Table 2.
Overview of single-arm studies
| Author (year) | Study phase | Number of patients enrolled | Treatment and GM-CSF dosing regimen | Clinical outcomes |
|---|---|---|---|---|
| Groenewegen et al. [58] | Phase 1/2 | 32 | Sequential treatment: DTIC 800 mg/m2 i.v. on day 1, followed by GM-CSF 2.5 µg/kg s.c. on days 2–12, IL-2 1.8 × 106 units on days 8–18 and IFN-α 6 × 106 units s.c. on days 15–20 |
Median OS: 244 days 1-year OS: 22 % 2-year OS: 12 % ORR (95 % CI): 32 % (16–49 %) CR: 13 % PR: 19 % |
| Adamina et al. [65] | Phase 1/2 | 16 | In combination with recombinant vaccinia virus and soluble peptide: intranodal vaccinia virus given on days 3 and 59; peptides given on days 17, 31, 45, 73, 87 and 101. GM-CSF 5 µg/kg s.c. given for 5 days, starting on the day of the intranodal injections |
Median OS: 488.5 days Mean OS (responsive patients): 1106 days Mean OS (non-responsive patients): 696 days Median PFS: 310 days Mean PFS (responsive patients): 547 days Mean PFS (non-responsive patients): 338 days |
| Scheibenbogen et al. [63] | Phase 2 | 18 | In combination with peptide vaccine: GM-CSF 75 or 150 µg i.d. and s.c. at the same site on days 1 and 4. Identical vaccinations were repeated at weeks 2, 4 and 6. If PD not observed, additional vaccinations were administered in weeks 10 and 14 |
Stable disease: 2 Mixed response: 1 NED: 2a PD: 13 |
| Pilla et al. [68] | Phase 2 | 38 | In combination with peptide vaccine: weekly vaccine for 4 weeks, starting 5–8 weeks after surgery. If no PD after 4 weeks, patients received four injections Q2W. GM-CSF 75 µg s.c. was given on days −1, 0 and 1 and then Q2W at the same time as the vaccine. IFN-α 3 × 106 units s.c. was given on days 1 and 3 after the last administration of GM-CSF during the first cycle. During the second cycle, IFN-α was given three times per week during the weeks in between vaccinations |
Median OS (95 % CI): 583 days (291 days–NR) Time to progression (95 % CI): 145 days (97–188 days) CR: 5 % Stable disease: 55 % PD: 40 % |
| Bins et al. [64] | Phase 1 | 11 | In combination with peptide vaccine and gp100: GM-CSF 100 µg s.c. weekly for 4 weeks |
Median OS: 4 months ORR: 0 % |
| Boasberg et al. [56] | Phase not specified | 54 | Biochemotherapy: DTIC, cis-platinum and vinblastine i.v., IFN-α s.c. and IL-2 i.v. with decrescendo dosing. Maintenance biotherapy: low-dose IL-2 (1 MIU/m2) + GM-CSF 125 µg/m2 s.c. on days 1–14 of each cycle (treatment began 4 weeks after the first day of the qualifying patient’s last cycle of biochemotherapy) |
Median OS (95 % CI) (vitiligo): 18.2 months (12.3 months–NR) Median OS (95 % CI) (no vitiligo): 8.5 months (6.7–12.7 months) P = 0.027 |
| Daud et al. [42] | Phase 2 | 42 | Adjuvant to surgery: GM-CSF 125 µg/m2 s.c. on days 1–14 of each 28-day cycle (maximum 13 cycles) |
Median OS (95 % CI): 65.3 months (47.4–67.0 months) Median recurrence-free survival (95 % CI): 5.6 months (3.5–11.7 months) |
| Spitler et al. [55] | Phase not specified | 102 | Adjuvant to surgery: GM-CSF 125 µg/m2 s.c. on days 1–14 of each 28-day cycle for at least 3 years or until unresectable recurrence |
5-year MSS (95 % CI) (stage III): 67 % (56–79 %) 5-year MSS (95 % CI) (stage IV): 40 % (19–60 %) |
| Weide et al. [67] | Phase 1/2 | 15 | In combination with autologous mRNA: GM-CSF 150 µg s.c. 24 h after mRNA injection in weeks 0, 2, 4 and 6, then Q4W until week 34 |
Stable disease: 1 PD: 9 NED: 3 Mixed response: 2 |
