Table 2.
Characteristics of studies on mIDH-inhibitors, n:7
| Number of patients | Main Findings in relation to mIDH-inhibitor administration | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Design | mIDH-inhibitor | Median treatment duration (range) | Total, n | Tumor Grade (G), | Previous therapy, n (%) | Aim | Survival | QoL | Toxicities | Treatment Response/ORR (%) |
| Cho et al. (2022) [9] | R |
-Ivosidenib (AG-120) -Vorasidenib (AG-881) |
Follow-up: Up to 4 months post-treatment |
Ivosidenib: 18 Vorasidenib: 11 |
G2/3/4: n:19/7/3 %: 66/24/10 |
NR | To investigate MRI changes in gliomas during mIDH-inhibitor treatment at 3–6 weeks and/or 2–4 months after treatment start | NA | NR | NR |
Radiological observations: At 3–6 weeks: Increase in nrCBV and median nrCBV/ADC but not in ADC or FLAIR At 2–4 months: No changes from baseline |
| Mellinghoff et al. (2021) [32] | P, Open-label | Vorasidenib (AG-881) | Enhancing: 3.3 months (0.2–53.6) Non-enhancing: 26.8 months (1.0–50.9) |
Total Glioma: 52 Enhancing: 30 Non-enhancing: 22 |
G2/3/4: n:25/22/4 %: 48/42/8 Unknown: n:1 %: 2 |
Enhancing: -RT: 22 (73) -Systemic: 25 (83) -Only Surgery: 4 (13) Non-enhancing: -RT: 8 (36) -Systemic: 14 (64) -Only surgery: 7 (32) |
Investigate safety and outcomes of Vorasidenib |
Median PFS: -Overall Cohort: 7.5 months -Enhancing: 3.6 months -Non-enhancing: 36.8 months |
NR |
Any CTCAE, n: 52, most common: Headache 46.2% ALT elevation 44.2% CTCAE ≥ 3, n:10 ALT/AST elevation, Fatigue, Nausea, Seizure, Vomiting, Decreased neutrophil count |
Enhancing: ORR (0.0) Non-enhancing: ORR (18.2) |
| Mellinghoff et al. (2023) [30] | RCT, Open-label | Ivosidenib (AG-120) Vorasidenib (AG-881) |
Vorasidenib: 14.3 months (0.9 −22.6) Ivosidenib: 15.1 months (1.8–22.1) |
Vorasidenib: 24 Ivosidenib: 25 |
Vorasidenib: G2/3: n: 22/2 %: 92/8 Ivosidenib: G2/3: n:21/4 %: 84/16 |
Vorasidenib:-Surgery:24 (100)-RT:7 (29)-Systemic:10 (42)Ivosidenib:-Surgery:25 (100)-RT: 7 (28)-Systemic: 14 (56) | To investigate the mechanism of action of Vorasidenib and Ivosidenib | Median PFS not reached in either mIDH-inhibitor | NR |
Vorasidenib: -Any CTCAE, n: 24, most common: Nausea, Headache 41.7%, Diarrhea, Fatigue 29.2% -CTCAE ≥ 3, n:7 Anemia, ALT-elevation, hyperglycemia, hypophosphatemia Ivosidenib: -Any CTCAE, n:25, most common: Headache, Anemia 36.0%, Diarrhea, Seizure 28.0% -CTCAE ≥ 3, n:6, hyponatremia |
Vorasidenib −50mg q.d.: ORR (42.9) −10mg q.d.: ORR (10.0) Ivosidenib −500 mg q.d.: ORR (35.7) −250 mg b.i.d.: ORR (12.5) 2-HG concentration reduction: -Vorasidenib 50 mg q.d.: 92.6% reduction -Ivosidenib 500 mg q.d.: 91.1% reduction |
| Mellinghoff et al. (2023) [31] | RCT, Double-blinded | Vorasidenib (AG-881) |
Median follow-up (Interquartile range): Vorasidenib: 14.0 months (10.1 to 17.9) Placebo: 14.3 months (10.0 to 18.1) |
Vorasidenib: 168 Placebo: 163 |
