Summary Basis of Decision for Lazcluze

Clinical Pharmacology

Lazertinib is a third generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. It selectively inhibits both primary activating EGFR mutations (exon 19 deletions and exon 21 L858R substitution mutations) while having less activity against wild-type EGFR.

The formulation of lazertinib tablets used in the clinical studies differs from that of the proposed commercial tablets. The sponsor provided the results of a pivotal comparative bioavailability study to bridge the tablets used in the Phase III clinical study to those proposed for marketing. The results of the study successfully bridged the proposed commercial tablets (80 mg tablets and 240 mg tablets) to the formulation used in the pivotal clinical safety and efficacy studies (80 mg tablets).

A dedicated QT study was not performed with Lazcluze. As a substitute, an exposure‑response analysis was performed with clinical data from a Phase I/II study, which suggested no clinically relevant relationship between lazertinib plasma concentration and change in corrected QT interval.

Following single and multiple once daily oral administration of Lazcluze, the maximum concentration (C_max) and the area under the plasma concentration time curve (AUC) of lazertinib increased approximately dose proportionally across the 20 to 320 mg dose range. Steady-state plasma exposure was achieved by Day 15 following administration of 240 mg Lazcluze once daily and approximately two-fold accumulation of lazertinib was observed. Lazertinib plasma exposure was comparable when administered either in combination with amivantamab or as a monotherapy.

The median time to reach lazertinib C_max after a single dose or multiple once daily oral administrations of Lazcluze was comparable and ranged from 2 to 4 hours. Following the administration of 240 mg lazertinib with a high-fat meal, the C_max and AUC of lazertinib were comparable to the corresponding values under fasting conditions, suggesting lazertinib can be taken with or without food.

Lazertinib was extensively distributed, with a mean (coefficient of variation [CV]%) apparent volume of distribution of 4,264 L (43.2%) following a single 240 mg dose. Lazertinib mean (CV%) plasma protein binding was approximately 99.2% (0.13%) in humans.

Lazertinib is primarily metabolized by glutathione conjugation, either enzymatically via glutathione-S-transferase (GST) or non-enzymatically, as well as by cytochrome P450 (CYP)3A4 to a lesser extent. The most abundant metabolites are glutathione catabolites which are considered clinically inactive. The plasma exposure of lazertinib was affected by glutathione S-transferase mu 1 (GSTM1)-mediated metabolism, leading to higher exposure (up to two-fold difference) in null GSTM1 patients. No clinically significant differences in safety or efficacy were observed as a function of GSTM1 genotype in patients receiving Lazcluze in combination with amivantamab.

The mean (CV%) apparent clearance and terminal elimination half-life of lazertinib at the 240 mg dose were 44.5 L/h (29.5%) and 64.7 hours (32.8%), respectively.

Following a single oral dose of radiolabeled lazertinib, approximately 86% of the dose was recovered in feces (less than 5% as unchanged) and 4% was recovered in urine (less than 0.2% as unchanged).

Lazertinib is an inhibitor of CYP3A4 and may increase exposure of co-administered CYP3A4 substrates and the risk of exposure-related toxicity. Lazertinib is an inhibitor of breast cancer resistance protein (BCRP) transporter and may increase exposure of co-administered BCRP substrates and the risk of exposure-related toxicity. Appropriate safety-related dose modifications have been included in the Lazcluze Product Monograph.

The clinical pharmacology data support the use of Lazcluze for the recommended indication. For further details, please refer to the Product Monograph for Lazcluze, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Lazcluze in combination with amivantamab was evaluated in the pivotal Phase III MARIPOSA study. This study was a randomized, multicentre, active-controlled study that compared the efficacy and safety of the combination therapy of Lazcluze and amivantamab versus (vs.) osimertinib monotherapy as first-line treatment for patients with locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations).

