Amivantamab/Lazertinib Combo Approaches EU Approval in EGFR+ Advanced NSCLC

The EMA’s CHMP has issued a positive opinion regarding the use of amivantamab plus lazertinib in select patients with EGFR+ non–small cell lung cancer.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the marketing authorization of lazertinib (Lazcluze) paired with amivantamab (Rybrevant) in the frontline treatment of adult patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations.1 The committee also recommended the approval of a Type II extension of indication for amivantamab in the same combination.

The positive opinions are supported by findings from the phase 3 MARIPOSA study (NCT04487080). Primary results presented at the 2023 ESMO Congress showed that at a median follow-up of 22.0 months, the amivantamab combination (n = 429) led to a median progression-free survival (PFS) of 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 (Tagrisso; n = 429), translating to a 30% reduction in the risk of disease progression or death (HR, 0.70; 95% CI, 0.58-0.85; P < .001).2

With longer follow-up of a median of 31.1 months, the median overall survival (OS) was NE (95% CI, NE-NE) by BICR vs 37.3 months (95% CI, 32.5-NE) with osimertinib (HR, 0.77; 95% CI, 0.61-0.96; P = .019).3 At 3 years, 61% of those on the doublet arm were alive vs 53% of those in the monotherapy arm.

“Lung cancer remains the leading cause of cancer-related deaths globally, and patients with EGFR-mutated advanced non-small-cell lung cancer are in need of new targeted treatment options,” Henar Hevia, PhD, senior director, EMEA Therapeutic Area Lead of Oncology at Johnson & Johnson Innovative Medicine, stated in a news release.1 “Pending European Commission approval, the combination of amivantamab with lazertinib could establish a new first-line standard of care, with the potential to significantly delay disease progression and improve outcomes early in the treatment pathway while reserving chemotherapy regimens for later stages of treatment when resistance becomes more complex.”

Making Sense of MARIPOSA: Eligibility, Treatment, End Points

The phase 3 study enrolled patients with locally advanced or metastatic NSCLC who were treatment naive for advanced disease, had documented EGFR exon 19 deletion or L858R substitution mutations, and an ECOG performance status of 0 or 1.2

Study participants were randomly assigned 2:2:1 to receive amivantamab plus lazertinib (open-label), osimertinib (blinded), or single-agent lazertinib (n = 216; blinded). Amivantamab was given at a dose of 1050 weekly for the first 4 weeks and then every 2 weeks and lazertinib was given at a daily dose of 240 mg; osimertinib was administered at a daily dose of 80 mg. Patients were stratified based on EGFR mutation type (exon 19 deletion vs L858R), 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 1.1 criteria for amivantamab/lazertinib vs osimertinib. Secondary end points of the doublet vs osimertinib include OS, objective response rate (ORR), duration of response (DOR), PFS after first subsequent therapy (PFS2), symptomatic PFS, intracranial PFS, and safety.

Additional Primary Data

The extracranial PFS by BICR in the amivantamab/lazertinib arm was 27.5 months (95% CI, 22.1-NE) vs 18.5 months (95% CI, 16.5-20.3) in the osimertinib arm (HR, 0.68; 95% CI, 0.56-0.83; P < .001). Consistent PFS benefit was observed with the doublet regardless of whether patients had (HR, 0.69; 95% CI, 0.53-0.92) a history of brain metastases or they did not (HR, 0.69; 95% CI, 0.53-0.89).

The ORRs with amivantamab/lazertinib or osimertinib were 86% (95% CI, 83%-89%) and 85% (95% CI, 81%-88%), respectively. Moreover, the median DOR was 25.8 months (95% CI, 20.1-not estimable [NE]) in the doublet arm vs 16.8 months (95% CI, 14.8-18.5) in the monotherapy arm. The doublet reduced the risk of second progression or death by 25% vs osimertinib (HR, 0.75; 95% CI, 0.58-0.98; P = .03).

The primary data supported the August 2024 FDA approval of amivantamab plus lazertinib for frontline use in adult patients with locally advanced or metastatic NSCLC and EGFR exon 19 deletions or exon 21 L858R substitution mutations.4

Longer-Term Data Presented at the 2024 IASLC WCLC

With additional follow-up, the median intracranial DOR was NE (95% CI, 21.4-NE) with the doublet and 24.4 months (95% CI, 22.1-31.2) with osimertinib.3 The intracranial ORR was 77% in both treatment arms. The median time to treatment discontinuation was 26.3 months (95% CI, 22.3-30.4) with amivantamab plus lazertinib and 22.6 months (95% CI, 20.3-24.5) with osimertinib.

Moreover, median time to subsequent therapy in the respective arms was 30.0 months (95% CI, 20.3-36.0) and 24.0 months (95% CI, 22.5-20.2; HR, 0.77; 95% CI, 0.65-0.93; P = .005). With longer follow-up, the doublet reduced the risk of PFS2 by 27% vs osimertinib (HR, 0.73; 95% CI, 0.59-0.91; P = .004); landmark PFS2 rates at 3 years were 57% and 49%, respectively.

Safety Insights

The most common any-grade treatment-emergent adverse effects (TEAEs) experienced with the doublet were paronychia (68%), infusion-related reactions (63%), and rash (62%).1 The most frequently experienced grade 3 or higher TEAEs included rash (15%), paronychia (11%), and dermatitis acneiform (8%). Treatment-related AEs led to discontinuation of all study treatments for 10% of patients in the combination arm.

References

  1. CHMP recommends RYBREVANT®▼ (amivantamab) in combination with LAZCLUZE®▼ (lazertinib) for the first-line treatment of patients with EGFR-mutated advanced non-small cell lung cancer. News release. Janssen-Cilag International NV. November 15, 2024. Accessed November 15, 2024. https://www.jnj.com/media-center/press-releases/chmp-recommends-rybrevant-amivantamab-in-combination-with-lazcluze-lazertinib-for-the-first-line-treatment-of-patients-with-egfr-mutated-advanced-non-small-cell-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;
  3. Gadgeel S, Cho BC, Lu S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: longer follow-up of the MARIPOSA study. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA02.03.
  4. Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) approved in the U.S. as a first-line chemotherapy-free treatment for patients with EGFR-mutated advanced lung cancer. News release. Johnson & Johnson. August 20, 2024. Accessed November 15, 2024. https://www.investor.jnj.com/news/news-details/2024/RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-approved-in-the-U.S.-as-a-first-line-chemotherapy-free-treatment-for-patients-with-EGFR-mutated-advanced-lung-cancer/default.aspx