.0 | 23.7 | NA | 23 | |||||||
| Reardon DA,
et al., 2017 (72) |
48 | II | ANG | Trebananib
(AMG386) |
Trebananib + bevacizumab | 3.6 (1.9−5.5) | 9.5 (7.5−14.7) | 24.3 | 27 | circulating vascular VEGF and interleukin-8 levels | NA | 5 | Trebananib was ineffective as monotherapy and combination with BEV |
| Trebananib | 0.7 (0.17−1.2) | 11.4 (4.6−18.5) | 0 | 0 | NA | 0 | |||||||
| Taylor JW
et al., 2018 (73) |
22 | II | CDK4/6 | Palbociclib | 125 mg palbociclib | 1.3 (0.2−35.5) | 3.9 (0.5−68.5) | 5 | NA | NA | NA | 17 | Palbociclib was not effective for rGBM |
| Schiff D,
et al., 2018 (74) |
41 | II | VEGFR/mTOR | Sorafenib + temsirolimus | BEV naive | 2.7 (0.62−44.7) | 6.3 | 17.1 | 9 | NA | 49 | 37 | Limited activity of sorafenib and temsirolimus |
| BEV failure | 1.9 (0.43−24.6) | 3.9 | 6.8 | 2 | 46 | 34 | |||||||
| Sharma M,
et al., 2019 (75) |
33 | II | FGFR/VEGFR | Dovitinib | 500 mg | 1.8 (1.4−2.0) | 5.6 (4.2−8.1) | 6 | NA | BEV naïve; higher BMP 9, CD73, endoglin and VEGF D, and lower TSP 2 | 33 | 27 | Not efficacious in prolonging the PFS in BEV failure patients |
| Sautter L,
et al., 2019 (76) |
32 | II | PDGF-R | Imatinib | 600 mg | 2.1 (0−11.8) | 6.5 (0.3−51.5) | NA | NA | NA | NA | NA | Imatinib showed no measurable activity |
| Kaley TJ,
et al., 2019 (77) |
16 | II | AKT | Perifosine | 600 mg | 1.58 (1.08−1.84) | 3.68 (2.50−7.79) | 0 | 0 | NA | NA | NA | PRF is tolerable but ineffective |