Adagrasib (Krazati®): A Comprehensive Pharmacological and Clinical Monograph of a Covalent KRAS G12C Inhibitor

Executive Summary

Adagrasib, marketed as Krazati®, represents a significant therapeutic advancement in the field of precision oncology. It is an orally available, potent, and irreversible small-molecule inhibitor specifically designed to target the KRAS G12C mutant protein, an oncogenic driver long considered "undruggable".[1] Developed by Mirati Therapeutics and now part of the Bristol Myers Squibb portfolio, Adagrasib has successfully translated a deep understanding of molecular oncology into a clinically meaningful therapy for patients with specific, genetically defined cancers.

The drug has secured regulatory approvals in major markets for two distinct indications. In the United States, it is approved as a monotherapy for 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. It is also approved in combination with cetuximab for adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.[3] These approvals were granted under accelerated pathways based on compelling efficacy data from the pivotal, multi-cohort KRYSTAL-1 clinical trial.

In the KRYSTAL-1 study, Adagrasib monotherapy demonstrated an objective response rate (ORR) of 43% in the NSCLC cohort, with a median overall survival (OS) of 14.1 months observed in a two-year follow-up analysis, providing a durable clinical benefit in a heavily pretreated population.[5] For CRC, the combination of Adagrasib with cetuximab yielded an ORR of 34%, addressing the challenge of adaptive resistance seen with monotherapy in this tumor type.[7] A key differentiating feature of Adagrasib is its optimized pharmacokinetic profile, characterized by a long plasma half-life of approximately 23 hours and significant central nervous system (CNS) penetration. This has translated into notable intracranial activity in patients with NSCLC and untreated brain metastases, a common and challenging clinical scenario.[9]

The safety profile of Adagrasib is well-characterized and considered manageable. The most common adverse reactions are gastrointestinal (nausea, diarrhea, vomiting) and constitutional (fatigue), which are typically low-grade. However, the prescribing information includes important warnings and precautions for potentially serious toxicities, including QTc interval prolongation, hepatotoxicity, and interstitial lung disease (ILD)/pneumonitis, necessitating diligent patient monitoring and adherence to dose modification guidelines.[4] Adagrasib stands as a cornerstone therapy that validates KRAS G12C as a druggable target, offering a new standard of care and tangible hope for patients with these molecularly defined malignancies.

Introduction: Targeting the "Undruggable" KRAS Oncogene

The Role of KRAS Mutations in Oncogenesis

The Kristen Rat Sarcoma Viral Oncogene Homolog (KRAS) gene encodes a small GTPase protein that functions as a critical molecular switch in cellular signaling. As a member of the RAS family of oncogenes, KRAS plays a central role in transducing extracellular signals to the cell nucleus, thereby regulating fundamental processes such as cell proliferation, differentiation, and survival.[13] In its normal physiological state, the KRAS protein cycles between an inactive, guanosine diphosphate (GDP)-bound state and an active, guanosine triphosphate (GTP)-bound state. This "on/off" cycle is tightly controlled and ensures that downstream signaling pathways, most notably the mitogen-activated protein kinase (MAPK/ERK) and phosphoinositide 3-kinase (PI3K/AKT) pathways, are activated only in response to appropriate external stimuli.[9]

Mutations in the KRAS gene are among the most frequently identified oncogenic drivers in human cancers, accounting for approximately 85% of all RAS family mutations.[9] These mutations typically occur at specific codons, most commonly 12, 13, or 61, and result in single amino acid substitutions that impair the intrinsic GTPase activity of the protein. This impairment prevents the hydrolysis of GTP to GDP, effectively locking the KRAS protein in a constitutively active, GTP-bound "on" state.[10] The consequence is persistent and uncontrolled activation of downstream signaling pathways, which promotes relentless cellular proliferation, inhibits apoptosis, and drives malignant transformation and metastasis.[14] The prevalence of KRAS mutations is particularly high in some of the most lethal cancers, including non-small cell lung cancer (NSCLC), where they are found in 25-30% of cases, and colorectal cancer.[2]

The Challenge of the G12C Mutation and the Advent of Covalent Inhibitors

For decades, KRAS was famously deemed an "undruggable" target in oncology.[2] This reputation stemmed from the protein's challenging biochemical and structural features. The picomolar affinity of KRAS for its natural ligand, GTP, made the development of competitive inhibitors exceedingly difficult. Furthermore, the protein's surface is relatively smooth and lacks the deep, well-defined hydrophobic pockets that are typically exploited by small-molecule drugs.[15] These obstacles thwarted numerous drug discovery efforts, leaving patients with KRAS-mutant cancers with limited therapeutic options beyond conventional chemotherapy.

