Kras G12c Covalent Inhibitor Phase 1 Clinical Trial

The development of targeted therapies for KRAS-mutated cancers has been a challenging yet pivotal pursuit in oncology. The KRAS G12C mutation, found in a significant subset of lung, colorectal, and other cancers, has long been considered an "undruggable" target. However, the advent of covalent inhibitors, particularly those targeting KRAS G12C, represents a significant breakthrough. This article delves into the landscape of KRAS G12C covalent inhibitors, focusing on the phase 1 clinical trials that have paved the way for their clinical application and future development.

The KRAS Mutation: A Persistent Challenge

KRAS (Kirsten rat sarcoma viral oncogene homolog) is a gene that belongs to the RAS family of oncogenes. These genes encode proteins involved in cell signaling pathways that control cell growth, differentiation, and apoptosis. When KRAS is mutated, it can lead to constitutive activation of these signaling pathways, resulting in uncontrolled cell proliferation and tumor formation.

Why KRAS Was Considered "Undruggable"

For decades, KRAS was notoriously difficult to target due to several factors:

• High Affinity for GTP/GDP: The KRAS protein binds tightly to guanosine triphosphate (GTP) and guanosine diphosphate (GDP), which are crucial for its activation and inactivation, respectively. The high affinity of KRAS for these molecules made it challenging to develop drugs that could effectively compete for binding.
• Smooth Protein Surface: The KRAS protein lacks a deep binding pocket or a distinct structural feature that could be easily targeted by small-molecule inhibitors. Its relatively smooth surface made it difficult to design drugs that could selectively bind and inhibit its function.
• Ubiquitous Expression: KRAS is expressed in nearly all human cells, making it difficult to target cancer cells specifically without affecting normal cells.

The G12C Mutation: A Druggable Vulnerability

The G12C mutation involves the substitution of glycine at position 12 with cysteine. This specific mutation creates a unique vulnerability:

• Cysteine Reactivity: Cysteine contains a reactive thiol group (-SH), which can form covalent bonds with electrophilic compounds. This property has been exploited to develop covalent inhibitors that specifically target KRAS G12C.
• Prevalence in Specific Cancers: The G12C mutation is particularly prevalent in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors, making it a high-priority target for drug development in these cancers.

Covalent Inhibitors: A Novel Approach

Covalent inhibitors form a strong, irreversible bond with their target protein. This approach offers several advantages:

• High Potency: Covalent binding can lead to potent and sustained inhibition of the target protein.
• Selectivity: By targeting specific amino acid residues (like the cysteine in KRAS G12C), covalent inhibitors can achieve high selectivity, reducing off-target effects.
• Prolonged Duration of Action: The irreversible nature of covalent binding can result in a prolonged duration of action, potentially requiring less frequent dosing.

Phase 1 Clinical Trials: Laying the Groundwork

Phase 1 clinical trials are the first step in evaluating a new drug in humans. These trials primarily focus on assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the drug. In the context of KRAS G12C covalent inhibitors, phase 1 trials were crucial for establishing the foundation for their clinical development.

Key Objectives of Phase 1 Trials

• Safety and Tolerability: Determine the maximum tolerated dose (MTD) and identify dose-limiting toxicities (DLTs).
• Pharmacokinetics (PK): Characterize the absorption, distribution, metabolism, and excretion (ADME) of the drug.
• Pharmacodynamics (PD): Assess the drug's effect on the target (e.g., KRAS G12C inhibition) and downstream signaling pathways.
• Preliminary Efficacy: Evaluate early signs of anti-tumor activity, such as tumor shrinkage or disease stabilization.

Leading KRAS G12C Covalent Inhibitors in Phase 1 Trials

Several KRAS G12C covalent inhibitors have undergone phase 1 clinical trials, with two notable examples being sotorasib (AMG 510) and adagrasib (MRTX849).

