Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver
Abstract
1. Introduction
2. The RAS Pathway and Downstream Signaling
3. Development of KRAS G12C Inhibitors
3.1. KRAS Inhibitors in Monotherapy
3.1.1. Sotorasib
3.1.2. Adagrasib
3.1.3. Divarasib
3.1.4. Other Inhibitors
3.2. A Step Forward in Boosting Antitumor Activity: Combining KRAS G12C Inhibitors with Anti-EGFR
3.2.1. Adagrasib Cetuximab
3.2.2. Sotorasib Panitumumab
3.2.3. Divarasib Cetuximab
3.3. Ongoing Clinical Trials and New KRAS G12C Inhibitors in Colorectal Cancer
4. Mechanisms of Resistance
4.1. EGFR-Mediated Adaptive Feedback Reactivation of the RAS-MAPK Pathway
4.2. Acquired Genomic Events
4.3. KRAS Switch-II Pocket Mutations
4.4. Histological Switch
5. Discussion
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Clinical Trials Targeting KRAS G12C in mCRC, Completed or with Already Published Data | ||||
---|---|---|---|---|
Study Name/ID | Population (n. of Patients) | Treatment Regimen (n. of Patients Treated) | Results | Grade 3 or Higher TRAEs |
Phase | ||||
CodeBreaK 100/NCT03600883 | advanced KRAS G12C mutant solid tumors (124, including 42 mCRC) | Sotorasib (AMG510) | limited to mCRC treated with any dose | 52.7%, in the overall population |
Phase I | ORR 7.1% (3/42) | |||
DCR 73.8% (31/42) | ||||
mPFS 4 mo | ||||
CodeBreaK 100 (CRC expansion cohort)/NCT03600883 | advanced KRAS G12C mutant mCRC (62) | Sotorasib (AMG510) 960 mg qd | ORR 9.7% (6/62) | 10% (6/62) |
DCR 82.3% (51/62) | ||||
Phase II | mPFS 4 mo | |||
KRYSTAL-1/NCT03785249 | advanced KRAS G12C mutant solid tumors (25, including 4 mCRC) | Adagrasib (MRTX849) | limited to evaluable mCRC treated with 600 mg bid | 36% (9/25) |
Phase I/Ib | ORR 50% (1/2) | |||
DOR 4.2 mo | ||||
KRYSTAL-1 (monotherapy arm)/NCT03785249 | advanced KRAS G12C mutant mCRC (44) | Adagrasib (MRTX849) 600 mg bid | ORR 19% (8/43) | 34% (15/43) |
Phase I/II | DCR 86% (37/43) | |||
mPFS 5.6 mo | ||||
NCT04449874 | advanced KRAS G12C mutant solid tumors (137, including 55 mCRC) | Divarasib (GDC-6036) | limited to mCRC population | 7% (4/55) |
Phase Ib | ORR 29.1% (20/55) | |||
mPFS 5.6 mo | ||||
limited to mCRC treated with 400 mg qd | ||||
ORR 35.9% (14/39) | ||||
mPFS 6.9 mo | ||||
pooled analysis of NCT05005234 and NCT05497336 | advanced KRAS G12C mutant solid tumors, including 45 mCRC | Fulzerasib (IBI531) | limited to mCRC patients treated with 600 mg bid | 20% (9/32) |
Phase I | ORR 43.8% (14/32) | |||
DCR 87.5% (28/32) | ||||
Clinical trials targeting EGFR-KRAS G12C in mCRC, completed or with already published data | ||||
CodeBreaK 101/NCT04185883 | advanced KRAS G12C mutant mCRC (48) | Sotorasib (AMG510) + panitumumab | limited to patients treated with 960 mg qd | 27% (13/48) |
Phase Ib | ORR 30% (12/40) | |||
DCR 92.5% (37/40) | ||||
mPFS 5.7 mo | ||||
CodeBreaK 101 (subprotocol H)/NCT04185883 | advanced KRAS G12C mCRC previously treated ≥1 prior treatment (33) | Sotorasib (AMG510) 960 mg qd + panitumumab + FOLFIRI (54) | ORR 58.1% | 45.5% (15/33) |
DCR 93.5% | ||||
Phase Ib | mPFS 5.7 mo | |||
CodeBreaK 300/NCT05198934 | advanced KRAS G12C mutant mCRC (160) | Sotorasib (AMG510) 960 qd mg + panitumumab (53) | ORR 26.4% DCR 71.7% | 35.8% (19/53) |
Phase III | mPFS 5.6 mo | |||