A paradigm shift occurred with the specific characterization of the KRAS G12C mutation. This mutation, which involves the substitution of glycine with a cysteine residue at codon 12, is present in approximately 14% of patients with lung adenocarcinoma and 3-4% of those with colorectal cancer.[17] The critical breakthrough was the recognition that the thiol group of the mutant cysteine residue, which is absent in wild-type KRAS, could serve as a unique, targetable nucleophile. This discovery opened a therapeutic window for the development of covalent inhibitors specifically designed to form an irreversible bond with this reactive cysteine.[10] By forming this covalent adduct, such inhibitors could permanently lock the KRAS G12C protein in its inactive state, overcoming the challenges of GTP competition and the lack of a traditional binding pocket. This structure-based drug design approach successfully transformed a specific vulnerability of the mutant protein into a therapeutic opportunity, heralding a new era of targeted therapy for KRAS-driven cancers.

Adagrasib: Development and Molecular Design Rationale

Adagrasib (formerly MRTX-849) emerged from this new understanding as a second-generation, orally available KRAS G12C inhibitor developed by Mirati Therapeutics.[1] The molecule was intentionally engineered with an optimized pharmacological profile to maximize its therapeutic potential. A key element of its design rationale was to achieve sustained target inhibition sufficient to overcome the natural biology of the KRAS protein, which is known to regenerate with a half-life of approximately 24 to 48 hours.[10]

To meet this challenge, Adagrasib was optimized for several desirable pharmacokinetic properties, including high oral bioavailability and, most notably, a long plasma half-life of approximately 23-24 hours.[10] This long half-life ensures that therapeutic drug concentrations are maintained throughout the entire twice-daily dosing interval, providing continuous pressure on the KRAS G12C target that can effectively suppress signaling even as new protein is synthesized. This contrasts with first-generation inhibitors with shorter half-lives, which may allow for pathway reactivation between doses. Adagrasib was developed as a highly potent and selective agent, demonstrating nanomolar efficacy in preclinical models and establishing a new therapeutic option for patients with KRAS G12C-mutated solid tumors.[1] In October 2023, Bristol Myers Squibb announced its acquisition of Mirati Therapeutics, incorporating Adagrasib into its oncology portfolio and underscoring the drug's perceived value and clinical importance.[23]

Physicochemical Properties and Formulations

Adagrasib is a synthetic organic small molecule classified as an antineoplastic agent and a specific inhibitor of the KRAS protein.[9] It is administered orally in the form of 200 mg, oval-shaped, white to off-white, immediate-release film-coated tablets, with "200" debossed on one side and a stylized "M" on the other.[26] For research purposes, Adagrasib is typically supplied as a crystalline solid and demonstrates solubility in solvents such as dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).[22] The key identifying and chemical properties of Adagrasib are consolidated in Table 3.1.

Table 3.1: Key Identifiers and Chemical Properties of Adagrasib

Property	Value	Source(s)
Generic Name	Adagrasib	1
Brand Name	Krazati®	3
DrugBank ID	DB15568	3
CAS Number	2326521-71-3	3
Code Names	MRTX-849, MRTX849	1
Drug Class	Small Molecule, Antineoplastic Agent, KRAS Protein Inhibitor	9
Chemical Formula	C32​H35​ClFN7​O2​	3
Molecular Weight	604.13 g·mol⁻¹	3
IUPAC Name	{(2S)-4-methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl}acetonitrile	3
Formulation	200 mg oral film-coated tablet	26

Preclinical and Clinical Pharmacology

Mechanism of Action: Irreversible Inhibition of the KRAS G12C Inactive State

The mechanism of action of Adagrasib is centered on its highly specific and irreversible covalent inhibition of the KRAS G12C mutant protein.[1] The G12C mutation results in a constitutively active KRAS protein that is perpetually bound to GTP, driving oncogenic signaling.[9] Adagrasib was designed to exploit the unique chemical properties of the mutant cysteine residue at position 12. It selectively binds to a pocket on the KRAS G12C protein known as the switch-II pocket, which is accessible only when the protein is in its inactive, GDP-bound conformation.[10]

