Lumakras Drug Information

Patient Selection KRAS G12C-mutated Locally Advanced or Metastatic NSCLC Select patients for treatment of locally advanced or metastatic NSCLC with LUMAKRAS based on the presence of KRAS G12C mutation in tumor or plasma specimens. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of KRAS G12C mutations is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage and Administration

LUMAKRAS as a Single Agent for KRAS G12C-mutated Locally Advanced or Metastatic NSCLC The recommended dosage of LUMAKRAS is 960 mg (three 320 mg tablets or four 240 mg tablets or eight 120 mg tablets) orally once daily until disease progression or unacceptable toxicity. LUMAKRAS in Combination with Panitumumab for KRAS G12C-mutated mCRC The recommended dosage of LUMAKRAS is 960 mg (three 320 mg tablets or four 240 mg tablets or eight 120 mg tablets) orally once daily in combination with panitumumab until disease progression or unacceptable toxicity. Administer the first dose of LUMAKRAS prior to first panitumumab infusion.

Refer to the panitumumab full prescribing information for recommended panitumumab dosage information. Take the daily dose of LUMAKRAS at the same time each day with or without food. Swallow tablets whole.

Do not chew, crush or split tablets. If a dose of LUMAKRAS is missed by more than 6 hours, take the next dose as prescribed the next day. Do not take 2 doses at the same time to make up for the missed dose.

If vomiting occurs after taking LUMAKRAS, do not take an additional dose. Take the next dose as prescribed the next day. Administration to Patients Who Have Difficulty Swallowing Solids Disperse tablets in 120 mL (4 ounces) of non-carbonated, room-temperature water without crushing.

No other liquids should be used. Stir or swirl the cup for approximately 3 minutes until tablets are dispersed into small pieces (the tablets will not completely dissolve) and drink immediately or within 2 hours. The appearance of the mixture may range from pale yellow to bright yellow.

Swallow the tablet dispersion. Do not chew pieces of the tablet. Rinse the container with an additional 120 mL (4 ounces) of water and drink.

If the mixture is not consumed immediately, stir the mixture again to ensure that tablets are dispersed.

Dosage Modifications for Adverse Reactions

LUMAKRAS dose reduction levels are summarized in Table 1. If adverse reactions occur, a maximum of two dose reductions are permitted. Discontinue LUMAKRAS if patients are unable to tolerate the minimum dose of 240 mg once daily.

When LUMAKRAS is administered in combination with panitumumab, and LUMAKRAS is temporarily withheld or permanently discontinued, temporarily withhold or permanently discontinue panitumumab, respectively. Refer to the full prescribing information of panitumumab for dose modifications for adverse reactions associated with the use of panitumumab. Treatment with LUMAKRAS as a single agent may be continued if panitumumab is permanently discontinued.

Refer to Table 2 for dose modification guidelines and management of adverse reactions associated with the use of LUMAKRAS as a single agent or as combination therapy with panitumumab. Table 1. Recommended LUMAKRAS Table 2.

Recommended LUMAKRAS Dosage Modifications for Interstitial Lung Disease (ILD)/ pneumonitis Any Grade Withhold LUMAKRAS if ILD/pneumonitis is suspected. Nausea or vomiting despite appropriate supportive care (including anti-emetic therapy) Grade 3 to 4 Withhold LUMAKRAS until recovery to ≤ Grade 1 or baseline. Other adverse reactions Grade 3 to 4 Withhold LUMAKRAS until recovery to ≤ Grade 1 or baseline.

Resume LUMAKRAS at the next lower dose level.

Coadministration of LUMAKRAS with Acid-Reducing Agents

Avoid coadministration of proton pump inhibitors (PPIs) and H 2 receptor antagonists with LUMAKRAS. If treatment with an acid-reducing agent cannot be avoided, take LUMAKRAS 4 hours before or 10 hours after administration of a local antacid.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LUMAKRAS as a single agent at 960 mg orally once daily until disease progression or unacceptable toxicity in 549 patients with NSCLC with KRAS G12C mutation in the following trials: CodeBreaK 0753. The pooled safety population described in WARNINGS AND PRECAUTIONS also reflects exposure to LUMAKRAS 960 mg once daily in combination with panitumumab in 126 patients who received LUMAKRAS in combination with panitumumab for mCRC in CodeBreaK, 40% were exposed for 6 months or longer and 10% were exposed for greater than one year.

Metastatic Non-Small Cell Lung Cancer The safety of LUMAKRAS was evaluated in a subset of patients with KRAS G12C -mutated locally advanced or metastatic NSCLC in CodeBreaK 100. Patients received LUMAKRAS 960 mg orally once daily until disease progression or unacceptable toxicity (n = 204). Among patients who received LUMAKRAS, 39% were exposed for 6 months or longer and 3% were exposed for greater than one year.

Serious adverse reactions occurred in 50% of patients treated with LUMAKRAS. Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 9% of patients. Adverse reactions resulting in permanent discontinuation of LUMAKRAS in ≥ 2% of patients included hepatotoxicity (4.9%).

