Amg 510 First Patient Dosed July 2018

The journey of AMG 510, now known as sotorasib (Lumakras®), began with a momentous milestone: the first patient dosed in July 2018. This marked the initiation of clinical trials for a drug specifically designed to target the KRAS G12C mutation, a long-sought-after goal in cancer research. This article delves into the development of AMG 510, its significance, the clinical trials that shaped its path to approval, and its potential impact on the landscape of cancer treatment.

The KRAS Challenge: A Target Decades in the Making

For decades, the KRAS gene has been a formidable challenge for cancer researchers. KRAS mutations are among the most common oncogenic drivers, implicated in approximately 25% of all human cancers. These mutations are particularly prevalent in lung, colorectal, and pancreatic cancers. The KRAS protein, a small GTPase, acts as a molecular switch, regulating cell growth, differentiation, and survival. When KRAS is mutated, it becomes constitutively active, driving uncontrolled cell proliferation and contributing to tumor development.

Despite its significance, KRAS was long considered "undruggable." Its smooth, globular protein structure lacked obvious binding pockets for traditional small-molecule inhibitors. This perceived lack of druggability led many researchers to focus on other, more tractable targets. However, the persistent prevalence of KRAS-driven cancers spurred continued efforts to find a way to inhibit its activity.

The Breakthrough: Targeting KRAS G12C

The breakthrough came with the discovery of a cryptic pocket on the KRAS G12C mutant protein. The G12C mutation involves a substitution of glycine with cysteine at position 12, creating a unique cysteine thiol that could be targeted by covalent inhibitors. This offered a new avenue for drug development, paving the way for the creation of molecules specifically designed to bind to and inhibit the activity of KRAS G12C.

AMG 510 was one such molecule. Developed by Amgen, it is a selective and irreversible inhibitor of KRAS G12C. It works by covalently binding to the cysteine residue at position 12, locking the KRAS G12C protein in an inactive state. This inactivation prevents the downstream signaling that drives cancer cell growth and survival.

The First Patient Dosed: A Turning Point

The dosing of the first patient with AMG 510 in July 2018 represented a pivotal moment in KRAS inhibitor development. It marked the transition from preclinical research to clinical evaluation, bringing hope to patients with KRAS G12C-mutated cancers who had limited treatment options. This event signified the culmination of years of research and development, and the beginning of a new era in targeted cancer therapy.

Clinical Trials: Evaluating the Efficacy and Safety of Sotorasib

Following the first-in-human study, AMG 510 (sotorasib) underwent rigorous clinical evaluation to assess its efficacy and safety. The CodeBreaK 100 trial, a Phase 1/2 open-label study, played a crucial role in establishing the drug's potential.

CodeBreaK 100 Trial:

• Design: This trial enrolled patients with advanced solid tumors harboring the KRAS G12C mutation. The primary focus was on non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors.
• Objectives: The primary objective was to assess the objective response rate (ORR), defined as the proportion of patients who experienced a partial or complete response to treatment. Secondary objectives included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
• Key Findings (NSCLC): The NSCLC cohort demonstrated promising results. The ORR was approximately 36%, with a disease control rate (DCR) of around 80%. The median duration of response was approximately 10 months. These findings were significant, as many of these patients had previously failed multiple lines of therapy.
• Key Findings (CRC): The CRC cohort showed more modest results, with an ORR of around 7%. However, a subset of patients with specific tumor characteristics, such as microsatellite stable (MSS) tumors, appeared to derive some benefit.
• Safety Profile: Sotorasib was generally well-tolerated. The most common adverse events were gastrointestinal in nature, such as diarrhea, nausea, and vomiting. Liver enzyme elevations were also observed in some patients, but were generally manageable with dose modifications.

Other Clinical Trials:

In addition to CodeBreaK 100, other clinical trials have explored sotorasib in combination with other therapies, such as immunotherapy and chemotherapy. These trials are aimed at further improving the efficacy of sotorasib and expanding its potential applications.

FDA Approval and Beyond

Based on the compelling data from the CodeBreaK 100 trial, the U.S. Food and Drug Administration (FDA) granted accelerated approval to sotorasib (Lumakras®) in May 2021 for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy. This marked a historic moment, as sotorasib became the first targeted therapy approved for a KRAS mutation.

The approval of sotorasib has had a profound impact on the treatment landscape for KRAS G12C-mutated NSCLC. It provides a much-needed new option for patients who have exhausted other lines of therapy. The availability of a targeted therapy also allows for more personalized treatment approaches, tailoring therapy to the specific genetic characteristics of each patient's tumor.

The Science Behind Sotorasib: Mechanism of Action and Selectivity

Sotorasib's effectiveness stems from its unique mechanism of action and high selectivity for the KRAS G12C mutant protein.

Mechanism of Action:

1. Covalent Binding: Sotorasib contains an electrophilic warhead that forms a covalent bond with the sulfhydryl group of the cysteine residue at position 12 in the KRAS G12C protein.
2. Inactivation of KRAS: This covalent binding locks the KRAS G12C protein in an inactive, GDP-bound state. This prevents the protein from cycling to the active, GTP-bound state, which is necessary for signaling.
3. Inhibition of Downstream Signaling: By inhibiting KRAS G12C activity, sotorasib disrupts the downstream signaling pathways that drive cancer cell growth and survival. These pathways include the MAPK and PI3K/AKT pathways.
4. Tumor Regression: The inhibition of these pathways leads to a reduction in cell proliferation, induction of apoptosis (programmed cell death), and ultimately, tumor regression in some patients.