Upon binding, the acrylamide "warhead" of the Adagrasib molecule forms a permanent, covalent bond with the thiol group of the Cys12 residue.[13] This irreversible binding event effectively traps the KRAS G12C protein in its inactive state, preventing it from cycling back to the active, GTP-bound form.[1] By locking the mutant protein "off," Adagrasib completely shuts down its ability to engage with and activate downstream effector proteins. A crucial aspect of its mechanism is its high selectivity; it does not bind to or inhibit wild-type KRAS, which lacks the targetable cysteine residue. This ensures that the drug's activity is confined to tumor cells harboring the G12C mutation, minimizing off-target effects on normal cellular processes regulated by wild-type KRAS.[1]

Pharmacodynamics: Downstream Pathway Suppression and Antitumor Activity

The functional consequence of Adagrasib's irreversible inhibition of KRAS G12C is the profound suppression of downstream oncogenic signaling pathways.[15] By neutralizing the mutant KRAS protein, Adagrasib effectively blocks signal transduction through the MAPK/ERK and PI3K/AKT pathways, which are critical for the proliferation and survival of KRAS-driven cancer cells.[2]

Preclinical studies have robustly demonstrated these pharmacodynamic effects. In biochemical assays, Adagrasib inhibits KRAS G12C with high potency (inhibition constant, Ki​≈0.3 nM) and exhibits over 1,000-fold selectivity for the mutant protein compared to wild-type KRAS.[10] In KRAS G12C-mutant cancer cell lines, such as NCI-H358 (NSCLC) and MIA PaCa-2 (pancreatic), Adagrasib potently suppresses the phosphorylation of ERK and inhibits cell proliferation with half-maximal inhibitory concentrations (

IC50​) in the low nanomolar range (typically 5-15 nM).[1] This potent antitumor activity was further validated in

in vivo patient- and cell-derived xenograft models. Oral administration of Adagrasib in mice bearing KRAS G12C-mutated tumors led to sustained MAPK pathway inhibition, significant tumor growth inhibition, and in many cases, complete tumor regression.[1] This activity was highly selective, as no significant antitumor effect was observed in wild-type KRAS xenograft models at equivalent drug exposures.[28]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion

The clinical pharmacology of Adagrasib is defined by a pharmacokinetic (PK) profile that was intentionally optimized to support sustained and effective target inhibition.[10] This profile is a key differentiator and is fundamentally linked to its observed clinical efficacy, including its durability and CNS activity.

Absorption: Following oral administration of the recommended 600 mg dose, Adagrasib is absorbed with a median time to reach maximum plasma concentration (Tmax​) of approximately 6 hours.[9] The drug's exposure, as measured by area under the curve (AUC) and maximum concentration (

Cmax​), increases in a dose-proportional manner between 400 mg and 600 mg.[9] At the recommended twice-daily dosing regimen, Adagrasib reaches steady-state plasma concentrations within 8 days, exhibiting a notable 6-fold accumulation, which contributes to maintaining therapeutic levels.[9] The administration of Adagrasib with a high-fat, high-calorie meal does not result in clinically significant changes to its pharmacokinetics, allowing it to be taken with or without food.[9]

Distribution: Adagrasib is extensively distributed throughout the body, as indicated by a large apparent volume of distribution of 942 L.[9] It is highly bound to human plasma proteins (approximately 98%)

in vitro.[9] A clinically significant feature of its distribution is its ability to penetrate the central nervous system.[10] This PK property is the direct basis for the clinically observed intracranial activity in patients with NSCLC and untreated brain metastases, a crucial advantage in a disease where CNS involvement is common and associated with a poor prognosis.[11]

Metabolism: The metabolism of Adagrasib is complex and time-dependent. Following a single dose, it is primarily metabolized by the cytochrome P450 enzyme CYP3A4.[9] However, with multiple doses, Adagrasib functions as a mechanism-based inhibitor of CYP3A4. As it inhibits its own primary metabolic pathway upon reaching steady state, other CYP enzymes—including CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6—begin to contribute more significantly to its clearance.[9] This metabolic shift has important implications for drug-drug interactions. Initially, Adagrasib is a "victim" of strong CYP3A4 modulators, but after approximately 8 days of treatment, it becomes a "perpetrator," capable of inhibiting the metabolism of other drugs that are sensitive CYP3A4 substrates.[27] This dual role necessitates careful management of concomitant medications.

