LUMYKRAS 120mg tablets medication leaflet

LUMYKRAS 120 mg film-coated tablets

LUMYKRAS 240 mg film-coated tablets

LUMYKRAS 120 mg film-coated tablets

Each film-coated tablet contains 120 mg of sotorasib.

Each film-coated tablet contains 114 mg of lactose (as monohydrate).

LUMYKRAS 240 mg film-coated tablets

Each film-coated tablet contains 240 mg of sotorasib.

Each film-coated tablet contains 53 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

LUMYKRAS 120 mg film-coated tablets

Yellow film-coated tablet, oblong-shaped (7 mm × 16 mm), debossed with “AMG” on one side and“120” on the opposite side.

LUMYKRAS 240 mg film-coated tablets

Yellow film-coated tablet, oval-shaped (8 mm × 18 mm), debossed with “AMG” on one side and“240” on the opposite side.

LUMYKRAS as monotherapy is indicated for the treatment of adults with advanced non-small celllung cancer (NSCLC) with KRAS G12C-mutation and who have progressed after at least one prior lineof systemic therapy.

Treatment with LUMYKRAS must be initiated by a physician experienced in the use of anticancermedicinal products.

The presence of a KRAS G12C-mutation must be confirmed using a validated test prior to initiation of

LUMYKRAS therapy.

The recommended dose is 960 mg sotorasib (eight 120 mg tablets or four 240 mg tablets) once daily,at the same time each day.

Treatment with LUMYKRAS is recommended until disease progression or unacceptable toxicity.

If less than 6 hours have passed since the scheduled time of dosing, the patient should take the dose asnormal. If more than 6 hours have passed since the scheduled time of dosing, the patient must not takethe dose. Treatment should be continued as prescribed the next day.

If vomiting occurs after taking LUMYKRAS, the patient must not take an additional dose on the sameday, and treatment must be continued as prescribed the next day.

Dosing should be modified based on LUMYKRAS toxicity. The dose reduction rules outlined insection 4.2 are based on clinical data. Pharmacokinetic (PK) data do suggest a similar exposure atlower sotorasib doses (see section 5.2). Dose reduction levels are summarised in table 1. Dosemodifications for adverse reactions are provided in table 2.

A maximum of two dose reductions are recommended for management of an adverse reaction (seetable 1). Discontinue LUMYKRAS if an adverse reaction cannot be managed after two dosereductions and patients are unable to tolerate the minimum dose of 240 mg once daily.

Table 1. Recommended sotorasib dose reduction levels

Dose reduction level Dose

Starting dose 960 mg (eight 120 mg tablets or four 240 mgtablets) once daily

First dose reduction 480 mg (four 120 mg tablets or two 240 mgtablets) once daily

Second dose reduction 240 mg (two 120 mg tablets or one 240 mgtablet) once daily

Table 2. Recommended dose modifications for sotorasib

Adverse reaction Severitya Dose modification

Hepatotoxicity AST or ALT > 3 × and up to * Withhold treatment5 × ULN (or > 3 × and up to * Closely monitor liver5 × baseline if baseline function until recovered toabnormal) with symptoms ≤ 3 × ULN or to≤ 3 × baseline if baselineor abnormal.

* After recovery, resume

AST or ALT > 5 × ULN (or treatment at the next dose> 5 × baseline if baseline reduction levelabnormal), in the absence of * Consider initiation ofalternative causes. corticosteroids

AST or ALT > 3 × ULN with * Permanently discontinuetotal bilirubin > 2 × ULN treatment if no alternativecause is identified.or * If alternative cause isidentified, do not resume

AST or ALT > 3 × ULN and treatment until

INR > 1.5 × ULN (for AST/ALT/bilirubin return tosubjects not on baseline.anticoagulation therapy), inthe absence of alternativecauses.

Interstitial Lung Disease Any grade * Stop treatment if(ILD)/pneumonitis ILD/pneumonitis issuspected

* Permanently discontinuetreatment if ILD/pneumonitisis confirmed and no othercause is identified.