Selectivity:

Sotorasib is highly selective for the KRAS G12C mutant protein. It has minimal activity against wild-type KRAS or other KRAS mutants. This selectivity is crucial for minimizing off-target effects and improving the drug's safety profile. The high selectivity is achieved through the specific interaction of sotorasib with the unique conformation of the KRAS G12C protein, which is created by the G12C mutation.

Challenges and Future Directions

Despite the significant progress represented by sotorasib, challenges remain.

• Resistance: Like many targeted therapies, resistance to sotorasib can develop over time. This resistance can be mediated by various mechanisms, including:
  • Acquired KRAS Mutations: The development of secondary KRAS mutations that prevent sotorasib binding or restore KRAS activity.
  • Bypass Mechanisms: Activation of alternative signaling pathways that circumvent the need for KRAS signaling.
  • Upregulation of Efflux Pumps: Increased expression of drug efflux pumps that pump sotorasib out of cancer cells.
• Limited Efficacy in Some Tumor Types: While sotorasib has shown promising activity in NSCLC, its efficacy in other tumor types, such as colorectal cancer, has been more limited.
• Combination Strategies: To overcome these challenges, researchers are exploring combination strategies that combine sotorasib with other therapies. These include:
  • Immunotherapy: Combining sotorasib with immune checkpoint inhibitors to enhance anti-tumor immune responses.
  • MEK Inhibitors: Combining sotorasib with MEK inhibitors to more completely block the MAPK pathway.
  • SHP2 Inhibitors: Combining sotorasib with SHP2 inhibitors to prevent adaptive resistance mechanisms.

Future Directions:

• Developing Next-Generation KRAS G12C Inhibitors: Researchers are working on developing next-generation KRAS G12C inhibitors with improved potency, selectivity, and pharmacokinetic properties.
• Targeting Other KRAS Mutations: Efforts are underway to develop inhibitors that target other KRAS mutations, such as G12D and G12V, which are also common in cancer.
• Personalized Medicine Approaches: Further research is needed to identify biomarkers that can predict which patients are most likely to benefit from sotorasib and to develop personalized treatment strategies based on individual tumor characteristics.

The Broader Impact on Cancer Research and Drug Development

The development and approval of sotorasib have had a significant impact on the broader field of cancer research and drug development.

• Proof of Concept for Targeting "Undruggable" Targets: Sotorasib demonstrated that even targets previously considered "undruggable" can be successfully targeted with the right approach. This has spurred renewed interest in targeting other challenging cancer targets.
• Advancements in Covalent Inhibitor Design: The development of sotorasib has advanced the field of covalent inhibitor design. Researchers are now using covalent inhibitors to target a wide range of proteins involved in cancer and other diseases.
• Increased Investment in KRAS Research: The success of sotorasib has led to increased investment in KRAS research. This has fueled the discovery of new KRAS inhibitors and other therapeutic strategies for KRAS-driven cancers.
• Paradigm Shift in Cancer Treatment: The approval of sotorasib represents a paradigm shift in cancer treatment, moving towards more personalized and targeted therapies. This approach has the potential to improve outcomes for patients with cancer while minimizing side effects.

Sotorasib: Frequently Asked Questions (FAQ)

1. What is sotorasib (Lumakras®)?

Sotorasib is a targeted therapy that inhibits the KRAS G12C mutant protein. It is approved for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy.

2. How does sotorasib work?

Sotorasib works by covalently binding to the KRAS G12C protein, locking it in an inactive state. This prevents the protein from driving cancer cell growth and survival.

3. What are the common side effects of sotorasib?

The most common side effects of sotorasib are gastrointestinal in nature, such as diarrhea, nausea, and vomiting. Liver enzyme elevations can also occur.

4. How is sotorasib administered?

Sotorasib is administered orally as a tablet, once daily.

5. Is sotorasib effective for all types of cancer?

Sotorasib is currently approved for the treatment of KRAS G12C-mutated NSCLC. Its efficacy in other tumor types is being investigated in clinical trials.

6. What should I discuss with my doctor before starting sotorasib?

Discuss your medical history, any medications you are taking, and any potential side effects with your doctor before starting sotorasib.

7. How do I know if my tumor has the KRAS G12C mutation?

Your doctor can order a genetic test to determine if your tumor has the KRAS G12C mutation.

8. What are the alternatives to sotorasib?

Alternatives to sotorasib may include chemotherapy, immunotherapy, or other targeted therapies, depending on the specific characteristics of your cancer.

9. Can sotorasib be used in combination with other therapies?

Sotorasib is being investigated in combination with other therapies, such as immunotherapy and chemotherapy, in clinical trials.

10. Where can I find more information about sotorasib?

You can find more information about sotorasib on the FDA website, the Amgen website, or by talking to your doctor.

Conclusion: A New Hope for Patients with KRAS-Mutated Cancers

The development and approval of sotorasib represent a significant milestone in the fight against cancer. The first patient dosed in July 2018 marked the beginning of a journey that has brought new hope to patients with KRAS G12C-mutated NSCLC. While challenges remain, sotorasib has demonstrated the feasibility of targeting previously "undruggable" targets and has paved the way for the development of new and innovative cancer therapies. As research continues, sotorasib and other KRAS inhibitors hold the promise of transforming the treatment landscape for a wide range of KRAS-driven cancers, ultimately improving outcomes and quality of life for patients around the world. The journey of AMG 510 is a testament to the power of scientific innovation and the unwavering commitment to finding better treatments for cancer.