Excretion: Adagrasib is eliminated from the body primarily through the feces. Following a single radiolabeled dose, approximately 75% of the dose was recovered in feces (with 14% as the unchanged parent drug), while a much smaller fraction, 4.5%, was recovered in urine (2% as unchanged drug).[9] The drug has a long terminal elimination half-life of approximately 23 hours and an apparent oral clearance (CL/F) of 37 L/h.[9] This long half-life is a cornerstone of its design, enabling sustained drug exposure above the required therapeutic threshold to continuously inhibit the KRAS G12C protein, which regenerates every 24-48 hours.[10] This sustained inhibition is believed to be critical for achieving durable clinical responses.

Clinical Efficacy in KRAS G12C-Mutated Malignancies

The KRYSTAL-1 Trial: A Pivotal Multi-Cohort Study

The clinical development of Adagrasib has been anchored by the KRYSTAL-1 trial (NCT03785249), a foundational Phase 1/2, multicenter, open-label study.[3] This trial was designed with multiple expansion cohorts to evaluate the safety, tolerability, pharmacokinetics, and efficacy of Adagrasib, both as a monotherapy and in combination with other anticancer agents, across a range of advanced solid tumors harboring the KRAS G12C mutation.[17] The Phase 1 portion of the study utilized an accelerated titration design to establish the safety profile and determine the optimal dose. Based on a comprehensive evaluation of safety, tolerability, and pharmacokinetic properties, the recommended Phase 2 dose (RP2D) was established at 600 mg administered orally twice daily.[10] The subsequent Phase 2 cohorts provided the pivotal efficacy data that supported Adagrasib's regulatory approvals.

Efficacy in Previously Treated Non-Small Cell Lung Cancer (NSCLC)

Primary and Secondary Efficacy Endpoints

The registrational cohort for the NSCLC indication included 112 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC whose disease had progressed on or after treatment with both a platinum-based chemotherapy regimen and an immune checkpoint inhibitor.[3] This represents a heavily pretreated population with limited therapeutic options. The primary efficacy outcomes were confirmed objective response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review (BICR) according to RECIST 1.1 criteria.[5]

In this cohort, Adagrasib monotherapy demonstrated significant and durable clinical activity:

• Objective Response Rate (ORR): The confirmed ORR was 43% (95% Confidence Interval [CI]: 34%, 53%).[5] The disease control rate (DCR), which includes patients with stable disease, was 80%.[36]
• Duration of Response (DOR): The median DOR was 8.5 months (95% CI: 6.2, 13.8).[5]
• Progression-Free Survival (PFS): The median PFS was 6.5 months (95% CI: 4.7, 8.4).[18]
• Overall Survival (OS): At a median follow-up of 15.6 months, the median OS was 12.6 months (95% CI: 9.2, 19.2).[18] A subsequent pooled analysis from the KRYSTAL-1 trial with a two-year follow-up (N=132) reported a median OS of 14.1 months, with one- and two-year survival rates of 52.8% and 31.3%, respectively, underscoring the durability of the benefit.[6]

Intracranial Activity in Patients with CNS Metastases

A critical area of unmet need in NSCLC is the management of brain metastases, which occur frequently and confer a poor prognosis.[17] Adagrasib's ability to penetrate the CNS was prospectively evaluated in a Phase 1b cohort of the KRYSTAL-1 trial, which enrolled patients with KRAS G12C-mutated NSCLC and active, untreated CNS metastases.[11] This cohort provided the first prospective clinical evidence of intracranial activity for a KRAS G12C inhibitor.

Among 19 radiographically evaluable patients, Adagrasib demonstrated compelling CNS-specific efficacy:

• Intracranial ORR: The confirmed intracranial ORR was 42%.[11]
• Intracranial DCR: The intracranial disease control rate was 90%.[11]
• Intracranial DOR: The median duration of intracranial response was 11.2 months.[18]
• Survival: In the full cohort of 25 patients, the median OS was 11.4 months.[11]

These data establish that Adagrasib provides meaningful clinical benefit not only systemically but also within the CNS, representing a significant advantage for this patient population.

