Table 2.
Performance of GSIs as anti-cancer strategies in clinical trials.
| Cancer Types | Name | Phase | Case selection | Usage | Outcome | Reference |
|---|---|---|---|---|---|---|
| Lung cancer | MK-0752 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors that had failed to respond to standard therapies or for which no proven treatments existed. | Oral administration; Specific dose and time are not given (Despite providing the drug dose and duration of use in each schedule, the specific cancer type was not specified); | None of the patients received any clinical benefit (n=3). | PMID: 22547604 84 |
| PF-03084014 | I | Advanced patients who were resistant to standard therapy or for which no therapy was available. | Oral administration for 21 days in a test dose range of 20 to 330 mg BID (Please refer to this article for specific usage); | None of the patients received any clinical benefit (n=5). | PMID: 25231399 106 | |
| LY900009 | I | Age ≥ 18 years; patients with advanced cancer refractory to standard therapy (or no available standard therapy) and a 12-week expectancy. | LY900009 was administered orally thrice weekly (Monday, Wednesday, and Friday) on a 28-d cycle; Dose escalation was performed at a pre-specified dose level (2 - 60 mg); | Of the 2 patients evaluable for response, 1 patient was observed with SD (73d). | PMID: 26798966 107 | |
| RO4929097 + Cediranib | I | Age ≥ 18 years; Patients had histologically or cytologically documented advanced solid malignancy, refractory to standard therapy or for which conventional therapy was not effective. | Patients received a progressively increased dose of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). The first cycle, which lasted 42 days, was given RO4929097 alone for the first 3 weeks, followed by RO4929097 and cediranib in combination from day 22. The second and subsequent periods were 21 days. | None of the patients received any clinical benefit (n=1). | PMID: 23868004 108 | |
| Pancreatic cancer | MK-0752 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors that had failed to respond to standard therapies or for which no proven treatments existed. | Oral administration; Specific dose and time are not given (Despite providing the drug dose and duration of use in each schedule, the specific cancer type was not specified). | None of the patients received any clinical benefit (n=2). | PMID: 22547604 84 |
| LY900009 | I | Age ≥ 18 years; patients with advanced cancer refractory to standard therapy (or no available standard therapy) and a 12-week expectancy. | LY900009 was administered orally thrice weekly (Monday, Wednesday, and Friday) on a 28-d cycle; Dose escalation was performed at a pre-specified dose level (2-60 mg). | None of the patients received any clinical benefit (n=3). | PMID: 26798966 107 | |
| PF-03084014 | I | Advanced patients who were resistant to standard therapy or for which no therapy was available. | Oral administration for 21 days in a test dose range of 20 to 330 mg BID (Please refer to this article for specific usage); | None of the patients received any clinical benefit (n=2). | PMID: 25231399 106 | |
| RO4929097 | II | Age ≥ 18 years; patients with previously treated metastatic pancreatic adenocarcinoma. | Oral administration; 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles; | Three (25%) of 12 evaluable patients achieved stable disease. Median PFS was 1.5 months. | PMID: 24668033 83 | |
| R04929097 + Gemcitabine | II | Patient was 18 years or older, had histologically or cytologically proven advanced solid tumors with no further standard treatment options available. | RO4929097 was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. RO4929097 dose levels were 20 mg, 30 mg, 45 mg and 90 mg; Gemcitabine was administered at 1000 mg/m2 on d1, 8, and 15 in 28 d cycles. | One in three patients with pancreatic cancer achieved long-term stable disease (> 4 months). | PMID: 23645447 109 | |
| MK-0752 + Gemcitabine | I | Patients with stage III (inoperable) and stage IV pancreatic ductal adenocarcinoma (Of the 44 patients included, 93% had stage IV pancreatic cancer, and 30% had received prior chemotherapy) | MK-0752 was administered orally weekly; Gemcitabine was administered intravenously at 800 or 1000 mg m-2 on days 1,8, and 15 (28-day cycles). | Of the 19 patients undergoing response assessment, one confirmed partial response and 13 had stable disease. | PMID: 29438372 110 | |
| Melanoma | RO4929097 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors refractory to standard therapy or for which no standard therapy exists. | Oral increasing doses of RO4929097 by two regimens: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. | Of the 24 melanoma patients with evaluable efficacy, one nearly complete FDG-PET response. | PMID: 22529266 111 |
