Kras G12c Covalent Inhibitor Clinical Trial List

KRAS G12C covalent inhibitors are a novel class of targeted therapies designed to selectively and irreversibly bind to the KRAS G12C mutant protein, a common oncogenic driver in various cancers. These inhibitors have shown promising clinical activity and are revolutionizing the treatment landscape for patients with KRAS G12C-mutated tumors.

Introduction to KRAS G12C Covalent Inhibitors

The KRAS gene encodes a small GTPase protein involved in cell signaling pathways that regulate cell growth, differentiation, and survival. Mutations in KRAS are among the most frequent oncogenic drivers, with the G12C mutation being particularly prevalent in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors. KRAS G12C covalent inhibitors specifically target the cysteine residue at position 12 in the KRAS protein, leading to inactivation of the mutant protein and subsequent anti-tumor effects.

Mechanism of Action

KRAS G12C covalent inhibitors work by forming a strong, irreversible bond with the cysteine residue at the G12C position. This covalent bond disrupts the interaction of KRAS with downstream signaling molecules, such as RAF and MEK, thereby inhibiting the MAPK pathway. By selectively targeting the mutant KRAS protein, these inhibitors spare normal cells and minimize off-target effects, leading to improved therapeutic outcomes.

Clinical Trial Landscape

Several KRAS G12C covalent inhibitors have entered clinical development, demonstrating significant anti-tumor activity and manageable safety profiles. This article provides an overview of prominent KRAS G12C covalent inhibitors and a comprehensive list of clinical trials evaluating their efficacy and safety in various cancer types.

Key KRAS G12C Covalent Inhibitors in Clinical Development

Sotorasib (AMG 510)
Adagrasib (MRTX849)
LY3497366
JDQ-443

Sotorasib (AMG 510)

Overview: Sotorasib, developed by Amgen, was the first KRAS G12C inhibitor to receive regulatory approval. It has shown significant clinical benefit in patients with advanced NSCLC harboring the KRAS G12C mutation.
Clinical Trials:
- CodeBreaK 100 (NCT03600883): A Phase 1/2 open-label study evaluating sotorasib in patients with advanced solid tumors, including NSCLC, CRC, and other cancers. The NSCLC cohort demonstrated promising objective response rates (ORR) and progression-free survival (PFS), leading to accelerated approval by the FDA.
- CodeBreaK 200 (NCT04303780): A Phase 3 randomized controlled trial comparing sotorasib to docetaxel in previously treated NSCLC patients with the KRAS G12C mutation. This trial aims to confirm the clinical benefit observed in earlier studies and establish sotorasib as a standard of care.
- CodeBreaK 101 (NCT04185883): A Phase 1b study evaluating sotorasib in combination with other anti-cancer therapies, such as chemotherapy, immunotherapy, and other targeted agents, to assess synergistic effects and improve patient outcomes.
- NCT04933695: A Phase 2 trial evaluating sotorasib in patients with KRAS G12C-mutated CRC.
- NCT04625647: A Phase 1/2 study evaluating sotorasib in combination with pembrolizumab in patients with KRAS G12C-mutated NSCLC.

Adagrasib (MRTX849)

Overview: Adagrasib, developed by Mirati Therapeutics, is another potent and selective KRAS G12C inhibitor. It has demonstrated encouraging clinical activity in NSCLC, CRC, and other solid tumors, with a longer half-life and potentially improved central nervous system penetration compared to sotorasib.
Clinical Trials:
- KRYSTAL-1 (NCT03785249): A Phase 1/2 open-label study evaluating adagrasib in patients with advanced solid tumors harboring the KRAS G12C mutation. The NSCLC and CRC cohorts have shown promising ORR and PFS.
- KRYSTAL-7 (NCT04613596): A Phase 2 trial evaluating adagrasib in combination with pembrolizumab in patients with treatment-naïve KRAS G12C-mutated NSCLC.
- KRYSTAL-10 (NCT04793958): A Phase 3 randomized controlled trial comparing adagrasib to chemotherapy in previously treated CRC patients with the KRAS G12C mutation.
- KRYSTAL-12 (NCT05536488): A Phase 1b study evaluating adagrasib in combination with other targeted therapies, such as EGFR inhibitors, in patients with KRAS G12C-mutated NSCLC.
- NCT04909857: A Phase 2 trial evaluating adagrasib in patients with KRAS G12C-mutated solid tumors, including pancreatic cancer and biliary tract cancer.