Efficacy in Previously Treated Colorectal Cancer (CRC) in Combination with Cetuximab

Rationale for Dual EGFR/KRAS G12C Blockade

While Adagrasib monotherapy showed modest activity in KRAS G12C-mutated CRC, preclinical and early clinical data revealed that its efficacy was limited by a mechanism of adaptive resistance. In colorectal cancer cells, the inhibition of the KRAS G12C protein can trigger a rapid feedback loop that leads to the upregulation and reactivation of the Epidermal Growth Factor Receptor (EGFR) on the cell surface. This reactivated EGFR signaling can then bypass the KRAS G12C blockade and reactivate the MAPK pathway, allowing tumor cells to escape inhibition and continue to proliferate.[8]

This biological understanding provided a strong rationale for a combination therapy strategy. By concurrently administering Adagrasib with an anti-EGFR antibody, such as cetuximab, it is possible to achieve a dual blockade of both KRAS G12C and the EGFR-mediated escape pathway. This approach is designed to mitigate adaptive resistance, deepen the antitumor response, and improve clinical outcomes compared to either agent alone.[8]

Combination Therapy Efficacy Endpoints

The efficacy of Adagrasib in combination with cetuximab was evaluated in a pooled analysis of 94 patients from the KRYSTAL-1 trial with heavily pretreated, unresectable or metastatic KRAS G12C-mutated CRC.[7] All patients had received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

The combination therapy demonstrated promising clinical activity:

• ORR: The confirmed ORR by BICR was 34.0% (95% CI: 25%, 45%). All observed responses were partial responses.[7]
• DOR: The median DOR was 5.8 months (95% CI: 4.2, 7.6).[7] Notably, 31% of responding patients had a response lasting at least 6 months.[7]
• PFS: The median PFS was 6.9 months (95% CI: 5.7, 7.4).[8]
• OS: The median OS was 15.9 months (95% CI: 11.8, 18.8), a notable outcome in this late-line setting.[8]

Table 5.1: Summary of Efficacy Results from the KRYSTAL-1 Trial (NSCLC and CRC Cohorts)

Efficacy Endpoint	NSCLC (Adagrasib Monotherapy)	CRC (Adagrasib + Cetuximab)
Patient Population (N)	112	94
Objective Response Rate (ORR)	43% (95% CI: 34-53)	34% (95% CI: 25-45)
Median Duration of Response (DOR)	8.5 months (95% CI: 6.2-13.8)	5.8 months (95% CI: 4.2-7.6)
Median Progression-Free Survival (PFS)	6.5 months (95% CI: 4.7-8.4)	6.9 months (95% CI: 5.7-7.4)
Median Overall Survival (OS)	12.6 months (95% CI: 9.2-19.2)¹	15.9 months (95% CI: 11.8-18.8)
Intracranial ORR (Untreated CNS Mets)	42% (N=19)	Not Applicable
¹ A 2-year pooled analysis (N=132) reported a median OS of 14.1 months.
Sources: 5

Safety and Tolerability Profile

Overview of Adverse Reactions from Clinical Trials

The safety profile of Adagrasib has been extensively characterized in the KRYSTAL-1 trial and other supporting studies. While treatment-related adverse events (TRAEs) are nearly universal, they are predominantly Grade 1 or 2 in severity and are generally considered manageable with supportive care and dose modifications.[10] The profile of common adverse events differs slightly between its use as a monotherapy in NSCLC and its use in combination with cetuximab in CRC, reflecting the additive toxicities of the anti-EGFR agent.

• NSCLC (Monotherapy): In patients treated with Adagrasib as a single agent, the most frequently reported adverse reactions (occurring in ≥20% of patients) were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity (liver enzyme elevations), renal impairment (creatinine increase), dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.[3]
• CRC (Combination with Cetuximab): When used in combination with cetuximab, the most common adverse reactions (≥20%) included rash (a well-known toxicity of EGFR inhibitors), nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy.[7]

Detailed Analysis of Warnings and Precautions

The prescribing information for Adagrasib highlights four key warnings and precautions for serious or life-threatening adverse reactions that require diligent monitoring and management.

Gastrointestinal Adverse Reactions

Adagrasib can cause severe gastrointestinal (GI) adverse reactions. Nausea, diarrhea, and vomiting are extremely common, occurring in 89% of patients on monotherapy, with 9% experiencing Grade 3 events.[39] These symptoms led to dose interruptions or reductions in 29% of patients.[39] More serious GI events, including GI bleeding, obstruction, colitis, and stenosis, have also been reported.[12] Proactive management with supportive care, such as antiemetic and antidiarrheal medications, and fluid replacement is essential. Dose modification or discontinuation may be necessary based on the severity of the reaction.[20]

