SUMMARY

• LAZCLUZE (lazertinib) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).¹
• LASER301 (NCT04248829) is a phase 3, randomized, double-blind, multinational study that compared the efficacy and safety of LAZCLUZE with that of gefitinib in 393 treatment-naïve patients with EGFR-mutated (EGFRm; Exon 19 deletions or Exon 21 L858R substitution mutations) locally advanced or metastatic non-small cell lung cancer (NSCLC).¹
  • At a median follow-up of 20.5 months for LAZCLUZE and 20.6 months for gefitinib, the median progression-free survival (PFS) was 20.6 months and 9.7 months, respectively (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.34-0.58; P<0.001).
  • Any treatment-emergent adverse events (TEAEs) in the LAZCLUZE and gefitinib groups were reported in 189 patients (96%) and 188 patients (95%), respectively; of these, 172 (88%) and 168 (85%) were TEAEs.
  • A subset analysis in patients with measurable and/or non-measurable baseline central nervous system (CNS) metastasis (LAZCLUZE group [n=45] and gefitinib group [n=41]) showed the following results²:
    • Median intracranial PFS: 28.2 months (95% CI, 14.8-28.2) and 8.4 months (95% CI, 6.7-not reached [NR]), respectively (HR, 0.42; 95% CI, 0.20-0.89; P=0.02).
    • Intracranial objective response rate (ORR): 94% and 73%, respectively.
    • Median intracranial duration of response (DoR): NR (95% CI, 8.3-NR) and 6.3 months (95% CI, 2.8-NR), respectively.
    • Median best change from baseline in CNS target lesion size: -57% and -47%, respectively.
    • No new safety signals were identified in this analysis.
• LASER201 (NCT03046992) is a phase 1/2, first-in-human, multicenter, open-label study that evaluated the safety, antitumor activity, and pharmacokinetics of LAZCLUZE in patients with locally advanced or metastatic or EGFRm NSCLC with or without stable brain lesions that had progressed after EGFR TKI therapy (dose escalation, n=38; dose expansion, n=89; phase 2 dose extension, n=43).^3,4
  • Dose escalation and expansion³
    • The median duration of treatment was 9.7 months and the median follow-up for PFS was 11.0 months.
    • No dose-limiting toxicities were reported, and the maximum tolerated dose was NR.
    • Adverse events (AEs) of any grade were reported in 119 of 127 patients (94%).
  • Phase 2 dose extension⁴
    • In the long-term study with a median follow-up of 28.8 months, the ORR was 70% (95% CI, 56.0-83.5), with a complete response (CR) of 14% and partial response (PR) of 56%.
    • All 43 patients reported at least 1 TEAE, of whom 41 (95%) reported drug-related TEAEs, and 22 patients (51%) reported grade ≥3 TEAEs.

clinical study

LASER301 Study

Study Design/Methods

This phase 3, randomized, double-blind, multinational study compared the efficacy and safety of LAZCLUZE with that of gefitinib in treatment-naïve patients with EGFRm locally advanced or metastatic NSCLC (NSCLC; N=393).¹

• Patients were randomized (1:1) to receive either LAZCLUZE 240 mg/day (reduced to 160 mg/day if required due to toxicity) once daily (n=196) or gefitinib 250 mg/day once daily (n=197) until disease progression or treatment discontinuation.
• Patients also received a LAZCLUZE- or gefitinib-matched placebo to maintain double-dummy blinding.
• Patients receiving gefitinib could crossover to open-label LAZCLUZE on central confirmation of progression and T790M1-positive status.
• Primary endpoint: PFS using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1).
• Secondary endpoints: Overall survival (OS), overall response rate, DoR, disease control rate (DCR), and safety.

Results

Baseline Characteristics¹

• Demographics and baseline disease characteristics were balanced between the treatment groups.
• The median age was 67 years and 64 years in the LAZCLUZE group (females, 67%) and the gefitinib group (females, 60%), respectively. Both groups consisted of 66% Asian and 34% non-Asian patients.
• Exon 19 deletions and L858R mutations were reported in 62% and 38% of patients in both groups, respectively.
• CNS metastasis was reported in 26% and 24% of patients in the LAZCLUZE group and the gefitinib group, respectively. Metastatic disease was present in 97% of the patients in both groups, while 3% had locally advanced disease.
• In terms of smoking status, 69% and 76% were never smokers, 26% and 21% were former smokers, and 6% and 3% were current smokers in the LAZCLUZE group and the gefitinib group, respectively.
• The World Health Organization (WHO) performance status score was similar between groups, with 25% of patients in the LAZCLUZE group and 27% in the gefitinib group having a score of 0, while the remaining 75% and 73%, respectively, had a score of 1.

