Health Canada Approves Amivantamab/Lazertinib Combo for EGFR+ Advanced NSCLC

Health Canada has approved the combination of amivantamab (Rybrevant) and lazertinib (Lazcluze) for the first-line treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations.1

The notice of compliance issued for the combination was supported by data from the phase 3 MARIPOSA trial (NCT04487080). Topline data presented at the 2023 ESMO Congress demonstrated that at a median follow-up of 22.0 months, patients treated with amivantamab plus lazertinib (n = 429) achieved a median progression-free survival (PFS) of 23.7 months (95% CI, 19.1-27.7) compared with 16.6 months (95% CI, 14.8-18.5) for patients given osimertinib (Tagrisso) monotherapy (n = 429; HR, 0.70; 95% CI, 0.58-0.85; P < .001).2 The 12- and 24-month PFS rates for the combination were 73% and 48%, respectively. These respective rates were 65% and 34% in the osimertinib arm.

“While we have seen much progress in the treatment of lung cancer, many patients with EGFR-mutated NSCLC don’t reach second-line therapy when initial treatment stops working. This underscores the critical need for better options in the first-line setting,” Natasha Leighl, BSc, MMSc, MD, Lung Site lead, Medical Oncology at the Princess Margaret Cancer Centre and professor of medicine at the University of Toronto, stated in a news release.1 “The approval of this new targeted combination represents a significant advance in treatment, providing patients with a new option that extends PFS and [overall] survival [OS] in the first line compared [with] previously available treatments.”

In August 2024, the FDA approved amivantamab-vmjw in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.3 This approval was also based on data from MARIPOSA.

MARIPOSA Deep Dive

The phase 3 study enrolled patients with locally advanced or metastatic NSCLC with documented EGFR exon 19 deletions or exon 21 L858R substitution mutations who were treatment naive in the advanced setting.2 Patients also needed to have an ECOG performance status of 0 or 1.

Patients were randomly assigned in a 2:2:1 fashion to receive open-label amivantamab at 1050 mg per week (1400 mg patients weighing at least 80 kg) once every week for 4 weeks, then once every 2 weeks thereafter, in combination with lazertinib at 240 mg per day; blinded osimertinib monotherapy at 80 mg per day; or blinded lazertinib at 240 mg per day (n = 216).

Key stratification factors included EGFR mutation type (exon 19 deletion vs exon 21 L858R mutation), race (Asian vs other), and history of brain metastases (yes vs no).

PFS for amivantamab plus lazertinib vs osimertinib served as the trial’s primary end point. Secondary end points for the combination vs osimertinib included OS, objective response rate (ORR), duration of response (DOR), time to second progression, symptomatic PFS, intracranial PFS, and safety.

Additional Efficacy and Safety Data

Further topline findings showed that patients in the combination arm achieved a median extracranial PFS of 27.5 months (95% CI, 22.1-not evaluable [NE]) vs 18.5 months (95% CI, 16.5-20.3) for those given osimertinib (HR, 0.68; 95% CI, 0.56-0.83; P < .001).

In patients with a history of brain metastases at baseline, the median PFS was 18.3 months (95% CI, 16.6-23.7) for the combination (n = 178) vs 13.0 months (95% CI, 12.2-16.4) for osimertinib (n = 172; HR, 0.69; 95% CI, 0.53-0.92). In those without brain metastases, the median PFS was 27.5 months for amivantamab plus lazertinib (n = 229) vs 19.9 months (95% CI, 16.6-22.9) for osimertinib (n = 257; HR, 0.69; 95% CI, 0.53-0.89).

The ORR was 86% (95% CI, 83%-89%) in the combination arm vs 85% (95% CI, 81%-88%) in the osimertinib arm. Ongoing responses were reported in 62% and 48% of patients, respectively.

OS data were immature at the time of the topline analysis; however, in January 2025, Johnson & Johnson announced that the combination generated a clinically meaningful and statistically significant improvement in OS, meeting the prespecified secondary end point.4

Regarding safety, any-grade adverse effects occurred in all patients in the combination arm (n = 421) vs 99% of patients in the osimertinib arm (n = 428).2 The rates of grade 3 or higher AEs were 75% and 43%, respectively. Serious AEs were observed in 49% and 33% of patients, respectively. AEs led to death in 8% of patients in the combination arm vs 7% of patients in the control arm.

For patients treated with amivantamab plus lazertinib, AEs led to dose interruption of any agent, dose reduction of any agent, and discontinuation of any agent in 83%, 59%, and 35% of patients, respectively. These respective rates were 39%, 5%, and 14% in the osimertinib arm.

“This approval strengthens our commitment to redefining care in areas of high unmet need by advancing innovative regimens that have the potential to extend survival in this deadly disease,” Berkeley Vincent, president of Johnson & Johnson Innovative Medicine, Canada, added in a news release.1 “Today’s Health Canada authorization for [lazertinib] in combination with [amivantamab] further reinforces the critical role of precision medicine in driving enhanced outcomes for patients living with lung cancer. By offering this targeted first-line treatment, we are continuing our efforts to alter the trajectory of this disease.”

References

1. Health Canada authorizes Lazcluze (lazertinib) in combination with Rybrevant (amivantamab) as a first-line chemotherapy-free treatment for patients with EGFR-mutated advanced lung cancer. News release. Johnson & Johnson. March 11, 2025. Accessed March 11, 2025. https://www.biospace.com/press-releases/health-canada-authorizes-lazcluze-lazertinib-in-combination-with-rybrevant-amivantamab-as-a-first-line-chemotherapy-free-treatment-for-patients-with-egfr-mutated-advanced-lung-cancer
2. Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1306. doi:10.1016/j.annonc.2023.10.062
3. FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. FDA. August 19, 2024. Accessed March 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer
4. Rybrevant (amivantamab-vmjw) plus lazcluze (lazertinib) show statistically significant and clinically meaningful improvement in overall survival versus osimertinib. News release. Johnson & Johnson. January 7, 2024. Accessed March 11, 2025. https://www.investor.jnj.com/news/news-details/2025/RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-show-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-versus-osimertinib/default.aspx