Table 1.
Kirsten rat sarcoma virus-rapidly accelerated fibrosarcoma-mitogen-activated protein kinase/extracellular regulated protein kinases-extracellular regulated protein kinases pathway inhibitors
| Agent | FDA approved1 |
Clinical trials2
|
||
|
Conditions (phase)
|
Combination
|
NCT number
|
||
| SOS inhibitors | ||||
| BI-1701963 | N/A | Advanced solid tumors (I); advanced solid tumors (I); metastatic colorectal cancer (I) | Trametinib; BI 3011441; irinotecan | NCT04111458; NCT04835714; NCT04627142 |
| SHP2 inhibitors | ||||
| ERAS-601 | N/A | Advanced/ metastatic solid tumors (I) | Cetuximab, pembrolizumab | NCT04670679 |
| JAB-3312 | N/A | Advanced solid tumors (I); advanced solid tumors (I/II) | N/A; binimetinib, pembrolizumab, sotorasib, osimertinib | NCT04045496; NCT04720976 |
| BBP-398 (IACS-15509) | (+ sotorasib) fast track designation for metastatic NSCLC | Advanced solid tumor (I); advanced NSCLC (I); advanced solid tumors (I); advanced solid tumors (I) | N/A; nivolumab; N/A; sotorasib | NCT05621525; NCT05375084; NCT04528836; NCT05480865 |
| RLY-1971 | N/A | Advanced/metastatic solid tumors (I) | N/A | NCT04252339 |
| TNO155 | N/A | Advanced solid tumors (I); advanced solid tumors (I) | EGF816 (nazartinib); spartalizumab, ribociclib | NCT03114319; NCT04000529 |
| RMC-4630 | N/A | Relapsed/refractory solid tumors (I); NSCLC (II); metastatic KRAS mutant cancers (I); relapsed/refractory solid tumors, locally advanced/metastatic EGFR positive NSCLC (I/II) | N/A; sotorasib LY3214996; cobimetinib, osimertinib | NCT03634982; NCT05054725; NCT04916236; NCT03989115 |
| Direct KRAS inhibitors | ||||
| G12C | ||||
| Sotorasib (AMG 510, Lumakras) | Advanced NSCLC | Colorectal cancer (III); advanced solid tumors (Ib/II) | Panitumumab; N/A | NCT05198934; NCT04185883 |
| Adagrasib (MRTX849, Krazati) | Locally advanced or metastatic NSCLC | Metastatic PC (Ib); colorectal cancer (I); solid tumors (I/II); advanced solid tumors (I); advanced/metastatic cancers (I/II) | N/A; cetuximab and irinotecan; N/A; BI-1701963; TNO155 | NCT05634525; NCT05722327; NCT05162443; NCT04975256; NCT04330664 |
| JNJ-74699157 | N/A | Advanced solid tumors (I) | N/A | NCT04006301 |
| LY3499446 | N/A | Advanced solid tumors (I/II) | Abemaciclib, cetuximab, erlotinib, docetaxel | NCT04165031 |
| GDC 6036 | N/A | Advanced/metastatic solid tumors (I) | Atezolizumab, cetuximab, bevacizumab, erlotinib, GDC-1971, inavolisib | NCT04449874 |
| D-1553 | N/A | Advanced/metastatic solid tumors (I/II); NSCLC (I/II) | N/A; N/A | NCT04585035; NCT05383898 |
| G12D | ||||
| MRTX1133 | N/A | Pancreatic, lung, and colorectal cancers (I/II) | N/A | Enters phase I in 2023 |
| Tricomplex inhibitors | ||||
| RMC-6236 | N/A | Advanced solid tumors (I) | N/A | NCT05379985 |
| RMC-6291 | N/A | Advanced solid tumors (I) | N/A | NCT05462717 |
| RAF inhibitors | ||||
| Sorafenib (BAY43-9006, NEXAVAR) | Unresectable HCC; advanced RCC; thyroid cancer | PC that cannot be removed by surgery (II); unresectable PC (I); metastatic PC (II) | Erlotinib; gemcitabine, sorafenib and radiotherapy; alone or with gemcitabine | NCT00837876; NCT00375310; NCT00114244 |
| Vemurafenib (PLX4032, RG7204, RO5185426, ZELBORAF) | BRAF V600E melanoma, ECD | PC (II) | Sorafenib | NCT05068752 |
| Dabrafenib (GSK2118436, TAFINLAR) | (+ Trametinib) BRAF V600E or V600K melanoma, NSCLC, anaplastic thyroid cancer, solid tumors | Colorectal cancer (II); advanced/metastatic BRAF V600 colorectal cancer (I) | Trametinib + PDR001; trametinib, LTT462, LXH254, TNO155, spartalizumab, tislelizumab | NCT03668431; NCT04294160 |
| Encorafenib (BRAFTOVI) | BRAF V600E metastatic colorectal cancer | Localized colon or upper rectum cancer with BRAF V600E mutation (II) | Cetuximab | NCT05706779 |
| Regorafenib (BAY 73-4506, STIVARGA) | Metastatic colorectal cancer; advanced GIST | Solid tumors (II) | Nivolumab | NCT04704154 |
| Lifirafeni (BGB-283) | N/A | Advanced or refractory solid tumors (I/II) | Mirdametinib | NCT03905148 |
| Paradox breakers | ||||
| PLX7904/ PLX8394 (PB04) | N/A | Advanced cancers (I/IIa) | N/A | NCT02012231 |
| Pan-RAF inhibitors | ||||
| LY3009120 | N/A | Advanced cancer (I) | N/A | NCT02014116 |
| MLN2480 (BIIB-024, TAK580, Tovorafenib) | N/A | Relapsed or refractory solid tumors followed by a dose expansion in participants with metastatic melanoma (I); advanced non-hematologic malignancies (I) | N/A; MLN0128 or alisertib, or paclitaxel, or cetuximab, or irinotecan | NCT01425008; NCT02327169 |