| RO4929097 | II | Patient had stage IV melanoma of histologically confirmed skin or unknown origin (excluding ocular and mucosal sources), had not received chemotherapy (immunotherapy and adjuvant therapy were allowed) and had no history of central nervous system metastasis. | Taken orally on an empty stomach at a dose of 20 mg daily 3 consecutive days per week. | Of the 32 evaluable patients, 1 confirmed partial response persisted for 7 months and 8 patients had stable disease until at least week 12, with 1 continuing for 31 months. | PMID: 25250858 112 | |
| MK-0752 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors that had failed to respond to standard therapies or for which no proven treatments existed. | Oral administration; Specific dose and time are not given (Despite providing the drug dose and duration of use in each schedule, the specific cancer type was not specified) | None of the patients received any clinical benefit (n=3). | PMID: 22547604 84 | |
| LY3039478 | I | Age ≥ 20 years; Japanese patients with advanced solid tumors for whom standard therapies failed or would not be appropriate. | 2 dose levels of crenigacestat (25 mg and 50 mg) were administered orally 3 times weekly (TIW) over a 28-day cycle. | None of the patients received any clinical benefit (n=2). | PMID: 32939607 113 | |
| Ovarian cancer | RO4929097 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors refractory to standard therapy or for which no standard therapy exists. | Oral increasing doses of RO4929097 by two regimens: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. | Of the 9 ovarian cancer patients with evaluable efficacy, 0 showed clinical benefit. | PMID: 22529266 111 |
| LY900009 | I | Age ≥ 18 years; patients with advanced cancer refractory to standard therapy (or no available standard therapy) and a 12-week expectancy. | LY900009 was administered orally thrice weekly (Monday, Wednesday, and Friday) on a 28-d cycle; Dose escalation was performed at a pre-specified dose level (2-60 mg). | None of the patients received any clinical benefit (n=11). | PMID: 26798966 107 | |
| RO4929097 | II | Age ≥ 18 years; Women with progressive platinum-resistant epithelial ovarian cancer treated with ≤ 2 chemotherapy regimens for recurrent disease; | RO4929097 administered orally at 20 mg once daily, 3 days on/4 days off each week in a three-week cycle. | No objective responses were observed. 15 patients (33%) had SD as their best response, with a median duration of 3.1 months. | PMID: 25769658 114 | |
| MK-0752 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors that had failed to respond to standard therapies or for which no proven treatments existed. | Oral administration; Specific dose and time are not given (Despite providing the drug dose and duration of use in each schedule, the specific cancer type was not specified) | None of the patients received any clinical benefit (n=3). | PMID: 22547604 84 | |
| R04929097 + Gemcitabine | II | Patient was 18 years or older, had histologically or cytologically proven advanced solid tumors with no further standard treatment options available. | RO4929097 was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. RO4929097 dose levels were 20 mg, 30 mg, 45 mg and 90 mg; Gemcitabine was administered at 1000 mg/m2 on d1, 8, and 15 in 28 d cycles. | None of the patients received any clinical benefit (n=2). | PMID: 23645447 109 | |
| RO4929097 + Temsirolimus | Ib | Age ≥ 18 years; patients with histologically confirmed advanced, incurable solid malignancy refractory to conventional therapy or for which no standard therapy existed. | RO4929097 and Temsirolimus were given in three progressively incremented dose levels. RO4929097 was orally administered on an empty stomach on a 3 days on/4 days off schedule, weekly; Intravenous temsirolimus every week. | No objective responses were observed. | PMID: 23860641 115 | |
| RO4929097 + Cediranib | I | Age ≥ 18 years; Patients had histologically or cytologically documented advanced solid malignancy, refractory to standard therapy or for which conventional therapy was not effective. | Patients received a progressively increased dose of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). The first cycle, which lasted 42 days, was given RO4929097 alone for the first 3 weeks, followed by RO4929097 and cediranib in combination from day 22. The second and subsequent periods were 21 days. | None of the patients received any clinical benefit (n=1). | PMID: 23868004 108 | |
| Sarcoma | RO4929097 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors refractory to standard therapy or for which no standard therapy exists. | Oral increasing doses of RO4929097 by two regimens: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. | Of the 12 sarcoma patients with evaluable efficacy, 1 showed mixed response (stable disease). | PMID: 22529266 111 |
| MK-0752 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors that had failed to respond to standard therapies or for which no proven treatments existed. | Oral administration; Specific dose and time are not given (Despite providing the drug dose and duration of use in each schedule, the specific cancer type was not specified) | None of the patients received any clinical benefit (n=3). | PMID: 22547604 84 | |
