Introduction to KRAS and G12C mutation in NSCLC
Direct KRASG12C Inhibitors for the treatment of NSCLC
Early inhibition efforts
ARS-853
ARS-1620
FDA approved inhibitors for treatment in advanced/metastatic NSCLC
AMG-510 (sotorasib/LUMAKRAS)
MRTX849 (adagrasib/KRAZATI)
Agent | AMG-510 (sotorasib) | MRTX849 (adagrasib) |
---|---|---|
Company | Amgen | Mirati therapeutics Inc |
FDA approval date | May 18, 2021 | December 12, 2022 |
Type of inhibitor | Irreversible covalent inhibitor of KRASG12C | Irreversible covalent inhibitor of KRASG12C |
Mechanism of inhibition | Forms water bridges between the tyrosine residue found in the KRASG12C protein and the carboxyl group in sotorasib | Uses hydrogen mediated bonding of the hydroxyl group on the KRASG12C pocket with adagrasib’s pyrimidine ring |
Number of NSCLC patients in phase I/II trial | N = 124 (NCT03600883) | N = 116 (NCT03785249) |
Prior platinum-based chemotherapy and immunotherapy | Platinum based chemotherapy only: 11 (8.7%) Both therapies: 102 (81.0%) | Platinum based chemotherapy only: 2 (1.7%) Both therapies: 114 (98.3%) |
Recommended starting dose based on phase I/II trial data | 960 mg once daily | 600 mg twice daily |
Half-life | 5.5 h | 24.0 h |
Cmax of steady state (µg/ml) | 7.5 | 3.25 |
Objective response rate (ORR) | 37.1% | 42.9% |
Disease control rate (DCR) | 80.6% | 96% |
Progression-free survival (PFS) | 6.8 months (5.6 months in phase III) | 6.5 months |
Overall survival rate | 12.5 months (10.6 months in phase III) | 12.6 months |
TRAEs occurring in > 5% of patients, all grades | Gastrointestinal toxicities, nausea, vomiting, elevated alanine transaminase (ALT) and aspartate aminotransferase (AST) | Gastrointestinal toxicities including nausea, vomiting, diarrhea; fatigue, increased AST and ALT, EKG QTc prolongation |
Grade 3+ TRAEs in phase II trial | 20.6% | 45% |
TRAEs leading to discontinuation | 7.1% | 6.9% |
Preclinical data indicating ability to penetrate the brain and cerebrospinal fluid | n/a | Presence of adagrasib detected in brain and cerebrospinal fluid |
Other inhibitors entering clinical trial
LY3537982
GDC-6036 (divarasib)
Agent | Pharmaceutical Company | Clinical Trial (CT) | ORR of CT | DCR of CT | TRAEs |
---|---|---|---|---|---|
LY3537982 | Eli Lilly and Company | Phase I (NCT04956640) | 60% | 80% | Diarrhea, constipation, fatigue, peripheral edema, nausea, neutropenia |
GDC-6036 | Genentech | Phase I (NCT04449874) | 53.4% | – | Rash, diarrhea, nausea, vomiting, dry skin, and paronychia |
D-1553 | InvestisBio | Phase I/II (NCT04585035) | 40.5% | 91.9% | Elevated AST/ALT increased, diarrhea, hypertension, hypokalemia, increased total or conjugated bilirubin, hypothyroidism, and nausea |
HBI-2438 | Huyabio International | Phase I (NCT05485974) | – | – | – |
JDQ443 | Novartis | Phase Ib/II (NCT04699188) | 41.7% 54.5% (RP2D of 200 mg BID) | – | Fatigue, edema, diarrhea, nausea, vomiting, and peripheral neuropathy |
JAB-21822 | Jacobio Pharma | Phase I/II (NCT05009329) | 70% (400 & 800 mg QD groups) | 100% (400 & 800 mg QD groups) | Anemia, total bilirubin increase, and proteinuria |
HS-10370 | Jiangsu Hansoh Pharmaceutical company | Phase I/II (NCT05367778) | – | – | – |
IBI-351 (GFH925) | Innovent Biologics Inc | Phase I/II (NCT05005234) | 61.2% 53.3% (RP2D of 600 mg BID) | 92.5% 96.7% (RP2D of 600 mg BID) | Anemia, white blood cell count decreased, ALT increases, and pruritus |
BI-1823911 | Boehringer Ingelheim | Phase I (NCT04973163) | – | – | – |
JNJ-74699157 | Johnson & Johnson | Phase I (NCT04006301) | – | – | Increased blood creatinine phosphokinase (grade 3–4) |
D-1553 (garsorasib)
HBI-2438
JDQ443 (opnurasib)
JAB-21822
HS-10370
IBI-351 (GFH925)
BI-1823911
JNJ-74699157
Resistance mechanisms to direct inhibitors of KRASG12C
