Table 4.
Clinical trials of WEE1 inhibitors.
| Trial Phase |
Disease Setting |
Treatments | Most Common Grade ≥ 3 Toxicity |
Efficacy | Reference |
|---|---|---|---|---|---|
| Adavosertib/MK-1775/AZD1775 | |||||
| 1 | Solid tumors | Escalating doses of AZD1775 | Lymphopenia (20%) Neutropenia (16%) Anemia (16%) |
PR 2/25 (8%) | [104] |
| 1 | Solid tumors | AZD1775 alone or in combination with standard chemotherapy | AZD1775 + Gemcitabine: Neutropenia (33%) AZD1775 + Cisplatin: Neutropenia (12%) AZD1775 + Carboplatiin: Thrombocytopenia (31%) Neutropenia (18%) |
AZD1775 + Gemcitabine: PR 4/81 (5%) AZD1775 + Cisplatin: PR 9/58 (16%) AZD1775 + Carboplatiin: PR 4/62 (6%) |
[105] |
| 1 | Locally advanced pancreatic cancer | Escalating doses of AZD1775 with gemcitabine and radiation | Neutropenia (12%) Fatigue (9%) Fever (9%) Anorexia/Nausea/ Vomiting (9%) |
Median OS 21.7 months (90% CI 16.7–24.8) Median PFS 9.4 months (90% CI 8.0–9.9) |
[106] |
| 1 | Locally advanced head and neck cancer | Escalating doses of AZD1775 in combination with radiation | Lymphopenia (92%) | CR 8/10 (80%) PR 2/10 (20%) |
[107] |
| 2 | TP53-mutated refractory ovarian cancer | AZD1775 in combination with carboplatin | Thrombocytopenia (48%) Neutropenia (39%) |
CR 1/21 (5%) PR 8/21 (38%) SD 7/21 (33%) |
[108] |
| 2 | TP53-mutated, platinum-sensitive ovarian cancer | Randomization (1:1) Paclitaxel and Carboplatin +/− AZD1775 | AZD1775 + Chemotherapy: Neutropenia (36%) Placebo + Chemotherapy: Neutropenia (33%) |
AZD1775 + Chemotherapy: PFS 7.9 months Placebo + Chemotherapy: PFS 7.3 months HR for PFS: 0.63 (95% CI 0.38–1.06) |
[109] |
| 2 | Platinum-refractory ovarian cancer | Randomization (2:1) Gemcitabine +/− Adavosertib | AZD1775 + Gemcitabine: Neutropenia (62%) Placebo + Gemcitabine Neutropenia (30%) |
AZD1775 + Gemcitabine: PFS 4.6 months Placebo + Gemcitabine: PFS 3.0 months HR for PFS: 0.55 (95% CI 0.35–0.90) |
[110] |
| 2 | Platinum-resistant ovarian cancer | Adavosertib in combination with - Gemcitabine - Paclitaxel - Carboplatin - Pegylated liposomal doxorubicin (PLD) |
with Gemcitabine Neutropenia (78%) with Paclitaxel Neutropenia (53%) with Carboplatin Thrombocytopenia (63%) with PLD Neutropenia (17%) |
with Gemcitabine PR 1/9 (11%) with Paclitaxel PR 10/38 (26%) with Carboplatin PR 13/35 (37%) with PLD PR 3/12 (25%) |
[111] |
| 2 | TNBC | Adavosertib in combination with cisplatin | Diarrhea (21%) Neutropenia (18%) |
CR 3/34 (9%) PR 6/34 (18%) SD 13/34 (38%) |
[112] |
| 2 | Colorectal cancer with TP53 and RAS mutations | Randomization (2:1) (maintenance) Adavosertib or active monitoring |
Adavosertib Diarrhea (9%) |
Adavosertib PFS 3.6 months OS 14.0 months Active monitoring PFS 1.9 months OS 12.8 months HR for PFS: 0.35 (95% CI 0.18–0.68) HR for OS: 0.92 (95% CI 0.44–1.94) |
[113] |
| 2 | Small cell lung cancer | Adavosertib monotherapy (biomarker-selected patients) | Diarrhea 1/31 (3%) | PR 0/31 (0%) SD 9/31 (29%) |
[114] |
| 2 | Uterine serous sarcoma | Adavosertib monotherapy | Neutropenia (32%) | CR 1/34 (3%) PR 9/34 (26%) |
[115] |
| 2 | Solid tumor with mutations in DNA repair genes | Adavosertib in combination with carboplatin | Anemia (39%) Thrombocytopenia (39%) Neutropenia (32%) |
PR 0/24 (0%) | [116] |
PR, partial response; SD, stable disease; TNBC, triple-negative breast cancer.