FDA Approval Sought for Amivantamab Plus Chemo in EGFR+ Advanced NSCLC Following Osimertinib Progression

A supplemental biologics license application (sBLA) seeking the approval of amivantamab-vmjw (Rybrevant) in combination with platinum-based chemotherapy for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or L858R substitutions who have progressed on or after treatment with osimertinib (Tagrisso) has been submitted to the FDA.¹

The sBLA is based on data from the phase 3 MARIPOSA-2 trial (NCT04988295), which were presented during the 2023 ESMO Congress.² Findings showed that amivantamab plus chemotherapy, as well as amivantamab plus lazertinib (Leclaza) and chemotherapy, improved progression-free survival (PFS) per blinded independent central review (BICR) vs chemotherapy alone, meeting the study’s primary end points.

At a median follow-up of 8.7 months, patients treated with amivantamab plus lazertinib and chemotherapy (n = 263) achieved a median PFS of 8.3 months per BICR, and the median PFS was 6.3 months for those treated with amivantamab plus chemotherapy (n = 131). Patients given chemotherapy alone (n = 263) experienced a median PFS of 4.2 months. The addition of amivantamab and lazertinib to chemotherapy led to a 56% reduction in the risk of progression or death compared with chemotherapy alone (HR, 0.44; 95% CI, 0.35-0.56; P < .001); adding amivantamab to chemotherapy led to a 52% reduction in the risk of progression or death vs chemotherapy alone (HR, 0.48; 95% CI, 0.36-0.64; P < .001).

The 6-month PFS rate per BICR was 59% for amivantamab plus lazertinib and chemotherapy, 51% for amivantamab plus chemotherapy, and 30% for chemotherapy alone. The 12-month PFS rates were 37%, 22%, and 13%, respectively.

Furthermore, per investigator assessment, the median PFS for the amivantamab plus lazertinib and chemotherapy group was 8.3 months, 8.2 months for amivantamab plus chemotherapy, and 4.2 months for chemotherapy alone. This translated to a 62% reduction in the risk of disease progression or death with the triplet (HR, 0.38; P < .001) and a 59% reduction in the risk of progression or death for the doublet (HR, 0.41; P < .001) vs chemotherapy alone.

“New treatment options are urgently needed in the post-osimertinib setting, where patients continue to face unacceptable survival rates,” Kiran Patel, MD, vice president of Clinical Development and Solid Tumors at Janssen Research & Development, stated in a news release.¹ “As we strive to transform the standard of care in patients with EGFR-mutated NSCLC, we are committed to working closely with the FDA during review of this submission for amivantamab in this expanded patient population.”

In May 2021, the FDA granted accelerated approval to amivantamab for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.³ Furthermore, in August 2023, an sBLA was submitted to the FDA seeking the expanded approval of amivantamab in combination with carboplatin and pemetrexed for the first-line treatment of patients with EGFR exon 20 insertion–mutated NSCLC.⁴

MARIPOSA-2 was an open-label, randomized, global trial that enrolled patients with advanced or metastatic NSCLC who harbored EGFR exon 19 deletions or L858R mutations and had an ECOG performance status of 0 or 1. Additionally, patients must have experienced disease progression on or after osimertinib monotherapy. Patients with stable brain metastases were allowed to enroll. Stratification of eligible patients was based on setting of osimertinib treatment (first line vs second line), race (Asian vs non-Asian), and on history of brain metastases (yes vs no).^2,5

Upon enrollment, patients were randomly assigned in a 2:2:1 ratio to receive amivantamab plus lazertinib and chemotherapy; chemotherapy alone; or amivantamab plus chemotherapy. The dosing schedule followed 21-day cycles. Amivantamab was administered at a dose of 1400 mg (1750 mg if patients were 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 completion of carboplatin. Chemotherapy was given at the start of each cycle, consisting of carboplatin at an area under the curve of 5 for the initial 4 cycles and pemetrexed at 500 mg/m² until disease progression.²

The study’s key end points included PFS, safety, objective response rate, duration of response, and intracranial PFS.

Additional data showed that amivantamab plus lazertinib and chemotherapy elicited an intracranial PFS of 12.8 months compared with 12.5 months for amivantamab plus chemotherapy vs 8.3 months for chemotherapy alone. This translated to a 42% (HR, 0.58; 95% CI, 0.44-0.78; P < .001) and 45% (HR, 0.55; 95% CI, 0.38-0.79; P = .001) reduction in the risk of intracranial disease progression or death vs chemotherapy, respectively.

Interim OS data demonstrated that both amivantamab plus lazertinib and chemotherapy as well as amivantamab plus chemotherapy displayed an OS benefit compared with chemotherapy alone. The reductions in the risk of death vs chemotherapy alone were 4% (HR, 0.96; 95% CI, 0.67-1.35) and 23% (HR, 0.77; 95% CI, 0.49-1.21), respectively.

Regarding safety, the rates of any-grade adverse effects (AEs) for the triplet, doublet, and chemotherapy alone were 100%, 100%, and 93%, respectively. The rates of grade 3 or higher AEs were 92%, 72%, and 48% respectively. Serious AEs occurred in 52%, 32%, and 20% of patients respectively. AEs led to death in 5% of patients treated with the triplet, 2% given the doublet, and 1% administered chemotherapy alone. AEs led to treatment interruptions in 77%, 65%, and 33% of patients, respectively. The rates of dose reductions were 65%, 41%, and 15%, respectively, and dose discontinuations occurred in 34%, 18%, and 4% of patients, respectively.

References

1. Janssen submits supplemental biologics license application to the US FDA seeking approval of Rybrevant (amivantamab-vmjw) plus chemotherapy for the treatment of patients with EGFR-mutated non-small cell lung cancer who progressed on or after osimertinib. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. November 20, 2023. Accessed November 20, 2023. https://www.investor.jnj.com/files/doc_news/2023/Nov/20/final-mariposa-2-fda-filing-press-release_as-of-11-17-23.pdf
2. Passaro A, Cho BC, Banuml JM, et al. Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: MARIPOSA-2, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1307. doi:10.1016/j.annonc.2023.10.063
3. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed November 20, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer
4. Janssen submits supplemental biologics license application to the US Food and Drug Administration seeking approval of Rybrevant (amivantamab-vmjw) in combination with chemotherapy for the first-line treatment of patients with locally advanced or metastatic EGFR exon 20 insertion mutation-positive non-small cell lung cancer. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. August 25, 2023. Accessed November 20, 2023. https://www.prnewswire.com/news-releases/janssen-submits-supplemental-biologics-license-application-to-the-us-food-and-drug-administration-seeking-approval-of-rybrevant-amivantamab-vmjw-in-combination-with-chemotherapy
5. 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 November 20, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04988295