Nausea, vomiting, or Grade ≥ 3 * Stop treatment untildiarrhoea persisting despite recovered to ≤ grade 1 or tosupportive care (including baseline gradeanti-emetic or anti-diarrhoeal * After recovery, resumetherapy) treatment at the next dosereduction level

Other medicinal Grade ≥ 3 * Stop treatment untilproduct-related toxicity recovered to ≤ grade 1 or tobaseline grade

* After recovery, resumetreatment at the next dosereduction level

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; INR = International Normalised Ratio

The limited data on the safety and efficacy of LUMYKRAS in patients aged 75 years and older do notsuggest that a dose adjustment is required in elderly patients (see sections 4.8 and 5.2).

No dose adjustment is recommended for patients with mild hepatic impairment.

LUMYKRAS is not recommended for use in patients with moderate (Child-Pugh B) and severe(Child-Pugh C) hepatic impairment (see section 5.2).

No dose adjustment is recommended for patients with mild renal impairment (creatine clearance,

CrCL ≥ 60 mL/min). LUMYKRAS has not been studied in patients with moderate or severe renalimpairment (CrCL < 60 mL/min). Therefore, caution should be exercised when treating patients withmoderate, severe and end stage renal impairment (see section 5.2).

There is no relevant use of LUMYKRAS in the paediatric population in the treatment of non-smallcell lung cancer.

LUMYKRAS is for oral use. The tablets must be swallowed whole. There are no data to support theadministration of LUMYKRAS if the tablets are chewed, crushed, or split but the tablets can bedispersed in water (see below). The tablets can be taken with or without food.

Patients should disperse tablets in 120 mL of non-carbonated, room temperature water, withoutcrushing them. Other liquids must not be used. Patients should stir until the tablets are dispersed intosmall pieces (the tablet will not dissolve completely) and drink it immediately. The appearance of themixture may range from pale to bright yellow. The container must be rinsed with an additional120 mL of water, which should be drunk immediately. If it is not drunk immediately, patients must stiragain to ensure that the tablets are dispersed. The dispersion must be discarded if it is not drunk within2 hours.

If administration through a nasogastric (NG) tube or percutaneous endoscopic gastrostomy (PEG) tubeis required, follow the process above for the initial dispersion and for the residual rinse of the 120 mgor 240 mg tablets. The dispersed suspension and rinse should be administered as per the NG or PEGtube manufacturer’s instructions with appropriate water flushes. Administer the dispersion within2 hours of preparation, stored at room temperature.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Sotorasib can cause hepatotoxicity, which may lead to drug-induced liver injury (DILI) and hepatitis.

Sotorasib has been associated with transient elevations of serum transaminases (ALT and AST),alkaline phosphatase and total bilirubin in 960 mg monotherapy clinical trials. In a total of740 patients with KRAS G12C-mutated solid tumours who received LUMYKRAS 960 mgmonotherapy daily, the incidence for hepatotoxicity is highest in the sub-group of patients with recent(≤ 3 months) immunotherapy (38%) prior to starting LUMYKRAS, as compared to those who started

LUMYKRAS either more than 3 months after last dose of immunotherapy (17%) or those who neverreceived immunotherapy (22%). Regardless of time from prior immunotherapy, 87% of elevationsimproved or resolved with interruption of LUMYKRAS treatment and treatment with corticosteroids.

Elevated liver enzymes led to discontinuation of treatment in 10%, 2% and 0% of patients with priorimmunotherapy within ≤ 3 months, with prior immunotherapy within > 3 months and no priorimmunotherapy, respectively. Among 740 patients with KRAS G12C-mutated solid tumours whoreceived 960 mg orally once daily, 26% experienced hepatotoxicity and 13% had hepatotoxicityleading to dose interruption and/or dose reduction. Overall, 41% of patients with hepatotoxicityreceived concurrent corticosteroids. Cases of liver enzyme increase can be asymptomatic. Patientsshould be monitored for liver function (ALT, AST, alkaline phosphatase and total bilirubin) prior tothe start of LUMYKRAS, every 3 weeks for the first 3 months of treatment, then once a month or asclinically indicated, with more frequent testing in patients with recent immunotherapy and in patientswith serious hepatotoxicity events. Based on the severity of the laboratory abnormalities, treatmentwith LUMYKRAS must be interrupted until recovered to ≤ 3 × ULN or to ≤ 3 baseline (if baselineabnormal) and treatment with corticosteroids considered, and the dose of LUMYKRAS must be eithermodified or permanently discontinued (see section 4.2).

