Daraxonrasib RMC-6236 50 mg × 28 tablets per box

Currently, RMC-6236 (Generic Name: Daraxonrasib) remains in the clinical research phase and has not yet received regulatory approval for commercialization from any regulatory body; therefore, there is no formal commercial product launch at this time. This product is intended solely for use in clinical trials; please refrain from purchasing it unless medically necessary. Phase 3 clinical trials for pancreatic cancer (RASolute 302) and non-small cell lung cancer (RASolve 301) are currently underway.

Generic Name: Daraxonrasib

Development Code: RMC-6236

Specification: 50 mg/capsule; 28 capsules/box

Developer: Revolution Medicines, Inc.

Manufacturer: Indar Pharmaceutical

Drug Class: RAS(ON) Multi-selective Inhibitor (capable of simultaneously inhibiting various mutant and wild-type RAS proteins)

Primary Indications: Advanced solid tumors harboring RAS mutations, including Pancreatic Ductal Adenocarcinoma and Non-Small Cell Lung Cancer.

[Indications]

Indicated for the treatment of malignant tumors harboring RAS gene mutations, including but not limited to:

- KRAS G12C mutation-positive Non-Small Cell Lung Cancer (including both treatment-naïve patients and those whose disease has progressed following prior treatment);

- Pancreatic cancer with RAS mutations (including subtypes such as G12D, G12V, etc.—e.g., tumors associated with HPAC and Capan-2 cell lines);

- Other RAS-driven tumors (including malignancies associated with NRAS and HRAS mutations); specific indications should be determined based on molecular testing results and clinical assessment.

This product inhibits tumor cell proliferation by specifically blocking the activity of mutant RAS proteins. It is suitable for patients with RAS-mutated tumors that are refractory to or have progressed following prior treatment regimens; it may also serve as a first-line treatment option for certain eligible patients. **Pharmacological Action**

RMC6236 is an orally active, non-covalent, multi-selective inhibitor of RAS(ON). It specifically targets wild-type and mutant RAS proteins (including KRAS, NRAS, and HRAS) in their active, GTP-bound state. By disrupting the interaction between RAS proteins and the RAS-binding domain of BRAF, it blocks the transmission of downstream pro-proliferative signaling pathways—such as the MAPK pathway—thereby inhibiting tumor cell growth and inducing tumor cell apoptosis.

The EC₅₀ values of this agent against wild-type KRAS, NRAS, and HRAS, as well as various oncogenic RAS variants, range from 28 to 220 nM. It demonstrates significant anti-tumor activity against KRAS-mutated tumors while exerting minimal impact on wild-type RAS, thereby maximally preserving normal cellular function. Furthermore, this agent inhibits PERK protein activity; when used in combination with KO-2806, it effectively mitigates the rebound of mTOR activity, thereby enhancing the anti-tumor effect.

**[Pharmacokinetics]**

1. **Absorption:** Absorption is rapid following oral administration. The drug may be taken either on an empty stomach or after a meal, as food has a minimal effect on absorption. The time to reach peak plasma concentration (Tmax) is approximately 2 to 4 hours, and steady-state plasma concentrations are rapidly achieved with regular daily dosing.

2. **Distribution:** Following absorption, the drug is widely distributed throughout body tissues, with particularly high concentrations observed in tumor tissues. Tumor exposure levels are significantly higher than blood exposure levels, and elimination from tumor tissues is slow, allowing for the sustained maintenance of effective drug concentrations over time.

3. **Metabolism:** The drug is primarily metabolized by the liver, with metabolic pathways consisting mainly of oxidation and hydrolysis reactions. Moderate to severe hepatic impairment affects drug metabolism, necessitating dose adjustment.

4. **Excretion:** The drug is primarily excreted via feces and urine. It possesses a relatively long elimination half-life, allowing for the maintenance of stable plasma concentrations with once-daily dosing, thereby reducing the risk of drug resistance.

5. **Clinical PK/PD Modeling:** Studies indicate that a daily dose of 100 mg achieves tumor control, while a daily dose of 300 mg achieves objective clinical response. This latter dose enables sustained inhibition of the RAS pathway—defined as ≥90% inhibition, as evidenced by a reduction in DUSP6 mRNA levels—while maintaining a manageable tolerability profile. [Dosage and Administration]

I. Recommended Dosage

Recommended Dosage for Adults: 300 mg orally once daily. It may be taken either on an empty stomach or after a meal. It is recommended to take the medication at a fixed time each day to ensure consistent dosing intervals and to avoid missed doses.