LY3497366

Overview: LY3497366, developed by Eli Lilly, is an investigational KRAS G12C inhibitor currently being evaluated in clinical trials. Early data suggest promising anti-tumor activity and a manageable safety profile.
Clinical Trials:
- NCT04165031: A Phase 1/2 open-label study evaluating LY3497366 in patients with advanced solid tumors harboring the KRAS G12C mutation. This trial is assessing the safety, tolerability, pharmacokinetics, and preliminary efficacy of LY3497366.
- NCT04989145: A Phase 1b study evaluating LY3497366 in combination with other anti-cancer therapies in patients with KRAS G12C-mutated NSCLC and other solid tumors.

JDQ-443

Overview: JDQ-443, developed by Novartis, is another KRAS G12C inhibitor in clinical development. It has demonstrated preclinical activity and is being evaluated in early-phase clinical trials.
Clinical Trials:
- NCT04690384: A Phase 1/2 open-label study evaluating JDQ-443 in patients with advanced solid tumors harboring the KRAS G12C mutation. This trial is assessing the safety, tolerability, pharmacokinetics, and preliminary efficacy of JDQ-443.
- NCT05573552: A Phase 1b study evaluating JDQ-443 in combination with other targeted therapies in patients with KRAS G12C-mutated NSCLC.

Detailed Clinical Trial List

To provide a comprehensive overview, the following is an expanded list of clinical trials involving KRAS G12C covalent inhibitors:

Sotorasib (AMG 510) Clinical Trials:
- CodeBreaK 100 (NCT03600883)
  - Phase: 1/2
  - Status: Completed
  - Description: An open-label study evaluating sotorasib in patients with advanced solid tumors, including NSCLC, CRC, and other cancers with the KRAS G12C mutation.
  - Primary Outcome Measures: Objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS).
- CodeBreaK 200 (NCT04303780)
  - Phase: 3
  - Status: Active, not recruiting
  - Description: A randomized, controlled trial comparing sotorasib to docetaxel in previously treated NSCLC patients with the KRAS G12C mutation.
  - Primary Outcome Measure: Progression-free survival (PFS).
- CodeBreaK 101 (NCT04185883)
  - Phase: 1b
  - Status: Active, not recruiting
  - Description: A study evaluating sotorasib in combination with other anti-cancer therapies, such as chemotherapy, immunotherapy, and other targeted agents.
  - Primary Outcome Measures: Safety, tolerability, maximum tolerated dose (MTD).
- NCT04933695
  - Phase: 2
  - Status: Recruiting
  - Description: A trial evaluating sotorasib in patients with KRAS G12C-mutated CRC.
  - Primary Outcome Measure: Objective response rate (ORR).
- NCT04625647
  - Phase: 1/2
  - Status: Active, not recruiting
  - Description: A study evaluating sotorasib in combination with pembrolizumab in patients with KRAS G12C-mutated NSCLC.
  - Primary Outcome Measures: Safety, tolerability, objective response rate (ORR).
- NCT05610532
  - Phase: 2
  - Status: Recruiting
  - Description: Sotorasib plus trametinib in advanced KRAS G12C-mutated solid tumors
  - Primary Outcome Measures: Objective response rate (ORR), Adverse events
Adagrasib (MRTX849) Clinical Trials:
- KRYSTAL-1 (NCT03785249)
  - Phase: 1/2
  - Status: Active, not recruiting
  - Description: An open-label study evaluating adagrasib in patients with advanced solid tumors harboring the KRAS G12C mutation.
  - Primary Outcome Measures: Objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS).
- KRYSTAL-7 (NCT04613596)
  - Phase: 2
  - Status: Recruiting
  - Description: A trial evaluating adagrasib in combination with pembrolizumab in patients with treatment-naïve KRAS G12C-mutated NSCLC.
  - Primary Outcome Measure: Objective response rate (ORR).
- KRYSTAL-10 (NCT04793958)
  - Phase: 3
  - Status: Active, not recruiting
  - Description: A randomized, controlled trial comparing adagrasib to chemotherapy in previously treated CRC patients with the KRAS G12C mutation.
  - Primary Outcome Measure: Progression-free survival (PFS).
- KRYSTAL-12 (NCT05536488)
  - Phase: 1b
  - Status: Recruiting
  - Description: A study evaluating adagrasib in combination with other targeted therapies, such as EGFR inhibitors, in patients with KRAS G12C-mutated NSCLC.
  - Primary Outcome Measures: Safety, tolerability, objective response rate (ORR).
- NCT04909857
  - Phase: 2
  - Status: Recruiting
  - Description: A trial evaluating adagrasib in patients with KRAS G12C-mutated solid tumors, including pancreatic cancer and biliary tract cancer.
  - Primary Outcome Measure: Objective response rate (ORR).
- NCT05400680 * Phase: 1b * Status: Recruiting * Description: Adagrasib Plus Cetuximab in KRAS G12C-Mutated Colorectal Cancer * Primary Outcome Measures: Adverse events, Objective response rate (ORR)
- NCT05630825 * Phase: 1b * Status: Recruiting * Description: Adagrasib With TNO155 (SHP2 Inhibitor) in Advanced Solid Tumors With KRAS G12C Mutation * Primary Outcome Measures: Adverse events, Objective response rate (ORR)
- NCT05400821 * Phase: 1b * Status: Recruiting * Description: Adagrasib With MRTX1133 (KRAS Inhibitor) in Advanced Solid Tumors With KRAS G12C Mutation * Primary Outcome Measures: Adverse events, Objective response rate (ORR)
LY3497366 Clinical Trials:
- NCT04165031
  - Phase: 1/2
  - Status: Active, not recruiting
  - Description: An open-label study evaluating LY3497366 in patients with advanced solid tumors harboring the KRAS G12C mutation.
  - Primary Outcome Measures: Safety, tolerability, pharmacokinetics, objective response rate (ORR).
- NCT04989145
  - Phase: 1b
  - Status: Active, not recruiting
  - Description: A study evaluating LY3497366 in combination with other anti-cancer therapies in patients with KRAS G12C-mutated NSCLC and other solid tumors.
  - Primary Outcome Measures: Safety, tolerability, objective response rate (ORR).
JDQ-443 Clinical Trials:
- NCT04690384
  - Phase: 1/2
  - Status: Recruiting
  - Description: An open-label study evaluating JDQ-443 in patients with advanced solid tumors harboring the KRAS G12C mutation.
  - Primary Outcome Measures: Safety, tolerability, pharmacokinetics, objective response rate (ORR).
- NCT05573552
  - Phase: 1b
  - Status: Recruiting
  - Description: A study evaluating JDQ-443 in combination with other targeted therapies in patients with KRAS G12C-mutated NSCLC.
  - Primary Outcome Measures: Safety, tolerability, objective response rate (ORR).