Efficacy¹

• The median duration of drug exposure in the LAZCLUZE and gefitinib groups was 15.1 months and 10.9 months, respectively.
• The median duration of follow-up in the LAZCLUZE and gefitinib groups was 20.5 months and 20.6 months, respectively.
• The efficacy endpoints of LASER301 have been shown in Table: LASER301: Efficacy Endpoints below.

Safety¹

• Any TEAEs in the LAZCLUZE and gefitinib groups were reported in 189 patients (96%) and 188 patients (95%), respectively; of these, 172 (88%) and 168 (85%) were TEAEs related to study treatment.
  • Grade ≥3 TEAEs related to study drug were reported in 39 patients (20%) and 42 patients (21%) in the LAZCLUZE and gefitinib groups, respectively.
• The most common AEs due to any cause (treatment-related or not) in the LAZCLUZE and gefitinib groups, respectively, were paresthesia (39% and 7%), rash (36% and 37%), pruritus (27% and 18%), and diarrhea (26% and 39%).
• Increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported in 15% and 11% of patients receiving LAZCLUZE and 30% and 26% of patients receiving gefitinib, respectively.
• Interstitial lung disease (ILD; including pneumonitis) was reported in 3% and 2% of patients receiving LAZCLUZE and gefitinib, respectively.
• Grade ≥3 QTc prolongation was reported in 1% of patients in both treatment groups; with no clinically relevant decrease in left ventricular ejection fraction (LVEF).
• Any grade ≥3 TEAE was reported in 41% and 43% of patients receiving LAZCLUZE and gefitinib, respectively.
• TEAEs related to study treatment resulting in death in the LAZCLUZE and gefitinib groups were reported in 10 patients (1%; caused by ILD) and 0 patients, respectively.

Subset Analysis of Patients With CNS Metastases²

• A total of 45 (23%) and 41 (21%) patients in the LAZCLUZE and gefitinib group, respectively, had measurable and/or non-measurable baseline CNS metastasis and were included in this subset analysis.
• The baseline characteristics were balanced between groups, with 91% and 83% of patients in the LAZCLUZE group and the gefitinib group, respectively, having 1-3 CNS lesions.
• Median intracranial PFS in the LAZCLUZE group and gefitinib group was 28.2 months (95% CI, 14.8-28.2) and 8.4 months (95% CI, 6.7-NR), respectively (HR, 0.42; 95% CI, 0.20-0.89; P=0.02).
• Intracranial ORR in the LAZCLUZE group (n=17) and the gefitinib group (n=11) was 94% and 73%, respectively.
• Median intracranial DoR in the LAZCLUZE group and the gefitinib group was NR (95% CI, 8.3-NR) and 6.3 months (95% CI, 2.8-NR), respectively.
• The median best change from baseline in CNS target lesion size in the LAZCLUZE group (n=17) and the gefitinib group (n=14) was -57% and -47%, respectively.
• No new safety signals were identified in this analysis.

LASER201 Study

Study Design/Methods

This phase 1/2, first-in-human, multicenter, open-label study evaluated the safety, antitumor activity, and pharmacokinetics of LAZCLUZE in patients with locally advanced or metastatic or EGFRm NSCLC with or without stable brain lesions that had progressed after EGFR TKI therapy.^3,4