Dosage interruptions of LUMAKRAS due to an adverse reaction occurred in 34% of patients. Dose reductions of LUMAKRAS due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included increased ALT (2.9%) and increased AST (2.5%).

The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium. Table 3 summarizes the common adverse reactions observed in CodeBreaK 100.

Table 3. Table 4. Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with KRAS G12C-Mutated NSCLC who Received LUMAKRAS in CodeBreaK Metastatic Colorectal Cancer The safety of LUMAKRAS in combination with panitumumab was evaluated in the CodeBreaK 300 study.

Serious adverse reactions occurred in 26% of patients receiving LUMAKRAS 960 mg in combination with panitumumab. Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 1 patient for decreased corrected calcium. Adverse reactions which required dosage interruption in ≥ 2 patients were rash, hepatotoxicity and intestinal obstruction.

A dose reduction of LUMAKRAS due to an adverse reaction occurred in 1 patient for nausea. The most common adverse reactions (≥ 20%) in patients receiving LUMAKRAS 960 mg in combination with panitumumab were rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain. The most common Grade 3-4 laboratory abnormalities in ≥ 2 patients (4.3%) were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium.

Table 5 and Table 6 summarize the adverse reactions and laboratory abnormalities, respectively, identified in CodeBreaK 300. Table 5. Adverse Reactions (≥ 10%) in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in Combination with Panitumumab in CodeBreaK % that Worsened from Baseline in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in combination with panitumumab in CodeBreaK 300 The denominator used to calculate the rate varied from 44 to 46 in the LUMAKRAS + panitumumab arm and 18 to 50 in the trifluridine/tipiracil or regorafenib arm based on the number of patients with a baseline value and at least one post-treatment value.

Effects of Other Drugs on LUMAKRAS Acid-Reducing Agents

The solubility of sotorasib is pH-dependent. Coadministration of LUMAKRAS with gastric acid-reducing agents decreased sotorasib concentrations, which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with proton pump inhibitors (PPIs), H 2 receptor antagonists, and locally acting antacids.

If coadministration with an acid-reducing agent cannot be avoided, administer LUMAKRAS 4 hours before or 10 hours after administration of a locally acting antacid. Strong CYP3A4 Inducers Sotorasib is a CYP3A4 substrate. Coadministration of LUMAKRAS with a strong CYP3A4 inducer decreased sotorasib concentrations, which may reduce the efficacy of sotorasib.

Avoid coadministration of LUMAKRAS with strong CYP3A4 inducers.

Effects of LUMAKRAS on Other Drugs CYP3A4 Substrates Sotorasib is a CYP3A4 inducer. Coadministration of LUMAKRAS with a CYP3A4 substrate decreased its plasma concentrations, which may reduce the efficacy of the substrate. Avoid coadministration of LUMAKRAS with CYP3A4 sensitive substrates, for which minimal concentration changes may lead to therapeutic failures of the substrate.

If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. P-glycoprotein (P-gp) Substrates Sotorasib is a P-gp inhibitor. Coadministration of LUMAKRAS with a P-gp substrate increased its plasma concentrations, which may increase the adverse reactions of the substrate.

Avoid coadministration of LUMAKRAS with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the P-gp substrate dosage in accordance with its Prescribing Information. Breast Cancer Resistance Protein (BCRP) Substrates Sotorasib is a BCRP-inhibitor.

Coadministration of LUMAKRAS with a BCRP substrate increased its plasma concentrations, which may increase the risk of adverse reactions of the substrate. When coadministered with LUMAKRAS, monitor for adverse reactions of the BCRP substrate and decrease the BCRP substrate dosage in accordance with its Prescribing Information.

Pregnancy Risk Summary There are no available data on LUMAKRAS use in pregnant women. In rat and rabbit embryo-fetal development studies, oral sotorasib did not cause adverse developmental effects or embryo-lethality at exposures up to 4.6 times the human exposure at the 960 mg clinical dose (see Data ). Refer to the Full Prescribing Information of panitumumab for pregnancy risk information and contraception recommendations when LUMAKRAS is administered in combination with panitumumab.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data In a rat embryo-fetal development study, once daily oral administration of sotorasib to pregnant rats during the period of organogenesis resulted in maternal toxicity at the 540 mg/kg dose level (approximately 4.6 times the human exposure based on area under the curve (AUC) at the clinical dose of 960 mg). Sotorasib did not cause adverse developmental effects and did not affect embryo-fetal survival at doses up to 540 mg/kg.

In a rabbit embryo-fetal development study, once daily oral administration of sotorasib during the period of organogenesis resulted in lower fetal body weights and a reduction in the number of ossified metacarpals in fetuses at the 100 mg/kg dose level (approximately 2.6 times the human exposure based on AUC at the clinical dose of 960 mg), which was associated with maternal toxicity including decreased body weight gain and food consumption during the dosing phase.

Pediatric Use The safety and effectiveness of LUMAKRAS have not been established in pediatric patients.