Opportunities and Challenges of Small Molecule Inhibitors in Glioblastoma Treatment: Lessons Learned from Clinical Trials
Abstract
:Simple Summary
Abstract
1. Introduction
2. Clinical Trials with Small Molecule Inhibitors in GBM
2.1. Mono-Target Small Molecule Inhibitors
2.2. Multitarget Small Molecule Inhibitors
2.3. Small Molecule Inhibitors Combined with Chemotherapy/Bevacizumab
2.4. Combinations of Small Molecule Inhibitors
3. Discussion
3.1. Intrinsic Versus Acquired Resistance
3.2. Influence of the Tumour Microenvironment
3.3. Clinical Trial Design
4. Conclusions and Future Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Compound | Target | PMID | Trial | De Novo/Recurrent | Study Population | PFS/OS | Response Rate | Biomarker Analysis |
---|---|---|---|---|---|---|---|---|
Adavosertib (AZD1775) | Wee1 | 29798906 | Phase 0 | Recurrent | GBM n = 20 | NA | NA | NA |
Buparlisib | PI3K | 30715997 | Phase II | Recurrent | GBM n = 65 | PFS 1.7m (95% CI, 1.4–1.8). OS 9.8m (95% CI, 8.4–12.1) | CR 0%, PR 0%, SD 42%, PD 54% DRC 43.8% (95% CI 31–58%) | No statistically significant association was found between PTEN, PIK3CA, PIK3R1, EGFR, PDGFRA, IDH1/2 and TP53, and PFS6 or OS. No statistically significant association in PFS between PIK3CA/PIK3R1-mutant or PTEN mutant PIK3CA/PIK3R1-wildtype or PTEN wildtype. |
Capmatinib | c-MET | 31776899 | Phase II | Recurrent | GBM n = 10, altered PTEN status | PFS not assessed due to insufficient sample size | CR 0%, PR 0%, SD 30% | NA |
Deforolimus | mTOR | 22037923 | Phase I | Recurrent | Grade IV malignant glioma n = 3 | NA | SD 33% as best response | NA |
Erlotinib | EGFR | 20150372 | Phase II | Recurrent | GBM n = 42 | PFS 2m OS 6m | CR 0%, PR 0%, SD 7.1%, PD 62% | NA |
22946346 | Phase I + II | Recurrent | GBM n = 8 | PFS 1.9m OS 6.9m | NA | NA | ||
24352766 | Phase II | Recurrent | GBM n = 40, EGFR or PTEN-mutated | PFS 3.9m (95% CI 1.6–6.1) OS 7m (95% CI 1.41–4.7) | CR 0%, PR 7%, SD 21%, PD 72% | NA | ||
20615922 | Phase II | Recurrent | GBM n = 48 | PFS6 20% (95% CI 10.0–32.4) OS 9.7m (95% CI 5.9–11.6) | CR 2.1%, PR 6.3%, SD 33.3%, PD 54.2% | No conclusion could be draw from molecular subgroup analyses due to low response rate. EGFR amplified: OS 8.3m (95% CI 4.1–10.7) CR 4.3%, PR 4.3%, SD 43.5%, PD 47.8% Non-EGFR amplified: OS 10.6m (95% CI 4.7–14.1) CR 0%, PR 8.0%, SD 43.5%, PD 60.0% | ||
19204207 | Phase II | Recurrent | GBM n = 110 | PFS 1.8m OS 7.7m | NA | EGFRvIII was correlated with poor PFS in the erlotinib arm (p = 0.003). EGFR amplification was significant for poor outcome in the entire study population (p = 0.048). | ||
Gefitinib | EGFR | 29492119 | Phase II | De novo | GBM n = 40 | PFS 6m OS 14m | NA | PFS and OS were significantly (p = 0.005) higher in EGFR +ve/PTEN-ve compared to EGFR-ve/PTEN+ve with 9 months versus 6 months, and 20 months versus 13 months, respectively. |
14638850 | Phase II | Recurrent | GBM n = 53 | EFS 8.1w (95% CI, 7.9–9.1) OS 39.4w(95% CI, 24.3–59.4) | CR 0%, PR 0%, SD 42%, PD 58.4% within 2 months. PD 96.2% at end of follow-up | Epidermal growth factor receptor expression did not correlate with either EFS or OS. | ||
17353924 | Phase II | Recurrent | GBM n = 16 AO n = 3 AA n = 9 | PFS 8.4w OS 24.6w | DCR 12.5% (95% CI 1.6–38.4%). SD 12.5% | EGFR expression or gene status, and p-Akt expression predict activity of gefitinib. | ||
20510539 | Phase II | De novo | GBM n = 96 | PFS-1year 16.7%, OS-1year 54.2% | NA | Clinical outcome was not affected by EGFR amplification or EGFRvIII mutation. | ||
21471286 | Phase II | Recurrent | GBM n = 22 | OS 8.8m | NA | No difference between patients with an amplified or a normal EGFR status. | ||
GSK2256098 | FAK kinase | 29788497 | Phase I | Recurrent | GBM n = 13 | PFS 5.7w (95% CI 3.1–8.3) | SD 27%, PD 73% | NA |