Sotorasib (AMG 510)

• Development: Sotorasib was developed by Amgen and was one of the first KRAS G12C inhibitors to enter clinical trials.
• Phase 1 Trial Design: The phase 1 trial of sotorasib was an open-label, dose-escalation study designed to evaluate the safety, tolerability, PK, and preliminary anti-tumor activity of sotorasib in patients with advanced solid tumors harboring the KRAS G12C mutation.
• Key Findings:
  • Safety: Sotorasib was generally well-tolerated, with most adverse events being mild to moderate in severity. Common adverse events included diarrhea, fatigue, nausea, and liver enzyme elevations.
  • Pharmacokinetics: Sotorasib exhibited dose-proportional PK, with increased exposure at higher doses.
  • Pharmacodynamics: Sotorasib demonstrated KRAS G12C inhibition in tumor samples, as well as downstream signaling pathway modulation.
  • Efficacy: The trial showed promising anti-tumor activity, particularly in NSCLC. Objective responses were observed, and a subset of patients experienced durable disease control.
• Impact: The positive results from the phase 1 trial of sotorasib led to its further development in larger, randomized clinical trials, ultimately resulting in its approval by regulatory agencies for the treatment of KRAS G12C-mutated NSCLC.

Adagrasib (MRTX849)

• Development: Adagrasib was developed by Mirati Therapeutics and is another leading KRAS G12C inhibitor.
• Phase 1 Trial Design: The phase 1/2 KRYSTAL-1 trial evaluated the safety, tolerability, PK, and anti-tumor activity of adagrasib in patients with advanced solid tumors harboring the KRAS G12C mutation. The phase 1 portion of the trial focused on dose escalation and determination of the recommended phase 2 dose (RP2D).
• Key Findings:
  • Safety: Adagrasib was also generally well-tolerated, with common adverse events including nausea, diarrhea, fatigue, and vomiting.
  • Pharmacokinetics: Adagrasib exhibited favorable PK properties, with a long half-life allowing for once-daily dosing.
  • Pharmacodynamics: Adagrasib demonstrated strong KRAS G12C inhibition and downstream signaling pathway modulation.
  • Efficacy: The trial showed promising anti-tumor activity across multiple tumor types, including NSCLC and CRC. Objective responses and durable disease control were observed.
• Impact: The encouraging results from the phase 1/2 KRYSTAL-1 trial led to the continued development of adagrasib in larger clinical trials and its eventual approval for the treatment of KRAS G12C-mutated NSCLC.

Key Learnings from Phase 1 Trials

The phase 1 clinical trials of KRAS G12C covalent inhibitors provided valuable insights into their safety, PK, PD, and preliminary efficacy. These learnings have been crucial for guiding their further development and clinical application.

Safety and Tolerability

• Overall Manageable Safety Profile: Both sotorasib and adagrasib were generally well-tolerated in phase 1 trials. Most adverse events were mild to moderate in severity and manageable with supportive care.
• Common Adverse Events: Common adverse events included gastrointestinal toxicities (e.g., diarrhea, nausea, vomiting), fatigue, and liver enzyme elevations. These adverse events are likely related to the on-target or off-target effects of KRAS inhibition.
• Importance of Dose Optimization: Phase 1 trials helped to identify the MTD and RP2D for these inhibitors, balancing efficacy with safety and tolerability.

Pharmacokinetics

• Favorable PK Properties: Both sotorasib and adagrasib exhibited favorable PK properties, allowing for oral administration and convenient dosing schedules.
• Dose-Proportional Exposure: Sotorasib demonstrated dose-proportional PK, with increased exposure at higher doses.
• Long Half-Life: Adagrasib has a long half-life, supporting once-daily dosing and potentially leading to sustained target inhibition.

Pharmacodynamics

• KRAS G12C Inhibition: Both inhibitors demonstrated effective KRAS G12C inhibition in tumor samples, confirming their on-target activity.
• Downstream Signaling Modulation: Inhibition of KRAS G12C led to modulation of downstream signaling pathways, such as the MAPK and PI3K/AKT pathways, which are critical for cell growth and survival.
• Correlation with Efficacy: PD data correlated with anti-tumor activity, suggesting that effective KRAS G12C inhibition is necessary for clinical benefit.