QTc Interval Prolongation

Treatment with Adagrasib can cause prolongation of the QTc interval on an electrocardiogram (ECG), which increases the risk for potentially fatal ventricular tachyarrhythmias, such as torsades de pointes, and sudden death.[9] In clinical studies, 6% of patients on monotherapy had an average QTc interval greater than 501 ms, and 11% had an increase from baseline of more than 60 ms.[39] The effect is concentration-dependent. The use of Adagrasib should be avoided in patients with congenital long QT syndrome. Baseline and periodic monitoring of ECGs and serum electrolytes (especially potassium and magnesium) is recommended for all patients, with more frequent monitoring for those at higher risk.[29]

Hepatotoxicity

Adagrasib can cause hepatotoxicity, which may manifest as drug-induced liver injury and hepatitis.[12] Elevations in liver transaminases (ALT and AST) are common, occurring in 32% of patients on monotherapy, with 5% experiencing Grade 3 and 0.5% Grade 4 elevations.[39] Overall hepatotoxicity led to dose interruption or reduction in 12% of patients.[39] Liver function tests (AST, ALT, alkaline phosphatase, and total bilirubin) should be monitored at baseline, monthly for the first three months of treatment, and as clinically indicated thereafter.[39]

Interstitial Lung Disease / Pneumonitis

A serious and potentially fatal risk associated with Adagrasib is interstitial lung disease (ILD) or pneumonitis. In the pooled safety population, ILD/pneumonitis occurred in 4.1% of patients, with 1.4% being Grade 3 or 4, and one case was fatal.[12] The median time to first onset was 12 weeks.[41] Patients should be closely monitored for any new or worsening respiratory symptoms, such as dyspnea, cough, or fever. If ILD/pneumonitis is suspected, Adagrasib should be withheld immediately and permanently discontinued if no other potential causes can be identified.[12]

Common Laboratory Abnormalities

In addition to clinical adverse events, treatment with Adagrasib is associated with a number of common laboratory abnormalities that require routine monitoring.

• NSCLC (Monotherapy): The most common laboratory abnormalities (≥25%) were decreased lymphocytes, increased aspartate aminotransferase (AST), decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase (ALT), increased lipase, decreased platelets, decreased magnesium, and decreased potassium.[3]
• CRC (Combination with Cetuximab): Common laboratory abnormalities included decreased lymphocytes, potassium, magnesium, and hemoglobin, as well as increased AST, lipase, albumin, and ALT.[4]

Table 6.1: Incidence of Common (≥20%) Adverse Reactions in NSCLC and CRC Trials

Adverse Reaction	NSCLC (Adagrasib Monotherapy)	CRC (Adagrasib + Cetuximab)
	All Grades (%)	Grade 3-4 (%)
Nausea	70	4.3
Diarrhea	69	4.3
Vomiting	57	2.6
Fatigue	55	7
Rash	16	0
Musculoskeletal Pain	38	5
Hepatotoxicity	37	7
Renal Impairment	33	3.5
Edema	30	0.8
Dyspnea	26	5
Decreased Appetite	29	2.6
Headache	16	0
Dry Skin	10	0
Data compiled from pooled safety populations and specific trial cohorts as reported in prescribing information and clinical study publications. Percentages may vary slightly between sources.
Sources: 3

Dosage, Administration, and Management of Adverse Events

Recommended Dosing Regimen

The recommended dosage of Adagrasib (Krazati), for use either as a single agent for NSCLC or in combination with cetuximab for CRC, is 600 mg administered orally twice daily.[1] This regimen should be continued until disease progression or the development of unacceptable toxicity. Adagrasib can be taken at approximately the same time each day, with or without food. The 200 mg tablets should be swallowed whole and should not be chewed, crushed, or split.[27]

If a patient vomits after taking a dose, they should not take an additional dose but should resume dosing at the next scheduled time. If a dose is missed by more than 4 hours from the scheduled time, that dose should be skipped, and the patient should resume the normal dosing schedule at the next appointed time.[27]

Guidelines for Dose Modification and Discontinuation

A structured approach to dose modification is crucial for managing adverse reactions and maintaining patients on therapy. A maximum of two dose reductions are permitted for Adagrasib. The first dose reduction is to 400 mg twice daily. The second dose reduction is to 600 mg once daily. If a patient is unable to tolerate the 600 mg once-daily dose, Adagrasib should be permanently discontinued.[27] Specific guidelines for dose modification based on the type and severity of adverse reactions are detailed in Table 7.1.

