EU Approval Sought for Frontline Lazertinib Plus Amivantamab in EGFR+ NSCLC

A marketing authorization application seeking the approval of the combination of lazertinib and amivantamab (Rybrevant) in the first-line treatment of adult patients with advanced non­–small cell lung cancer (NSCLC) harboring EGFR mutations has been submitted to the European Medicines Agency.¹

The application is based on findings from the phase 3 MARIPOSA study (NCT04487080) in which the doublet (n = 429) significantly extended progression-free survival (PFS) over osimertinib (Tagrisso; n = 429) in this population (HR, 0.70; 95% CI, 0.58-0.85; P < .001).² At a median follow-up of 22.0 months, the median PFS with lazertinib plus amivantamab was 23.7 months (95% CI, 19.1-27.7) by blinded independent central review (BICR) vs 16.6 months (95% CI, 14.8-18.5) with osimertinib. The 24-month PFS rates were 48% and 34%, respectively.

“Despite significant advances in the treatment of EGFR-mutated NSCLC, the PFS rate with the current first-line therapies remains low,” Catherine Taylor, vice president of EMEA Medical Affairs, Therapy Area Strategy at Janssen-Cilag AG, stated in a press release.¹ “Novel targeted therapies are necessary to address resistance and disease progression, and provide new options for patients in this area of high unmet medical need.”

Patients with locally advanced or metastatic NSCLC were enrolled in MARIPOSA. They could have had either treatment-naïve or advanced disease, but they needed to have documented EGFR exon 19 deletions or L858R substitution mutations. All patients had an ECOG performance status of 0 or 1.²

A total of 1074 patients were randomly assigned 2:2:1 to one of the following arms: amivantamab at 1050 mg weekly or 1400 mg weekly if 80 kg or greater for the first 4 weeks and then every 2 weeks plus lazertinib at 240 mg daily (open-label), osimertinib at 80 mg daily (blinded), or single-agent lazertinib at 240 mg daily (blinded). Randomization was stratified based on EGFR mutation (exon 19 deletions vs L858R substitution mutations), Asian race (yes vs no), and history of brain metastases (yes vs no).

The primary end point of the study was PFS by BICR and RECIST v1.1 criteria and secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DOR), PFS after first subsequent therapy, symptomatic PFS, intracranial PFS, and safety.

The median patient age across the arms was 63.3 years (range, 25-88). More than half of patients were female (62%), Asian (58.7%), and had an ECOG performance status of 1 (65.7%). About one-third of patients had a history of smoking and 40.3% had a history of brain metastases. In terms of EGFR mutation type, more than half of patients spanning the arms (60.3%) had exon 19 deletion and 40% had L858R. The majority (97.3%) of patients had adenocarcinoma.

In the study, investigators conducted serial brain MRIs on all participants, which is not routinely done in trials done in this disease. The median extracranial PFS with lazertinib plus amivantamab was 27.5 months (95% CI, 22.1-not evaluable [NE]) vs 18.5 months (95% CI, 16.5-20.3%) with osimertinib (HR, 0.68; 95% CI, 0.56-0.83; P < .001).

Consistent PFS benefit was observed with lazertinib/amivantamab over osimertinib irrespective of brain metastases. In those with a history of brain metastases, the doublet (n = 178) resulted in a median PFS of 18.3 months (95% CI, 16.6-23.7) vs 13.0 months (95% CI, 12.2-16.4) with osimertinib (n = 172; HR, 0.69; 95% CI, 0.53-0.92). In those without a history of brain metastases, amivantamab plus lazertinib (n = 251) resulted in a median PFS of 27.5 months (95% CI, 22.1-NE) vs 19.9 months (95% CI, 16.6-22.9) with osimertinib (n = 257; HR, 0.69; 95% CI, 0.53-0.89).