Sotorasib (AMG510) 240 qd mg + panitumumab (53) | ORR 5.7% DCR 67.9% | 30.2% (16/53) | ||
mPFS 3.9 | ||||
SOC (54) | ORR 0% DCR 46.3% | 43.1% (23/54) | ||
mPFS 2.2 mo | ||||
KRYSTAL-1 (combination arm)/NCT03785249 | advanced KRAS G12C mutant mCRC (32) | Adagrasib (MRTX849) 600 mg bid + cetuximab | ORR 46% (13/28) | 16% (5/32) |
Phase I/II | DCR 100% (28/28) | |||
mPFS 6.9 mo | ||||
mOS 13.4 mo | ||||
NCT04449874 (arm C) | advanced KRAS G12C mutant mCRC (29) | Divarasib (GDC-6036) at 400 mg qd (26) + cetuximab | limited to KRAS G12C inhibitor naive population | 37.9% (11/29) |
Phase Ib | ORR 62.5% (14/24) | |||
mPFS 8 mo | ||||
NCT04585035 | advanced KRAS G12C mutant solid tumors, including 29 mCRC | Garsorasib (D-1553) 600 mg bid (29) + cetuximab | ORR 51.7% (15/29) | 10.3% (3/29) |
Phase I/II | DCR 93.1% (27/29) | |||
mPFS 7.56 mo |
Study ID/Name | Treatment Regimen | Population |
---|---|---|
Phase | ||
Ongoing clinical trials evaluating well established anti-KRAS G12C in combination with other compounds | ||
NCT04975256/KRYSTAL 14 | Adagrasib (MRTX849) + BI 1701963 (inhibitor of KRAS and SOS1 interaction) | advanced KRAS G12C mutant solid tumors |
Phase I/Ib | ||
NCT05578092 | Adagrasib (MRTX849) + MRTX0902 (SOS1 inhibitor) | advanced solid tumors KRAS G12C mutant or harboring any mutations in MAPK pathway effectors |
Phase I/II | ||
NCT05178888/KRYSTAL-16 | Adagrasib (MRTX849) + palbociclib | advanced KRAS G12C mutant solid tumors |
Phase I/Ib | ||
NCT04330664/KRYSTAL-2 | Adagrasib (MRTX849) + TNO155 (SHP2 inhibitor) | advanced KRAS G12C mutant solid tumors |
Phase I/II | ||
NCT04793958/KRYSTAL-10 | Adagrasib (MRTX849) + cetuximab vs chemotherapy | advanced KRAS G12C mutant mCRC |
Phase III | ||
NCT05722327 | Adagrasib (MRTX849) + cetuximab and irinotecan | advanced KRAS G12C mutant mCRC |
Phase I | ||
NCT06024174 | Adagrasib (MRTX849) + BMS-986466 (SHP2 Inhibitor) +/− cetuximab | advanced KRAS G12C mutant NSCLC, PDCA, BTC and CRC |
Phase 1/2 | ||
NCT04418661 | Adagrasib (MRTX849) + RMC-4630 (SHP2 inhibitor) | advanced KRAS G12C mutant solid tumors |
Phase I | ||
NCT04892017 | DCC-3116 (ULK inhibitor) +/− trametinib, binimetinib, or sotorasib (AMG510) | advanced solid tumors harboring any mutation in RAS/MAPK pathway |
Phase I/II | ||
NCT05480865/Argonaut | Sotorasib (AMG510) + BBP-398 (SHP2 inhibitor) | advanced KRAS G12C mutant solid tumors |
Phase I | ||
NCT04929223/INTRINSIC | Divarasib (GDC-6036) + Cetuximab +/− FOLFOX or FOLFIRI (in KRAS G12C) | advanced mutant mCRC |
Phase I/Ib | ||
NCT05497336 | Fulzerasib (IBI351) + cetuximab (phase Ib) and versus SOC (phase III in mCRC) | advanced KRAS G12C mutant solid tumors (phase Ib) |
Phase Ib/III | pretreated KRAS G12C mutant mCRC (phase III) | |
NCT06166836 | Garsorasib (D-1553) + ifebemtinib (IN10018) (FAK inhibitor) | advanced KRAS G12C mutant solid tumors |
Phase Ib/II | ||
Ongoing clinical trials evaluating other anti-KRAS G12C inhibitors | ||
NCT04165031 | LY3499446 +/− several compounds, based on histology (cetuximab in mCRC) | advanced KRAS G12C mutant solid tumors |
Phase I/II | ||
NCT 04956640/LOXO-RAS-2000 | LY3537982 +/− several compounds, based on histology (cetuximab in mCRC) | advanced KRAS G12C mutant solid tumors |
