Table 1.
Trials Including Combination Strategies with AKT Inhibitors
| Reported AKT Combination Trials | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase | NCT | Population | Biomarker Required | AKT Inhibitor | Combination Agent | Comparator Agent (s) | N | DCR/CBR | ORR | PFS | OS | Ref |
| Combinations with Chemotherapy | ||||||||||||
| 3 | NCT01097018 | CRC | None | Perifosine | Capecitabine | Capecitabine + Placebo | 468 | NR | NR* | 6.4 v 6.8 m | [114]* | |
| 1b | NCT 01653912 | PPROC | None | Afuresertib | Carbo + Paclitaxel | None | 59 | NR | 32% | 7.1m | [115] | |
| PROC | ||||||||||||
| 1b | NCT02476955 | Solid Tumors | None | Miransertib (ARQ092) | Carboplatin + Paclitaxel | None | 13 | NR | 31% | NR | [116] | |
| Miransertib (ARQ092) | Paclitaxel | NR | NR | NR | NR | NR | ||||||
| Endometrial Cancer | AKT1, PIK3CA, or PIK3R1 mutations in endometrial Ca | Miransertib (ARQ092) | Anastrozole | NR | NR | NR | NR | NR | ||||
| Targeted Combinations | ||||||||||||
| 1 | NCT01476137 | Solid Tumors + Myeloma | None | Afuresertib | Trametinib | None | 20 | 25% | 5% | NR | NR | [117] |
| 1 | NCT02338622 | Solid Tumors | Germline BRCA1/2; BRCA WT with somatic DDR or AKT alterations | Capivasertib (AZD5363) | Olaparib | None | 56 | 44.6% | 25% RECIST 34 Tumor Response** | NR | NR | [100] |
| 1/2 | NCT02208375 | TNBC, Ovarian, primary peritoneal, fallopian tube, or Endometrial | None | Capivasertib (AZD5363) | Olaparib | None | 30 | NR | 24% overall | NR | NR | [118] |
| 50% endometrial | ||||||||||||
| 1 | NCT02525068 | mCRPC | None | Capivasertib (AZD5363) | Enzalutamide | None | 15 | NR | 20% | NR | NR | [105] |
| 1 | NCT04087174 | mCRPC | None | Capivasertib (AZD5363) | Abiraterone | None | 15 | NR | 20%** | NR | NR | [106] |
| 1 | NCT01281163 | Solid Tumors | None; HER2 + BC expansion cohort | MK-2206 | Lapatinib | None | 28 | 14% | 0% | NR | NR | [91] |
| 1 | NCT01021748 | Solid Tumors | None; KRAS NSCLC expansion cohort | MK-2206 | Selumetinib (AZD6244) | None | 51 | NR | 14% | NR | NR | [92] |
| 2 | NCT01333475 | CRC | KRAS mutant versus KRAS WT | MK-2206 | Selumetinib (AZD6244) | None | 21 | 8% | 0% | NR | NR | [93] |
| 2 | NCT01658943 | Pancreatic CA | None | MK-2206 | Selumetinib (AZD6244) | mFOLFOX | 137 | NR | 3% v 22% | 1.9 v 2.0m | 3.9 v 6.7m | [94] |
| 2 | NCT01964924 | TNBC | None | GSK2141795 | Trametinib | None | 16 | NR | 6% | NR | NR | [86] |
| 1 | NCT01138085 | TNBC or BRAF WT Melanoma | None | Uprosertib (GSK 2141795) | Trametinib | None | 126 | NR | 4.8% | TNBC= 56d | NR | [81] |
| MM= 114d | ||||||||||||
| 1 | NCT01935973 | Endometrial Cancer | None | Uprosertib (GSK 2141795) | Trametinib | None | 26 | NR | 8.3% | 3.4m | NR | [80] |
| 2 | NCT01941927 | BRAF WT Melanoma | NRAS Mutant versus NRAS WT | Uprosertib (GSK 2141795) | Trametinib | None | 20 | 65% | 0% | 2.75 | NR | [82] |