In the total population, the BICR-assessed ORR achieved with amivantamab plus lazertinib was 86% (95% CI, 83%-89%) vs 85% (95% CI, 81%-88%) with osimertinib; confirmed ORRs were 80% (95% CI, 76%-84%) and 76% (95% CI, 71%-80%), respectively. The respective median DOR in both groups were 25.8 months (95% CI, 20.1-NE) and 16.8 months (95% CI, 14.8-18.5).

Moreover, amivantamab plus lazertinib reduced the risk of second disease progression or death by 25% (HR, 0.75; 95% CI, 0.58-0.98; P = .03). Ninety-eight patients in the doublet arm began subsequent treatment vs 137 in the osimertinib arm. The most common first subsequent treatment received in the doublet arm was a single-agent EGFR TKI (49%) followed by chemotherapy alone (33%). In the osimertinib arm, the most common first subsequent therapy was chemotherapy alone (39%) followed by EGFR TKI monotherapy (27%).

Interim OS data demonstrated a trend favoring amivantamab plus lazertinib vs osimertinib, with a HR of 0.80 (95% CI, 0.61-1.05; P = .11). The estimated 24-month OS rates were 74% and 69%, respectively.

Regarding safety, any-grade adverse effects (AEs) occurred in all patients given the combination vs 99% of those who received osimertinib; these effects were grade 3 or greater in 75% and 43% of patients, respectively. Serious AEs occurred in 49% and 33% of patients, respectively. In the doublet arm, AEs led to interruption, reduction, or discontinuation in 83%, 59%, and 35% of patients, respectively; in the osimertinib arm, these respective rates were 39%, 5%, and 14%. AEs resulted in death for 8% of those who received the doublet vs 7% of those given osimertinib.

The toxicity profile of amivantamab plus lazertinib aligned with what has previously been reported with the regimen. Most AEs were grade 1 or 2 in severity. The most common AEs reported with the doublet included paronychia (grade 1/2, 57%; grade ≥3, 11%), rash (46%; 15%), diarrhea (27%; 2%), dermatitis acneiform (21%; 8%), stomatitis (28%; 1%), pruritus (23%; 0.5%), hypoalbuminemia (43%; 5%), peripheral edema (34%; 2%), infusion-related reaction (57%; 6%), increased alanine aminotransferase (31%; 5%), constipation (29%; 0%), increased aspartate aminotransferase (25%; 3%), COVID-19 (24%; 2%), reduced appetite (24%; 1%), anemia (19%; 4%), nausea (20%; 1%), hypocalcemia (19%; 2%), and cough (15%; 0%).

In December 2023, a supplemental biologics license application and new drug application seeking approval of amivantamab plus lazertinib for frontline use in patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R substitution mutations, as detected by an approved test, were submitted to the FDA.³ The applications were based on MARIPOSA data, which had been presented at the 2023 ESMO Congress.

References

1. Janssen submits marketing authorisation application to the European Mediciens Agency seeking approval of lazertinib, in combination with Rybrevant (amivantamab), for the first-line treatment of patients with EGFR-mutated non-small cell lung cancer. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. December 21, 2023. Accessed January 15, 2024. https://www.janssen.com/janssen-submits-marketing-authorisation-application-european-medicines-agency-seeking-approval-0
2. Cho BC, Felip E, Spira AI, et al. LBA14 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. Johnson & Johnson submits supplemental biologics license application and new drug application to US FDA seeking approval of Rybrevant (amivantamab-vmjw) plus lazertinib for the treatment of patients with EGFR-mutated non-small cell lung cancer (NSCLC). News release. Johnson & Johnson. December 21, 2023. Accessed January 15, 2024. https://www.prnewswire.com/news-releases/johnson--johnson-submits-supplemental-biologics-license-application-and-new-drug-application-to-us-fda-seeking-approval-of-rybrevant-amivantamab-vmjw-plus-lazertinib-for-the-treatment-of-patients-with-egfr-mutated-non-small--302020967.html