Navtemadlin (AMG-232) | MDM2 | 31359240 | Phase I | De novo and recurrent | GBM n = 10, p53wt | NA | SD 60% | NA |
Pegdinetanib (CT-322) | VEGFR-2 | 25388940 | Phase II | Recurrent | GBM n = 63 | PFS 1.8m | 1mg/kg: ORR 14.3% 2mg/kg: ORR 3.8% | NA |
Perifosine | Akt | 31325145 | Phase II | Recurrent | GBM n = 16 | PFS 1.58m (95% CI 1.08–1.84) OS 3.68m (95% CI 2.50–7.79) | SD 12.5%, PD 75% | NA |
PF-06840003 | IDO-1 | 32436060 | Phase I | Recurrent | GBM n = 14 AA gr III n = 2 AO gr III n = 1 | PFS 1.9–2.8m | DCR 47% | NA |
Picropodophyllin (AXL1717) | IGF-1R | 29113409 | Phase I/II | Recurrent | GBM n = 8 Gliosarcoma n = 1 | PFS 8w OS 15w | CR 0%, PR 11.1%, SD 44.4%, PD 44.4% | NA |
Rapamycin | mTOR | 18215105 | Phase I | Recurrent | GBM n = 14, PTEN-deficient | No PFS or OS reported | NA | NA |
Selinexor | XPO-1 | 34728525 | Phase II | Recurrent | GBM n = 76 | Arm B: PFS6 10% (95% CI 2.67–35.4) OS 10.5m (95% CI, 4.9–17.0) Arm C: PFS6 7.7% (95% CI 1.2–50.6) OS 8.5m (95% CI, 7.3–not evaluable) Arm D: 17.2% (95% CI, 7.78–38.3) OS 10.2m (95% CI, 7.0–15.4) | Arm B: ORR 8.3%, SD 25%, PD 62.5% Arm C: ORR 7.7%, SD 30.8%, PD 61.5% Arm D: ORR 10%, SD 23.3%, PD 56.7% | Patients with mutations in pancreatic and duodenal homeobox 1 (PDX1), E1A Binding Protein P400 (EP400) or Dedicator of Cytokinesis 8 (DOCK8) survived longer than patients with wildtype tumours |
Tipifarnib | FTase subunit ß | 16877733 | Phase II | Recurrent | GBM n = 67 | Non-EIAED: PFS 9w (95% CI 7–14) EAIED: PFS 6w (95% CI 4–8w) | CR 0%, PR 7.5% Non-EIAED: PR 11% EAIED: PR 3% | NA |
Trotabresib | BET | 36455228 | Phase I | Recurrent | GBM n = 19 AA n = 1 | PFS 1.9m (95% CI 1.4–3.4) IDH-wt: PFS 3.0m (95% CI 1.4–3.6) | SD 41%, PD 59% | NA |
Vismodegib (GDC-0449) | SMO | 36581779 | Phase 0/II | Recurrent | GBM n = 41 | PFS 2.3m (95% CI 1.9–2.6) OS 7.8m (95% CI 5.4–10.1) | CR 0%, PR 0%, SD 25.8%, PD 74.2% | NA |
Targets | Compound | Targets Specified | PMID | Trial | De Novo/ Recurrent GBM | Study Population | PFS/OS | Response Rate | Biomarker Analysis |
---|---|---|---|---|---|---|---|---|---|
Tumourcell | Abemaciclib | CDK 4 & 6 | 27217383 | Phase I | Recurrent | GBM n = 17 | NA | SD 17.6% | NA |
Afatinib | EGFR, ERBB2, ERBB4 | 25140039 | Phase I + II | Recurrent | GBM n = 119 | PFS 0.99m (p = 0.032) OS 9.8m (p = 0.386) | DCR 36.6% (95% CI 22.1–53.1). CR 0%, PR 2.4%, SD 34.1%, PD 34.1% | EGFR vIII+ tumours showed higher PFS versus EGFRvIII- tumours. | |
Bortezomib | 20S proteasome | 20213332 | Phase I | Recurrent | GBM n = 51 AA n = 8 AO n = 3 Other n = 4 | PFS 2.1m (95% CI 1.7–2.8) OS 6.0m (95% CI 3.9–7.4) | ORR 3%, CR 0%, PR 3%, SD 23% | NA | |
Cilengitide | Integrins ανβ3 and ανβ5 | 17470857 | Phase I | Recurrent | GBM n = 37 AA n = 11 AO n = 1 Mixed AG n = 2 | OS 5.6m (95% CI 4.3–8.4) | ORR 9.8%, CR 3.9%, PR 5.9%, SD 31.4% | NA | |
18981465 | Phase II | Recurrent | GBM n=81 | 500 mg/d: TTP 7.9w (95% CI 7.7–15.6) OS 6.5m (95% CI 5.2–9.3) 2000 mg/d: TTP 8.1w (95% CI 7.9–15.0) OS 9.9m (95% CI 6.4–15.7) | 500 mg/d: ORR 5%2000 mg/d: ORR 13% | NA | |||
21739168 | Phase II | Recurrent | GBM n = 26 | PFS 8w (95% CI 4–16) | NA | NA | |||
Dacomitinib | EGFR, ERBB2 and ERBB4 | 28575464 | Phase II | Recurrent | GBM n = 30, EGFR amplification GBM n = 19, EGFR amplification and EGFRvIII mutation | PFS 2.7m (95% CI 2.3–3.1) OS 7.4m (95% CI 5.6–9.2) | CR 2%, PR 4.1%, SD 24.5%, PD 61.2% | EGFR amplification without EGFRvIII mutation: PFS 2.7m, OS 7.8m. CR 3.3%, PR 3.3%, SD 26.7%, PD 56.7% EGFR amplification with EGFRvIII mutation: PFS 2.6m, OS 6.7m. CR 0%, PR 5.3%, SD 21.1%, PD 68.4% | |
Dasatinib (BMS-354825) | Abl1, Src, c-Kit, Lck, Yes, induces autophagy | 25758746 | Phase II | Recurrent | GBM n = 50 | PFS 1.7m (95% CI 1.3–1.9) OS 7.9m (95% CI 5.6–10.2) | CR 0%, PR 0%, SD 24%, PD 72% | NA | |
Enzastaurin | PKCβ, PKCα, PKCγ and PKCε Chk1/Chk2 | 20150385 | Phase I/II | Recurrent | GBM n = 57 | PFS 1.3m OS 4.6m | ORR 30%, PR 3.5% | NA | |
