Amivantamab Plus Chemotherapy Wins EU Approval for Pretreated EGFR+ Advanced NSCLC

The European Commission (EC) has approved amivantamab-vmjw (Rybrevant) in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) who harbor EGFR exon 19 deletions or exon 21 L858R substitution mutations following progression on prior therapy including an EGFR TKI.¹

The approval was supported by data from the phase 3 MARIPOSA-2 study (NCT04988295), which met its primary end point of progression-free survival (PFS) vs chemotherapy alone in patients who experienced disease progression on or after treatment with osimertinib (Tagrisso). The median PFS was 6.3 months with the combination vs 4.2 months with chemotherapy (HR, 0.48; 95% CI, 0.36-0.64; P < 0.001). Furthermore, patients treated with the amivantamab regimen achieved an objective response rate (ORR) of 64% vs 36% with chemotherapy alone.

Amivantamab plus chemotherapy also reduced the risk of intracranial progression or death by 45% vs chemotherapy alone. The median intracranial PFS was 12.5 months vs 8.3 months with these respective regimens (HR, 0.55; 95% CI, 0.38-0.79).

The safety profile of amivantamab plus chemotherapy was deemed consistent with that of the individual agents. A total of 72% of patients reported grade 3 or higher adverse effects (AEs) with amivantamab plus chemotherapy compared with 48% of patients who received chemotherapy alone. These were mainly attributed to hematologic toxicities. The most common grade 3 or higher AEs were neutropenia, thrombocytopenia, anemia, and leukopenia.

Grade 3 or 4 bleeding events were observed in 1% of patients in the amivantamab plus chemotherapy arm and no patients in the chemotherapy arm. Serious treatment-emergent AEs (TEAEs) were reported in 32% and 20% of patients treated in these respective arms. Any-grade infusion-related reactions were reported in 58% of patients in the amivantamab plus chemotherapy arm. Treatment-related AEs leading to death occurred at respective rates of 2% and 1%.

“[Although] much progress has been made in the lung cancer treatment landscape over the past decade, resistance to existing therapies continues to pose a major challenge for patients with advanced or metastatic NSCLC harboring EGFR mutations, underscoring the critical need for ongoing innovation,” Antonio Passaro, MD, PhD, a medical oncologist in the Division of Thoracic Oncology at the European Institute of Oncology in Milan, Italy, stated in a news release. “The addition of the bispecific antibody amivantamab to chemotherapy offers an important new treatment option for patients with EGFR exon 19 deletions or [exon 21] L858R mutations progressing on or after osimertinib. In this setting, this combination set a new landmark for ORR and reduced the risk of disease progression or death by more than half compared with standard chemotherapy alone. It also demonstrated significant improvements in intracranial PFS.”

MARIPOSA-2 Trial Design

MARIPOSA-2 was a randomized, open-label study that enrolled 657 patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations who experienced disease progression on or after treatment with osimertinib. Notably, those with stable brain metastases were permitted to enroll onto the study.^1,2

Patients were randomly assigned in a 2:2:1 ratio to receive either amivantamab plus chemotherapy, amivantamab plus chemotherapy and lazertinib (Lazcluze), or chemotherapy alone.

Amivantamab was administered at 1400 mg (or 1750 mg if patients weighed at least 80 kg) for the initial 4 weeks, followed by 1750 mg (2100 mg if at least 80 kg) once every 3 weeks starting in cycle 3. Lazertinib was given at 240 mg daily following the completion of carboplatin. Chemotherapy was administered at the start of each 21-day cycle and comprised carboplatin at area under the curve of 5 for the initial 4 cycles and pemetrexed at 500 mg/m² until disease progression.

The trial’s dual primary end points comprised PFS per RECIST 1.1 criteria as assessed by blinded independent central review (BICR) for each experimental arm vs chemotherapy alone. Key secondary end points included ORR as assessed by BICR, overall survival, duration of response, time to subsequent therapy, time to second progression, and intracranial PFS. Notably, all patients underwent serial brain imaging to allow for the robust assessment of intracranial end points and assess the central nervous system activity of both amivantamab combinations.

“The approval of amivantamab in combination with chemotherapy addresses a major unmet need for those whose disease has progressed following treatment with an EGFR TKI and who, until now, have faced limited treatment options,” Henar Hevia, PhD, senior director and EMEA Therapeutic Area Lead of Oncology at Johnson & Johnson Innovative Medicine, added in the news release.¹ “This milestone further reinforces the critical role of precision medicine in driving enhanced outcomes for patients living with lung cancer.”

Amivantamab Indications Supported by MARIPOSA-2

In addition to the current approval, amivantamab has received marketing authorization from the EC for the following indications:

• In combination with carboplatin and pemetrexed for the first-line treatment of adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations
• As monotherapy for the treatment of adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after progression on platinum-based chemotherapy

Findings from MARIPOSA-2 have also supported the submission of several other extension of indication applications for amivantamab to the European Medicines Agency (EMA).

In February 2024, a type 2 extension of indication application for amivantamab plus lazertinib to include adult patients with advanced NSCLC in the first line harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations was submitted. This was followed by an application for the extension of the amivantamab marketing authorization to include use of a subcutaneous (SC) formulation of the agent plus lazertinib for the first-line treatment of adult patients with advanced NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations; and for the use of SC amivantamab monotherapy in adult patients with advanced NSCLC harboring activating EGFR exon 20 insertion mutations after progressing on platinum-based therapy.

Additionally, the FDA approved amivantamab in combination with lazertinib in August 2024 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, based on data from MARIPOSA-2.³

References

1. European Commission approves Rybrevant (amivantamab) in combination with chemotherapy for the treatment of adult patients with advanced EGFR-mutated non-small cell lung cancer after failure of prior therapy. News release. Janssen. August 27, 2024. Accessed August 27, 2024. https://www.jnj.com/media-center/press-releases/european-commission-approves-rybrevant-amivantamab-in-combination-with-chemotherapy-for-the-treatment-of-adult-patients-with-advanced-egfr-mutated-non-small-cell-lung-cancer-after-failure-of-prior-therapy
2. A study of amivantamab and lazertinib in combination with platinum-based chemotherapy compared with platinum-based chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer after osimertinib failure (MARIPOSA-2). ClinicalTrials.gov. Updated November 8, 2023. Accessed August 27, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04988295
3. 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 August 27, 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