A total of 1,074 treatment-naïve patients were randomized (2:2:1) to receive open-label treatment with Lazcluze in combination with amivantamab (Arm A - total number [n] = 429), double-blinded treatment with osimertinib monotherapy (Arm B - n = 429), or Lazcluze monotherapy (Arm C - n = 216). Note that Lazcluze monotherapy is not authorized for treatment of NSCLC. Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), race (Asian or non-Asian), and history of brain metastasis (yes or no). The evaluation of efficacy relied upon comparison between the Lazcluze + amivantamab arm and the osimertinib arm. The active control arm was acceptable as osimertinib was the current standard of care in Canada for the proposed indication at the time of the study. It was administered at the recommended dose, as per its product monograph.

In Arm A, patients received Lazcluze 240 mg once daily in combination with amivantamab 1,050 mg (or 1,400 mg if body weight was 80 kg or higher) by intravenous infusion in 28-day cycles (once weekly for the first 4 weeks [with a split dose on Days 1-2] and then once every 2 weeks from Week 5 onwards). In Arm B, patients received osimertinib 80 mg once daily, while in Arm C, patients received Lazcluze 240 mg monotherapy once daily. Patients received treatment until disease progression or unacceptable toxicity.

Baseline demographics and disease characteristics were balanced across the treatment arms. The median patient age in the Lazcluze + amivantamab arm was 64 years (range: 25 to 88 years) vs. 63 years (range: 28 to 88 years) in the osimertinib arm. In the Lazcluze + amivantamab arm, 45% of patients were 65 years or older, 64% were female, 58% were Asian, and 38% were White. In the osimertinib arm, 45% of patients were 65 years or older, 59% were female, 59% were Asian, and 38% were White. In the Lazcluze + amivantamab arm, baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (fully active, able to carry on all pre-disease performance without restriction; 33%) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 67%); 70% never smoked; 41% had prior brain metastases; and 97% had Stage IV cancer at screening. In the osimertinib arm, baseline ECOG performance status was 0 (35%) or 1 (65%); 69% never smoked; 40% had prior brain metastases, and 97% had Stage IV cancer at screening. With regard to EGFR mutation status, 60% were exon 19 deletions and 40% were exon 21 L858R substitution mutations for both treatment arms.

The primary efficacy endpoint of the study was progression-free survival (PFS), defined as the time from randomization until the date of objective disease progression or death, whichever came first, based on blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key secondary endpoints were objective response rate (ORR), duration of response (DOR), and overall survival (OS).

Progression-free survival, based on BICR, showed a statistically significant and clinically meaningful improved treatment effect for the Lazcluze + amivantamab arm as compared with the osimertinib arm (hazard ratio [HR] = 0.70 [95% Confidence Interval [CI]: 0.58, 0.85], p = 0.0002). The corresponding median PFS was 23.7 months (95% CI: 19.12, 27.66) for the Lazcluze + amivantamab arm vs. 16.6 months (95% CI: 14.78, 18.46) for the osimertinib arm.

The ORR in the Lazcluze + amivantamab therapy arm was similar to the ORR in the Osimertinib arm. In the intention-to-treat (ITT) analysis, the proportion of patients with a confirmed response was 78.3% (95% CI: 71.4%, 82.1%) in the Lazcluze + amivantamab arm and 73.4% (95% CI: 69.0%, 77.5%) in the osimertinib arm. The median DOR was prolonged in the Lazcluze + amivantamab arm (25.8 months [95% CI: 20.14, not estimable]) compared with the osimertinib arm (16.7 months [95% CI: 14.75, 18.53]).

The intracranial ORR based on confirmed responses was 67.8% (95% CI: 60.4, 74.5) in the Lazcluze + amivantamab arm and 69.0% (95% CI: 61.8%, 75.5%) in the osimertinib arm. The median intracranial DOR was not reached for the Lazcluze + amivantamab or the osimertinib arms. These results suggested similar intracranial ORR with Lazcluze + amivantamab compared to osimertinib.

The OS results submitted to Health Canada were immature. No trend toward a detriment was observed in the full analysis set.