LUMYKRAS can cause ILD/pneumonitis that can be fatal. ILD/pneumonitis occurred in patientstreated with LUMYKRAS with prior exposure to immunotherapy or radiotherapy (see section 4.8).

Recent (≤ 3 months) immunotherapy prior to starting LUMYKRAS may be considered a risk factorfor ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of

ILD/pneumonitis (e.g. dyspnoea, cough, fever). Immediately withhold LUMYKRAS in patients withsuspected ILD/pneumonitis and permanently discontinue LUMYKRAS if no other causes of

ILD/pneumonitis are identified (see section 4.2).

Use in population with hepatic impairment

There are no data on the clinical safety and efficacy of multiple doses of LUMYKRAS whenadministered to patients with moderate and severe hepatic impairment (Child-Pugh B and C). No doserecommendation can be made.

LUMYKRAS contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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

In vitro studies indicate that sotorasib is metabolised by cytochrome P450 (CYP) 2C8, CYP3A4, and

CYP3A5, and is a substrate of P-glycoprotein (P-gp). Sotorasib was an inducer of CYP3A4, CYP2B6,

CYP2C8, CYP2C9, and CYP2C19 in vitro. Sotorasib is an in vitro inhibitor of CYP2C8, CYP2D6,and CYP3A. In vitro studies indicate that sotorasib is an inhibitor of human organic anion transporter(OAT)1/3, OATP1B1, Breast Cancer Resistance Protein (BCRP) and P-gp.

Co-administration of sotorasib with a PPI (omeprazole) or an H2 receptor antagonist (famotidine) ledto a decrease in sotorasib concentrations.

Under fed conditions (standard-calorie moderate-fat meals), co-administration of multiple doses ofomeprazole with a single dose of 960 mg sotorasib decreased sotorasib Cmax by 65% and area underthe curve (AUC) by 57%. Co-administration of a single dose of famotidine given 10 hours prior and2 hours after a single dose of 960 mg sotorasib decreased sotorasib Cmax by 35% and AUC by 38%.

Under fasted conditions, co-administration of multiple doses of omeprazole with a single dose of960 mg sotorasib decreased sotorasib Cmax by 57% and AUC by 42%. Under fasted conditions,co-administration of repeat doses of omeprazole with a single dose of 960 mg sotorasib and 240 mL ofan acidic beverage (non-diet cola) decreased sotorasib Cmax by 32% and AUC by 23%. The clinicalrelevance of the decreased sotorasib exposure when co-administered with omeprazole and cola isunclear and efficacy might be reduced.

If co-administration of LUMYKRAS with an acid-reducing agent (such as a PPI or an H2 receptorantagonist) is required, LUMYKRAS should be taken with an acidic beverage (such as cola).

Alternatively, LUMYKRAS should be taken 4 hours before or 10 hours after administration of a localantacid.

Co-administration of multiple dose itraconazole (a strong CYP3A4 and P-gp inhibitor) did notincrease sotorasib exposures to a clinically significant extent. No dose adjustment of LUMYKRAS isrecommended when co-administered with CYP3A4 inhibitors.

Co-administration of sotorasib with multiple doses of a strong CYP3A4 inducer (rifampicin)decreased sotorasib Cmax by 35% and AUC by 51%. Co-administration of strong CYP3A4 inducers(e.g. rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s wort) with

LUMYKRAS is not recommended because they may decrease sotorasib exposure.

Sotorasib is a moderate CYP3A4 inducer. Co-administration of sotorasib with CYP3A4 substrates ledto a decrease in their plasma concentrations, which may reduce the efficacy of these substrates.

Co-administration of sotorasib with midazolam (a sensitive CYP3A4 substrate) decreased midazolam

Cmax by 48% and AUC by 53%.

Avoid co-administration of LUMYKRAS with CYP3A4 substrates with narrow therapeutic indices,including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonalcontraceptives, pimozide, quinidine, sirolimus, tacrolimus, amlodipine and manidipine. Ifco-administration cannot be avoided, adjust the CYP3A4 substrate dose in accordance with the currentsummary of product characteristics.