Primary resistance to KRAS G12C inhibitors
Acquired resistance to KRAS G12C inhibitors
Approaches to target resistance
Novel inhibitors to counteract the resistance to KRAS G12C (OFF)-inhibitors
RM-018
RMC-6291
RMC-6236
BI-2852
BI-2493/BI-2865
Vertical pathway coupled inhibition
Parallel pathway coupled inhibition
Other combinational approaches
KRASG12C inhibitor | Identifier | Phase | Objective | Current Status |
---|---|---|---|---|
AMG-510 Sotorasib (LUMAKRAS) | NCT03600883 (CodeBreaK 100) | 1/2 | Estimate maximum tolerated dose (MTD) and/or recommended dose for phase 2 regimen (RP2D) followed by safety and tolerability of sotorasib in combination with anti PD-1/L1 and midazolam (GABA-A receptor agonist) | Active, not recruiting |
NCT04185883 (CodeBreaK 101) | 1b/2 | Evaluate the safety and tolerability of sotorasib in monotherapy and in combination with AMG 404 (PD-1 inhibitor), trametinib (MEK inhibitor), RMC-4630 (SHP2 inhibitor), afatinib (EGFR inhibitor), pembrolizumab (PD-1 inhibitor), panitumumab (EGFR inhibitor), carboplatin/pemetrexed/docetaxel/paclitaxel (chemotherapy), atezolizumab (PD-L1 inhibitor), everolimus (mTORC1 inhibitor), palbociclib (CDK4/6 inhibitor), MVASI (VEGF inhibitor), TNO155 (SHP2 inhibitor), FOLFIRI (chemotherapy), FOLFOX (chemotherapy, and BI 1701963 (SOS1 inhibitor) | Recruiting | |
NCT04720976 | 1/2a | Assess the safety and tolerability and determine RP2D of JAB-3312 (SHP2 inhibitor) in combination with binimetinib (MEK inhibitor), pembrolizumab (PD-1 inhibitor), osimertinib (EGFR inhibitor), and sotorasib | Recruiting | |
NCT05480865 (Argonaut) | 1a/1b | Dose escalation/expansion and optimization of BBP-398 (SHP2 inhibitor) in combination with sotorasib | Recruiting | |
NCT05074810 (RAMP203) | 1/2 | Safety, tolerability, and efficacy of avutometinib (MEK inhibitor) in combination with sotorasib | Recruiting | |
NCT05118854 | 2 | Safety and tolerability of sotorasib in combination with chemotherapy (cisplatin/carboplatin) AND pemetrexed (chemotherapy) | Recruiting | |
NCT05180422 | 1/2 | Dose expansion followed by safety and tolerability of sotorasib in combination with MVASI (VEGF inhibitor) | Recruiting | |
NCT05374538 | 1a/1b | Dose escalation of VIC-1911 (AURKA inhibitor) as monotherapy or in combination with sotorasib | Recruiting | |
NCT05313009 | 1b/2 | Dose expansion followed by safety and efficacy of sotorasib in combination with tarloxotinib (EGFR inhibitor) | Recruiting | |
NCT05638295 | 2 | Testing the use of sotorasib as monotherapy or in combination with panitumumab (EGFR inhibitor) in patients with advanced/metastatic malignant solid KRASG12C mutant cancers | Not yet recruiting | |
NCT04892017 | 1/2 | Dose escalation/expansion of DCC-3116 (ULK1/2 inhibitor) as monotherapy and in combination with sotorasib and other RAS/MAPK inhibitors in patients with advanced or metastatic solid tumors harboring RAS/MAPK pathway mutations | Recruiting | |
MRTX849 Adagrasib (KRAZATI) | NCT03785249 (KRYSTAL-1) | 1/2 | Evaluate safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of adagrasib in monotherapy and in combination with pembrolizumab (PD-1 inhibitor), cetuximab (EGFR inhibitor) | Recruiting |
NCT04330664 (KRYSTAL-2) | 1/2 | Dose escalation and expansion followed by safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of adagrasib in combination with TNO155 (SHP2 inhibitor) | Active, not recruiting | |
NCT04418661 | 1/2 | Dose escalation/expansion followed by safety, tolerance, and efficacy of SAR442720 (SHP2 inhibitor) in combination with adagrasib and pembrolizumab (PD-1 inhibitor) | Active, not recruiting | |
NCT04613596 (KRYSTAL-7) | 2 | Efficacy and safety of adagrasib monotherapy and in combination with pembrolizumab (PD-1 inhibitor) | Recruiting | |