• The study had three parts:
  • Dose escalation (n=38): Enrolled 3-6 patients per dose level of LAZCLUZE (20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 240 mg, or 320 mg). LAZCLUZE was initiated at 20 mg once daily and was increased in 100% increments to 80 mg. The safety review committee determined further increase.
  • Dose expansion (n=89): Enrolled additional patients with T790M-positive tumors to selected dose levels, provided that the maximum tolerated dose had not been reached.
  • Phase 2 dose extension (n=43): Long-term follow-up where LAZCLUZE 240 mg once daily was administered orally continuously until disease progression, occurrence of unacceptable toxicity, death, or other discontinuation criteria were met.
• Patients received LAZCLUZE orally once daily in 21 day cycles until disease progression, unacceptable toxicity, noncompliance, withdrawal of consent, or the investigator decided otherwise.
• Primary endpoints:
  • Dose escalation and expansion: Safety and tolerability.
  • Phase 2 dose extension: ORR.
• Secondary endpoints:
  • Dose escalation and expansion: ORR, DoR, the proportion of patients with disease control, tumor shrinkage, and pharmacokinetics.
  • Dose expansion: PFS and OS.
    • For patients with brain metastases: the proportion of patients with an intracranial objective response, duration of intracranial response, and intracranial PFS.
  • Phase 2 dose extension: DoR, DCR, PFS, tumor shrinkage, and OS.

Results

Baseline Characteristics³

• The median age was 60 years in the dose-escalation group (females, 66%) and 63 years in the dose-expansion group (females, 57%).
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score: 37% of patients in the dose-escalation group and 24% in the dose-expansion group had a score of 0, while the remaining 63% and 76%, respectively, had a score of 1.
• Exon 19 deletions and L858R mutations were reported in 55% and 34% of patients in the dose-escalation group and 62% and 38% of patients in the dose-expansion group, respectively. Other mutations were reported in 3% of patients in the dose-escalation group and 8% of patients had no mutations.
• Positive EGFR T790M status was reported in 50% and 100% of patients in the dose-escalation group and dose-expansion group, respectively.
• Brain metastases were reported in 29% and 42% of patients in the dose-escalation group and dose-expansion group, respectively.

Primary Endpoints

• Dose escalation³:
  • The median duration of treatment was 9.7 months and the median follow-up for PFS was 11.0 months.
  • No dose-limiting toxicities were reported, and the maximum tolerated dose was NR.
• Dose escalation and expansion³:
  • Dose-expansion cohorts were opened for the 5 doses between 40 mg and 240 mg.
  • AEs of any grade were reported in 119 of 127 patients (94%), with grade 1/2 rash or acne (n=38 of 127; 30%) and pruritus (34 of 127; 27%) being the most common AEs.
  • Grade 3 or 4 AEs were reported in 20 patients (16%), with grade 3 pneumonia (n=4; 3%) being the most common AE.
  • No AEs leading to death were reported.
• Phase 2 dose extension⁴:
  • Median (quartile [Q]1, Q3) follow-up: 28.8 months (17.8, 28.9).
  • ORR: 70% (95% CI, 56.0-83.5).
    • CR: 14%.
    • PR: 56%.

Secondary Endpoints

• Dose escalation and expansion³:
  • Of 127 evaluable patients in the dose-escalation and -expansion phases, 108 had a T790M-positive tumor.
  • The secondary efficacy endpoints in the dose-escalation and -expansion parts of the LASER201 study have been shown in Table: LASER201: Secondary Endpoints of the Dose-Escalation and -Expansion Parts.
  • Pharmacokinetics: Based on the available data for the dose-response relationship for activity and safety, the 240 mg dose was selected for evaluation in the dose-extension part of the study.

• Phase 2 dose extension⁴:
  • The secondary efficacy endpoints in the phase 2 dose-extension part of the LASER201 study have been shown in Table: LASER201: Secondary Endpoints of the Dose-Expansion Part.
  • Safety: All 43 patients reported at least 1 TEAE, of whom 41 (95%) reported drug-related TEAEs, and 22 patients (51%) reported grade ≥3 TEAEs.
    • No drug-related TEAEs led to death.
    • Rash (n=23; 54 %), diarrhea (n=20; 47%), pruritus (n=20; 47%) and paresthesia (n=15; 35%) were the most commonly reported TEAEs.
    • No cases of ILD were reported. Pneumonitis (not drug related) was reported in 1 patient (2%), and no clinically relevant cardiac events (including significant QT prolongation or decrease in LVEF) were reported.
    • No drug-related TEAEs of grade ≥3 rash or pruritus were reported. Diarrhea and paresthesia of grade ≥3 were reported in 3 (7%) and 1 (2%) patients, respectively.
    • No clinically relevant cardiac events were reported, including significant QT prolongation or decrease in LVEF.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 24 October 2024. Summarized in this response are relevant data limited to the LASER 301 and LASER 201 studies.