In vitro data indicated that sotorasib may have the potential to induce CYP2B6, CYP2C8, CYP2C9and CYP2C19; the clinical relevance of these findings is unknown. When sotorasib is co-administeredwith medicinal products metabolised by these enzymes, appropriate monitoring is recommended.

In vitro data indicated that sotorasib may have the potential to inhibit CYP2D6, the clinical relevanceof these findings is unknown. When LUMYKRAS is co-administered with CYP2D6 substrates (e.g.

flecainide, propafenone, metoprolol), appropriate monitoring is recommended.

LUMYKRAS is a weak BCRP inhibitor. Co-administration of LUMYKRAS with a BCRP substrateled to an increase in the plasma concentrations of the BCRP substrate, which may increase the effectof the substrate.

Co-administration of LUMYKRAS with rosuvastatin (a BCRP substrate) increased the rosuvastatin

Cmax by 70% and AUC by 34%.

When LUMYKRAS is co-administered with a BCRP substrate, including but not limited to lapatinib,methotrexate, mitoxantrone, rosuvastatin and topotecan, monitor for adverse reactions of the BCRPsubstrate and reduce the BCRP substrate dose in accordance with its current summary of productcharacteristics.

Co-administration of sotorasib with digoxin (a P-glycoprotein [P-gp] substrate) increased digoxin Cmaxby 1.9-fold and AUCinf by 1.2-fold of digoxin administered alone. Co-administration of LUMYKRASwith P-gp substrates with narrow therapeutic indices is not recommended. If co-administration cannotbe avoided, adjust the P-gp substrate dosage in accordance with the current summary of productcharacteristics.

Women of childbearing potential must be advised to avoid pregnancy while on LUMYKRAS. Femalepatients of childbearing potential receiving LUMYKRAS must use highly effective contraceptivemethods during treatment and for at least 7 days following the last dose of LUMYKRAS.

LUMYKRAS may reduce the effectiveness of hormonal contraceptives, and therefore women usinghormonal contraceptives should add a barrier method.

There are no data from the use of sotorasib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). LUMYKRAS is not recommended during pregnancy and inwomen of childbearing potential not using contraception. Patients must be informed of the potentialhazards to the foetus if LUMYKRAS is used during pregnancy, or if the patient becomes pregnantwhile taking LUMYKRAS.

It is unknown if sotorasib or its metabolites are excreted in human milk. A risk to breast-fednewborns/infants cannot be excluded. LUMYKRAS should not be used during breast-feeding.

There are no clinical studies to evaluate the effect of sotorasib on fertility.

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

Adverse drug reactions (ADRs) described in table 3 reflect exposure to sotorasib 960 mg once daily asmonotherapy in 740 patients with KRAS G12C-mutated solid tumours across multiple clinical studies,including CodeBreaK 200, CodeBreaK 100 phase 2 part A, and CodeBreaK 100 phase 2 part B (dosecomparison sub-study) and three phase 1 studies.

The most common adverse reactions in patients treated with LUMYKRAS 960 mg once daily werediarrhoea (36.6%), nausea (24.7%), fatigue (19.1%), vomiting (16.1%), arthralgia (15.3%), anddecreased appetite (15.1%). The most common severe (grade ≥ 3) adverse reactions were diarrhoea(6.9%), increased ALT (5.9%) and increased AST (4.6%). The most common adverse reactionsleading to permanent discontinuation of treatment were increased ALT (1.5%) and increased

AST (1.1%) and DILI (1%). The most common adverse reactions leading to dose modification werediarrhoea (11.4%), increased ALT (5.9%), increased AST (5.7%), nausea (3.8%), increased bloodalkaline phosphatase (2.4%) and vomiting (2%).

Adverse reactions reported in LUMYKRAS clinical studies are displayed in table 3 below. Frequencycategories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon(≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannotbe estimated from available data). Within each system organ class, adverse reactions are presented inorder of decreasing seriousness.