3 | Compares efficacy of adagrasib and pembrolizumab against pembrolizumab and chemotherapy (cisplatin OR carboplatin) | Recruiting | ||
NCT04975256 (KRYSTAL-14) | 1/1b | Safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of BI 1701963 (SOS1 pan-KRAS inhibitor) in combination with adagrasib | Completed | |
NCT05178888 (KRYSTAL-16) | 1/1b | Evaluate pharmacodynamics and preliminary clinical activity of adagrasib in combination with palbociclib (CDK4/6 inhibitor) | Active, not recruiting | |
NCT05375994 (RAMP204) | 1/2 | Safety, tolerability, and efficacy of avutometinib (MEK inhibitor) in combination with adagrasib | Recruiting | |
NCT05472623 (NeoKan) | 2 | Evaluate clinical safety, feasibility, and efficacy of adagrasib in monotherapy or in combination with nivolumab (PD-1 inhibitor) | Not yet recruiting | |
NCT05578092 | 1/2 | Evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity of MRTX0902 (SOS1 inhibitor) as monotherapy or adagrasib | Recruiting | |
NCT05609578 (KRYSTAL-17) | 2 | Clinical efficacy and safety of pembrolizumab (PD-1 inhibitor) in combination with adagrasib | Recruiting | |
GDC-6036 | NCT04449874 | 1a/1b | Dose escalation/expansion, safety, pharmacokinetics, and preliminary activity of GDC-6036 (KRASG12C inhibitor) in monotherapy and in combination with atezolizumab (PD-L1 inhibitor), cetuximab (EGFR inhibitor), bevacizumab (VEGF inhibitor), erlotinib (EGFR), GDC-1971 (SHP2 inhibitor, and inavolisib (PI3K inhibitor) | Recruiting |
D-1553 (garsorasib) | NCT04585035 | 1/2 | Identify the MTD/RP2D and evaluate the safety and tolerability of D-1553 (KRASG12C inhibitor) as monotherapy or in combination with other standard treatments of solid tumors, NSCLC, or colorectal cancer (CRC) | Recruiting |
NCT05492045 | 1b/2 | Dose escalation followed by safety, tolerability, pharmacokinetics, and efficacy of D-1553 (KRASG12C inhibitor) in combination with other targeted therapies or immunotherapy | Not yet recruiting | |
JDQ443 | NCT04699188 (KontRASt-01) | 1b/2 | Dose escalation/expansion assessing safety, anti-tumor activity, tolerability, pharmacokinetics, and pharmacodynamics of JDQ443 (KRASG12C inhibitor) in monotherapy or in combination with TNO155 (SHP2 inhibitor) and tislelizumab (PD-1 inhibitor) | Recruiting |
NCT05358249 (KontRASt-03) | 1b/2 | Dose escalation followed by safety, tolerability, and anti-tumor activity of backbone JDQ443 (KRASG12C inhibitor) in combination with trametinib (MEK inhibitor), ribociclib (CDK4/6 inhibitor, or cetuximab (EGFR inhibitor) | Recruiting | |
LYS3537982 | NCT04956640 | 1a/1b | Evaluate safety, tolerability, and preliminary efficacy of LY3537982 (KRASG12C inhibitor) in combination with abemaciclib (CDK4/6 inhibitor), erlotinib (EGFR (PD-1 inhibitor), temuterkib (ERK inhibitor), LY3295668 (AURKA inhibitor), cetuximab (EGFR inhibitor), and TNO155 (SHP2 inhibitor) | Recruiting |
BI 1823911 | NCT04973163 | 1a/1b | Dose escalation/expansion to investigate the safety, pharmacokinetics and preliminary efficacy of BI 1823911 (KRASG12C inhibitor) in monotherapy or in combination with BI 1701963 (SOS1 inhibitor) and midazolam (GABA-A receptor agonist) | Recruiting |
JAB-21822 | NCT05002270 | 1/2 | Dose escalation/expansion followed by safety and tolerability of JAB-21822 (KRASG12C inhibitor) as monotherapy or in combination with cetuximab (EGFR inhibitor) | Recruiting |
NCT05288205 | 1/2a | Dose escalation/expansion evaluating efficacy and safety of JAB-21822 (KRASG12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) | Recruiting | |
IBI351 | NCT05504278 | 1b/2 | Evaluate efficacy and safety of IBI351 (KRASG12C inhibitor) in combination with sintilimab (PD-1 inhibitor), chemotherapy (pemetrexed and/or cisplatin/carboplatin), and cetuximab (EGFR inhibitor) | Not yet recruiting |