| 2 | NCT01979523 | Uveal Melanoma | None | Uprosertib (GSK 2141795) | Trametinib | Trametinib Alone | 40 | NR | 5% v 6% | 15.6 v 15.7 weeks | NR | [83] |
| 1/2 | NCT01902173 | Solid Tumors | BRAF-V600E/K mutant | Uprosertib (GSK 2141795) | Trametinib + Dabrafenib | None | 11 | NR | 50% | NR | NR | [85] |
| Uprosertib (GSK 2141795) | Dabrafenib | 9 | NR | 38% | NR | NR | ||||||
| 2 | NCT01958112 | Cervical CA | None | Uprosertib (GSK2141795) | Trametinib | None | 14 | 57% | 8% | NR | NR | [87] |
| 1 | NCT01147211 | NSCLC | EGFR mutant | MK-2206 | Gefitinib | None | 14 | NR | 0% | NR | NR | [90] |
| 1b | NCT01562275 | Solid Tumors | None; Expansion in PTEN deficient, TNBC, or endometrial CA | Ipatasertib (GDC-0068) | Cobimetinib (GDC-0973) | None | 66 | 47% | 5% | NR | NR | [58] |
| 2 | NCT01294306 | NSCLC EGFR mutant | Stratified by EGFR mutant status | MK2206 | Erlotinib | None | 45 | 40% | 9% | 4.4m | NR | [119] |
| EGFR WT | 35 | 47% | 4% | 4.6m | ||||||||
| Combination with Hormones | ||||||||||||
| 2 | NCT01251861 | High Risk Prostate Cancer | None | MK2206 | Bicalutamide | Bicalutamide | 108 | NR | NR | NR | NR | [104] |
| 1b | NCT03959891 | HR+/HER2 – MBC | None | Ipatasertib | Fulvestrant + Palbociclib | None | 12 | NR | 17% | NR | NR | [96] |
| 1 | NCT01344031 | Metastatic Breast Cancer | None | MK2206 | Anastrozole with or without fulvestrant | None | 31 | NR | 7.7% | NR | NR | [42] |
| 2 | NCT01992952 | ER+ MBC after AI | None | Capivasertib | Fulvestrant | Fulvestrant Alone | 140 | NR | 29% v 8% | 10.3 v 4.8m | 23.7 v 20.3m | [44] |
| 3 | NCT03072238 | mCRPC | Stratified by PTEN loss by IHC ≥50% tumor cells | Ipatasertib | Abiraterone | Placebo + Abiraterone | 1101 | NR | NR | PTEN Loss: 19.1 v 14.2 m | NE | [108] |
| ITT: 61 v 44% | ITT: 19.2 v 16.6 m | |||||||||||
| Ongoing AKT Inhibitor Trials Without Reported Results | ||||||||||||
| Phase | NCT | Selection Criteria | AKT Drug | Combination | Comparator | |||||||
| 1 | NCT01783171 | Pancreatic Cancer | None | MK2206 | Dinaciclib (SCH727965) | None | ||||||
| 1 | NCT01705340 | HER2+ Breast, GE, or gastric | HER2 + | MK2206 | Trastuzumab + Lapatinib | None | ||||||
| 1 | NCT04253561 | HER2 Positive BC | PI3K mutant | Ipatasertib | Pertuzumab + Trastuzumab | None | [97] | |||||
| 2 | NCT04374630 | Platinum Resistant Ovarian Cancer | None | Afuresertib | Paclitaxel | Paclitaxel alone | ||||||
| 2 | NCT04467801 | Metastatic/Advanced NSCLC | None | Ipatasertib | Docetaxel | None | ||||||
Notes: *Not reported but noted to be not improved; **Partial or complete response or GCIG or PCWG2 responses.
Abbreviations: CRC, colorectal cancer; Mut, mutant; NR, not reported; NE, not yet evaluable; PPROC, primary platinum refratory ovarian cancer; PROC, platinum resistant ovarian cancer; WT, wild type.