20124186 | Phase III | Recurrent | GBM n = 174 | PFS 1.51m OS 6.60m | ORR 2.9%, SD 38.5%, PD 41.4% | NA | |||
Lapatinib | EGFR, ERBB2 | 19499221 | Phase I + II | Recurrent | GBM n = 17 | NA | SD 23.5% | No relation between PTEN loss or EGFRvIII and outcome | |
Marimastat | MMP-9, MMP-1, MMP-2, MMP-14, MMP-7 | 16636750 | Phase II | De novo | GBM n = 154 Gliosarcoma n = 8 | PFS 17.1w, OS 42.9w | NA | NA | |
Palbociclib | CDK4 & 6 | 30151703 | Phase II | Recurrent | GBM n = 22, Rb1-positive | PFS 5.14 weeks, OS 15.4 weeks | PD 95% | NA | |
Paxalisib (GDC-0084) | PI3K, mTOR | 31937616 | Phase I | Recurrent | WHO grade III n = 14 WHO grade IV n = 33 | NA | ORR 0%, SD 40%, PD 55% | No correlation between PTEN loss or PI3K mutations and response to GDC-0084. | |
NCT03522298 | Phase II | De novo | GBM n = 30 | PFS 8.6m OS 15.9m | NA | NA | |||
Ribociclib | CDK4 & 6 | 31399936 | Phase Ib | Recurrent | GBM n = 3, Rb+ | Patient 1: PFS 2 m OS 10m Patient 2: PFS 5m OS 19m Patient 3: PFS 2m OS 12m | NA | NA | |
31285369 | Phase 0 | Recurrent | GBM n = 6 | PFS 9.7w OS 7.8m | NA | NA | |||
Romidepsin | HDAC 1, 2 (4 and 6) | 21377994 | Phase I/II | Recurrent | Phase I: GBM n = 8 Phase II: GBM n = 35 | PFS 8w (95% CI 5–8) OS 34w (95% CI 21–47) | CR 0%, PR 0%, SD 28%, PD 72% | NA | |
Sonolisib (PX-866) | PI3K (p110α), (p120γ), (p110δ) | 25605819 | Phase II | Recurrent | GBM n = 33 | PFS-6 17% (95% CI 5–32%) | CR 0%, PR 3%, SD 24%, PD 73% | No statistically significant association between stable disease and PTEN, EGFRvIII, PIK3CA mutation or PIK3R1 mutation | |
Tandutinib | FLT3, c-Kit, PDGFR | 27663390 | Phase I + II | Recurrent | Phase I: GBM n = 19 Phase II: GBM n = 30 | First stage: PFS 1.9m (95% CI: 1.5–3.7) OS 8.8m (95% CI: 5.9–15.4) Time of analysis: PFS6 16% | CR 3% | NA | |
Vistusertib | mTOR, PI3K isoforms α/β/γ/δ | 31707687 | Phase I | Recurrent | GBM n = 14 | PFS6 26.6% | ORR 8%, PR8%, SD 38% | No correlation between pS6 status and response. | |
Vorinostat | HDAC 1, 2, 3, 6, 8 | 19307505 | Phase II | Recurrent | GBM n = 66 | PFS 1.9m OS 5.7m | ORR 3% | NA | |
WP1066 | JAK2, STAT3 | 35575067 | Phase I | Recurrent | GBM n = 8 | PFS 2.3m (95% CI 1.7–NA) OS form initial diagnosis 25m (95% CI 22.5–NA) | PD 100% | NA | |
Tumourcell + angiogenesis | Axitinib | VEGFR1, VEGFR2, VEGFR3 PDGFRß, c-Kit | 28988341 | Phase II | Recurrent | GBM n = 50 | PFS 12.4w (95% CI 11–13) OS 29w (95% CI 20–38) | NA | MGMT-promoter hypermethylation is significantly correlated with PFS and OS |
26935577 | Phase II | Recurrent | GBM n = 22 | PFS 13w (95% CI 11–14) OS 29w (95% CI, 17–40) | CR 9%, PR 18%, SD 14% | No difference in PFS or OS for tested mutations. | |||
33067319 | Phase II | Recurrent | GBM n = 27 | PFS6 18.5% OS 18w | ORR 22.2%, CR 3.7%, PR 18.5%, SD 25.9%, PD 51.9% | NA | |||
Cabozantinib | VEGFR1-3, c-Met, Ret, Kit, Flt-1/3/4, Tie2, AXL | 29016998 | Phase II | Recurrent | GBM n = 152 | PFS 3.7m OS 7.7–10.4m (depending on dose) | 140 mg/day: ORR 17.6%, PR 17.6%, SD 58.8%, PD 11.8% 100 mg/day: ORR 14.5%, PR 14.5%, SD 67.5%, PD 12.0% | NA | |
29036345 | Phase II | Recurrent | GBM n = 70 | PFS 2.3m OS 4.6m | 140 mg/day: ORR 8.3%, PR 8.3%, SD 50.0%, PD 16.7% 100 mg/day: ORR 3.4%, PR 3.4%, SD 46.6%, PD 27.6% | NA | |||
Dovitinib | FLT3/c-Kit, FGFR1/3, VEGFR1-4, PDGF | 31292802 | Phase II | Recurrent | GBM n = 19 | TTP 1.8m (95% CI 1.4–1.8) OS 5.6m (95% CI 4.2–8.1) | NA | No impact on OS. Higher BMP 9, CD73, endoglin and VEGF D, and lower TSP 2 were associated with poorer PFS | |
27100354 | Phase I | Recurrent | GBM n = 12 | PFS 1.8m (95% CI 1.7–1.9) OS 9.5m (95% CI 2.6–16.4) | CR 0%, PR 0%, SD 36.4%, PD 63.4% | Presence of FGFR-TACC gene fusion did not affect PFS-6 | |||