The safety of LUMYKRAS was evaluated in 740 patients with KRAS G12C-mutated solid tumourswho received 960 mg orally once daily as monotherapy. The median duration of exposure to

LUMYKRAS was 4.2 months (range: 0 to 41).

Table 3. Adverse reactions

MedDRA system Very common Common Uncommonorgan class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100)

Blood and Anaemialymphatic systemdisorders

Nervous system Headachedisorders

Respiratory, Cough ILD/pneumonitisthoracic and Dyspnoeamediastinaldisorders

Gastrointestinal Diarrhoeadisorders Nausea

Abdominal paina

Hepatobiliary Drug-induced liver Hepatitisdisorders injury

Renal and urinary Renal impairmentdisorders Renal failure

Acute kidney injury

Musculoskeletal Arthralgiaand connective Back paintissue disorders

General disorders Fatigue Pyrexiaand administrationsite conditions

Investigations Aspartate Blood alkalineaminotransferase phosphatase increasedincreased Blood bilirubin

Alanine increasedaminotransferase Gamma-increased glutamyltransferaseincreased

Metabolism and Decreased appetite Hypokalaemianutrition disordersa Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower

In clinical studies, transient elevations of serum transaminases were observed (see section 4.4).

Among 740 patients who received LUMYKRAS 960 mg once daily as monotherapy, elevations of

ALT occurred in 12.8% of patients and elevations of AST in 13.1% of patients, with a median time toonset of 6 weeks (range: 1 to 103) and 6 weeks (range: 0 to 42), respectively. Elevations of ALTresulted in dose interruption and/or reduction in 5.9% of patients, and elevations of AST resulted indose interruption and/or reduction in 5.7% of patients. Elevated bilirubin occurred in 3.2% of patientsand resulted in dose interruption and/or reduction in 0.9% of patients.

In clinical studies, among 740 patients who received LUMYKRAS 960 mg once daily asmonotherapy, ILD/pneumonitis occurred in 1.9% of patients; ILD/pneumonitis was grade 3 or 4 atonset on 0.8% of patients. A case of fatal ILD occurred in a patient with metastatic NSCLC stage IVBtreated with LUMYKRAS in a clinical trial. The patient developed lower respiratory tract infectionwith a fatal outcome despite steroids and antibiotics treatment. The fatal ILD occurred in a setting ofmassive disease progression. The median time to first onset for ILD/pneumonitis was 10.6 weeks(range: 2 to 43.3 weeks). LUMYKRAS was discontinued due to ILD/pneumonitis in 0.9% of patients(see sections 4.2 and 4.4).

In clinical studies, no overall differences in safety or efficacy were observed between elderly patients(≥ 65 years old) and younger patients (see sections 4.2 and 5.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XX73

Sotorasib is a selective KRASG12C (Kirsten rat sarcoma viral oncogene homologue) inhibitor, whichcovalently and irreversibly binds to the unique cysteine of KRASG12C. Inactivation of KRASG12C bysotorasib blocks tumour cell signalling and survival, inhibits cell growth, and promotes apoptosisselectively in tumours harbouring KRASG12C, an oncogenic driver of tumourigenesis.

LUMYKRAS for the treatment of patients with previously treated KRAS G12C-mutated NSCLC

CodeBreaK 100 phase 2 part A

The efficacy of LUMYKRAS was studied in a single-arm, open-label, multicentre trial(CodeBreaK 100 phase 2 part A) that enrolled patients with locally advanced or metastatic

KRAS G12C-mutated NSCLC who had disease progression after receiving prior therapy. Keyeligibility criteria included progression on an immune checkpoint inhibitor and/or platinum-basedchemotherapy and after targeted therapy if actionable oncogenic driver mutations were identified, an

Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and at least onemeasurable lesion as defined by Response Evaluation Criteria in Solid Tumours (RECIST v1.1). Allpatients were required to have KRAS G12C-mutated NSCLC prospectively identified in tumoursamples using a validated test (Qiagen therascreen® KRAS RGQ PCR Kit) performed in a centrallaboratory. Patients with renal impairment, hepatic impairment and active brain metastases wereexcluded.