Phase I/II | ||
NCT04699188/KontRASt-01 | Opnurasib (JDQ443) +/− TNO155 (SHP2 inhibitor) + tislelizumab | advanced KRAS G12C mutant solid tumors |
Phase Ib/II | ||
NCT05358249/KontRASt-03 | Opnurasib (JDQ443) + cetuximab (in mCRC) | advanced KRAS G12C mutant solid tumors |
Phase Ib/II | ||
NCT05002270 | Glecirasib (JAB-21822) | advanced KRAS G12C mutant solid tumors |
Phase I/II | ||
NCT05194995 | Glecirasib (JAB-21822) + cetuximab | advanced KRAS G12C CRC, small intestine cancer and appendiceal cancer |
Phase Ib/II | ||
NCT05288205 | Glecirasib (JAB-21822) + JAB-3312 (SHP2 inhibitor) | advanced KRAS G12C mutant solid tumors |
Phase I/IIa | ||
NCT04006301 | JNJ-74699157 | advanced KRAS G12C mutant solid tumors |
Phase I | ||
NCT05462717 | RMC-6291 | advanced KRAS G12C mutant solid tumors |
Phase I | ||
NCT06128551 | RMC-6291 + RMC-6236 (pan-RAS inhibitor) | advanced KRAS G12C mutant solid tumors |
Phase Ib | ||
NCT06117371 | BEBT-607 | advanced KRAS G12C mutant solid tumors |
Phase I/Ib | ||
NCT06006793 | SY-5933 | advanced KRAS G12C mutant solid tumors |
Phase I | ||
NCT06006793 | BPI-421286 | advanced KRAS G12C mutant solid tumors |
Phase I | ||
NCT04973163 | BI 1823911 | advanced KRAS G12C mutant solid tumors |
Phase Ia/Ib | ||
NCT05410145 | D3S-001 | advanced KRAS G12C mutant solid tumors |
Phase I | ||
NCT05768321 | GEC255 | advanced KRAS G12C mutant solid tumors |
Phase I | ||
NCT05485974 | HBI-2438 | advanced KRAS G12C mutant solid tumors |
Phase I |
Main Pharmacokinetics Characteristic of KRAS G12C Inhibitors | |||
---|---|---|---|
Name | Sotorasib (AMG510) | Adagrasib (MRTX849) | Divarasib (GDC-6036) |
Mechanism of action | covalent inhibitor of KRAS G12C | covalent inhibitor of KRAS G12C | covalent inhibitor of KRAS G12C |
Half-life (hours) | 5.5 ± 1.8 | 24 | 17.6 ± 2.7 |
Dose | 960 mg qd | 600 mg bid | 400 mg qd |
Median time to maximum concentration (hours) | 1 | 6 | 2 |
Other features | CNS penetration |
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Ros, J.; Vaghi, C.; Baraibar, I.; Saoudi González, N.; Rodríguez-Castells, M.; García, A.; Alcaraz, A.; Salva, F.; Tabernero, J.; Elez, E. Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver. Int. J. Mol. Sci. 2024, 25, 3304. https://doi.org/10.3390/ijms25063304
Ros J, Vaghi C, Baraibar I, Saoudi González N, Rodríguez-Castells M, García A, Alcaraz A, Salva F, Tabernero J, Elez E. Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver. International Journal of Molecular Sciences. 2024; 25(6):3304. https://doi.org/10.3390/ijms25063304
Chicago/Turabian StyleRos, Javier, Caterina Vaghi, Iosune Baraibar, Nadia Saoudi González, Marta Rodríguez-Castells, Ariadna García, Adriana Alcaraz, Francesc Salva, Josep Tabernero, and Elena Elez. 2024. "Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver" International Journal of Molecular Sciences 25, no. 6: 3304. https://doi.org/10.3390/ijms25063304
APA StyleRos, J., Vaghi, C., Baraibar, I., Saoudi González, N., Rodríguez-Castells, M., García, A., Alcaraz, A., Salva, F., Tabernero, J., & Elez, E. (2024). Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver. International Journal of Molecular Sciences, 25(6), 3304. https://doi.org/10.3390/ijms25063304