Infigratinib | FGFR 1/2/3 | 35344029 | Phase II | Recurrent | GBM n = 19 AA n = 5 Other n = 2 | PFS 1.7m (95% CI 1.1–2.8) OS 6.7m (95% CI 4.2–11.7) | ORR 4.8%, PR 4.8%, SD 28.6%, PD 61.9% | Tumours harbouring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions showed durable disease control for more than 1 year | |
Nintedanib | VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β | 23184145 | Phase II | Recurrent | GBM n = 25 | PFS-6 4.0% (95% CI 0.1–20.4) OS 6m (95% CI 3.6–8.4) | CR 0%, PR 0%, SD 12.0%, PD 88.0% | NA | |
25338318 | Phase II | Recurrent | GBM n = 22 | Bevacizumab-naive: PFS 28d (95% CI 27–83) OS 6.9m (95% CI 3.7–8.1). bevacizumab-treated: PFS 28d (95% CI 22–28) OS 2.6m (95% CI 1.0–6.9) | Bevacizumab-naive: CR 0%, PR 0%, SD 33%, PD 67% Bevacizumab-treated: CR 0%, PR 0%, SD 10%, PD 90% | NA | |||
Regorafenib | VEGFR1, VEGFR2, VEGFR3, PDGFRa, PDGFRβ, Kit (c-Kit), RET (c-RET) and Raf-1, FGFR1, FGFR2, Abl | 30522967 | Phase II | Recurrent | GBM n = 59 | PFS 2.0m (95% CI 1.9–3.6) OS 7.4m (95% CI 5.8–12.0) | CR 2%, PR 3%, SD 39%, PD 56% | NA | |
Sunitinib | VEGFR1, VEGFR2 VEGFR3, PDGFRa, PDGFRß, c-Kit, FLT3, CSF-1R, RET | 22832897 | Phase II | Recurrent | GBM n = 16 | PFS 1.4m (95% CI 1.2–4.8) OS 12.6m (95% CI 3.9–18.1) | CR 0%, PR 0%, SD 31.3% | NA | |
23086433 | Phase II | Recurrent | GBM n = 31 | PFS 1.08m (95% CI 0.92–2.47) OS 9.4m (95% CI 6.15–21.90) | Rate of radiographic response 10%, Levin 23% | NA | |||
24311637 | Phase II | Recurrent | GBM n = 40 | PFS 2.2m (95% CI 1.8–3.3) OS 9.2m (95% CI 11.9–49.2) | ORR 0%, SD 12.5%, PD 82.5% | c-KIT expression in vascular endothelial cells was associated with improved PFS (2.3m) versus c-KIT negative vascular endothelial cells (1.7m) (p = 0.025). No or low expression of PDGFR-α in tumour cells was associated with improved PFS (p = 0.043) but not with OS. | |||
24424564 | Phase II | De novo | GBM n = 12 | PFS 7.7w (95% CI 7.2–8.2) OS 12.8w (95% CI 0.5–23.8) | ORR 0%, SD 8.3%, PD 91.7% | NA | |||
SYHA1813 | VEGFR, CSF1R | 36884148 | Phase I | Recurrent | GBM n = 4 | NA | PR 25% | NA | |
Tivozanib | VEGFR1/2/3, PDGFR, c-Kit Low activity against FGFR-1, Flt3, c-Met, EGFR and IGF-1R | 27853960 | Phase II | Recurrent | GBM n = 10 | PFS 2.3m (95% CI 1.5–4.0) OS 8.1m (95% CI 5.2–12.5) | CR 10%, PR 10%, SD 40%, PD 40% | None of the investigated blood biomarkers were associated with OS or PFS. | |
Tumourcell + micro-environment | AEE788 | EGFR, HER2/ErbB2, VEGFR2/KDR, c-Abl, c-Src, Flt-1 | 22392572 | Phase I | Recurrent | GBM n = 64 | PFS 2.7m (90% CI 1.9–2.8) | CR 0%, PR 0% SD 17% | p-KDR was a significant predictor of PFS (p = 0.01) |
Bosutinib | Src/Abl, PI3K/AKT/mTOR, MAPK/ERK, JAK/STAT3. Lyn, HCK. Promotes autophagy | 25411098 | Phase II | Recurrent | GBM n = 9 | PFS 7.71w (95% CI 2.6–7.9) OS 50w (95% CI 2.9–NA) | PD 100% | NA | |
Cediranib | VEGFR(KDR), Flt1/4, c-Kit, PDGFRβ, induces autophagic vacuole accumulation. | 20458050 | Phase II | Recurrent | GBM n = 30 | PFS 117d (95% CI 82–145) OS 227d (95% CI 177–293) | 2D measurements: PR 26.6% 3D measurements: PR 56.7% | At baseline, no biomarkers showed correlations with PFS or OS | |
23940216 | Phase III | Recurrent | GBM n = 131 | PFS 92d OS 8m | CR 0,8%, PR 14.4%, SD 64.4%, PD 8.5% | Baseline VEGF levels did not have a significant effect on PFS or OS | |||
Diazepinomicin (TLN-4601) | RAS, peripheral benzodiazepine receptor (PBR) | 22048878 | Phase II | Recurrent | GBM n = 17 | PFS-6 0% OS 150d | CR + PR + SD 21.4% | NA | |
Erdafitinib (JNJ-42756493) | FGFR1/2/3/4, RET (c-RET), CSF-1R, PDGFR-α/PDGFR-β, FLT4, Kit (c-Kit), VEGFR-2 | 26324363 | Phase I | Recurrent | GBM n = 3 | NA | PR 66.7% | NA | |
Imatinib | v-Abl, c-Kit, SCF, and PDGFR, induces autophagy | 18824712 | Phase II | Recurrent | GBM n = 51 | PFS 1.8m (95% CI 1.7–2.3) OS 5.9m (95% CI 4.2–7.8) | PR 6%, SD 26% | PFS was not correlated with PDGFRα SNPs. | |