Challenges and Future Directions

Despite the significant progress in developing KRAS G12C inhibitors, several challenges remain. These include:

Resistance Mechanisms: Acquired resistance to KRAS G12C inhibitors is a significant concern. Mechanisms of resistance include KRAS mutations, activation of bypass signaling pathways, and histologic transformation. Strategies to overcome resistance, such as combination therapies and next-generation inhibitors, are being actively investigated.
Combination Therapies: Combining KRAS G12C inhibitors with other anti-cancer agents, such as chemotherapy, immunotherapy, and targeted therapies, is a promising approach to enhance efficacy and overcome resistance. Clinical trials evaluating various combination strategies are ongoing.
Expanding Indications: While KRAS G12C inhibitors have shown efficacy in NSCLC and CRC, their activity in other cancer types is being explored. Clinical trials are evaluating these inhibitors in pancreatic cancer, biliary tract cancer, and other solid tumors with the KRAS G12C mutation.
Improving Drug Delivery: Optimizing the delivery of KRAS G12C inhibitors to tumor cells is crucial for maximizing their therapeutic potential. Novel drug delivery systems and formulations are being developed to improve bioavailability and tumor penetration.
Biomarker Development: Identifying predictive biomarkers that can identify patients most likely to benefit from KRAS G12C inhibitors is essential for personalized medicine. Research efforts are focused on identifying biomarkers related to drug sensitivity and resistance.

Patient Selection and Biomarker Considerations

Selecting the right patients for KRAS G12C inhibitor therapy is critical for optimizing treatment outcomes. KRAS G12C mutation testing should be performed on tumor tissue or liquid biopsies to identify eligible patients. Immunohistochemistry (IHC), next-generation sequencing (NGS), and other molecular diagnostic techniques can be used to detect the KRAS G12C mutation.