Table 7.1: Recommended Dose Modifications for Key Adverse Reactions

Adverse Reaction	Severity (NCI CTCAE v5.0 Grade)	Recommended Dosage Modification
Nausea or Vomiting	Grade 3 or 4 (despite supportive care)	Withhold until ≤ Grade 1 or baseline. Resume at the next lower dose level.
Diarrhea	Grade 3 or 4 (despite supportive care)	Withhold until ≤ Grade 1 or baseline. Resume at the next lower dose level.
QTc Interval Prolongation	QTc > 500 ms OR > 60 ms increase from baseline	Withhold until QTc < 481 ms or baseline. Resume at the next lower dose level.
	Torsade de pointes, polymorphic ventricular tachycardia, or signs of serious arrhythmia	Permanently discontinue.
Hepatotoxicity	Grade 2 AST or ALT	Decrease to the next lower dose level.
	Grade 3 or 4 AST or ALT	Withhold until ≤ Grade 1 or baseline. Resume at the next lower dose level.
	AST/ALT >3x ULN with total bilirubin >2x ULN (without alternative causes)	Permanently discontinue.
Interstitial Lung Disease / Pneumonitis	Any Grade (suspected)	Withhold therapy.
	Any Grade (confirmed)	Permanently discontinue.
Other Adverse Reactions	Grade 3 or 4	Withhold until ≤ Grade 1 or baseline. Resume at the next lower dose level.
Source: 29

Drug-Drug Interaction Profile

Adagrasib's complex metabolic profile results in several clinically significant drug-drug interactions that require careful management.

• Effect of Other Drugs on Adagrasib:
• Strong CYP3A4 Inducers: Concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John's Wort) should be avoided, as they can significantly decrease Adagrasib plasma concentrations and reduce its efficacy.[27]
• Strong CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) should be avoided until Adagrasib has reached steady-state concentrations (approximately 8 days). These inhibitors can increase Adagrasib exposure and the risk of adverse reactions.[27]
• Effect of Adagrasib on Other Drugs:
• Sensitive CYP3A4 Substrates: Adagrasib is a moderate CYP3A inhibitor at steady state. Concomitant use with sensitive CYP3A4 substrates (e.g., midazolam, alfentanil) should be avoided, as Adagrasib can increase their plasma concentrations and the risk of toxicity.[12]
• Sensitive CYP2C9, CYP2D6, or P-gp Substrates: Adagrasib is also an inhibitor of CYP2C9, CYP2D6, and the transporter P-glycoprotein (P-gp). Co-administration with sensitive substrates of these pathways where minimal concentration changes could lead to serious adverse reactions (e.g., warfarin, digoxin) should be avoided.[12]
• QTc-Prolonging Drugs: Concomitant use of Adagrasib with other medicinal products known to prolong the QTc interval (e.g., certain antiarrhythmics, antipsychotics, macrolide antibiotics) should be avoided due to the potential for additive effects and an increased risk of serious arrhythmias.[12]

Regulatory Status and Future Directions

Global Regulatory Approvals: FDA and EMA

Adagrasib has navigated the regulatory landscape to secure approvals in the United States and Europe, supported by a robust data package and expedited review designations reflecting the high unmet need in its target populations.

• U.S. Food and Drug Administration (FDA):
• Adagrasib received Breakthrough Therapy Designation from the FDA for both NSCLC and, in combination with cetuximab, for CRC.[42]
• On December 12, 2022, the FDA granted accelerated approval to Adagrasib for adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.[3]
• On June 21, 2024, the FDA granted a second accelerated approval for Adagrasib in combination with cetuximab for adult patients with KRAS G12C-mutated locally advanced or metastatic CRC who have received prior treatment with standard chemotherapy regimens.[3]
• Both accelerated approvals are contingent upon the verification and description of clinical benefit in confirmatory clinical trials.[4]
• European Medicines Agency (EMA):
• Following a re-examination procedure, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion in November 2023.[3]
• On January 5, 2024, the European Commission granted conditional marketing authorization for Adagrasib as a monotherapy for adult patients with advanced NSCLC with a KRAS G12C mutation and disease progression after at least one prior systemic therapy.[34]
• This conditional authorization is also contingent upon the company providing comprehensive clinical data from an ongoing confirmatory trial comparing Adagrasib with docetaxel.[45]

Companion Diagnostics and Patient Selection

The use of Adagrasib is predicated on a precision medicine approach, where treatment is strictly guided by the molecular profile of the patient's tumor. Patient selection is mandatory and must be based on the confirmed presence of a KRAS G12C mutation as determined by an FDA-approved test.[27] This regulatory requirement highlights the inextricable link between the targeted therapy and its corresponding diagnostic test.