16914578 | Phase I+II | Recurrent | Phase I: GBM n = 35 Phase II: GBM n = 24 | PFS6 3% | Phase I: CR 0%, PR 2.9%, SD 34.3% Phase II: CR 0%, PR 5,9%, SD 17.6% | NA | |||
31514200 | Phase II | De novo and recurrent | De novo: GBM n = 19 Recurrent: GBM n = 32 | De novo: PFS 2.8m (95% CI 0.3–8) OS 5.0m (95% CI 0.8–30) Recurrent: PFS 2.1m (95% CI 0.3–19.3) OS 6.5m (95% CI 0.3–51.5) | NA | NA | |||
19789313 | Phase II | De novo | GBM n = 20 | OS 6.2m | CR 0%, PR 0%, SD 90%, PD 5%, nonevaluable 5% | NA | |||
ONC201 | Akt and ERK to induce TNF-related apoptosis-inducing ligand (TRAIL) | 31702782 | Phase II | Recurrent | GBM n = 20 | PFS 1.8m OS 7.5m | CR 0% | NA | |
Pazopanib | VEGFR1, VEGFR2, VEGFR3, PDGFRa/β,c-Kit, FGFR1, c-Fms Induces autophagy | 20200024 | Phase II | Recurrent | GBM n = 35 | PFS 12w (95% CI 8–14) OS 35w (95% CI 24–47) | ORR 5.9% (95% CI: 0.7–21%). SD 59%, PD 32% | NA | |
Pexidartinib (PLX3397) | CSF-1R, Kit (c-Kit), FLT3, PDGFRβ | 26449250 | Phase II | Recurrent | GBM n = 37 | PFS-6 8.8% (90% CI 3.5%, 21.6%) OS 9.4m (90% CI 6.67–NA) | CR 0%, PR 0% | PDGFRA amplification and gains did not correlate significantly with PFS6 or other parameters. | |
Ponatinib | Abl, PDGFRα, VEGFR2, FGFR1, Src | 31444999 | Phase II | Recurrent | GBM n = 15, Bevacizumab-refractory | PFS 28d (95% CI 27–30) OS 98d (95% CI 56–257) | SD 13.7%, PD 66.7% | NA | |
Temsirolimus | mTOR, induces autophagy | 16012795 | Phase II | Recurrent | GBM n = 43 | PFS 9w | PR 4.7%, SD 46.5% | NA | |
15998902 | Phase II | Recurrent | GBM n = 65 | TTP 2.3m (95% CI 1.9–3.2) OS 4.4m (95% CI 3.6–4.8) | ORR 0% | Significant association between neuroimaging response and p70s6 kinase phosphorylation in baseline tumour samples (p = 0.04) | |||
Vandetanib | VEGFR2, VEGFR3, EGFR, RET, induces autophagy by increasing the level of reactive oxygen species (ROS) | 23099652 | Phase I/II | Recurrent | GBM n = 32 | PFS 1.3m (95% CI 0.9–1.9) OS 6.3m (95% CI 3.8–8.5) | ORR 15%, CR 3.7% | NA | |
Vemurafenib | B-RafV600E, induces cell autophagy | 30351999 | Phase II | Recurrent | GBM n = 6, BRAFV600mt AA n = 5, BRAFV600mt | PFS 5.3m (95% CI 1.8–12.9), OS 11.9m (95% CI 8.3–40.1) | CR 0%, PR 9.1%, SD 45.5%, PD 27.3% | NA | |
Stemcell | RO4929097 | y-secretase, Aβ40 and Notch | 33027815 | Phase II | Recurrent | GBM n = 47 | PFS 1.7m (95% CI 1.2–1.8) OS 7.0m (95% CI 5.4–9.1) | CR 2%, PR 0%, SD 6%, PD 81% | NA |
NCT01122901 | Phase II | Recurrent | GBM n = 40 | PFS 1.7m (95% CI 1.1–1.8) OS 6.6m (95% CI 5.3–10.5) | CR 2.5%, PR 0%, SD 7.5%, PD 82.5% | NA |
Compounds | Targets Specified | PMID | Trial | De Novo/ Recurrent | Study Population | PFS/OS | Response Rate | Biomarker Analysis |
---|---|---|---|---|---|---|---|---|
Afatinib + TMZ | Afatinib: EGFR, HER2, HER4 | 25140039 | Phase II | Recurrent | GBM n = 39 | PFS 1.53m OS 8.0m | CR 2.6%, PR 5.1%, SD 35.9%, PD 43.6% | No statistically significant relation between EGFRvIII and treatment outcome |
Anlotinib + TMZ | VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret | 37477938 | Phase II | Recurrent | GBM n = 21 | PFS 7.3m (95% CI 4.9–9.7) OS 16.9m (95% CI 7.8–26.0) | ORR 81% (95% CI 62.6–99.3), CR 43%, PR 38% | NA |
Bortezomib + bevacizumab | Bortezomib: 20S proteasome, inhibits NF-κB and induces ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy | NCT00611325 | Phase II | Recurrent | GBM n = 56 | EAIED: PFS 2m (95% CI 2–4) OS 8m (95% CI 5–11) Non-EAIED: PFS 2.5m (95% CI 1–4) OS 6m (95% CI 4–10) | EAIED: RRR 7.1% (95% CI 0–16.6) Non-EAIED: RRR 39.3% (95% CI 21.2–57.4) | NA |
Bortezomib + TMZ | Bortezomib: 20S proteasome, inhibits NF-κB and induces ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy | 27300524 | Phase II | Recurrent | GBM n = 9 AO grade III n = 1 | PFS 2.6m OS 8.9m | NA | NA |
32578964 | Phase Ib | Recurrent | GBM n = 10 | OS 21.4m | NA | NA | ||
