Lumakras

Yellow, oblong-shaped, immediate release, film-coated, debossed with "AMG" on one side and "120" on the opposite side.
Each film-coated tablet contains 120 mg of sotorasib.
Sotorasib is an inhibitor of the RAS GTPase family. The molecular formula is C₃₀H₃₀F₂N₆O₃, and the molecular weight is 560.6 g/mol. The chemical name of sotorasib is 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one.
Sotorasib has pKa values of 8.06 and 4.56. The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL.
LUMAKRAS is supplied as film-coated tablets for oral use containing 120 mg of sotorasib.
Excipients/Inactive Ingredients: Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and iron oxide yellow.

Pharmacology: Mechanism of Action: Sotorasib is an inhibitor of KRAS G12C, a tumor-restricted, mutant-oncogenic form of the RAS GTPase, KRAS. Sotorasib forms an irreversible, covalent bond with the unique cysteine of KRAS G12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS. Sotorasib blocked KRAS signaling, inhibited cell growth, and promoted apoptosis only in KRAS G12C tumor cell lines. Sotorasib inhibited KRAS G12C in vitro and in vivo with minimal detectable off-target activity. In mouse tumor xenograft models, sotorasib-treatment led to tumor regressions and prolonged survival, and was associated with anti-tumor immunity in KRAS G12C models.
In the setting of KRAS G12C-mutant CRC, epidermal growth factor receptor (EGFR) activation has been identified as a mechanism of resistance to KRAS G12C inhibition. In a murine patient-derived colorectal tumor xenograft model, the combination of sotorasib and panitumumab, an EGFR antagonist, had increased antitumor activity compared to either sotorasib or panitumumab alone.
Pharmacodynamics: Sotorasib exposure-response relationships and the time course of the pharmacodynamic response are unknown.
Cardiac Electrophysiology: At the approved recommended dosage, LUMAKRAS does not cause large mean increases in the QTc interval (>20 msec).
Clinical data: KRAS G12C-mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer: The efficacy of LUMAKRAS was demonstrated in a subset of patients enrolled in a single-arm, open-label, multicenter trial (CodeBreaK 100 [NCT03600883]). Eligible patients were required to have locally advanced or metastatic KRAS G12C-mutated NSCLC with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
All patients were required to have prospectively identified KRAS G12C-mutated NSCLC in tumor tissue samples by using the QIAGEN therascreen KRAS RGQ PCR Kit performed in a central laboratory. Of 126 total enrolled subjects, 2 (2%) were unevaluable for efficacy analysis due to the absence of radiographically measurable lesions at baseline. Of the 124 patients with KRAS G12C mutations confirmed in tumor tissue, plasma samples from 112 patients were tested retrospectively using the Guardant360 CDx. 78/112 patients (70%) had KRAS G12C mutation identified in plasma specimen, 31/112 patients (28%) did not have KRAS G12C mutation identified in plasma specimen and 3/112 (2%) were unevaluable due to Guardant360 CDx test failure.
A total of 124 patients had at least one measurable lesion at baseline assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1 and were treated with LUMAKRAS 960 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR), and duration of response (DOR) as evaluated by BICR according to RECIST v1.1.
The baseline demographic and disease characteristics of the study population were: median age 64 years (range: 37 to 80) with 48% ≥65 years and 8% ≥75 years; 50% Female; 82% White, 15% Asian, 2% Black; 70% ECOG PS 1; 96% had stage IV disease; 99% with non-squamous histology; 81% former smokers, 12% current smokers, 5% never smokers. All patients received at least 1 prior line of systemic therapy for metastatic NSCLC; 43% received only 1 prior line of therapy, 35% received 2 prior lines of therapy, 23% received 3 prior lines of therapy; 91% received prior anti-PD-1/PD-L1 immunotherapy, 90% received prior platinum-based chemotherapy, 81% received both platinum-based chemotherapy and anti-PD-1/PD-L1. The sites of known extra-thoracic metastasis included 48% bone, 21% brain, and 21% liver.
Efficacy results are summarized in Table 1. (See Table 1.)

