Targeting KRAS in pancreatic adenocarcinoma: Progress in demystifying the holy grail

doi:10.5306/wjco.v14.i8.285

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World J Clin Oncol. Aug 24, 2023; 14(8): 285-296
Published online Aug 24, 2023. doi: 10.5306/wjco.v14.i8.285

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
Agent	FDA approved¹	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

¹www.fda.gov.

²clinicaltrials.gov.

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.

Table 2 Phosphoinositide 3-kinase-protein kinase-mammalian target of rapamycin-pathway inhibitors

Agent	Combination	Phase	NCT number¹
PI3K inhibitors (p110α) isoform
Alpelisib (BYL719)	Gemcitabine and abraxane	I	NCT02155088
Buparlisib (BKM120)	mFOLFOX6; trametinib (MEKi)	I; I	NCT01571024; NCT01155453
Pan-PI3K inhibitors
Copanlisib(BAY 80–6946)	N/A	I	NCT00962611
PI3K and mTOR inhibitors
Voxtalisib (SAR245409, XL765)	N/A	I	NCT00485719
Dactolisib(NVP-BEZ235)	MEK162 (MEKi)	I	NCT01337765
Gedatolisib (PF-05212384, PKI-587)	Palbociclib (CDKi)	I	NCT03065062
Pan-Akt inhibitors
MK2206	Monotherapy; dinaciclib (CDKi); selumitinib (MEKi) vs mFOLFOX6	I; I; II	NCT00848718; NCT01783171; NCT01658943
Afuresertib (GSK2110183)	Trametinib (MEKi); N/A	I; II	NCT01476137; NCT01531894
Uprosertib (GSK2141795)	Trametinib (MEKi)	I	NCT01138085
Oleandrin (PBI-05204)	N/A	II	NCT02329717
Perifosine	N/A	II; II	NCT00053924; NCT00059982
RX-0201	Gemcitabine	II	NCT01028495
Rapalogs (mTORC1 inhibitors)
Sirolimus (rapamycin)	Sunitinib (RTKi); N/A; metformin; vismodegib (SMOi)	I; II; I/II; I	NCT00583063; NCT00499486; NCT02048384; NCT01537107
Temsirolimus (CCI-779, Torisel)	Lenalidomide; gemcitabine; nivolumab (PD-1i)	I; I; I/II	NCT01183663; NCT00593008; NCT02423954
Everolimus (RAD001)	Sorafenib (RTKi); trametinib (MEKi); gemcitabine; cetuximab (EGFRi) and capecitabine; N/A	I; I; I/II; I/II; II	NCT00981162; NCT00955773; NCT00560963; NCT01077986; NCT00409292
Ridafirolimus	Bevacizumab (VEGFRi)	I	NCT00781846
mTORC1/2 inhibitors
Vistusertib (AZD2014)	N/A; selumitinib (MEKi); olaparib (PARPi)	I; II; II	NCT01026402; NCT02583542; NCT02576444

¹clinicaltrials.gov

PI3K: Phosphoinositide 3-kinase; NCT: National clinical trial; MEKi: Mitogen-activated protein kinase/ extracellular regulated protein kinases inhibitor; CDKi: Cyclin-dependent kinase inhibitor; RTKi: Receptor tyrosine kinase inhibitor; SMOi: Smoothened inhibitor; PD-1i: Programmed cell death receptor-1 inhibitor; EGFRi: Epidermal growth factor receptor inhibitor; VEGFRi: Vascular endothelial growth factor receptor inhibitor; mTOR: mammalian target of rapamycin; PARPi: Poly (ADP-ribose) polymerase inhibitor; N/A: Not applicable.

Citation: Elhariri A, Alhaj A, Ahn D, Sonbol MB, Bekaii-Saab T, Wu C, Rutenberg MS, Stauffer J, Starr J, Majeed U, Jones J, Borad M, Babiker H. Targeting KRAS in pancreatic adenocarcinoma: Progress in demystifying the holy grail. World J Clin Oncol 2023; 14(8): 285-296
URL: https://www.wjgnet.com/2218-4333/full/v14/i8/285.htm
DOI: https://dx.doi.org/10.5306/wjco.v14.i8.285