| LY900009 | I | Age ≥ 18 years; patients with advanced cancer refractory to standard therapy (or no available standard therapy) and a 12-week expectancy. | LY900009 was administered orally thrice weekly (Monday, Wednesday, and Friday) on a 28-d cycle; Dose escalation was performed at a pre-specified dose level (2-60 mg). | Of the 2 patients evaluable for response, 1 patient was observed with SD (113d). | PMID: 26798966 107 | |
| Glioma | MK-0752 | I | Patients, aged between 3 and 21 years, were histologically proven malignant central nervous system tumor (diffuse pontine glioma does not require histology) and refractory to conventional therapy with Lansky or Karnofsky score 60. | MK-0752 was taken orally in a starting dose of 200 mg/m2 once every 7 days for three consecutive days. | Most patients experienced disease progression after 1 or 2 courses. Prolonged SD was observed only in 2 patients (≥3 courses). | PMID: 21825264 116 |
| RO4929097 +Bevacizumab | I | Patient was 18 years or older, had histologically proven malignant glioma, and progressed after radiotherapy and chemotherapy with temozolomide. | RO4929097 was taken orally for 3 days on/4 days off each week for 4 consecutive cycles (days 1-3, 8-10, 15-17, and 22-24), and intravenous infusion of bevacizumab (Day 1 and Day 15, 10mg /kg) every 2 weeks. | Two of the 12 patients had radiological responses (one patient gained CR and the other PR). | PMID: 27826680 117 | |
| MK-0752 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors that had failed to respond to standard therapies or for which no proven treatments existed. | Oral administration; Specific dose and time are not given (Despite providing the drug dose and duration of use in each schedule, the specific cancer type was not specified) | Of the 21 patients with evaluable efficacy, 5 showed SD. | PMID: 22547604 84 | |
| Breast cancer | MK-0752 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors that had failed to respond to standard therapies or for which no proven treatments existed. | Oral administration; Specific dose and time are not given (Despite providing the drug dose and duration of use in each schedule, the specific cancer type was not specified) | None of the patients received any clinical benefit (n=24). | PMID: 22547604 84 |
| RO4929097 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors refractory to standard therapy or for which no standard therapy exists. | Oral increasing doses of RO4929097 by two regimens: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. | None of the patients received any clinical benefit (n=10). | PMID: 22529266 111 | |
| PF-03084014 | I | Advanced patients who were resistant to standard therapy or for which no therapy was available. | Oral administration for 21 days in a test dose range of 20 to 330 mg BID (Please refer to this article for specific usage); | None of the patients received any clinical benefit (n=7). | PMID: 25231399 106 | |
| RO4929097 + Exemestane | Ib | Patients with ER+/HER2- metastatic breast cancer | RO4929097 was taken orally every day for 3 consecutive days, followed by 4 days of discontinuation, and the cycle was 21 days. Exemestane was used at a dose of 25 mg daily. | Of the 14 evaluable patients, 8 patients showed clinical responses (1 PR and 7 SD). The overall clinical benefit rate (CR + PR + SD >= 6 months) was 20% and PFS was 3.2 months. | PMID: 34903452 118 | |
| R04929097 + Gemcitabine | II | Patient was 18 years or older, had histologically or cytologically proven advanced solid tumors with no further standard treatment options available. | RO4929097 was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. RO4929097 dose levels were 20 mg, 30 mg, 45 mg and 90 mg; Gemcitabine was administered at 1000 mg/m2 on d1, 8, and 15 in 28 d cycles. | Of the 5 patients, 1 patient showed SD (> 4 months). | PMID: 23645447 109 | |
| PF-03084014 + Docetaxel | I | Adult women with advanced or metastatic triple-negative breast cancer or hormone-refractory ER/PR-positive breast cancer. | PF-03084014 was taken orally twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. | 4 of the 25 evaluable patients achieved a confirmed partial response. 9 (36%) patients had stable disease, 5 of whom had unconfirmed partial responses. 11 (44%) patients had the best overall response to progressive disease. The median PFS was 4.1 months, and the 6-month PFS rate was 17.1%. | PMID: 27906684 119 | |
| MK-0752 + Docetaxel | Ib | Male or female patients with advanced breast cancer not responsive to first-line anthracycline chemotherapy. | MK-0752 was used on days 1 to 3, with the dose determined by a dose-escalation protocol, followed by docetaxel on day 8 of each 21-day cycle. | Of the 24 patients evaluable for response, 11 patients were observed with PR, 9 SD, and 3 PD. | PMID: 23340294 120 | |