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KRAS G12C-mutated Metastatic Colorectal Cancer: The efficacy of LUMAKRAS in combination with panitumumab was evaluated in CodeBreaK 300 [NCT05198934], a multicenter, randomized, open-label, active-controlled study conducted in previously treated patients with KRAS G12C-mutated mCRC. Key eligibility criteria included patients 18 years of age or older, who had received at least one prior line of therapy for mCRC, and who had received fluoropyrimidine, oxaliplatin, and irinotecan for metastatic disease unless there was a medical contraindication. All patients were also required to have prospectively identified KRAS G12C-mutated mCRC in tumor tissue samples by using the QIAGEN therascreen KRAS RGQ PCR Kit performed in a central laboratory. Other eligibility criteria included an ECOG PS of ≤2 and at least one measurable lesion as defined by RECIST v1.1.
A total of 160 patients with previously treated mCRC with the KRAS G12C mutation were randomized 1:1:1 to receive either LUMAKRAS 960 mg orally once daily and panitumumab 6 mg/kg IV every 2 weeks (N=53), or LUMAKRAS 240 mg orally once daily and panitumumab 6 mg/kg IV every 2 weeks (N=53), or investigator's choice of SOC trifluridine/tipiracil or regorafenib (N=54). Randomization was stratified by prior anti-angiogenic therapy (yes or no), time from initial diagnosis of metastatic disease to randomization (≥18 months; <18 months), and ECOG status (0 or 1 versus 2). Patients received treatment until disease progression, lack of clinical benefit or intolerance to treatment. LUMAKRAS discontinuation required panitumumab discontinuation, however, patients could continue to receive LUMAKRAS if panitumumab was discontinued [see Posology under Dosage & Administration]. Four patients randomized to LUMAKRAS 960 mg in combination with panitumumab continued LUMAKRAS single agent therapy after discontinuing panitumumab.
The major efficacy outcome measure was progression-free survival (PFS) as evaluated by BICR according to RECIST 1.1.
Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR). Only the results of the approved dosing regimen LUMAKRAS 960 mg in combination with panitumumab are described as follows.
Of the 107 patients randomized to either LUMAKRAS 960 mg once daily in combination with panitumumab or the control arms, the median age was 64 years (range: 34-81 years); 46% were age 65 years or older; 50% were female; 74% were White; 17% were Asian and 97% of the patients had ECOG PS 0 or 1. The primary site of disease was colon (69%) or rectum (31%). The median number of prior lines of therapy for metastatic disease was 2. Among the 107 patients, 100% received prior fluoropyrimidine, 99% received prior oxaliplatin, 93% received prior irinotecan and 18% of patients had received prior trifluridine and tipiracil, or regorafenib.
The trial demonstrated a statistically significant improvement in PFS for patients randomized to LUMAKRAS 960 mg in combination with panitumumab compared to the investigator's choice SOC. The final analysis of OS was not statistically significant.
The final analysis of PFS for patients randomized to LUMAKRAS 240 mg in combination with panitumumab compared to investigator's choice of SOC was not statistically significant.
The efficacy results from CodeBreaK 300 are summarized in Table 2 and figure. (See Table 2 and figure.)