In addition to KRAS G12C mutation status, other biomarkers may help predict response to KRAS G12C inhibitors. These include:

STK11/LKB1 Mutations: Co-occurring STK11/LKB1 mutations have been associated with reduced sensitivity to KRAS G12C inhibitors in NSCLC.
KEAP1 Mutations: KEAP1 mutations may also impact the efficacy of KRAS G12C inhibitors.
PD-L1 Expression: PD-L1 expression levels may influence the response to KRAS G12C inhibitors in combination with immunotherapy.

Safety and Tolerability

KRAS G12C inhibitors have generally been well-tolerated in clinical trials. Common adverse events include gastrointestinal toxicities (e.g., nausea, diarrhea), fatigue, rash, and liver enzyme elevations. Serious adverse events, such as pneumonitis and QTc prolongation, have been reported in some patients. Careful monitoring and proactive management of adverse events are essential for ensuring patient safety.

Regulatory Landscape

Sotorasib (Lumakras) was the first KRAS G12C inhibitor to receive accelerated approval from the FDA for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. Adagrasib (Krazati) has also received accelerated approval for similar indications. The regulatory landscape for KRAS G12C inhibitors is evolving, with ongoing clinical trials and regulatory submissions expected to expand their indications and availability.

The Future of KRAS G12C Inhibition

The development of KRAS G12C covalent inhibitors represents a significant advancement in targeted cancer therapy. These inhibitors have demonstrated promising clinical activity and have the potential to transform the treatment landscape for patients with KRAS G12C-mutated tumors. Ongoing research efforts are focused on optimizing these inhibitors, overcoming resistance mechanisms, and expanding their application to other cancer types.

Conclusion

KRAS G12C covalent inhibitors are revolutionizing the treatment of KRAS G12C-mutated cancers, particularly in NSCLC and CRC. Sotorasib and adagrasib have already shown significant clinical benefit, leading to regulatory approvals. Numerous clinical trials are ongoing to evaluate these inhibitors in various combinations and cancer types, promising further advancements in the field. As research progresses, these targeted therapies hold great potential for improving patient outcomes and transforming the landscape of cancer treatment. The comprehensive list of clinical trials provided in this article serves as a valuable resource for researchers, clinicians, and patients interested in the latest developments in KRAS G12C inhibition.

FAQ: KRAS G12C Covalent Inhibitors

Q1: What are KRAS G12C covalent inhibitors?

KRAS G12C covalent inhibitors are targeted therapies designed to selectively and irreversibly bind to the KRAS G12C mutant protein, a common oncogenic driver in various cancers.

Q2: How do KRAS G12C covalent inhibitors work?

These inhibitors form a strong, irreversible bond with the cysteine residue at the G12C position, disrupting the interaction of KRAS with downstream signaling molecules, thereby inhibiting the MAPK pathway.

Q3: Which KRAS G12C inhibitors are currently in clinical development?

Key KRAS G12C inhibitors in clinical development include sotorasib (AMG 510), adagrasib (MRTX849), LY3497366, and JDQ-443.

Q4: What types of cancer are KRAS G12C inhibitors being used to treat?

KRAS G12C inhibitors are primarily being used to treat non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), but are also being investigated in other solid tumors with the KRAS G12C mutation.

Q5: What are some common side effects of KRAS G12C inhibitors?

Common side effects include gastrointestinal toxicities (e.g., nausea, diarrhea), fatigue, rash, and liver enzyme elevations. Serious adverse events, such as pneumonitis, have been reported in some patients.

Q6: How is patient selection determined for KRAS G12C inhibitor therapy?

Patient selection is based on the presence of the KRAS G12C mutation, determined through tumor tissue or liquid biopsies using techniques like immunohistochemistry (IHC) and next-generation sequencing (NGS).

Q7: What are the challenges in developing KRAS G12C inhibitors?

Challenges include acquired resistance, the need for combination therapies, expanding indications, improving drug delivery, and developing predictive biomarkers.

Q8: What is the regulatory status of KRAS G12C inhibitors?

Sotorasib (Lumakras) and adagrasib (Krazati) have received accelerated approval from the FDA for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.

Q9: How can I find more information about clinical trials for KRAS G12C inhibitors?

Information about clinical trials can be found on websites such as clinicaltrials.gov, cancer.gov, and the websites of pharmaceutical companies developing these inhibitors.

Q10: What is the future of KRAS G12C inhibition?

The future of KRAS G12C inhibition involves optimizing these inhibitors, overcoming resistance mechanisms, expanding their application to other cancer types, and developing personalized treatment strategies based on predictive biomarkers.