| HM95573 (Belvarafenib) | N/A | Locally advanced or metastatic solid tumors (I) | Cobimetinib or cetuximab | NCT03284502 |
| BMS-908662 (XL281) | N/A | Advanced or metastatic colorectal cancer (I/II); advanced solid tumors (I) | Alone or with cetuximab; N/A | NCT01086267; NCT00451880 |
| MEK inhibitors | ||||
| Trametinib (GSK1120212, JTP-74057) | (+Dabrafenib) BRAF V600E or V600K melanoma, NSCLC, anaplastic thyroid cancer, solid tumors | Cancers with BRAF V600E mutations (II); solid tumors (I); PC (II); metastatic PC (II); biliary tract cancer (II) | Dabrafenib; gemcitabine; SBRT + pembrolizumab; gemcitabine; N/A | NCT04439292; NCT01428427; NCT02704156; NCT01231581; NCT01943864 |
| Cobimetinib (XL-518, GDC-0973, RG7421, Cotellic) | Histiocytic neoplasms, melanoma | PC (I); locally advanced or metastatic PC (I) | N/A; calaspargase Pegol-mknl | NCT04005690; NCT05034627 |
| Selumetinib (AZD6244, ARRY-142886, Koselugo) | Pediatric neurofibromatosis type 1 | Advanced or metastatic PC who have failed first line gemcitabine (II); locally advanced or metastatic pancreatic cancer with KRAS G12R mutations (II); metastatic pancreatic cancer previously treated with chemotherapy (II); locally advanced or metastatic PC (II) | N/A; N/A; MK2206 (Akt inhibitor) or mFOLFOX; erlotinib hydrochloride | NCT00372944; NCT03040986; NCT01658943; NCT01222689 |
| Binimetinib (ARRY-438162, ARRY-162, MEK162, MektoviI) | Unresectable or metastatic melanoma with a BRAF V600E mutation | Advanced BRAF mutant cancers (I/II); PC with somatic BRAF V600E mutation (II); advanced solid tumors harboring RAS or BRAFV60330E mutations (I) | Encorafenib; Encorafenib; RAF 265 | NCT03843775; NCT04390243; NCT01352273 |
| Pimasertib (AS703026, SAR24550, EMD1036239, MSC1936369B) | N/A | PC (I/II) | Gemcitabine | NCT01016483 |
| Refametinib (RDEA119, BAY86-9766) | N/A | Advanced or metastatic cancer (I); RAS-mutant hepatocellular carcinoma (II); advanced cancer (Ib) | Regorafenib; N/A; copanlisib | NCT02168777; NCT01915589; NCT01392521 |
| E6201 (ER 806201) | N/A | BRAF V600 mutated metastatic melanoma (I); advanced solid tumors (I) | Dabrafenib; N/A | NCT05388877; NCT00794781 |
| PD-0325901 (Mirdametinib) | N/A | Advanced cancer (I) | PF-05212384 or Irinotecan | NCT01347866 |
| AZD8330 (ARRY-424704, ARRY-704) | N/A | Advanced malignancies (I) | N/A | NCT00454090 |
| GDC-0623 (RG7420, G-868) | N/A | Locally advanced or metastatic solid tumors (I) | N/A | NCT01106599 |
| RO4987655 (CH4987655, RG7167) | N/A | Advanced solid tumors (I) | N/A | NCT00817518 |
| RO5126766 (CH5126766, RG7304) | N/A | Advanced solid tumors (I) | N/A | NCT00773526 |
| TAK733 | N/A | Advanced nonhematologic malignancies (I) | N/A | NCT00948467 |
| ERK inhibitors | ||||
| Ulixertinib (BVD-523) | N/A | Advanced pancreatic and other solid tumors (I); metastatic PC (I); advanced MAPK pathway-altered malignancies | Palbociclib; Nab-paclitaxel and gemcitabine; N/A | NCT03454035; NCT02608229; NCT04566393 |
| GDC-0994 (RG7842) | N/A | Locally advanced or metastatic solid tumors (I) | N/A | NCT01875705 |
| MK-8353 (SCH900353) | N/A | Advanced/metastatic solid tumors (I); advanced malignancies (I) | Selumetinib; pembrolizumab | NCT03745989; NCT02972034 |
| JSI-1187 | N/A | Advanced solid tumors with MAPK pathway mutations (I) | Alone or with dabrafenib | NCT04418167 |
| ERAS-007 | N/A | Advanced or metastatic solid tumors (I/II); advanced gastrointestinal malignancies (I/II) | ERAS-601; encorafenib, cetuximab, palbociclib | NCT04866134; NCT05039177 |
| Menin inhibitor | ||||
| BMF-219 | N/A | NSCLC, pancreatic, colorectal cancers (I) | N/A | NCT05631574 |
1
FDA: Food and Drug Administration; SOS: Son of Sevenless; KRAS: Kirsten rat sarcoma virus; HCC: Hepatocellular carcinoma; RCC: Renal cell carcinoma; ECD: Erdheim-Chester disease; GIST: Gastrointestinal stroma tumors; PC: Pancreatic cancer; RAF: Rapidly accelerated fibrosarcoma; RAS: Rat sarcoma viral oncogene family; MAPK: Mitogen-activated protein kinases; NSCLC: Non-small-cell lung carcinoma; SHP2: Src homology-2 domain-containing protein tyrosine phosphatase-2; NCT: National clinical trial; MEK: Mitogen-activated protein kinase/extracellular regulated protein kinases; N/A: Not applicable.