What are the approved indications for Adagrasib?

Introduction to Adagrasib

Drug Overview and Mechanism of Action 
Adagrasib is a novel orally bioavailable, highly selective, small‐molecule inhibitor designed to target the KRAS G12C mutation found in various malignancies. Its mechanism of action involves irreversible covalent binding to the mutant KRAS G12C protein, locking it in the inactive GDP‐bound state and thereby preventing downstream oncogenic signaling cascades such as the MAPK and PI3K/AKT pathways. This inhibition stalls cell proliferation and induces tumor regression by selectively blocking the driver mutation that has historically been considered “undruggable” due to the high affinity of KRAS for GTP and the lack of obvious binding pockets in its oncogenic form. In preclinical investigations, adagrasib demonstrated favorable pharmacokinetic properties, including a long half‐life (approximately 24.7 hours in some studies) and evidence of central nervous system (CNS) penetration—attributes that may potentially contribute to better target coverage, especially when brain metastases are present.

Development History and FDA Approval 
The development of adagrasib has been a milestone in targeting KRAS mutations, a challenge that had long been unmet in oncology. Developed by Mirati Therapeutics in collaboration with Array BioPharma, the agent moved rapidly through clinical development. Early-phase studies, including the phase I/IB KRYSTAL-1 trial, provided robust efficacy and safety data that supported an accelerated regulatory pathway. Adagrasib was granted breakthrough therapy designation in the United States and achieved the status of “Approved” by the FDA on December 12, 2022. This approval is based on its demonstrable clinical efficacy in patients with locally advanced or metastatic KRAS G12C-mutant non–small cell lung cancer (NSCLC), particularly in those who have received prior systemic therapy. The approval milestone signifies a breakthrough in a field where KRAS mutations were once thought to be undruggable, marking a critical leap forward in precision oncology.

Approved Indications

Specific Medical Conditions 
The primary and currently only approved indication for adagrasib is for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) that harbors the KRAS G12C mutation. This approval applies to those patients who have already received at least one systemic therapy, reflecting adagrasib’s development as a second-line treatment option in a condition with limited effective therapeutic options. While adagrasib’s clinical development program includes investigations in other tumor types such as colorectal cancer (CRC), pancreatic cancer, and biliary tract cancers, the regulatory approval as of now is exclusively for KRAS G12C-mutant NSCLC. It is important to note that KRAS mutations occur in a variety of solid tumors; however, the molecular and clinical complexities differ among these tumor types. Therefore, the current indication is strictly defined as KRAS G12C-mutant NSCLC, where the mutation’s driver role has been clearly established, and where clinical trial results have shown significant therapeutic benefit.

Dosage and Administration 
While the precise dosing recommendations are defined in the prescribing information, clinical trials such as the KRYSTAL-1 study provide key details on adagrasib’s administration. In pivotal studies, a dosing regimen of 600 mg taken orally twice daily was found to achieve an optimal balance between efficacy and tolerability. This dosing schedule is designed to sustain target inhibition over the dosing interval, particularly given the regenerating nature of KRAS G12C protein over approximately 24–48 hours. The recommended dosage takes into account the drug’s long half-life and its pharmacokinetic profile, which allows for sufficient systemic and CNS exposure. Close monitoring is advised during the initial phase of treatment to manage any emerging adverse events, and dose modifications may be necessary in the event of significant toxicity. Although detailed administration guidelines (including potential requirements for dose modifications based on hepatic parameters and concomitant medications) are provided in the full prescribing information, the key takeaway is that the approved regimen is based on achieving a steady state that maintains continuous inhibition of the KRAS G12C mutant protein.

Clinical Trials and Efficacy

Key Clinical Trials 
The landmark clinical trial underpinning the approval of adagrasib is the KRYSTAL-1 study, a phase I/IB dose-finding and efficacy trial that explored different dosing regimens of adagrasib across various KRAS G12C-mutated solid tumors. In this study, which enrolled patients with advanced NSCLC, colorectal cancer, and other solid tumors, adagrasib demonstrated a clinically meaningful objective response rate (ORR) and a manageable safety profile. Among the NSCLC cohort, the trial reported an ORR of approximately 42.9% with a median duration of response of around 8.5 months. In addition, subsequent presentations at reputable oncology congresses and rapid communications in peer-reviewed journals have further reinforced adagrasib’s clinical efficacy, particularly in patients with previously treated KRAS G12C-mutant NSCLC. 
Moreover, data from supportive studies have highlighted adagrasib’s CNS activity. Early clinical data, along with translational research involving mouse models with intracranial tumors, have demonstrated that adagrasib penetrates the CNS to exert antitumor effects—a critical consideration given that brain metastases are a frequent complication in NSCLC. This aspect of the drug’s efficacy is particularly important in the context of NSCLC, where controlling CNS disease is pivotal for prolonging overall survival and improving quality of life. Thus, the comprehensive clinical research program for adagrasib encompasses not only systemic antitumor activity but also promising signals regarding intracranial control.

Efficacy Results 
The efficacy of adagrasib in the approved indication of KRAS G12C-mutant NSCLC is supported by robust clinical outcomes from the KRYSTAL-1 trial. Key efficacy endpoints reported include:
1.An objective response rate (ORR) of approximately 42.9%, indicating that nearly half of the patients achieved a partial response as confirmed by RECIST criteria. 
2.A median duration of response of around 8.5 months, suggesting that the benefits of treatment are durable in a substantial proportion of patients. 
3. Evidence of intracranial responses, with significant reduction in brain metastases, as a subset of patients demonstrated meaningful intracranial objective responses; this was particularly important given the high unmet need for CNS-active therapies in NSCLC. 
4.The overall progression-free survival (PFS) and overall survival (OS) data, while still maturing, provide strong indications of the drug’s clinical activity as a second-line treatment. 