Preliminary Efficacy

• Anti-Tumor Activity: Phase 1 trials showed promising anti-tumor activity, particularly in NSCLC and CRC. Objective responses and durable disease control were observed in a subset of patients.
• Tumor Type Specificity: While both inhibitors showed activity across multiple tumor types, NSCLC emerged as a particularly responsive tumor type, likely due to the higher prevalence of the KRAS G12C mutation in this cancer.
• Need for Predictive Biomarkers: While KRAS G12C mutation status is a key predictive biomarker, additional biomarkers are needed to identify patients who are most likely to benefit from these inhibitors and to understand mechanisms of resistance.

Challenges and Future Directions

Despite the significant progress in KRAS G12C inhibitor development, several challenges remain:

Resistance Mechanisms

• On-Target Resistance: Cancer cells can develop resistance to KRAS G12C inhibitors through various mechanisms, including secondary mutations in KRAS that prevent inhibitor binding or activate alternative signaling pathways.
• Off-Target Resistance: Resistance can also occur through activation of bypass signaling pathways that circumvent KRAS inhibition, such as activation of receptor tyrosine kinases (RTKs) or other oncogenic drivers.
• Immune Evasion: Tumors may also develop resistance by evading the immune system, limiting the effectiveness of KRAS G12C inhibitors.

Combination Strategies

• Combining with Other Targeted Therapies: Combining KRAS G12C inhibitors with other targeted therapies, such as EGFR inhibitors or BRAF inhibitors, may overcome resistance mechanisms and improve anti-tumor activity.
• Combining with Immunotherapy: Combining KRAS G12C inhibitors with immunotherapy, such as immune checkpoint inhibitors, may enhance anti-tumor immune responses and improve outcomes.
• Combining with Chemotherapy: Combining KRAS G12C inhibitors with chemotherapy may provide synergistic anti-tumor effects, although careful attention must be paid to potential overlapping toxicities.

Expanding to Other KRAS Mutations

• Developing Inhibitors for Other KRAS Mutations: While KRAS G12C inhibitors have shown significant promise, other KRAS mutations remain undruggable. Developing inhibitors for these mutations is a major priority.
• Pan-RAS Inhibitors: Developing pan-RAS inhibitors that can target multiple KRAS mutations is another potential strategy for overcoming the challenges posed by KRAS heterogeneity.

Improving Drug Delivery

• Novel Drug Delivery Systems: Developing novel drug delivery systems, such as nanoparticles or antibody-drug conjugates, may improve the delivery of KRAS G12C inhibitors to tumor cells, enhancing their efficacy and reducing off-target toxicities.
• PROTACs: Proteolysis-targeting chimeras (PROTACs) are a novel class of drugs that can induce the degradation of target proteins. Developing PROTACs targeting KRAS may provide a new approach to inhibiting its function.

The Future of KRAS G12C Inhibition

The development of KRAS G12C covalent inhibitors represents a significant milestone in cancer therapy. The phase 1 clinical trials of sotorasib and adagrasib have laid the groundwork for their clinical application and have provided valuable insights into their safety, PK, PD, and preliminary efficacy. As these inhibitors continue to be developed and combined with other therapies, they hold the promise of improving outcomes for patients with KRAS G12C-mutated cancers.

The ongoing research and clinical trials in this field are focused on addressing the challenges of resistance, optimizing combination strategies, expanding to other KRAS mutations, and improving drug delivery. With continued innovation and collaboration, the future of KRAS G12C inhibition looks bright, offering hope for more effective and personalized cancer treatments.

Conclusion

The journey of KRAS from an "undruggable" target to a druggable vulnerability is a testament to the power of scientific innovation and perseverance. The development of covalent inhibitors targeting KRAS G12C has transformed the landscape of cancer therapy, offering new hope for patients with KRAS-mutated tumors. The phase 1 clinical trials of sotorasib and adagrasib have been instrumental in establishing their safety and efficacy, paving the way for their clinical application and continued development. As research continues, these inhibitors hold the promise of further improving outcomes and transforming the lives of patients with cancer.