Table 1.
Summary of currently available data on combining KRAS G12C inhibitors with targeted therapies.
| Target | Combination and NCT number | Phase | Population* | N | Toxicity data | Efficacy data | Reference |
|---|---|---|---|---|---|---|---|
| RTK | Cetuximab + adagrasib NCT03785249 (KRYSTAL-1) |
1/2 | Pretreated metastatic CRC with no prior KRAS G12C treatment | 32 | Common TRAE: nausea, diarrhea, vomiting G3-4 TRAE: 16% TRAE to d/c regimen: 0% for adagrasib, 16% for cetuximab |
RR: 46% mPFS: 6.9m |
(20) |
| Cetuximab + divarasib NCT04449874 |
1b | Advanced or metastatic CRC (does not specify prior KRAS inhibition) | 29 | Common TRAE: rash, diarrhea, nausea G3-4 TRAE: 45% TRAE to d/c regimen: 0% for divarasib, 3.4% for cetuximab (rash) |
Previous G12C inhibition (N = 5) RR: 60% G12C inhibition naïve (N = 24) RR: 62.5% mPFS: 8.1m |
(27) | |
| Cetuximab + D1553 NCT04585035 |
2 | Metastatic CRC with no prior KRAS G12C treatment | 40 | Common TRAE: rash, increased AST/ALT, paronychia G3-4 TRAE: 12.5% TRAE to d/c regimen: 2.5% (cetuximab related) |
RR: 45.0% (not all confirmed) mPFS: 7.6m |
(28) | |
| Panitumumab + sotorasib NCT05198934 (CodeBreaK 300) |
3 | Pretreated metastatic CRC | 106 | 960 mg sotorasib cohort (N = 53) Common TRAE: hypomagnesemia, rash, dermatitis acneiform G3-4 TRAE: 35.8% TRAE to d/c regimen: 3.8% 240 mg sotorasib cohort (N = 53) Common TRAE: hypomagnesemia, rash, dermatitis acneiform G3-4 TRAE: 30.2% TRAE to d/c regimen: 1.9% |
960 mg sotorasib cohort (N = 53) RR: 26.4% mPFS: 5.6m 240 mg sotorasib cohort (N = 53) RR: 5.7% mPFS: 3.9m |
(29) | |
| Panitumumab + sotorasib NCT04185883 (CodeBreaK 101) |
1b | Pretreated metastatic CRC | 48 | G3-4 TRAE: 27% (most commonly dermatologic) TRAE to d/c regimen: 0% |
In the dose expansion cohort (N = 40) RR: 30% mPFS:5.7m mOS: 15.2m |
(30) | |
| Panitumumab + FOLFIRI + sotorasib NCT04185883 (CodeBreaK 101) |
1b | Pretreated metastatic CRC | 46 | Common TRAE: dermatitis acneiform, dry skin, nausea, and stomatitis G3-4 TRAE: 43% (most commonly dermatologic) TRAE to d/c regimen: 2% for sotorasib (ALT increased), 4% for panitumumab and 24% for FOLFIRI |
RR: 55% | (31) | |
| Afatinib + sotorasib NCT04185883 (CodeBreaK 101) |
1b | Pretreated advanced NSCLC | 33 | Common TRAE: diarrhea, nausea, vomiting G3-4 TRAE: 30% (most commonly diarrhea) TRAE to d/c regimen: 24% (most commonly diarrhea) |
Cohort 1 (N = 10)† RR: 0% (Previous G12C inhibition, N = 4) RR: 33% (G12C inhibition naïve, N = 6) Cohort 2 (N = 23)† RR: 34.8% |
(32) | |
| SHP2 | TNO155 + JDQ443 NCT04699188 (KontRASt-01) |
1b | Pretreated advanced solid tumor | 50‡ | Common TRAE: peripheral edema, neutropenia, thrombocytopenia G3-4 TRAE: 36% (most commonly neutropenia) TRAE to d/c regimen: unavailable |
Previous G12C inhibition RR (NSCLC, N = 12): 33% G12C inhibition naïve RR (NSCLC, N = 12): 33% |
(33) |
| RMC4630 + sotorasib NCT04185883 (CodeBreaK 101) |
1b | Pretreated advanced solid tumor | 27§ | Common TRAE: edema, diarrhea, fatigue, dry mouth G3-4 TRAE: 22% (most commonly diarrhea) TRAE to d/c regimen: 11% (diarrhea, ascites, and AST increased) |
Previous G12C inhibition RR (NSCLC, N = 5): 0% G12C inhibition naïve RR (NSCLC, N = 6): 50% One patient with ovarian cancer had PR |
(34) | |
| MEK | Trametinib + sotorasib NCT04185883 (CodeBreaK 101) |
1b | Pretreated advanced solid tumor | 41# | Common TRAE: diarrhea, rash, nausea G3-4 TRAE: 34.1% TRAE to d/c sotorasib: 4.9% |
Previous G12C inhibition RR (CRC, N = 6): 16.7% RR (NSCLC, N = 3): 0% G12C inhibition naïve RR (CRC, N = 12): 8.3% RR (NSCLC, N = 15): 20% |
(35) |
| Avutometinib + sotorasib NCT05074810 (RAMP203) |
1b/2 | Pretreated advanced NSCLC | 15 | Common TRAEs: nausea, AST increase, diarrhea, fatigue, and pruritus G3-4 TRAE: ALP increase (20%), diarrhea (13%), pruritus (13%) The majority of TRAEs were grades 1–2 |
Previous G12C inhibition (N = 7) RR: 14.3% G12C inhibition naïve (N = 5) RR: 40% |
(36) |
ALP, alkaline phosphatase; AST, aspartate aminotransferase; CRC, colorectal cancer; d/c, discontinue; G3-4, grades 3 to 4; mPFS, median progression-free survival (months); N, number of participants; NSCLC, non-small cell lung cancer; PR, partial response; RR, response rate; RTK, receptor tyrosine kinase; SD, stable disease; TRAE, treatment-related adverse event.
*All participants should have KRAS G12C mutation.
†In cohort 1, 10 patients were given afatinib 20 mg and sotorasib 960 mg. In cohort 2, 23 patients were given afatinib 30 mg and sotorasib 960 mg.
‡24 patients with NSCLC, 19 patients with CRC, 3 patients with pancreatic cancer, 2 patients with biliary tract cancer, 1 patient with duodenal cancer, and 1 patient with ovarian cancer.
§11 patients with NSCLC, 9 with CRC, and 7 with other solid tumors.
#18 patients with NSCLC, 18 with CRC, and 5 with other solid tumors.