Combinational pathway | Target | Combinations discussed (Ex./KRAS G12Ci) | Results |
---|---|---|---|
Vertical (upstream) | EGFR | Cetuximab or erlotinib/LY3537982 | Improved tumor regression in H358 xenografts compared to cetuximab monotherapy Clinical Trial: NCT04956640 |
Erlotinib/sotorasib | Strong synergy in H358 xenografts marked by score > 10 (12.4) | ||
HER | Afatinib/sotorasib | Strong synergy in H358 xenografts marked by score > 10 (21.3) Clinical Trial: NCT04185883 | |
SHP2 | RMC-4550/sotorasib | Strong synergy in H358 xenografts marked by score > 10 (22.8) | |
RMC-4550/D-1553 | Reduced tumor volume in H358 xenografts compared to either drug individually after 24 days of study | ||
TNO155/JDQ443 | Greater tumor efficacy when used together in NCI-H2030 CDX models Clinical Trial: NCT04699188 | ||
SOS1 | BAY-293/ARS-853 | Synergy identified with combination index significantly below 0.8 (according to median-effect model of Chou-Talalay) demonstrating parallel inhibition | |
BI-1701963/adagrasib | KRYSTAL-14: terminated due to toxicity concerns Clinical Trial: NCT04975256 | ||
BI-1701963/BI-1823911 | Tumor regression in 9/9 H2122 NSCLC cell models Clinical Trial: NCT04973163 | ||
(Downstream) | AURKA | LY3295668/ LY3537982 | Improved tumor regression in H358 xenografts compared to LY3295668 monotherapy Clinical Trial: NCT04956640 |
MEK/ERK | Trametinib/sotorasib | Strong synergy in H358 xenografts marked by score > 10 (14.7) CodeBreaK101 phase 1b results demonstrated a DCR of 83.3% in 18 KRASG12C mutant NSCLC patients (3 received prior G12C inhibitors) Clinical Trial: NCT04185883 | |
Trametinib/D-1553 | Reduced tumor volume in H358 xenografts compared to either drug individually after 24 days of study | ||
Parallel | PI3K | GDC0941/ARS-1620 | Well tolerated combination and reduced tumor growth compared to either therapy alone in patient-derived cell lines with G12C mutated lung cancer |
mTOR/IGF1R | Everolimus/linsitinib/ARS-1620 | Profound inhibition of cell viability using all 3 drugs in combination on H358 cells in both 2D and 3D conditions providing evidence of strong, durable reduction of tumor cell growth H358 xenografts were more sensitive to G12C direct inhibitor when combined with IGF1R and mTOR inhibition and achieved more durable regression whereas ARS-1620 monotherapy was ineffective as resistance developed | |
Chemotherapy | Carboplatin/sotorasib | Significant anti-tumor growth in combination compared to inhibited tumor growth in monotherapy Clinical Trials: NCT04185883 NCT05118854 | |
Carboplatin/D-1553 | Reduced tumor volume in H358 xenografts compared to either drug individually after 24 days of study Clinical Trial: NCT05492045 | ||
Immunotherapy | PD-1 & PD-L1 | Anti-PD-1 (unnamed)/sotorasib | 112 days of tumor regression in 9/10 mice compared to 1/10 in anit-PD-1 monotherapy |
Pembrolizumab/adagrasib | KRYSTAL-7: ORR = 49% and 9% increase in grade 3+ liver TRAEs Clinical Trials: NCT04613596 NCT03785249 NCT04418661 NCT05609578 | ||
Atezolizumab or pembrolizumab/sotorasib | CodeBreaK 100/101: liver toxicity noted as most common TRAE (49%) Clinical Trials: NCT03600883 NCT04185883 | ||
CDK4/6 | Abemaciclib/LY3537982 | Improved tumor regression in H358 xenografts compared to abemaciclib monotherapy Clinical Trial: NCT04956640 | |
Palbociclib/adagrasib | Near-complete inhibition in H2122 and SW1573 cells when used in combination compared to concentration-dependent partial inhibition with adagrasib alone Clinical Trial: NCT05178888 | ||
Autophagy | ULK1/2 | DCC-3116/sotorasib | Improved tumor inhibition compared to sotorasib monotherapy in KRASG12C NSCLC preclinical models Clinical Trial: NCT04892017 |