Buparlisib + bevacizumab | Buparlisib: PI3K | 31392595 | Phase II | Recurrent | GBM n = 76 | PFS 4.0m (95% CI 3.4–5.4) Bevacizumab-naïve: OS 10.8m (95% CI 9.2–13.5) Bevacizumab treated: OS 6.6m (95% CI 4.0–14.6) | ORR 26%. CR 11%, PR 16%, SD 33%, PD 29% | PTEN and PIK3CA did not affect the treatment response. |
Buparlisib + lomustine | Buparlisib: PI3K | 32665311 | Phase Ib/II | Recurrent | GBM n = 18 | NA | CR 0%, PR 0%, SD 11.1%, PD 77.8% | NA |
CT-322 + irinotectan | CT-322: VEGFR-2 | 25388940 | Phase II | Recurrent | GBM n = 63 | PFS 8.8m | ORR 0% | NA |
Dasatinib + bevacizumab | Dasatinib: Abl, Src, c-Kit, induces autophagy | 31290996 | Phase II | Recurrent | GBM n = 83 | PFS 3.2m OS 7.3m | ORR 15.7%, SD 57.8% | No associations between VEGFR2, Y416.SRC (pSRC), CD31, LYN and YES and PFS or OS. |
Enzastaurin + bevacizumab | Enzastaurin: PKCβ, PKCα, PKCγ and PKCε | 26643807 | Phase II | De novo | GBM n = 37 | PFS 2.0m OS = 7.5m | ORR 22%, SD 54% | No correlation with treatment response and p-GSK-3 levels. |
Erlotinib + bevacizumab | Erlotinib: EGFR | 23132371 | NA | Recurrent | GBM n = 4 | PFS 10.5m OS 17.0m | Response rate 100% | NA |
20716591 | Phase II | Recurrent | GBM n = 25 | PFS 18w (95% CI 12.0–23.9) OS 44.6w (95% CI28.4–68.7) | CR 4%, PR 46%, SD 42%, PD 8% | Patients with positive pS6 had a 3.4 times greater risk of progression compared with patients with negative pS6 (p = 0.05). Patients with lower values for VEGFR-2 were more likely to survive more than 1 year than those with high values of VEGFR-2 (p = 0.0079) | ||
26476729 | Phase II | De novo after treatment RT and TMZ, no progression | GBM n = 46 | PFS 9.2m (95% CI 6.4–11.3) OS 13.2m (95% CI 10.8–19.6) | CR 8.7%, PR 26.1%, SD 60.9%, PD 0%, 4.3% unknown | NA | ||
Erlotinib + TMZ | Erlotinib: EGFR | 16443950 | Phase I | Stable or recurrent | GBM n=39 | NA | PR 2.6% | NA |
Everolimus + TMZ | Everolimus: mTOR inhibitor of FKBP12, autophagy | 22160854 | Phase I | De novo | GBM n = 17, non-EAIED GBM n = 11, EAIED | NA | Non-EIAED: ORR 17.6% (95% CI: 3.8–43.4%). CR 0%, PR 3/17, SD 9/17, PD 5/17 EIAED: CR 0%, PR 0%, SD 7/11, PD 4/11, | No differences in response and survival between patients with PTEN intact and deleted tumours. |
Imatinib + hydroxyurea | Imatinib: v-Abl, c-Kit and PDGFR, induces autophagy. | 16361636 | Phase II | Recurrent | GBM n = 33 | PFS 14.4w (95% CI 8.3–16.6) OS 48.9w (95% CI 25.7–71.1) | CR 3%, PR 6%, SD 42%, PD 48% | NA |
19904263 | Phase II | Recurrent | GBM n = 231 | PFS 5.6w (95% CI 4.1–7.9) OS 26w (95% CI 21.3–31.3) | CR 0.4%, PR 3.0%, SD 19.5%, PD 61.5% | Patients with increased c-KIT had significant longer PFS. | ||
19688297 | Phase III | Recurrent | GBM n = 120 | PFS 6w(95% CI 6–7) OS 21w | PD 40% | NA | ||
Imatinib mesylaat + TMZ | Imatinib: v-Abl, c-Kit and PDGFR, induces autophagy. | 18359865 | Phase I | Stable & recurrent | GBM n = 52 | PFS 26.6w (95% CI 9.9–36.4) OS 45.1w (95% CI 36.1–59.1) | CR 0%, PR 12%, SD 42% | NA |
Lapatinib + TMZ | Lapatinib: EGFR, ERBB2 | 23292205 | Phase I | Recurrent | GBM n = 14 AA n = 2 | PFS 2.4m OS 5.9m | CR 0%, PR 6.3%, SD 31.3% | NA |
Lonafarnib + TMZ | FPTase inhibitor for H-ras, K-ras-4B, N-ras | 23633392 | Phase I/Ib | Recurrent | GBM n = 35 | PFS 3.9m (95% CI 2.5–8.4) OS 13.7m (95% CI 8.9–22.1) | CR 5.9%, PR 17.6%, SD 47.1%, PD 29.4% | NA |
Olaparib + TMZ | Olaparib: PARP1, PARP2 | 32347934 | Phase I | Recurrent | GBM n = 36 | PFS6 39% (95% CI: 23.1–56.5%) | NA | NA |
Panobinostat + bevacizumab | Panobinostat: HDAC, autophagy | 25572329 | Phase II | Recurrent | GBM n = 24 | PFS 5m (95% CI 3–9) OS 9m (95% CI 6–19) | CR 0%, PR 29.2%, SD 58.3%, PD 12.5% | NA |
Sorafenib + bevacizumab | Sorafenib: Raf-1, B-Raf, VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, c-KIT | 23833308 | Phase II | Recurrent | GBM n = 54 | PFS 2.9m (95% CI 2.3–3.6) OS 5.6m (95% CI 4.7–8.2) | ORR 18.5%, SD 63% | PFS6 success was increased for VEGFR promoter mutant rs699947 and rs833061 and PFS6 success decreased for mutant rs1005230 and rs1570360. PFS6 success was increased for VEGFR2 promoter heterozygous rs2071559. |