Duration of Treatment: Continue administration until disease progression occurs, intolerable toxicity develops, or treatment is discontinued following a physician's assessment.

II. Dosage Adjustment

Dosage adjustment principles based on treatment-related adverse events (TRAEs) are as follows (data derived from clinical trial NCT05379985):

- First occurrence of Grade 3 rash, diarrhea, nausea, or elevated liver enzymes: Suspend medication. Once symptoms resolve to Grade ≤1, treatment may be resumed at the original dose or at a reduced dose of 200 mg.

- Recurrence of any of the aforementioned Grade 3 toxicities: Reduce the dose to 200 mg. If still not tolerated, the dose may be further reduced to 100 mg.

- Occurrence of Grade 4 toxicity (e.g., severe hepatic injury, Stevens-Johnson syndrome): Permanently discontinue the medication.

III. Dosage for Special Populations

- Patients with Hepatic Impairment: No dosage adjustment is required for patients with mild hepatic impairment. For patients with moderate to severe hepatic impairment, use with caution; a dose reduction to 200 mg once daily is recommended, accompanied by close monitoring of liver function parameters.

- Patients with Renal Impairment: Currently, no clinical data are available regarding the use of this medication in patients with renal impairment. Use with caution in patients with mild to moderate renal impairment; use is contraindicated in patients with severe renal impairment.

- Elderly Patients (≥65 years): No dosage adjustment is required; close monitoring for adverse reactions is sufficient.

- Children and Adolescents: The safety and efficacy of this medication have not been established in patients under 18 years of age; therefore, its use is not recommended in this population.

IV. Management of Missed Doses

If a dose is missed, do not take the missed dose. Resume the regular dosing schedule at the next scheduled time. Do not take a double dose to compensate for a missed dose, as this may increase the risk of toxicity. [Adverse Reactions]

I. Common Adverse Reactions (Incidence ≥ 10%)

Based on clinical trial data (n=614), this product is generally well-tolerated. Common adverse reactions primarily involve the skin and gastrointestinal tract; most are Grade 1 or 2 in severity and can be alleviated through symptomatic management:

- Skin System: Rash (52%–81%, manifesting as maculopapular rash, dryness, and desquamation), pruritus, dry skin;

- Digestive System: Nausea (21%–46%), diarrhea (21%–39%), vomiting (15%–33%), decreased appetite;

- Systemic Symptoms: Fatigue (approx. 20%), dizziness, headache;

- Liver Function: Elevated liver enzymes (ALT/AST, 10%–15%).

II. Serious Adverse Reactions (Incidence ≥ 3%)

- Grade 3 Rash: Incidence is 9% in the absence of prophylactic care; with prophylactic care, the incidence can be reduced to 0%;

- Grade 3 Diarrhea/Nausea: Approx. 3%–5%;

- Hepatotoxicity: 2%–3%, manifesting as severe elevations in liver enzymes and bilirubin;

- Others: Rare occurrences of severe allergic reactions, interstitial lung disease, and gastrointestinal bleeding (current data are insufficient and require further study).

III. Recommendations for Adverse Reaction Management

- Cutaneous Toxicity: Initiate treatment with a combination of topical moisturizers and low-potency corticosteroids (e.g., hydrocortisone cream); avoid using irritating skincare products and avoid sun exposure. This approach can significantly reduce the incidence of severe rash;

- Gastrointestinal Reactions: Use symptomatic treatment with antiemetics (e.g., ondansetron) and antidiarrheals (e.g., loperamide); use proton pump inhibitors for short-term relief if necessary;

- Liver Function Monitoring: Monitor ALT/AST and bilirubin levels prior to treatment initiation and before the start of each treatment cycle. If persistent elevations in liver enzymes occur, adjust the dosage or discontinue the medication promptly. [Contraindications]

- Contraindicated in patients with known hypersensitivity to RMC6236 or to any of the excipients contained in this product;

- Contraindicated in patients with severe renal impairment;

- Contraindicated in pregnant and breastfeeding women.

[Precautions]

1. Molecular Testing Requirements: Prior to administration, patients must undergo *RAS* gene mutation testing using either tissue or blood samples to confirm the presence of a *RAS* mutation (e.g., *KRAS* G12C, G12D, G12V, etc.). This product should only be used in patients with confirmed *RAS* mutations; it is ineffective in patients without such mutations.