Differences were seen in subgroup analyses for efficacy in geriatric patients (65 years of age and older), however no formal statistical testing of efficacy was planned for subgroup analyses by age and the interpretation of these differences was limited.

No patients less than 18 years of age and no pregnant women were included in the study.

The clinical benefit of Lazcluze + amivantamab therapy inpatients with Stage III NSCLC amenable to curative therapy has not been evaluated.

Most enrolled patients had Stage IV NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations. Therefore, the efficacy of the combination therapy in patients without an EGFR mutation has not been evaluated.

Indication

The New Drug Submission for Lazcluze was filed by the sponsor with the following proposed indication:

Lazcluze (lazertinib) tablets in combination with amivantamab is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations.

Health Canada approved the following indication:

Lazcluze (lazertinib) in combination with amivantamab is indicated for the first-line treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations.

For more information, refer to the Product Monograph for Lazcluze, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Lazcluze in combination with amivantamab was evaluated in the pivotal MARIPOSA study. The safety analysis set included randomized participants who received at least one dose of study treatment (421 subjects in the Lazcluze + amivantamab arm, 429 subjects in the osimertinib arm, and 216 subjects in the Lazcluze arm). The median duration of treatment was similar in each arm: 18.5 months in the Lazcluze + amivantamab arm (15.2 months for amivantamab and 18.5 months for Lazcluze), 18.0 months in the osimertinib arm , and 17.1 months in the Lazcluze arm.

The open-label design of the combination arm could have introduced a certain level of subjectivity in the assessment of the severity of treatment-emergent adverse events (TEAEs). The impact of this potential bias on the assessment of the safety profile of the combination arm is unclear, but cannot be ruled out. The inability to conduct a placebo control arm in this patient population complicated the assessment of the relationship between an adverse event (AE) and the Lazcluze + amivantamab combination therapy. Consequently, unless there was evidence showing otherwise, any TEAE that occurred in the Lazcluze + amivantamab arm with a frequency and severity that was at least similar as compared to the osimertinib arm was considered as being related to Lazcluze + amivantamab therapy.

The most frequently reported adverse reactions (occurring in 20% or more of participants) in the Lazcluze + amivantamab arm were: paronychia (68.4%), rash (61.8%), increased alanine transaminase (ALT; 36.1%), peripheral edema (35.6%), constipation (29.2%), diarrhea (29.2%), dermatitis acneiform (29.0%), stomatitis (29.0%), increased aspartate aminotransferase (AST; 28.7%), coronavirus disease 2019 (COVID-19; 26.4%), decreased appetite (24.5%), pruritus (23.5%), anemia (22.8%), nausea (21.4%) and hypocalcaemia (20.9%). Infusion-related reactions and hypoalbuminemia were related to amivantamab only and were reported by 62.9% and 48.5% of patients. Other clinically relevant adverse reactions or grouped adverse reactions reported in the Lazcluze + amivantamab arm were venous thromboembolism, ophthalmologic toxicity, interstitial lung disease/pneumonitis, and paraesthesia.

The addition of amivantamab to Lazcluze resulted in an increase in the incidence of adverse reactions as compared to osimertinib. Grade 3 and higher adverse reactions were reported with an increased incidence in the combination of Lazcluze + amivantamab arm (75.1%) compared with the osimertinib (42.8%). There was also a higher incidence of adverse reactions leading to dose modifications in the Lazcluze + amivantamab arm compared to osimertinib. Dose interruptions of Lazcluze due to adverse reactions occurred in 71% of patients. Of these adverse reactions, the following occurred in 5% or more of patients: rash, paronychia, COVID-19, dermatitis acneiform, increased ALT, and increased AST. Dose reductions of Lazcluze due to adverse reactions occurred in 42% patients. Of these adverse reactions the following occurred in 5% or more of patients: paronychia, rash, and dermatitis acneiform. Dose discontinuation of Lazcluze due to adverse reactions occurred in 20% of patients. Of these adverse reactions, the following occurred in 1% or more of patients: ILD/pneumonitis, pneumonia, and pulmonary embolism.