Sorafenib + TMZ | Sorafenib: Raf-1, B-Raf, VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, c-KIT | 20443129 | Phase II | Recurrent | GBM n = 32 | PFS 6.4w (95% CI 3.9–11.7) OS 41.5w (95% CI 24.1–55.1) | CR 0%, PR 3%, SD 47%, PD 50% | NA |
23898124 | Phase II | Recurrent | GBM n = 43 | TTP 3.2m (95% CI 1.8–4.8) OS 7.4m (95% CI 5.6–9.0) | CR 0%, PR 12%, SD 43%, PD 48% | NA | ||
Sunitinib + irinotecan | Sunitinib: VEGFR2, PDGFRß, c-Kit, IRE1α | 21744079 | Phase I | Recurrent, | GBM n = 15 MG grade III n = 10 | PFS 6.9w (95% CI 5.7–17.7), OS 53.1w (95% CI 30.3–87.9) | CR 0%, PR 4%, SD 36%, PD 60% | NA |
27680966 | Phase II | Recurrent | GBM n = 6 | PFS-6 not reached | ORR 17% | NA | ||
Tandutinib + bevacizumab | Tandutinib: FLT3, c-Kit, PDGFR | 26860632 | Phase II | Recurrent | GBM n = 37 | PFS 4.1m OS 11m | PR 24% | NA |
Temsirolimus + bevacizumab | Temsirolimus: mTOR, induces autophagy | 23564811 | Phase II | Recurrent | GBM n = 10 | PFS 8w OS 15w | CR 0%, PR 0%, SD 20% | NA |
Trebananib + bevacizumab | Trebananib: Angiopoietin 1 and angiopoietin 2 blocking peptibody | 29266174 | Phase II | Recurrent | GBM n = 37 | PFS 3.6m (95% CI 1.9–5.5) OS 9.5m (95% CI 7.5–14.7) | ORR 27%, CR 0%, PR 27%, SD 41% | High plasma VEGF was associated with poor PFS and OS. High plasma IL-8 was associated with shorter OS (p < 0.05) |
32154928 | Phase II | Recurrent | GBM n = 57 | PFS 4.2m (95% CI 3.7–5.6) | CR 0%, PR 4.2%, SD 18.8% PD, 77.1% | NA | ||
NCT01290263 | Phase I/II | Recurrent | GBM n = 37 | PFS 108d OS 285d | CR 0%, PR 10.8%, SD 54%, PD 27% | NA | ||
Velparib + TMZ | Velparib: PARP1, PARP2, autophagy | 26508094 | Phase I/II | Recurrent | GBM n = 146, bevacizumab naïve GBM n = 69, bevacizumab failure | BEV-naïve: OS 10.3m low TMZ dose OS 10.7m high TMZ dose BEV failure: OS 4.7m low TMZ dose OS 4.7m high TMZ dose | BEV-naïve CR 1.9%, PR 1.9%, SD 1.9% BEV failure: CR 5.3%, PR 0% | NA |
Vorinostat + bevacizumab | Vorinostat: HDAC | 29133513 | Phase II | Recurrent | GBM n = 40 | PFS 3.7m (95% CI 2.9–4.8) OS 10.4m (95% CI 7.6–12.8) | RRR 22.5%, CR 0%, PR 22.5% | NA |
32166308 | Phase II | Recurrent | GBM n = 44 | PFS 3.68m (95% CI 2.33–3.94) OS 7.79m (95% CI 5.06–9.63) | NA | NA | ||
Vornistat + bevacizumab + TMZ | 29264836 | Phase I/II | Recurrent | GBM n = 39 | PFS 6.7m (95% CI 4.8–9.4) OS 12.5m (95% CI 8.8–14.3) | RRR 56% (95% CI 41–71) | NA |
Compounds | Targets Specified | PMID | Trial | De Novo/ Recurrent | Study Population | PFS/OS | Response Rate | Biomarker Analysis |
---|---|---|---|---|---|---|---|---|
Cediranib + cilengitide | Cediranib: VEGFR(KDR), Flt1/4, c-Kit, PDGFRβ, induces autophagic vacuole accumulation. Cilengitide: Integrins ανβ3 and ανβ5 | 26008604 | Phase I | Recurrent | GBM n = 45 | PFS 1.9m (95% CI 1.5–2.8) OS 6.5m (95% CI 5.2–7.6) | CR 4.4%, PR 4.4%, SD 28.9%, PD 46.7% | NA |
Cediranib + gefitinib | Cediranib: VEGFR(KDR), Flt1/4, c-Kit, PDGFRβ, induces autophagic vacuole accumulation. Gefitinib: EGFR | 27232884 | Phase II | Recurrent | GBM n = 19 | PFS 3.6m OS 7.2m | CR 0%, PR 42% | NA |
Erlotinib + sirolimus | Erlotinib: EGFR Sirolimus: mTOR | 19562254 | Phase II | Recurrent | GBM n = 32 | PFS 6.9w (95% CI 3.9–11) OS 33.8w (95% CI 21.9–53.6) | SD 27%, CR 0%, PR 0% | No association between EGFR, PTEN, EGFRvIII, pS6 and pMAPK PFS6, borderline significance with p-AKT (p = 0.045). |
Erlotinib + sorafenib | Erlotinib: EGFR Sorafenib: Raf-1, B-Raf, VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, c-KIT | 23328813 | Phase II | Recurrent | GBM n = 56 | PFS 2.5m (95% CI 1.8–3.7) OS 5.7m (95% CI 4.5–7.9) | CR 0%, PR 5% (all unconfirmed), SD 41%, PD 45% | NA |