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Pharmacokinetics: The pharmacokinetics of sotorasib have been characterized in healthy subjects and in patients with KRAS G12C-mutated solid tumors, including NSCLC. Sotorasib exhibited non-linear, time-dependent, pharmacokinetics over the dose range of 180 mg to 960 mg (0.19 to 1 time the approved recommended dosage) once daily with similar systemic exposure (i.e., AUC_0-24h and C_max) across doses at steady state. Sotorasib systemic exposure was comparable between film-coated tablets and film-coated tablets predispersed in water administered under fasted conditions. Sotorasib plasma concentrations reached steady state within 22 days. No accumulation was observed after repeat LUMAKRAS dosages with a mean accumulation ratio of 0.56 (coefficient of variation (CV): 59%).
Absorption: The median time to sotorasib peak plasma concentration is 1 hour.
Effect of Food: When 960 mg LUMAKRAS was administered with a high-fat, high-calorie meal (containing approximately 800 to 1,000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively) in patients, sotorasib AUC_0-24h increased by 25% compared to administration under fasted conditions.
Distribution: The sotorasib mean volume of distribution (V_d) at steady state is 211 L (CV: 135%). In vitro, sotorasib plasma protein binding is 89%.
Elimination: The sotorasib mean terminal elimination half-life is 5 hours (standard deviation (SD): 2). At 960 mg LUMAKRAS once daily, the sotorasib steady state apparent clearance is 26.2 L/hr (CV: 76%).
Metabolism: The main metabolic pathways of sotorasib are non-enzymatic conjugation and oxidative metabolism with CYP3As.
Excretion: After a single dose of radiolabeled sotorasib, 74% of the dose was recovered in feces (53% unchanged) and 6% (1% unchanged) in urine.
Specific Populations: No clinically meaningful differences in the pharmacokinetics of sotorasib were observed based on age (28 to 86 years), sex, race (White, Black and Asian), body weight (36.8 to 157.9 kg), line of therapy, ECOG PS (0, 1), mild and moderate renal impairment (eGFR: ≥30 mL/min/1.73 m²), or mild hepatic impairment (AST or ALT <2.5 × ULN or total bilirubin <1.5 × ULN). The effect of severe renal impairment on sotorasib pharmacokinetics has not been studied.
Hepatic Impairment: The mean AUC of sotorasib decreased by 25% in subjects with moderate hepatic impairment (Child-Pugh B) and increased by 4% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function following a single dose of 960 mg LUMAKRAS.
Clinical Studies: Acid-Reducing Agents: Under fasted conditions, coadministration of repeat doses of omeprazole (PPI) with a single dose of 960 mg LUMAKRAS and 240 mL of an acidic beverage (non-diet cola) decreased sotorasib C_max by 32% and AUC by 23%. The clinical relevance of the decreased sotorasib exposure when coadministered with omeprazole and cola is unclear and efficacy might be reduced. Coadministration of repeat doses of omeprazole (PPI) with a single dose of LUMAKRAS decreased sotorasib C_max by 65% and AUC by 57% under fed conditions, and decreased sotorasib C_max by 57% and AUC by 42% under fasted conditions. Coadministration of a single dose of famotidine (H₂ receptor antagonist) given 10 hours prior to and 2 hours after a single dose of LUMAKRAS under fed conditions decreased sotorasib C_max by 35% and AUC by 38%.
Strong CYP3A4 Inducers: Coadministration of repeat doses of rifampin (a strong CYP3A4 inducer) with a single dose of LUMAKRAS decreased sotorasib C_max by 35% and AUC by 51%.
Other Drugs: No clinically meaningful effect on the exposure of sotorasib was observed following coadministration of LUMAKRAS with itraconazole (a combined strong CYP3A4 and P-gp inhibitor) and a single dose of rifampin (an OATP1B1/1B3 inhibitor), or metformin (a MATE1/MATE2-K substrate).
CYP3A4 substrates: Coadministration of LUMAKRAS with midazolam (a sensitive CYP3A4 substrate) decreased midazolam C_max by 48% and AUC by 53%.
P-gp substrates: Coadministration of LUMAKRAS with digoxin (a P-gp substrate) increased digoxin C_max by 91% and AUC by 21%.
MATE1/MATE2-K substrates: No clinically meaningful effect on the exposure of metformin (a MATE1/MATE2-K substrate) was observed following coadministration of LUMAKRAS.
BCRP substrates: Coadministration of LUMAKRAS with rosuvastatin (a BCRP substrate) increased rosuvastatin C_max by 70% and AUC by 34%.
In Vitro Studies: Cytochrome P450 (CYP) Enzymes: Sotorasib may induce CYP2C8, CYP2C9 and CYP2B6. Sotorasib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been performed with sotorasib.
Sotorasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not genotoxic in the in vivo rat micronucleus and comet assays.
Fertility/early embryonic development studies were not conducted with sotorasib. There were no adverse effects on female or male reproductive organs in general toxicology studies conducted in dogs and rats.
Animal Toxicology and/or Pharmacology: In rats, renal toxicity including minimal to marked histologic tubular degeneration/necrosis and increased kidney weight, urea nitrogen, creatinine, and urinary biomarkers of renal tubular injury were present at doses resulting in exposures approximately ≥0.5 times the human AUC at the clinical dose of 960 mg. Increases in cysteine S-conjugate β-lyase pathway metabolism in the rat kidney compared to human may make rats more susceptible to renal toxicity due to local formation of a putative sulfur-containing metabolite than humans.
In the 3-month toxicology study in dogs, sotorasib induced findings in the liver (centrilobular hepatocellular hypertrophy), pituitary gland (hypertrophy of basophils), and thyroid gland (marked follicular cell atrophy, moderate to marked colloid depletion, and follicular cell hypertrophy) at exposures approximately 0.4 times the human exposure based on AUC at the clinical dose of 960 mg. These findings may be due to an adaptive response to hepatocellular enzyme induction and subsequent reduced thyroid hormone levels (i.e., secondary hypothyroidism). Although thyroid levels were not measured in dogs, induction of uridine diphosphate glucuronosyltransferase known to be involved in thyroid hormone metabolism was confirmed in the in vitro dog hepatocyte assay.