| Weber et al. [61] | Phase 2 | 31 | In combination with chemotherapy: cycle 1 daily oral temozolomide 150–200 mg/m2 for 5 days followed by biotherapy (GM-CSF 125 µg/m2 up to a maximum dose of 250 µg/m2 s.c. + IFN 5 × 106 units + IL-2 4 × 106 units/m2) daily for 12 days. This 28-day cycle was repeated as clinically indicated |
Median OS (95 % CI): 13.1 months (7.8–18.3 months) 1-year OS: 52 % 2-year OS: 25 % Median PFS (95 % CI): 4.9 months (2.8–6.9 months) 1-year PFS: 29 % 2-year PFS: 10 % ORR (95 % CI): 26 % (12–45 %) CR: 4 (2 NED) PR: 4 Stable disease: 7 Overall benefit rate (95 % CI): 48 % (30–67 %) |
| Eroglu et al. [52] | Phase 2 | 52 | In combination with chemotherapy: docetaxel and vinorelbine every 14 days, followed by GM-CSF 250 mg/m2 s.c. on days 2–12 of each cycle |
Median OS (95 % CI): 320 days (190–390 days) 1-year OS: 48.1 % (historical control OS 24.3 %; P = 0.012) Median PFS (95 % CI): 134 days (91–214 days) ORR: 15.4 % CR: 0 % PR: 15.4 % Stable disease: 36.5 % PD: 30.7 % Clinical benefit rate: 52 % |
| Gunturu et al. [59] | Phase 2 | 20 | In combination with chemotherapy: cyclophosphamide and fludarabine followed by two 5-day courses of high-dose IL-2 6 × 106 units/kg i.v. on days 8–12 and 21–25. GM-CSF 250 µg/m2 s.c. per day from day 8 until granulocyte recovery |
Median OS: 1.1 yearsb Median PFS: 0.25 yearsb ORR: 22.2 % CR: 5.6 % PR: 16.7 % |
| Locke et al. [60] | Phase 2 | 20 | In combination with chemotherapy: docetaxel, oxaliplatin, dexamethasone and ondansetron. GM-CSF 250 µg/m2 s.c. on days 3–12 or until WBC count recovery, whichever comes first; treatment continued Q3W until progression or toxicity |
Median OS: 5.4 months (range, <1–17 monthsc) Median PFS: 1.4 months (range, <1–8 monthsc) ORR: 0 % Stable disease: 26.3 % PR: 64.3 % |
| Fruehauf et al. [57] | Phase not specified | 10 | In combination with chemotherapy: docetaxel and vinorelbine. GM-CSF 250 mg/m2 s.c. on days 2–12 of each cycle |
ORR: 50 % PR: 50 % Median time to progression: 8 months |
| O’Day et al. [62] | Phase 2 | 133 | Biochemotherapy: DTIC, cis-platinum and vinblastine, IFN-α s.c. and IL-2 i.v. with decrescendo dosing plus GM-CSF 500 µg s.c. for 10 days. Maintenance biotherapy: low-dose IL-2 (1 MIU/m2) + GM-CSF 125 µg/m2 s.c. on days 1–14 of each cycle |
Median OS (95 % CI): 13.5 months (11.5–15.4 months) 1-year OS (±SE): 56.5 % ± 4.0 2-year OS (±SE): 23 % ± 3.7 Median PFS (95 % CI): 9 months (7.8–12.0 months) Estimated 1-year PFS (±SE): 40.9 % ± 4.3 Estimated 2-year PFS (±SE): 15.9 % ± 3.2 |
| Dillman et al. [66] | Phase 2 | 56 | In combination with autologous DC vaccine: vaccine suspended in GM-CSF 500 µg before s.c. administration weekly for 3 weeks, then monthly for 5 months for up to 6 months or a maximum of eight doses |
Median OS: NR 1-year OS: 85 % 2-year OS: 72 % Predicted 5-year OS: 54 % Median PFS: 4.2 months 5-year PFS: 23 % ORR: 0 % Stable disease: 40 % PD: 60 % |
CI confidence interval, CR complete response, DTIC dacarbazine; gp100 glycoprotein-100, MIU million international unit, MSS melanoma-specific survival, NED no evidence of disease, NR not reached, ORR overall response rate, PD progressive disease, PFS progression-free survival, PR partial response, Q2W/Q3W/Q4W every 2/3/4 weeks, SE standard error
aTwo patients had complete surgical resection before study entry and therefore remained with NED throughout
bMedians estimated from Kaplan–Meier curves
cRange for deceased patients