There was a higher incidence of serious adverse events (SAEs) in the Lazcluze + amivantamab arm (48.7% of participants) vs. the osimertinib arm (33.4% of participants). Serious adverse events that were reported in more than 2% of participants in the Lazcluze + amivantamab arm were: pulmonary embolism (6.2%), pneumonia (4.0%), deep vein thrombosis (2.9%), ILD/pneumonitis (2.9%), COVID-19 (2.4%), infusion‑related reaction (2.1%), pleural effusion (2.1%).

Although the overall frequency of Grade 5 TEAEs (fatal events) was similar in the Lazcluze + amivantamab arm and the osimertinib arm, the safety results suggest a greater risk of sudden death or fatal cardiovascular adverse reactions while on treatment with Lazcluze + amivantamab, or within 30 days of the last dose of Lazcluze + amivantamab as compared to osimertinib.

In the MARIPOSA study, the incidence of left ventricular ejection fraction reduction and cardiomyopathy in the Lazcluze + amivantamab arm was similar to the osimertinib arm. Considering that Lazcluze and osimertinib share a similar mechanism of action and cardiotoxicity is a known risk associated with osimertinib, it is difficult to rule out a risk of cardiotoxicity with Lazcluze + amivantamab therapy that would be at least similar to the risk associated with osimertinib.

There is a degree of uncertainty regarding the risk of QT interval prolongation with Lazcluze since appropriate studies to evaluate such risk have not been performed.

Prophylactic anticoagulation therapy is recommended for at least the first 4 months of Lazcluze + amivantamab therapy to mitigate the risk of venous thromboembolic events.

Interstitial lung disease (ILD)/pneumonitis is a class effect of EGFR inhibitors. Cases of ILD/pneumonitis, including fatal events, have been reported with the Lazcluze + amivantamab therapy. This risk has been highlighted in the Serious Warnings and Precautions box in the Product Monograph for Lazcluze.

There were no data on the effect of lazertinib on human fertility. However, studies in animals have shown that lazertinib may impair female and male fertility.

There were no clinical data in pregnant women but, based on non-clinical studies, lazertinib may cause fetal harm. A risk of teratogenicity with lazertinib cannot be ruled out.

Age appears to be an intrinsic risk factor for an increased rate of serious toxicity in patients treated with Lazcluze + amivantamab. Overall, the incidence of serious toxicity (Grade 4 and Grade 5 TEAEs, SAEs, and TEAEs leading to discontinuation) in the Lazcluze + amivantamab arm was substantially increased in patients 65 years of age or older compared to the younger group of patients. In contrast, there was no difference of serious toxicity between age groups in the osimertinib arm. These results suggest that elderly patients may be at an increased risk of serious toxicity when treated with Lazcluze + amivantamab compared to those treated with osimertinib.

No studies on effects on the ability to drive or use machines have been performed. However, eye toxicities, including keratitis, as well as dizziness were reported in patients treated with Lazcluze + amivantamab, which may have an impact on their ability to drive or use machines.

Based on population pharmacokinetic (PK) analysis, no dose adjustment is required for patients with mild or moderate hepatic impairment. Data in patients with moderate hepatic impairment were limited at the time of authorization. Considering that hepatic CYP3A4 metabolism is one of the primary elimination pathways, close monitoring for adverse reactions is needed. No data were available in patients with severe hepatic impairment.

Based on population PK analysis, no dose adjustment is required for patients with mild or moderate renal impairment with estimated glomerular filtration rate (eGFR) of 15 to 89 mL/min. Data in patients with severe renal impairment (eGFR of 15 to 29 mL/min) were limited at the time of authorization. No data were available in patients with end stage renal disease (eGFR less than 15 mL/min).