33235994 | Phase I/II | Recurrent | GBM n = 19 | PFS 1.8m OS 5m | CR 0%, PR 0% | NA | ||
Erlotinib + temsirolimus | Erlotinib: EGFR Temsirolimus: mTOR, induces autophagy | 24470557 | Phase I/II | Recurrent | GBM n = 42 | PFS 8w (95% CI 8–10) | CR 0%, PR 0%, SD 29% | No significant correlation between EGFRvIII, EGFR amplification PTEN, p-AKT or pS6S235/236 and PFS. |
Gefitinib + sirolimus | Sirolimus: mTOR Gefitinib: EGFR | 16467100 | Phase I | Recurrent | GBM n = 29 AG n = 5 | PFS 8.2w (95% CI 7.5–18.6) | PR 5.9%, SD 41% | NA |
Pazopanib + lapatinib | Pazopanib: EGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit, c-Fms/CSF1R, cathepsin B activation, autophagy. Lapatinib: EGFR, ERBB2 | 23363814 | Phase I/II | Recurrent | GBM n = 19, biomarker positive (PTEN and/or EGFRvIII) GBM n = 22, biomarker negative | Biomarker positive: PFS 56d (95% CI 45–113) Biomarker negative: PFS 62d (95% CI 56–90) | Overall: CR 0%, PR 5%, SD 34%, PD 61% Biomarker positive: CR 0%, PR 5%, SD 37%, PD 58% Biomarker negative: CR 0%, PR 5%, SD 32%, PD 64% | NA |
Temsirolimus + perifosine | Temsirolimus: mTOR, induces autophagy Perifosine: Akt | 32293798 | Phase I | Recurrent | GBM n = 17 Other MG n = 19 | PFS 2.7m (95%CI 1.8–9.2) OS 10.4m (95% CI 7.2–16.7) | PR 3.4%, SD 44.8%, PD 51.7% | NA |
Temsirolimus + sorafenib | Temsirolimus: mTOR, induces autophagy Sorafenib: Raf-1, B-Raf, VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, c-KIT | 29313954 | Phase I + II | Recurrent | Arm B (anti-VEGF therapy naïve): GBM n = 49 Arm D (prior anti-VEGF therapy): GBM n = 44 | Arm B: PFS 2.7m OS 6.6m Arm D: PFS 1.9m OS 3.9m | Arm B: PR 2.4%, SD 64%, PD 27% Arm D: SD 46%, PD 51% | NA |
23099651 | Phase I/II | Recurrent | GBM n = 18 | PFS 8w (95% CI 5–9) | CR 0%, PR 11.8% | NA | ||
Tipifarnib + sorafenib | Tipifarnib: FTase Sorafenib: Raf-1, B-Raf, VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, c-KIT | 28988377 | Phase I | Recurrent | GBM n = 24 | PFS 55d OS 4.38m | NA | NA |
Trametinib + dabrafenib | Trametinib: MEK 1/2, activates autophagy Dabrafenib: BRAFV600 | PMC6217670 | Phase II | Recurrent | HGG n = 45, BRAFV600-mutant | PFS 1.9m (95% CI 1.7–18.5) OS 11.7m (95% CI 6.4–not reached) | NA | NA |
34838156 | Phase II | Recurrent | GBM n = 31, BRAFV600E-mutant | PFS 2.8Mm OS 13.7m | ORR 32%, PD 45%, CR 6%, PR 26% | NA | ||
Vandetanib + sirolimus | Vandetanib: VEGFR2, VEGFR3, EGFR, induces autophagy by increasing the level of reactive oxygen species (ROS) Sirolimus: mTOR | 25503302 | Phase I | Recurrent | GBM n = 19 | PFS 2.1m (95% CI 0.9–3.1) OS 7.7m (95% CI 4.7–9.3) | PR 10.5% | NA |
Vatalanib + imatinib + hydroxyurea | Imatinib: v-Abl, c-Kit and PDGFR, induces autophagy. Vatalanib: VEGFR2/KDR, VEGFR1/Flt-1, VEGFR3/Flt-4. | 19248046 | Phase I | Recurrent | GBM n = 34 MG grade III n = 3 | PFS 12w OS 48w | PR 24%, SD 49%, PD 27% | NA |
Vorinostat + bortezomib | Vorinostat: HDAC Bortezomib: 20S proteasome, inhibits NF-κB and induces ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy | 22090453 | Phase II | Recurrent | GBM n = 34 | TTP 1.5m OS 3.2m | Partial objective response 2.7% | NA |
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Hoosemans, L.; Vooijs, M.; Hoeben, A. Opportunities and Challenges of Small Molecule Inhibitors in Glioblastoma Treatment: Lessons Learned from Clinical Trials. Cancers 2024, 16, 3021. https://doi.org/10.3390/cancers16173021
Hoosemans L, Vooijs M, Hoeben A. Opportunities and Challenges of Small Molecule Inhibitors in Glioblastoma Treatment: Lessons Learned from Clinical Trials. Cancers. 2024; 16(17):3021. https://doi.org/10.3390/cancers16173021
Chicago/Turabian StyleHoosemans, Linde, Marc Vooijs, and Ann Hoeben. 2024. "Opportunities and Challenges of Small Molecule Inhibitors in Glioblastoma Treatment: Lessons Learned from Clinical Trials" Cancers 16, no. 17: 3021. https://doi.org/10.3390/cancers16173021