LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C‑mutated locally advanced or metastatic non‑small cell lung cancer (NSCLC), as determined by an approved test (see section 4.2), 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). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Patient selection

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.

Posology

The recommended dosage of LUMAKRAS is 960 mg (eight 120 mg tablets) orally once daily until disease progression or unacceptable toxicity.

Take LUMAKRAS at the same time each day with or without food (see section 4.4). 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.

Dosage Modifications for Adverse Reactions

LUMAKRAS dose reduction levels are summarized in Table 1. Dosage modifications for adverse reactions are provided in Table 2.

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.

Table 1. Recommended LUMAKRAS Dose Reduction Levels for Adverse Reactions

Table 2. Recommended LUMAKRAS Dosage Modifications for Adverse Reactions

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

a Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

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 section 4.5 and section 5.2).

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

Hepatotoxicity

LUMAKRAS can cause hepatotoxicity, which may lead to drug‑induced liver injury and hepatitis. Among 357 patients who received LUMAKRAS in CodeBreaK 100 (see section 4.8), hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A total of 18% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. The median time to first onset of increased ALT/AST was 9 weeks (range: 0.3 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 7% of patients. LUMAKRAS was discontinued due to increased ALT/AST in 2.0% of patients. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.

Monitor liver function tests (ALT, AST, 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, dose reduce or permanently discontinue LUMAKRAS based on severity of adverse reaction (see section 4.2 and section 4.8)

Interstitial Lung Disease (ILD)/Pneumonitis

LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357 patients who received LUMAKRAS in CodeBreaK 100 (see section 4.8), ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 2 weeks (range: 2 to 18 weeks). LUMAKRAS was discontinued due to ILD/pneumonitis in 0.6% of 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 section 4.2 and section 4.8).

Lactose intolerance

LUMAKRAS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium‑free’.

Effects of Other Drugs on LUMAKRAS

Acid‑Reducing Agents

Coadministration of LUMAKRAS with gastric acid‑reducing agents decreased sotorasib concentrations (see section 5.2), 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 section 4.2)

Strong CYP3A4 Inducers

Coadministration of LUMAKRAS with a strong CYP3A4 inducer decreased sotorasib concentrations (see section 5.2), which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with strong CYP3A4 inducers.

Effects of LUMAKRAS on Other Drugs

CYP3A4 Substrates

Coadministration of LUMAKRAS with a CYP3A4 substrate decreased its plasma concentrations (see section 5.2), 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

Coadministration of LUMAKRAS with a P‑gp substrate (digoxin) increased digoxin plasma concentrations (see section 5.2), which may increase the adverse reactions of digoxin. 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.

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)

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 final dose.

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.

LUMAKRAS has no or negligible influence on the ability to drive and use machines.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

·        Hepatotoxicity (see section 4.4)

·        Interstitial Lung Disease (ILD)/Pneumonitis (see section 4.4)

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 in 357 patients with NSCLC and other solid tumors with KRAS G12C mutation enrolled in CodeBreaK 100, 28% were exposed for 6 months or longer and 3% were exposed for greater than one year.

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.

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 3 summarizes the common adverse reactions observed in CodeBreaK 100.

Table 3.       Adverse Reactions (≥ 10%) of Patients With KRAS G12C‑Mutated NSCLC Who Received LUMAKRAS in CodeBreaK 100^*

Table 4 summarizes the selected laboratory adverse reactions observed in CodeBreaK 100.

Table 4.       Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients With KRAS G12C‑Mutated NSCLC Who Received LUMAKRAS in CodeBreaK 100

*N = number of patients who had at least one on‑study assessment for the parameter of interest.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to their local representative.

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

Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XX73

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.

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 efficacy and safety

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 5.

Table 5. Efficacy Results for Patients with KRAS G12C‑mutated NSCLC Who Received LUMAKRAS in CodeBreaK 100

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 1000 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 or moderate to severe hepatic impairment on sotorasib pharmacokinetics has not been studied.

Drug Interaction Studies

Clinical Studies

Acid‑Reducing Agents: 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.

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.

Transporter Systems: Sotorasib may inhibit BCRP.

NONCLINICAL TOXICOLOGY

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

Active Ingredient: sotorasib

Inactive Ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. Tablet film coating material contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow.

In the absence of compatibility studies, this medicinal product must not be dispersed with other liquids than that mentioned in section 4.2. Acidic beverages (e.g. fruit juices) should also be excluded.

Store at 20°C to 25°C. Excursions permitted from 15°C to 30°C

LUMAKRAS (sotorasib) 120 mg tablets are yellow, oblong‑shaped, film‑coated, debossed with “AMG” on one side and “120” on the opposite side are supplied as follows:

·     Carton containing two bottles of 120 tablets with child‑resistant closure

·     Carton containing one bottle of 240 tablets with child‑resistant closure

Not all pack sizes may be marketed

This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.