A total of 126 patients were enrolled and treated with LUMYKRAS 960 mg once daily asmonotherapy until disease progression or unacceptable toxicity; 124 patients had at least onemeasurable lesion at baseline as assessed by Blinded Independent Central Review (BICR) accordingto RECIST v1.1 and were included in the analysis for response-related efficacy outcomes. The medianduration of treatment was 5.5 months (range: 0 to 15) with 48% of patients treated for ≥ 6 months and33% of patients treated for ≥ 9 months.

The major efficacy outcome measure was objective response rate (ORR) defined as the proportion ofpatients who achieved CR or PR as evaluated by a BICR according to RECIST v1.1. Additionalefficacy outcome measures included duration of response (DOR), disease control rate (DCR) definedas the proportion of patients who achieved CR, PR and stable disease, time to response (TTR),progression-free survival (PFS), and overall survival (OS).

The baseline demographic and disease characteristics of the study population were: median age64 years (range: 37 to 80); 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% receivedonly 1 prior line of therapy, 35% received 2 prior lines of therapy, 22% received 3 prior lines oftherapy, 91% received prior anti-PD-1/PD-L1 immunotherapy, 90% received prior platinum-basedchemotherapy, 81% received both platinum-based chemotherapy and anti-PD-1/PD-L1. The sites ofknown extra-thoracic metastasis included 48% bone, 21% brain, and 21% liver.

Efficacy results are summarised in table 4.

Table 4. Efficacy results in CodeBreaK 100 for patients with KRAS G12C-mutated NSCLC(CodeBreaK 100 phase 2 part A)

Efficacy parameters LUMYKRAS

N = 124

ORR, % (95% CI)a,c 37.1 (28.6, 46.2)

Complete response (CR), % 2.4

Partial response (PR), % 34.7

DORa,d

Number of responders 46

Medianb, months (range) 11.1 (6.9, 15.0)

Censored, % 39.0

Patients with duration ≥ 6 months, % 63.0

CI = confidence interval; DOR = duration of response; ORR = objective response ratea Response-related efficacy outcomeb Estimated using Kaplan-Meier methodc Based on 01 December 2020 data cutd Based on 20 June 2021 data cut

The European Medicines Agency has waived the obligation to submit the results of studies with

LUMYKRAS in all subsets of the paediatric population in NSCLC (see section 4.2 for information onpaediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agencywill review new information on this medicinal product at least every year and this SmPC will beupdated as necessary.

Bioavailability of sotorasib has not been investigated in humans. Following an oral, single doseadministration, sotorasib was absorbed with median time to achieve peak concentration of 1-2 hours.

In a dose comparison sub-study (CodeBreaK 100 phase 2 part B) in patients receiving sotorasib240 mg or 960 mg once daily, after 8 daily doses, Cmax and AUC0-24 hour for 240 mg were both 22%lower than 960 mg.

Following administration of sotorasib with a high-fat, high-calorie meal, there was no effect on Cmax,and AUC increased by 38% compared to administration under fasted conditions. Sotorasib can beadministered with or without food.

The geometric mean apparent volume of distribution after 960 mg PO QD for 8 consecutive days ofsotorasib was 211 L (determined using noncompartmental analysis). In vivo, plasma protein binding ofsotorasib was 97.6% and sotorasib bound preferentially to alpha-1-acid glycoprotein in vitro.

The main metabolic pathways of sotorasib were non-enzymatic conjugation and oxidative metabolism.

In vitro data indicate that sotorasib is metabolised by cytochrome P4502C8, CYP3A4, and CYP3A5,and is a substrate of P-glycoprotein (P-gp). Following single oral administration of a radioactivesotorasib dose of 720 mg, a cysteine adduct (formed through hydrolysis of a glutathione adduct) andan oxidative metabolite resulting from CYP3A-mediated cleavage of the piperazine acrylamide moietywere the primary circulating metabolites. Neither of these metabolites were pharmacologically active.

The geometric mean apparent clearance after 960 mg orally once daily for 8 consecutive days ofsotorasib was 26.2 L/hour (determined using noncompartmental analysis). The mean half-life is5 hours. Steady state was reached within 22 days and remained stable. Sotorasib is primarilyeliminated in faeces, with approximately 74% of the dose recovered in faeces and 6% (1% unchanged)recovered in urine.