KRAS G12C-mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC): LUMAKRAS as a single agent is indicated 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.
This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR) [see Pharmacology: Pharmacodynamics: Clinical Data under Actions]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
KRAS G12C-mutated Metastatic Colorectal Cancer (mCRC): LUMAKRAS, in combination with panitumumab, is indicated for the treatment of adult patients with KRAS G12C‑mutated metastatic colorectal cancer (mCRC) who have received prior fluoropyrimidine‑, oxaliplatin‑ and irinotecan‑based chemotherapy [see Posology under Dosage & Administration and Pharmacology: Pharmacodynamics: Clinical Data under Actions].

Posology: 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 [see Pharmacology: Pharmacodynamics: Clinical Data under Actions].
KRAS G12C-mutated mCRC: Select patients for treatment of mCRC based on the presence of KRAS G12C mutation in tumor specimens [see Pharmacology: Pharmacodynamics: Clinical Data under Actions].
Recommended Dosage: LUMAKRAS as a Single Agent for KRAS G12C-mutated Locally Advanced or Metastatic NSCLC: The recommended dosage of LUMAKRAS is 960 mg (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 (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.
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.
Dosage Modifications for Adverse Reactions: LUMAKRAS dose reduction levels are summarized in Table 3.
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 [see Pharmacology: Pharmacodynamics: Clinical Data under Actions]. 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 [see Pharmacology: Pharmacodynamics: Clinical Data under Actions].
Refer to Table 4 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. (See Tables 3 and 4.)

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Coadministration of LUMAKRAS with Acid-Reducing Agents: Avoid coadministration of proton pump inhibitors (PPIs) and H₂ 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 [see Interactions and Pharmacology: Pharmacokinetics under Actions].
Special Populations: Pediatric Use: The safety and effectiveness of LUMAKRAS have not been established in pediatric patients.
Geriatric Use: Of the 357 patients with any tumor type who received LUMAKRAS 960 mg orally once daily in CodeBreaK 100, 46% were 65 and over, and 10% were 75 and over. No overall differences in safety or effectiveness were observed between older patients and younger patients treated with LUMAKRAS as a single agent.
In a pooled analysis of 132 patients who received LUMAKRAS 960 mg in combination with panitumumab for KRAS G12C-mutated mCRC, 30% were 65 and over while 9% were 75 and over. No overall differences in safety or efficacy were observed between older patients (≥65 years of age) compared to younger patients, treated with LUMAKRAS 960 mg in combination with panitumumab.
Hepatic Impairment: No dosage modification is recommended in patients with mild to moderate hepatic impairment (Child-Pugh A or B).
The effect of severe hepatic impairment (Child-Pugh C) on the safety of LUMAKRAS is unknown. Monitor for sotorasib adverse reactions in patients with hepatic impairment more frequently since these patients may be at increased risk for adverse reactions including hepatotoxicity [see Pharmacology: Pharmacokinetics under Actions].
Method of Administration: Take the daily dose of LUMAKRAS at the same time each day with or without food [see Pharmacology: Pharmacokinetics under Actions]. Swallow tablets whole. Do not chew, crush or split tablets.
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 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.
If administration through a nasogastric (NG) tube or percutaneous endoscopic gastrostomy (PEG) tube is required, follow the process as previously mentioned for the initial dispersion and for the residual rinse of the 120 mg tablets. The dispersed suspension and rinse should be administered as per the NG or PEG tube manufacturer's instructions with appropriate water flushes. Administer the dispersion within 2 hours of preparation, stored at room temperature.