| RO4929097 + Cediranib | I | Age ≥ 18 years; Patients had histologically or cytologically documented advanced solid malignancy, refractory to standard therapy or for which conventional therapy was not effective. | Patients received a progressively increased dose of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). The first cycle, which lasted 42 days, was given RO4929097 alone for the first 3 weeks, followed by RO4929097 and cediranib in combination from day 22. The second and subsequent periods were 21 days. | None of the patients received any clinical benefit (n=1). | PMID: 23868004 108 | |
| Colorectal cancer | MK-0752 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors that had failed to respond to standard therapies or for which no proven treatments existed. | Oral administration; Specific dose and time are not given (Despite providing the drug dose and duration of use in each schedule, the specific cancer type was not specified) | None of the patients received any clinical benefit (n=16). | PMID: 22547604 84 |
| PF-03084014 | I | Advanced patients who were resistant to standard therapy or for which no therapy was available. | Oral administration for 21 days in a test dose range of 20 to 330 mg BID (Please refer to this article for specific usage); | None of the patients received any clinical benefit (n=11). | PMID: 25231399 106 | |
| LY900009 | I | Age ≥ 18 years; patients with advanced cancer refractory to standard therapy (or no available standard therapy) and a 12-week expectancy. | LY900009 was administered orally thrice weekly (Monday, Wednesday, and Friday) on a 28-d cycle; Dose escalation was performed at a pre-specified dose level (2-60 mg). | Of the 5 patients evaluable for response, 1 patient (rectal carcinoma) was observed with SD (55d). | PMID: 26798966 107 | |
| RO4929097 + Cediranib | I | Age ≥ 18 years; Patients had histologically or cytologically documented advanced solid malignancy, refractory to standard therapy or for which conventional therapy was not effective. | Patients received a progressively increased dose of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). The first cycle, which lasted 42 days, was given RO4929097 alone for the first 3 weeks, followed by RO4929097 and cediranib in combination from day 22. The second and subsequent periods were 21 days. | Of the 6 patients evaluable for response, 2 patients were observed with SD (7 and 11 cycles). | PMID: 23868004 108 | |
| RO4929097 | I | Age ≥ 18 years; patients with histologically confirmed solid tumors refractory to standard therapy or for which no standard therapy exists. | Oral increasing doses of RO4929097 by two regimens: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. | None of the patients received any clinical benefit (n=12). | PMID: 22529266 111 | |
| LY3039478 | I | Age ≥ 20 years; Japanese patients with advanced solid tumors for whom standard therapies failed or would not be appropriate. | 2 dose levels of crenigacestat (25 mg and 50 mg) were administered orally 3 times weekly (TIW) over a 28-day cycle. | None of the patients received any clinical benefit (n=5). | PMID: 32939607 113 | |
| Desmoma | PF-03084014 | I | Advanced patients resistant to standard therapy or for which no therapy was available. | The oral dose of PF-03084014 ranges from 20 to 330 mg twice daily. | Of the 7 patients, 5 achieved a PR, with a mean time to achieve a response of 11.9 months. All patients who achieved PR continued responding over 47.9 to 73 months. | PMID: 28887726 121 |
| PF-03084014 | II | Age ≥ 18 years; Patients with histologically confirmed desmoid tumors who were not candidates for surgical resection or definitive radiation therapy and whose disease progressed aggressively after at least one line of standard treatment. | PF-03084014 was taken orally at a dose of 150mg twice daily in 21-day cycles. | Of the 16 patients evaluable, 5 achieved a confirmed partial response and had been on study for more than 2 years, and another 5 patients with prolonged SD remained on study. | PMID: 28350521 122 | |
| LY3039478 | I | Age ≥ 20 years; Japanese patients with advanced solid tumors for whom standard therapies failed or would not be appropriate. | 2 dose levels of crenigacestat (25 mg and 50 mg) was administered orally 3 times weekly (TIW) over a 28-day cycle. | None of the patients had a complete or partial response to the treatment. One patient with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. | PMID: 32939607 113 | |
| PF-03084014 | I | Advanced patients who were resistant to standard therapy or for which no therapy was available. | Oral administration for 21 days in a test dose range of 20 to 330 mg BID (Please refer to this article for specific usage); | Of the 7 patients evaluable, 5 achieved a partial response (71.4% objective response rate). | PMID: 25231399 106 | |
| Nirogacestat | III | Adults with progressing desmoid tumors | Oral administration in a test dose of 150mg BID | Patients receiving Nirogacestat performed better on progression-free survival, objective response, pain, symptom burden, physical function, role function, and health-related quality of life. Although adverse events with Nirogacestat are frequent, they are mostly low grade. | PMID: 3688432385 |