These efficacy outcomes were pivotal in securing regulatory approval and have led to widespread recognition of adagrasib as a valuable new option for patients with advanced KRAS G12C-mutated NSCLC. The clinical results have been consistent across several presentations and rapid communications at major oncology conferences, reinforcing the reliability and reproducibility of the findings.

Safety and Side Effects

Common Side Effects 
As with most anticancer agents, adagrasib is associated with a spectrum of adverse effects. The most commonly reported treatment-related adverse events (TRAEs) in clinical trials include gastrointestinal toxicities—such as diarrhea, nausea, and vomiting—as well as hepatic enzyme elevations, which necessitate careful monitoring of liver function tests. Fatigue has also been noted among patients receiving adagrasib, though these side effects are generally mild to moderate in severity and are often manageable through supportive care measures, dose modifications, or temporary treatment interruptions. Importantly, the majority of patients in the KRYSTAL-1 study experienced side effects early in treatment that resolved with appropriate intervention, and only a small percentage of patients required permanent discontinuation of therapy due to toxicity.

Long-term Safety Profile 
The long-term safety profile of adagrasib remains an area of ongoing research; however, current data from clinical studies, including extended follow-ups from the KRYSTAL-1 trial, suggest that the safety profile remains manageable over time. There has been particular attention to whether the CNS penetration of adagrasib might predispose patients to neurological adverse events, but both preclinical and limited clinical data indicate that CNS-specific side effects are few and do not frequently necessitate cessation of treatment. Additionally, the continuous monitoring of potential hepatotoxicity and QTc interval prolongation—as observed in pooled safety analyses—ensures that both patients and clinicians can manage these risks appropriately with regular assessments and supportive care measures. Overall, the clinical data support that, while adverse events are common, they are mostly predictable, controllable, and do not outweigh the clinical benefits of targeting what was once deemed an “undruggable” mutation.

Future Directions and Research

Ongoing Studies 
Beyond its current approval for KRAS G12C-mutant NSCLC, adagrasib is being actively investigated in several ongoing clinical trials aimed at broadening its therapeutic application. Current studies are evaluating adagrasib both as a monotherapy and in combination with other anticancer agents, including immunotherapies. For instance, a supplemental new drug application (sNDA) has been accepted for adagrasib in combination with cetuximab for patients with KRAS G12C-mutated metastatic colorectal cancer (CRC), with a target action date set for June 21, 2024. Additionally, combination regimens involving immunotherapy agents such as pembrolizumab are being explored. These trials aim to determine whether the combination can enhance response rates, extend durations of response, and provide a chemotherapy-free option for treatment-naïve patients, particularly in the context of first-line therapy for NSCLC with high PD-L1 expression.

Potential New Indications 
While the current approved indication for adagrasib is limited to KRAS G12C-mutant NSCLC, the drug shows promise in other tumor types in which the KRAS G12C mutation is present. Ongoing phase II studies are investigating its efficacy in colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), biliary tract cancers, and other solid tumors harboring KRAS G12C mutations. Preclinical models have further suggested that adagrasib might have activity against brain metastases, which is encouraging for malignancies known to metastasize to the central nervous system. The exploration of these additional indications may offer new therapeutic avenues for patients who currently have limited options, and they underscore the innovative approach of targeting a mutation that is a common oncogenic driver across multiple cancer types. Future research is also focused on understanding and overcoming mechanisms of resistance to KRAS G12C inhibitors, including secondary mutations and adaptive tumor responses, which may pave the way for combination therapies that can further enhance clinical outcomes.

Conclusion

In summary, the approved indication for adagrasib is for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring the KRAS G12C mutation, particularly in those who have received prior systemic therapy. This approval is founded on robust clinical evidence demonstrating an objective response rate of approximately 42.9% and a durable median duration of response of about 8.5 months, as highlighted by the KRYSTAL-1 trial. The drug’s mechanism of action—locking KRAS G12C in its inactive state—is a pioneering strategy in targeting a mutation once considered “undruggable”. Moreover, the favorable pharmacokinetics, including a long half-life and CNS penetration, further enhances its therapeutic potential, particularly in treating NSCLC patients with brain metastases. 

At present, the prescribing information recommends adagrasib at a dose of 600 mg twice daily, which has been shown to maintain effective target inhibition while keeping the treatment-related adverse events at a manageable level. The most common side effects include gastrointestinal disturbances and transient elevations in liver enzymes, which are generally mild to moderate and controllable with appropriate supportive care measures. Long-term safety data remain promising, with few CNS-specific adverse events noted despite the drug’s ability to cross the blood-brain barrier. 

Looking ahead, research on adagrasib is expanding beyond its current indication. Several clinical trials are evaluating its utility in combination with other agents such as cetuximab and pembrolizumab, potentially extending its use to colorectal cancer and other tumor types where the KRAS G12C mutation plays a pivotal role. These ongoing studies aim not only to improve clinical outcomes in NSCLC but also to broaden the therapeutic potential of adagrasib to other solid tumors, providing hope for a more comprehensive treatment strategy against KRAS-driven cancers. 

Thus, while the current approved indication confines adagrasib to the treatment of KRAS G12C-mutant NSCLC, the drug’s future may see its application broadened significantly as further data emerge from ongoing trials. The promising clinical efficacy, manageable safety profile, and evolving research landscape underscore adagrasib’s potential to transform the therapeutic approach to a mutation that was once considered intractable. This represents a significant advancement in precision oncology and offers new hope for patients with limited treatment options.

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