There is no clinical experience with overdose with LUMAKRAS. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

None.

Warning according to the Notification of the Ministry of Public Health: This medicine may cause serious hazard, must only be used under control by a doctor.

Hepatotoxicity: LUMAKRAS can cause hepatotoxicity and increased alanine aminotransferase (ALT) or increased aspartate aminotransferase (AST) which may lead to drug-induced liver injury and hepatitis.
In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg [see Clinical Trials Experience under Adverse Reactions], hepatotoxicity occurred in 27% of patients, of which 16% were Grade ≥3). Among patients with hepatotoxicity who required dosage modifications, 64% required treatment with corticosteroids.
In this pool safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, 17% of patients who received LUMAKRAS had increased ALT/increased AST; of which 9% were Grade ≥3. The median time to first onset of increased ALT/AST was 6.3 weeks (range: 0.4 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 9% of patients treated with LUMAKRAS. LUMAKRAS was permanently discontinued due to increased ALT/AST in 2.7% of patients. Drug-induced liver injury occurred in 1.6% (all grades) including 1.3% (Grade ≥3).
In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, a total of 40% patients with recent (≤3 months) immunotherapy prior to starting LUMAKRAS had an event of hepatotoxicity. An event of hepatotoxicity was observed in 18% of patients who started LUMAKRAS more than 3 months after last dose of immunotherapy and in 17% of those who never received immunotherapy. Regardless of time from prior immunotherapy, 94% of hepatotoxicity events improved or resolved with dosage modification of LUMAKRAS, with or without corticosteroid treatment.
In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab [see Clinical Trials Experience under Adverse Reactions], hepatotoxicity occurred in 15% of patients, of which 4.8% were Grade 3. A total of 7% of patients who received LUMAKRAS had increased ALT or increased AST, of which 0.8% were Grade 3. The median time to first onset of increased ALT or increased AST was 10 weeks (range: 2 to 22). Increased ALT or increased AST leading to dose interruption occurred in 2.4% of patients. A total of 3.2% of patients who received LUMAKRAS had hyperbilirubinemia, of which 2.4% were Grade 3. The median time to first onset of hyperbilirubinemia was 12 weeks (range: 0, 29).
Hyperbilirubinemia leading to dose interruption occurred in 1.6% of patients. Among patients with hepatotoxicity, 21% received corticosteroids.
Monitor liver function tests (ALT, AST, alkaline phosphatase and total bilirubin) prior to the start of LUMAKRAS, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations. Withhold, reduce the dose or permanently discontinue LUMAKRAS based on severity of the adverse reaction [see Posology under Dosage & Administration and Clinical Trials Experience under Adverse Reactions]. Consider administering systemic corticosteroids for the management of hepatotoxicity.
Interstitial Lung Disease (ILD)/Pneumonitis: LUMAKRAS can cause ILD/pneumonitis that can be fatal.
In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg [see Clinical Trials Experience under Adverse Reactions], ILD/pneumonitis occurred in 2.2% of patients, of which 1.1% were Grade ≥3, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 8.6 weeks (range: 2.1 to 36.7 weeks). LUMAKRAS was permanently discontinued due to ILD/pneumonitis in 1.3% of LUMAKRAS-treated patients. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified [see Posology under Dosage & Administration and Clinical Trials Experience under Adverse Reactions].
In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab, 1 patient experienced a Grade 1 event of ILD/pneumonitis [see Clinical Trials Experience under Adverse Reactions].
Effects on Ability to Drive and Use Machines: LUMAKRAS has no or negligible influence on the ability to drive and use machines.