2. Hepatic Function Monitoring: This product is primarily metabolized by the liver; therefore, hepatic function (ALT, AST, bilirubin) must be monitored regularly throughout the course of treatment. In the event of severe hepatotoxicity, administration must be immediately discontinued, and appropriate symptomatic treatment initiated.

3. Prevention of Cutaneous Toxicity: Patients are advised to maintain proper skin care during treatment, avoid sun exposure, and use prophylactic skin care products as directed by their physician to minimize the incidence of skin rashes.

4. Drug Interactions:

- Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin), as this may increase plasma concentrations of this product and heighten the risk of toxicity;

- Avoid concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine), as this may decrease plasma concentrations of this product and compromise therapeutic efficacy;

- When used in combination with KO-2806, the anti-tumor effect may be enhanced; however, adverse reactions must be closely monitored.

5. Special Populations:

- Pregnant and Breastfeeding Women: This product may pose potential risks to the fetus or infant. It is contraindicated in pregnant women. Breastfeeding women must discontinue breastfeeding while receiving this product and should not resume breastfeeding for at least one month after the final dose;

- Children and Adolescents: Use in this population is not recommended, as the safety and efficacy have not yet been established;

- Elderly Patients: Hepatic and renal function, as well as adverse reactions, must be closely monitored; dose adjustments should be made as necessary.

6. Drug Resistance: Resistance may develop with long-term use of this product. If a patient experiences disease progression (e.g., tumor enlargement, appearance of new lesions), they should seek immediate medical attention so that a physician may evaluate whether to continue treatment with this product or switch to an alternative therapeutic regimen. 7. Missed Doses and Overdosage: Do not arbitrarily make up for a missed dose, and do not take a double dose. Taking an excessive dose may increase the risk of adverse reactions. In the event of an overdose, discontinue the medication immediately and seek medical attention for symptomatic management.

8. Clinical Trial Findings: In Phase I/Ib clinical trials (NCT05379985), this product demonstrated objective efficacy in patients with advanced KRAS G12X-mutated lung cancer and pancreatic cancer. In the subgroup of patients with KRAS G12C mutations who had failed prior therapies, the objective response rate exceeded 50%, and the median progression-free survival was significantly prolonged compared to the control group.

[Drug Interactions]

I. Drug-Drug Interactions

- Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, voriconazole): Co-administration may inhibit the metabolism of this product, thereby increasing its plasma concentration and raising the risk of adverse reactions. Co-administration should be avoided; however, if co-administration is deemed necessary, the dosage of this product should be reduced to 200 mg once daily, and patients should be closely monitored for adverse reactions.

- Strong CYP3A4 Inducers (e.g., rifampin, carbamazepine, phenytoin sodium): Co-administration may accelerate the metabolism of this product, thereby reducing its plasma concentration and potentially compromising its therapeutic efficacy. Co-administration should be avoided.

- KO-2806: Co-administration may enhance the inhibitory effect of this product on mTOR activity, thereby augmenting its anti-tumor efficacy. However, patients must be closely monitored for adverse reactions, and dosage adjustments should be made as necessary.

- Other Targeted Therapies/Chemotherapeutic Agents: The safety and efficacy of this product in combination with other anti-tumor agents have not yet been established. Such combinations should be used only under the guidance of a physician; patients should refrain from self-administering such combinations.

II. Drug-Food Interactions

Food has a minimal impact on the absorption of this product; it may be taken either on an empty stomach or after a meal. It is recommended to take the medication at a consistent time each day. Avoid consuming grapefruit juice while taking this product, as grapefruit juice may inhibit CYP3A4 activity and increase the plasma concentration of the drug.

[Overdosage]

Currently, there are no definitive data regarding drug overdose with this product. Taking an excessive dose may lead to severe adverse reactions (e.g., severe rash, hepatotoxicity, severe diarrhea). In the event of an overdose, administration of the drug must be discontinued immediately. The patient's vital signs and adverse reactions should be closely monitored, and appropriate symptomatic and supportive care should be administered; there is no specific antidote.