G2: n:331 %: 100 |
Surgery: 331 (100) | Investigate PFS and time to next intervention in grade 2 tumors receiving Vorasidenib |
Vorasidenib vs placebo: -PFS: 27.7 vs. 11.1 months -Time to next intervention: not reached vs. 17.8 months |
NR |
-Any CTCAE, n:141, most common: ALT elevation 38.9%, Fatigue 32.3% -CTCAE ≥ 3, n:27, ALT/AST/gamma-glutamyl transferase elevation, Fatigue, Diarrhea, Seizure |
Vorasidenib 40 mg q.d.: ORR (10.7) Placebo: ORR (2.5) |
| Natsume et al. (2022) [39] | P, Open-label | Safusidenib (DS-1001) |
Enhancing: 7.3 weeks (0.0–190.0) Non-enhancing 91.2 weeks (15.0–207.0) |
Total: 47 Enhancing: 35 Non-enhancing: 12 |
G2/3/4 n:17/23/7 %36/49/15 |
RT:47 (100)Chemotherapy:38 (81)-TMZ:35 (75)-Nimusutine14 (30)-Bevacizumab 7 (15) |
To determine the safety, efficacy and pharmacology of Safusidenib/ DS-1001 |
Median PFS Non-enhancing vs. Enhancing: not reached vs.10.4 weeks |
NR |
-All CTCAE, n:45, most common: Skin hyperpigmentation 53.2% Diarrhea 46.8% -CTCAE 3, n: 20, Diarrhea, Arthralgia, headache, decreased neutrophil count, ALT/AST elevation |
-Significantly lower 2-HG in Safusidenib (DS-1001) tumor samples -Enhancing: ORR (17.1) (CR: n: 2, 5.7%, PR: n: 4, 11.4%) -Non-enhancing: ORR (33.3) (PR: n: 1, 8.3%, mR: n: 3, 25.0%) |
| Peters et al. (2023) [43] | R | Ivosidenib (AG-120) | 43.7 weeks (5.5- 74.1) |
Total: 30 Enhancing: 8 Non-enhancing: 22 |
G2/3/4: n:21/8/1 %:70/27/3 |
RT: 8 (27)TMZ: 18(60)mIDH-peptide vaccine: 2 (7)Bevacizumab1 (3) | To investigate the outcomes of Ivosidenib treatment | Deaths: n:2 (of total 30) | NR |
CTCAE 1, n:23, most common: Diarrhea 26.7%, Elevated creatine kinase 33.3% |
Enhancing: ORR (0.0) Non-enhancing: ORR (36.3) |
| Wick et al. (2021) [65] | P | BAY1436032 | NR |
Total glioma:39 Enhancing: 33 Non-enhancing: 2 Unknown: 4 Dose expansion glioma: 25 Dose escalation glioma: 14 |
NR | Dose expansion: -RT: 23 (92)Dose escalation:NR separately | To investigate the safety profile and pharmacology of BAY1436032 in mIDH solid tumors | PFS rate at 3 months: 0.31 | NR | NA due to analysis with other tumor types | ORR: (11) (CR: n:1, 3.0%, PR: n:3, 9.0%) |
2-HG; 2-hydroxyglutarate, ADC; Apparent diffusion coefficient, ALT; alanine aminotransferase, AST; aspartate aminotransferase, b.i.d.; bis in die, twice a day, CR; Complete Response, CTCAE; Common terminology criteria for adverse events, FLAIR; Fluid-attenuated inversion recovery, G; Tumor grade, mIDH; mutant-isocitrate dehydrogenase, mR; minor Response, MRI; Magnetic Resonance Imaging, NA; Not Applicable, NR; Not reported, nrCBV; normalized relative cerebral blood volume, ORR; Objective response rate, P; Prospective, PFS; Progression Free Survival, PR; Partial Response, q.d.; quaque die, once a day, QoL; Quality of Life, R; Retrospective, RCT; Randomized controlled trial, RT; Radiotherapy, TMZ; Temozolomide, vs.; versus