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 as follows].
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 2% to 4% and 15% to 20%, 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. Sotorasib did not cause adverse developmental effects and did not affect embryo-fetal survival at doses up to 100 mg/kg.
Lactation: Risk Summary: There are no data on the presence of sotorasib or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LUMAKRAS and for 1-week after the last dose.
Refer to the Full Prescribing Information of panitumumab for lactation recommendations when LUMAKRAS is administered in combination with panitumumab.
Fertility: Fertility/early embryonic development studies were not conducted with sotorasib.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Hepatotoxicity [see Hepatotoxicity under Precautions]; Interstitial Lung Disease (ILD)/Pneumonitis [see Interstitial Lung Disease (ILD)/Pneumonitis under Precautions].
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 Precautions section 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 200 (NCT04303780), CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883) and CodeBreaK 105 (NCT04380753). Among these 549 patients who received LUMAKRAS, 44% were exposed for 6 months or longer and 21% were exposed for greater than one year.
The pooled safety population described in Special Warnings and Precautions for Use 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 300 (NCT05198934) and CodeBreaK 101 (NCT04185883). Among the 126 patients who received LUMAKRAS 960 mg in combination with panitumumab, 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 [see Pharmacology: Pharmacodynamics: Clinical Data under Actions]. 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.
The median age of patients who received LUMAKRAS was 66 years (range: 37 to 86); 55% female; 80% White, 15% Asian, and 3% Black.
Serious adverse reactions occurred in 50% of patients treated with LUMAKRAS. Serious adverse reactions in ≥2% of patients were pneumonia (8%), hepatotoxicity (3.4%), and diarrhea (2%). Fatal adverse reactions occurred in 3.4% of patients who received LUMAKRAS due to respiratory failure (0.8%), pneumonitis (0.4%), cardiac arrest (0.4%), cardiac failure (0.4%), gastric ulcer (0.4%), and pneumonia (0.4%).
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. Adverse reactions which required dosage interruption in ≥2% of patients were hepatotoxicity (11%), diarrhea (8%), musculoskeletal pain (3.9%), nausea (2.9%), and pneumonia (2.5%).
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 5 summarizes the common adverse reactions observed in CodeBreaK 100. (See Table 5.)

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Table 6 summarizes the selected laboratory adverse reactions observed in CodeBreaK 100. (See Table 6.)

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Metastatic Colorectal Cancer: The safety of LUMAKRAS in combination with panitumumab was evaluated in the CodeBreaK 300 study [see Pharmacology: Pharmacodynamics: Clinical Data under Actions]. Patients with KRAS G12C-mutated mCRC received LUMAKRAS 960 mg orally once daily in combination with panitumumab 6 mg/kg intravenously (IV) once every 2 weeks (N=47), LUMAKRAS 240 mg orally once daily in combination with panitumumab 6 mg/kg IV once every 2 weeks (N=50), or the investigator's choice of standard of care (SOC) trifluridine/tipiracil or regorafenib (N=50). Among patients who received LUMAKRAS 960 mg orally once daily in combination with panitumumab, 36% were exposed to LUMAKRAS for greater than 6 months and 6% were exposed for greater than 12 months.
The median age of patients who received LUMAKRAS 960 mg in combination with panitumumab arm was 63 years (range: 37-79 years); 38% were age 65 years or older; 49% were female; 79% were White and 13% were Asian.
Serious adverse reactions occurred in 26% of patients receiving LUMAKRAS 960 mg in combination with panitumumab. Serious adverse reactions in ≥2 patients receiving LUMAKRAS 960 mg in combination with panitumumab were sepsis (6%) and intestinal obstruction (4.3%). Fatal adverse reactions occurred in 2 patients (4.3%) receiving LUMAKRAS 960 mg in combination with panitumumab, consisting of cardiac arrest and sepsis (1 patient each).
Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 1 patient for decreased corrected calcium.
Dosage interruptions of LUMAKRAS due to an adverse reaction occurred in 26% of patients. 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 7 and Table 8 summarize the adverse reactions and laboratory abnormalities, respectively, identified in CodeBreaK 300. (See Tables 7 and 8.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

LUMAKRAS may cause serious side effects, including: Liver problems: Abnormal liver blood tests are common with LUMAKRAS and can sometimes be severe. The healthcare provider should do blood tests before starting and during treatment with LUMAKRAS to check the liver function. Tell the healthcare provider right away if the patient develops any signs or symptoms of liver problems, including: the skin or the white part of the eyes turns yellow (jaundice), dark or "tea-colored" urine, light-colored stools (bowel movements), tiredness or weakness, nausea or vomiting, bleeding or bruising, loss of appetite, pain, aching, or tenderness on the right side of the stomach-area (abdomen).
Lung or breathing problems: LUMAKRAS may cause inflammation of the lungs that can lead to death. Tell the healthcare provider or get emergency medical help right away if the patient has new or worsening shortness of breath, cough, or fever.
The healthcare provider may change the dose, temporarily stop, or permanently stop treatment with LUMAKRAS if the patient develops side effects.
The most common side effects of LUMAKRAS when used alone for NSCLC include: Diarrhea, muscle or bone pain, nausea, tiredness, cough, changes in certain blood tests.
The most common side effects of LUMAKRAS when used in combination with panitumumab for CRC include: Skin rash, dry skin, diarrhea, mouth sores, tiredness, muscle and bone pain, changes in certain blood tests.
These are not all the possible side effects of LUMAKRAS.
Call the doctor for medical advice about side effects.