【Clinical Trials】

1. Clinical Trial Data: In a Phase I/Ib clinical trial (NCT05379985), a daily dose of 300 mg demonstrated objective efficacy in patients with advanced KRAS G12X-mutated lung cancer and pancreatic cancer. In the subgroup of patients with KRAS G12C mutations who had failed prior therapies, the objective response rate exceeded 50%; the median progression-free survival was significantly prolonged compared to the control group, and for the majority of responding patients, the duration of response lasted for more than six months.

2. *In Vitro* and *In Vivo* Studies: In *in vitro* experiments, this product demonstrated significant inhibitory effects against KRAS-mutated cancer cell lines (e.g., HPAC, Capan-2), with EC₅₀ values as low as 1.2 nM. In *in vivo* experiments involving various RAS-mutated tumor xenograft models, the product exhibited dose-dependent anti-tumor activity, effectively inhibiting tumor growth and, in some instances, leading to tumor regression.

【Notes】

1. This product is currently in the clinical research phase; specific indications, dosage and administration guidelines, adverse reactions, and other details may be further updated as clinical trials progress. Use of this medication must strictly adhere to a physician's guidance; self-medication is strictly prohibited.

2. Certain specifications of this product are intended solely for research purposes; for clinical use, only specifications that meet clinical standards should be selected.

3. Should a patient experience any discomfort or adverse symptoms during treatment, use of the medication must be discontinued immediately, and medical attention should be sought. **Product Specifications**

**Product Name:** Daraxonrasib Capsules 50 mg * 28 Capsules/Box (Daraxonrasib RMC-6236)

**Common Name:** Daraxonrasib

**Active Ingredient:** RMC-6236

**Dosage Form:** Capsules

**Specification:** 50 mg/capsule; 28 capsules/box

**Manufacturer:** Indar Pharmaceutical

**Indications:** Used for the treatment of malignant tumors harboring *RAS* gene mutations, including but not limited to:

- *KRAS* G12C mutation-positive non-small cell lung cancer (including both treatment-naïve patients and those with disease progression following prior treatment);

- Pancreatic cancer with *KRAS* mutations (including subtypes such as G12D, G12V, etc.) (e.g., tumors associated with HPAC or Capan-2 cell lines);

- Other *RAS*-driven tumors (including malignant tumors associated with *NRAS* or *HRAS* mutations); specific indications should be determined based on molecular testing results and clinical assessment.

This product inhibits tumor cell proliferation by specifically blocking the activity of mutant RAS proteins. It is indicated for patients with *RAS*-mutated tumors that are refractory to or have progressed following previous treatment regimens; it may also serve as a first-line treatment option for certain eligible patients.

**Dosage and Administration:** I. Recommended Dosage

**Recommended Adult Dosage:** 300 mg orally once daily. The medication may be taken either on an empty stomach or after a meal. It is recommended to establish a fixed daily dosing time to ensure consistent dosing intervals and to avoid missed doses.

**Duration of Treatment:** Continue administration until disease progression occurs, intolerable toxicity develops, or treatment is discontinued following a physician's clinical assessment. II. Dosage Adjustment

The principles for dosage adjustment based on treatment-related adverse events (TRAEs) are as follows (data derived from clinical trial NCT05379985):

- First occurrence of Grade 3 rash, diarrhea, nausea, or elevated liver enzymes: Suspend treatment; once symptoms resolve to Grade ≤1, treatment may be resumed at the original dose or at a reduced dose of 200 mg.

- Recurrence of any of the aforementioned Grade 3 toxicities: Reduce the dose to 200 mg; if still not tolerated, the dose may be further reduced to 100 mg.

- Occurrence of Grade 4 toxicity (e.g., severe hepatic injury, Stevens-Johnson syndrome): Permanently discontinue treatment.

III. Dosage for Special Populations

- Patients with Hepatic Impairment: No dosage adjustment is required for mild hepatic impairment; use with caution in patients with moderate to severe hepatic impairment; a dose reduction to 200 mg once daily is recommended, accompanied by close monitoring of liver function parameters.

- Patients with Renal Impairment: Currently, no clinical data are available regarding the use of this medication in patients with renal impairment; use with caution in patients with mild to moderate renal impairment; use is contraindicated in patients with severe renal impairment.

- Elderly Patients (≥65 years): No dosage adjustment is required; close monitoring for adverse reactions is sufficient.

- Children and Adolescents: The safety and efficacy of this medication have not been established in patients under 18 years of age; therefore, its use is not recommended.