Sotorasib exhibited nonlinear pharmacokinetics over a range of single and multiple oral administrationdoses studied between 180 to 960 mg once daily as Cmax and AUC0-24 hour were less than doseproportional. The average Cmax and AUC0-24 hour values following multiple doses were similar for alldosing regimens from 180 mg orally once daily to 960 mg orally once daily. Exposure to sotorasibdecreases over time following 960 mg orally once daily dosing regimen until steady state is reached.

Steady state plasma concentrations were achieved by approximately 3 weeks across the phase 1 andphase 2 clinical studies across all sotorasib doses.

Initial results of a population PK analysis suggests no clinically meaningful differences in thepharmacokinetics of sotorasib based on age, sex, race or ethnicity, body weight, line of therapy,

ECOG PS, serum albumin, mild renal impairment (CrCL ≥ 60 mL/min), or mild hepatic impairment(AST or ALT < 2.5 × ULN or total bilirubin < 1.5 × ULN). The effect of moderate to severe renalimpairment on sotorasib pharmacokinetics has not been studied.

Compared to subjects with normal hepatic function after a 960 mg LUMYKRAS administration, themean systemic exposure AUCinf of sotorasib decreased by 25.4% in subjects with moderateimpairment (Child-Pugh B) and increased by 3.6% in subjects with severe hepatic impairment(Child-Pugh C). The unbound AUCinf of sotorasib increased by 1.8-fold in subjects with moderatehepatic impairment and by 6-fold in patients with severe hepatic impairment.

Sotorasib was not mutagenic in a bacterial mutagenicity (Ames) assay. Sotorasib was not genotoxic inthe in vivo rat micronucleus and comet assays.

Carcinogenicity studies have not been performed with sotorasib.

In rat and rabbit embryo-foetal development studies, oral sotorasib was not teratogenic.

In the rat, there were no effects on embryo-foetal development up to the highest dose tested (3.9 timeshigher than the exposure at the maximum recommended human dose [MRHD] of 960 mg based onarea under the curve [AUC]).

In the rabbit, lower foetal body weights and a reduction in the number of ossified metacarpals infoetuses were observed only at the highest dose level tested (2.2 times higher than the exposure at the

MRHD of 960 mg based on AUC), which was associated with maternal effects such as decreasedbody weight gain and food consumption during the dosing phase. Reduced ossification, as evidence ofgrowth retardation associated with reduced foetal body weight, was interpreted as a non-specific effectin the presence of significant maternal toxicity.

Fertility/early embryonic development studies were not conducted with sotorasib. There were noadverse effects on male or female reproductive organs in general toxicology studies conducted in dogsand rats.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows:

* Renal toxicity observed in repeat-dose toxicity studies in rats.

Environmental risk assessment studies have shown that sotorasib has the potential to be very persistentto the environment (see section 6.6). There is no potential for bioaccumulation or toxicity.

Cellulose, microcrystalline (E460(i))

Lactose monohydrate

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

Macrogol 4000 (E1521)

Talc (E553b)

Iron oxide yellow (E172)

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

3 years.

This medicinal product does not require any special storage conditions.

LUMYKRAS 120 mg film-coated tablets

PVC/PE/PVDC blisters with aluminium foil backing containing 8 film-coated tablets. Pack sizes of240 film-coated tablets (1 carton with 30 blisters) and multipack with 720 (3 × 240) film-coatedtablets.

HDPE bottle with a child-resistant polypropylene cap and aluminium foil induction seal linercontaining 120 film-coated tablets. Pack size of 240 film-coated tablets (1 carton with 2 bottles).

LUMYKRAS 240 mg film-coated tablets

PVC/PCTFE perforated unit dose blisters with aluminium foil backing containing 8 film-coatedtablets. Pack size of 120 film-coated tablets (1 carton with 15 blisters).

Not all pack sizes may be marketed.

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

Amgen Europe B.V.,

Minervum 7061,4817 ZK Breda,

The Netherlands

EU/1/21/1603/001

EU/1/21/1603/002

EU/1/21/1603/003

EU/1/21/1603/004

Date of first authorisation: 06 January 2022

Date of latest renewal: 20 November 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.