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 [see Pharmacology: Pharmacokinetics under Actions], which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with proton pump inhibitors (PPIs), H₂ 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 [see Posology under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions].
Strong CYP3A4 Inducers: Sotorasib is a CYP3A4 substrate. Coadministration of LUMAKRAS with a strong CYP3A4 inducer decreased sotorasib concentrations [see Pharmacology: Pharmacokinetics under Actions] 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 [see Pharmacology: Pharmacokinetics under Actions], 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 [see Pharmacology: Pharmacokinetics under Actions], 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 [see Pharmacology: Pharmacokinetics under Actions], 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.

Incompatibilities: No known incompatibilities.

Special Precautions for Storage: Store below 30°C.

What should I tell my healthcare provider before taking LUMAKRAS: Before taking LUMAKRAS, tell your healthcare provider about all your medical conditions, including if you have liver problems; have lung or breathing problems other than lung cancer; are pregnant or plan to become pregnant. It is not known if LUMAKRAS will harm your unborn baby; are breastfeeding or plan to breastfeed. It is not known if LUMAKRAS passes into your breast milk. Do not breastfeed during treatment with LUMAKRAS and for 1-week after the last dose.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, dietary, and herbal supplements. LUMAKRAS can affect the way some other medicines work, and some other medicines can affect the way LUMAKRAS works.
Especially tell your healthcare provider if you take antacid medicines, including Proton Pump Inhibitor (PPI) medicines or H₂ blockers during treatment with LUMAKRAS. Ask your healthcare provider if you are not sure.
How should I take LUMAKRAS: Take LUMAKRAS exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking LUMAKRAS unless your healthcare provider tells you to.
Take your prescribed dose of LUMAKRAS 1 time each day, at the same time each day.
For colon or rectal cancer, you will also receive panitumumab through a vein in your arm (intravenously) given by your healthcare provider. You will first take LUMAKRAS before you receive your first dose of panitumumab. Your healthcare provider will temporarily or permanently stop your treatment with panitumumab if your treatment with LUMAKRAS is temporarily or permanently stopped.
Take LUMAKRAS with or without food.
Swallow LUMAKRAS tablets whole. Do not chew, crush, or split tablets.
If you cannot swallow LUMAKRAS tablets whole: Place your prescribed dose of LUMAKRAS in a glass of 4 ounces (120 mL) of non-carbonated, room temperature water without crushing the tablets. Do not use any other liquids.
Stir or swirl the cup for about 3 minutes until the tablets are in small pieces (the tablets will not completely dissolve). The color of the mixture may be pale yellow to bright yellow.
Drink the LUMAKRAS and water mixture right away or within 2 hours of preparing. Do not chew pieces of the tablet.
Rinse the glass with an additional 4 ounces (120 mL) of water and drink to make sure that you have taken the full dose of LUMAKRAS.
If you do not drink the mixture right away, stir or swirl the mixture again before drinking.
If you take an antacid medicine, take LUMAKRAS either 4 hours before or 10 hours after the antacid.
If you miss a dose of LUMAKRAS, take the dose as soon as you remember. If it has been more than 6 hours, do not take the dose. Take your next dose at your regularly scheduled time the next day. Do not take 2 doses at the same time to make up for a missed dose.
If you vomit after taking a dose of LUMAKRAS, do not take an extra dose. Take your next dose at your regularly scheduled time the next day.
Further information: General information about the safe and effective use of LUMAKRAS: Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LUMAKRAS for a condition for which it was not prescribed. Do not give LUMAKRAS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about LUMAKRAS that is written for healthcare professionals.

Targeted Cancer Therapy

L01XX73 - sotorasib ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.

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