The FDA has concurrently approved specific companion diagnostics for use with Adagrasib:

• QIAGEN therascreen KRAS RGQ PCR kit (for use with tissue specimens).[5]
• Agilent Resolution ctDx FIRST Assay (for use with plasma specimens, i.e., liquid biopsy).[5]

This dual approval of both tissue- and plasma-based diagnostics provides flexibility in clinical practice. The regulatory guidance specifies that if a KRAS G12C mutation is not detected in a plasma specimen, tumor tissue should be tested to confirm the patient's mutational status.[5] This co-development and co-approval strategy exemplifies the maturation of the precision oncology paradigm, ensuring that potent, highly targeted therapies are delivered exclusively to the patient population most likely to derive clinical benefit, thereby maximizing efficacy while avoiding unnecessary toxicity in non-eligible patients.

Ongoing Clinical Trials and Future Research Trajectories

The clinical development program for Adagrasib remains active and is aimed at solidifying its current indications and expanding its use into new areas.

• Confirmatory Trials: Ongoing Phase 3 trials are essential to convert the accelerated and conditional approvals into full approvals. These include the KRYSTAL-12 trial, comparing Adagrasib monotherapy to docetaxel in previously treated NSCLC, and the KRYSTAL-10 trial, evaluating Adagrasib plus cetuximab versus standard chemotherapy in the second-line setting for CRC.[43]
• Expansion into Other Tumors: Given that the KRAS G12C mutation occurs in other solid tumors, clinical studies are underway to evaluate Adagrasib's efficacy in malignancies such as pancreatic cancer and biliary tract cancers.[1]
• Novel Combinations: Research is actively exploring rational combination strategies to enhance efficacy and overcome resistance. This includes combining Adagrasib with other targeted agents, such as SHP2 inhibitors (e.g., TNO155), and with immunotherapy agents.[17]
• Corporate Development: The acquisition of Mirati Therapeutics by Bristol Myers Squibb in early 2024 is expected to provide the resources and global infrastructure to support the continued development and commercialization of Adagrasib, further cementing its role in the oncology landscape.[19]

Conclusion and Clinical Perspective

Adagrasib (Krazati®) marks a pivotal moment in the history of oncology, representing the successful culmination of decades of research aimed at conquering the "undruggable" KRAS oncogene. As a potent, selective, and irreversible covalent inhibitor of KRAS G12C, it provides a highly effective targeted therapy for patients with KRAS G12C-mutated non-small cell lung cancer and colorectal cancer—populations that have historically faced poor prognoses and lacked effective treatment options beyond conventional chemotherapy.[1]

The clinical efficacy demonstrated in the KRYSTAL-1 trial is compelling. In heavily pretreated NSCLC, Adagrasib monotherapy yields durable responses and a meaningful survival benefit. Its differentiated pharmacokinetic profile, particularly its long half-life and ability to penetrate the central nervous system, translates directly into tangible clinical advantages, including sustained target inhibition and significant intracranial activity in patients with brain metastases.[10] In CRC, the rational combination of Adagrasib with cetuximab effectively abrogates a key mechanism of adaptive resistance, leading to improved outcomes in this challenging disease.

This profound efficacy must be balanced with a pragmatic understanding of the drug's safety profile. While the majority of adverse events are low-grade and manageable, the potential for serious toxicities—including QTc interval prolongation, hepatotoxicity, and interstitial lung disease—demands rigorous patient monitoring and strict adherence to established guidelines for dose modification.[12] The successful integration of Adagrasib into clinical practice requires a comprehensive approach that includes proactive management of side effects and careful consideration of drug-drug interactions.

Ultimately, Adagrasib is more than just a single therapeutic agent. Its development and approval validate a novel drug design strategy, establish a new standard of care for thousands of patients worldwide, and serve as a powerful proof of concept that has invigorated the entire field of RAS-targeted drug discovery. The ongoing confirmatory trials and the exploration of new therapeutic combinations will continue to refine its clinical role, but its status as a landmark achievement in precision oncology is already firmly secured. Adagrasib has transformed a specific molecular vulnerability into a source of tangible hope, fundamentally altering the treatment landscape for KRAS G12C-mutated cancers.

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