Table 2.
Selected phase III clinical trials in patients with newly diagnosed glioblastoma
| Study Design | Study Population and Key Eligibility Criteria | Extent of Resection | Radiation Scheme | Systemic/Experimental Agent | Median OS, months | Median PFS/EFS, mo |
|---|---|---|---|---|---|---|
| Randomized phase III trial of RT ± TMZ (N = 573)58 | Newly diagnosed GBM Age 18–70 years WHO PS ≤ 2 | Biopsy: 16–17% Partial resection: 44–45% Complete resection: 39–40% | Fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for total of 60 Gy | TMZ 75mg/m2/day during radiation from the first to the last day of RT (up to 49 days) followed by 6 cycles of adjuvant TMZ 150–200 mg/m2 for 5 days during each 28-day cycle) | RT alone: 12.1 (95% CI, 11.2–13.0) RT + TMZ: 14.6 (95% CI, 13.2–16.8). Unadjusted HR for death 0.63; 95 % CI, 0.52–0.75; P < 0.001 | RT alone: 5.0 (95% CI, 4.2–5.5) RT + TMZ: 6.9 (95% CI, 5.8–8.2) |
| Randomized, open-label trial of adjuvant TMZ ± TTF (N = 695)143 | Newly diagnosed GBM who had completed concomitant RT + TMZ Age ≥ 18 years KPS ≥ 70 Supratentorial tumor | Biopsy: 13% Partial resection: 33–34% Gross total resection 53–54% | N/A | Adjuvant TMZ as per Stupp regimen above TTF initiated 4–7 weeks from last day of RT until second progression or for a maximum of 24 months | TMZ alone: 15.6 TMZ + TTF 20.5 HR 0.64; 99.4% CI, 0.42–0.98; P = 0.004 | TMZ alone: 4.0 TMZ + TTFields: 6.7 HR 0.63; 95% CI, 0.52–0.76; P < 0.001 |
| Studies in MGMT methylated GBM | ||||||
| Randomized, open-label, phase III trial of standard TMZ versus lomustine-TMZ 144 | Newly diagnosed GBM Age ≥ 18 years KPS ≥ 70 Centrally confirmed methylated MGMT promotor | Biopsy: 2–5% Partial resection: 35–36% Complete resection: 59–63% | Standard involved-field RT to total dose of 59–60 Gy in 30–33 single day fractions | Standard concurrent + adjuvant TMZ as per Stupp above Lomustine-TMZ: 6-week cycles of lomustine 100 mg/m2 on Day 1 and TMZ 100–200 mg/m2 on days 2–6 for up to 6 cycles, starting in the first week of RT | In modified intention to treat population. Standard TMZ: 31·4 (95% CI, 27·7–47·1) Lomustine-TMZ: 48·1 (95% CI, 32·6–not assessable) HR 0·60; 95% CI 0·35–1·03; P = 0.0492 | In modified intention to treat population. Standard TMZ: 16·7 (95% CI, 11·4–24·2) Lomustine-TMZ: 16·7 (95% CI, 12·0–32·0) HR 0·91; 95% CI 0·57–1·44; P = 0.4113 |
| Studies in elderly patients (age ≥65 years) | ||||||
| Randomized phase III trial of hypofractionated RT ± TMZ (N = 562) 145 | Newly diagnosed GBM Age ≥65 years ECOG PS ≤2 Deemed by their physicians not to be suitable to receive conventional RT | Biopsy: 31.7% Partial or complete resection: 68.3% | Fractionated focal irradiation administered in 15 daily fractions over a period of 3 weeks, for total of 40.05 Gy | TMZ 75 mg/m2/day during radiation from the first to the last day of RT (21 consecutive days) followed by adjuvant TMZ 150–200 mg/m2 for 5 days during each 28 day cycle) for up to 12 cycles | RT alone: 7.6 RT + TMZ: 9.3 HR 0.67 for death; 95% CI, 0.56 to 0.80; P < 0.001 | RT alone: 3.9 RT + TMZ: 5.3 HR 0.50 for disease progression or death; 95% CI, 0.41 to 0.60; P < 0.001 |
| NOA-08: Noninferiority, randomized phase III trial of TMZ vs RT (N = 373)146 | Newly diagnosed GBM or AA Age ≥ 65 years KPS ≥ 70 | Biopsy: 37–41% Partial resection: 31–35% Complete resection; 20–27% | Fractionated focal irradiation administered in 30 daily fractions over 6–7 weeks, total 60.0 Gy | TMZ 100 mg/m2 for 1 week on, 1 week off | TMZ: 8·6 (95% CI, 7·3–10·2) RT: 9·6 (95% CI, 8·2–10·8) HR 1·09, 95% CI 0·84–1·42, pnon-inferiority = 0·033 | TMZ: 3·3 (95% CI, 3·2–4·1) RT: 4·7 (p5% CI, 4·2–5·2) HR 1·15, 95% CI 0·92–1·43, pnon-inferiority = 0·043 |
| Nordic: Randomized, phase III trial of TMZ vs 6-week RT vs hypofractionated RT (N = 291)147 | Newly diagnosed GBM Age ≥60 y WHO PS ≤ 2 | Biopsy: 26–27% Partial or complete resection: 73–74% | Hypofractionated RT: 34·0 Gy administered in 3·4 Gy fractions over 2 weeks Standard RT: 60·0 Gy administered in 2·0 Gy fractions over 6 weeks | TMZ 200 mg/m2 for 5 days during each 28 day cycle for up to 6 cycles | In comparison with standard RT: 6·0 months (95% CI, 5·1–6·8) TMZ: 8·3; HR 0·70; 95% CI 0·52–0·93, P = 0.01 Hypofractionated RT: 7·5 (95% CI, 6·5–8·6), HR 0·85; 95% CI 0·64–1·12, P = 0.24 | Deliberately not collected |
Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EFS, event-free survival; HR, hazard ratio; KPS, Karnofsky performance status; OS, overall survival; PFS, progression-free survival; PS, performance status; RR, radiographic response rate; TTF, tumor-treating fields.