In conclusion, Lazcluze + amivantamab therapy was associated with significant toxicity. However, appropriate warnings and precautions are in place in the approved Product Monograph for Lazcluze to address the identified safety concerns. When used under the proposed conditions of use, with the recommended monitoring and risk mitigation measures, the safety profile of Lazcluze is expected to be manageable. For more information, refer to the Product Monograph for Lazcluze, approved by Health Canada and available through the Drug Product Database.

In vivo, lazertinib exhibited strong antitumor effects in NSCLC xenograft models, particularly in EGFR-mutant tumours, including brain metastases. Combination therapy with amivantamab enhanced efficacy, especially in mesenchymal epithelial transition (MET)-driven resistance models.

No pharmacokinetic interactions were observed with amivantamab in non-clinical models, supporting a low risk of drug-drug interactions.

Lazertinib was not mutagenic in the Ames test nor clastogenic in other genotoxicity assays. Carcinogenicity studies were not conducted, as they are not required for the proposed indication of NSCLC.

In 13-week oral toxicology studies in rats and dogs treated with lazertinib, expected EGFR inhibitor-related toxicities were observed affecting the skin, eyes, gastrointestinal tract, liver, kidneys, heart, lungs, reproductive organs, and bone marrow, with signs of multi-organ inflammation. Skin toxicity in rats included scaly skin, scabs, and follicle degeneration, while dogs showed epidermal atrophy; both species showed partial to full recovery.

Lazertinib had adverse effects in the eyes of rats including epithelial atrophy in the cornea, corneal erosion/ulcer of the eye with exudate or hyperplasia, and chronic/active inflammation in the eyelids.

Liver toxicity in rats included increased extramedullary hematopoiesis and hepatocyte necrosis, Kupffer cell hypertrophy, elevated alanine transaminase/aspartate transaminase levels, and bile duct hyperplasia. Mononuclear cell infiltrates were observed in dogs. Liver toxicity showed partial or full recovery. Similar liver enzyme elevations were observed in human subjects administered a combination of lazertinib and amivantamab.

Kidney toxicity in rats included increased kidney weights, higher urea nitrogen, creatinine, phosphorus, and potassium concentrations, with histologic changes such as papillary necrosis and tubule degeneration observed at high doses (approximately 4.6 times the human exposure). A decrease in urine volume, blood in urine, and an increased incidence of urine bilirubin were also noted. Most renal effects resolved after 8 weeks, though some kidney and heart damage persisted.

In a 4-week toxicology study, the administration of lazertinib at 20 mg/kg in dogs (approximately 4.8 times the clinical AUC at the 240 mg human dose) induced cardiac toxicity in two dogs. This was characterized by histologic findings in the heart (degeneration/necrosis of the myocardium and vessels, fibrosis, hemorrhage, thrombus, and mixed cell/vessel inflammation). One of these dogs also exhibited increased cardiac troponin I and premature ventricular complexes. Myocardial degeneration, vessel inflammation, and fibrosis were not seen after a 2-week recovery period.

In reproduction and developmental toxicology studies, an increase in post-implantation loss and decreased live litter size was observed in rats at approximately the recommended human exposure. Decrease in fetal body weights in association with maternal toxicity was observed at systemic exposure approximately four‑times higher than that at the recommended human dose. Embryo-fetal studies in rats showed no teratogenic effects at doses of up to 60 mg/kg (approximately four times the clinical AUC). In rabbits, lazertinib doses greater than or equal to 25 mg/kg caused maternal toxicity and minor fetal weight reduction, with skeletal malformations at the highest dose. Based on these findings, lazertinib may cause fetal harm when administered to pregnant patients. Appropriate warnings and precautionary measures are in place in the Product Monograph for Lazcluze to address the identified safety concerns. This includes a recommendation for effective contraception during treatment and for three weeks post treatment as well as a recommendation advising against breastfeeding due to unknown risks.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Lazcluze. In view of the intended use of Lazcluze, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Product Monograph for Lazcluze, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Lazcluze has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at 15 ºC to 30 ºC.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. In addition, none of the materials used in the formulation of Lazcluze is of human or animal origin.