Phase III MARIPOSA-2 study shows Rybrevant (amivantamab-vmjw) + chemotherapy given with or without lazertinib reduced risk of disease progresion or death in EGFR-mutated NSCLC who progressed on or after osimertinib

showing the regimen of rybrevant (amivantamab-vmjw) given with or without lazertinib and combined with chemotherapy reduced the risk of disease progression or death by 56 and 52 percent respectively (hazard ratio [hr]="0.44;" 95 percent confidence interval [ci], 0.35–0.56; p value <0.001 and hr="0.48;" 95 percent ci, 0.36–0.64; <0.001) compared to chemotherapy alone in patients with locally advanced or metastatic nsclc with epidermal growth factor receptor (egfr) exon 19 deletions (ex19del) or l858r substitution, after disease progression on or after osimertinib. results also showed that the two rybrevant regimens significantly improved objective response rate (orr), intracranial progression-free survival (pfs), and duration of response (dor) compared to chemotherapy alone in these patients. these data were presented in a presidential symposium at the european society for medical oncology (esmo) 2023 congress taking place october 20-24, 2023 in madrid, spain (abstract #lba15) and simultaneously published in annals of oncology.

“The promising results from the MARIPOSA-2 study show that by combining Rybrevant with chemotherapy, both with and without lazertinib, patients achieved longer progression-free survival compared with chemotherapy alone,” said Antonio Passaro,* M.D., Ph.D., medical oncologist of the Division of Thoracic Oncology, European Institute of Oncology in Milan, Italy, and presenting author. “The efficacy seen across the two Rybrevant regimens suggests that this treatment combination may address the diverse and often varied resistance that can occur in the post-osimertinib setting.”

Rybrevant plus chemotherapy reduced the risk of disease progression or death by 52 percent compared to chemotherapy alone (HR=0.48; 95 percent CI, 0.36–0.64; P<0.001). rybrevant plus chemotherapy with lazertinib reduced the risk of disease progression or death by 56 percent compared to chemotherapy alone (hr="0.44;" 95 percent ci, 0.35–0.56; p><0.001). the improved pfs was consistent across all pre-specified patient subgroups, including age, sex, race, history of brain metastasis, smoking history, and lines of prior osimertinib therapy. additionally, rybrevant plus chemotherapy showed an orr of 64 percent and rybrevant plus chemotherapy and lazertinib demonstrated an orr of 63 percent, compared to a response rate of 36 percent with chemotherapy alone.

The data from MARIPOSA-2 are also the first to show that Rybrevant combination regimens may provide intracranial activity, which is critical for a disease where nearly 30 percent of patients develop brain metastases. Specifically, Rebrevant plus chemotherapy and Rebrevant plus chemotherapy and lazertinib reduced the risk of intracranial progression or death by 45 percent and 42 percent, respectively compared to chemotherapy alone (HR=0.55; 95 percent CI, 0.38–0.79; P=0.001 and HR=0.58; 95 percent CI, 0.44–0.78; P<0.001, respectively).

Early interim overall survival (OS) data show a trend favoring Rebrevant plus chemotherapy compared with chemotherapy alone (HR=0.77; 95 percent CI, 0.49–1.21). No difference in OS was observed at the interim analysis for Rebrevant plus chemotherapy and lazertinib compared with chemotherapy alone (HR=0.96; 95 percent CI, 0.67–1.35).

The safety profile for Rybrevant was consistent with prior reports. The most common adverse events (AEs) in the Rybrevant-containing arms were hematologic, EGFR, and MET-related. Rybrevant plus chemotherapy had lower rates of hematologic AEs than treatment with Rybrevant plus chemotherapy with lazertinib. The overall incidence of adverse events of special interest for the Rybrevant combination arms, including infusion-related reaction, rash, and pneumonitis, was comparable to that seen with Rybrevant monotherapy experience. Serious AEs occurred in 52 percent of patients receiving Rybrevant plus chemotherapy with lazertinib and 32 percent of patients treated with Rybrevant plus chemotherapy, compared with 20 percent of patients who received chemotherapy alone. The incidence of treatment-related AEs leading to death was low and comparable between all treatment arms. Rates of venous thromboembolism (VTE) were higher in the Rybrevant combinations, mostly Grade 1 or 2 with no Grade 5 events and rates of discontinuations due to VTEs were less than or equal to Rybrevant combinations.

“Rybrevant plus chemotherapy, given with and without lazertinib, showed consistent disease control across all pre-specified patient subgroups in the MARIPOSA-2 study,” said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Janssen Research & Development, LLC. “These encouraging results reinforce the distinct profile of Rybrevant-based regimens as potential practice-changing treatment options and mark another important key milestone in our pursuit to transform the treatment of EGFR-mutated NSCLC.”

Rybrevant is a bispecific antibody targeting EGFR and MET with immune cell-directing activity, and in the MARIPOSA-2 study was combined with chemotherapy (carboplatin and pemetrexed) and given with and without lazertinib, an oral third-generation EGFR tyrosine kinase inhibitor (TKI) in patients with locally advanced or metastatic EGFR-mutated NSCLC after disease progression on or after osimertinib. In the study, 657 patients were randomized to receive treatment with RYBREVANT® and chemotherapy, either with or without lazertinib, or chemotherapy alone. Dual primary endpoints were used to compare PFS, as assessed by blinded independent central review (BICR), for each experimental arm to chemotherapy alone. Secondary endpoints included OS, ORR, DOR, and intracranial PFS.

About the MARIPOSA-2 Study: MARIPOSA-2 (NCT04988295), which enrolled 657 patients, is a randomized, open-label Phase III study evaluating the efficacy and safety of two combination regimens of Rybrevant (with and without lazertinib) and chemotherapy. Patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC who had disease progression on or after treatment with osimertinib were randomized to treatment with RYBREVANT® plus chemotherapy,Rybrevant plus chemotherapy with lazertinib, or chemotherapy alone. The dual primary endpoint was used to compare the PFS (using RECIST v1.1 guidelines†) as assessed by BICR for each experimental arm to chemotherapy alone. Secondary endpoints included objective response as assessed by BICR, OS, DOR, time to subsequent therapy, PFS2 and intracranial PFS.2

All study participants underwent serial brain imaging to allow for the robust assessment of intracranial endpoints and to assess the CNS activity of Rybrevent with and without lazertinib. As brain metastases can lead to significant burden and poor outcomes for patients, this aspect of the study design provides critical information in an area of high unmet need. The study enrolled 657 patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC who had disease progression on or after treatment with osimertinib.

See-"Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase III MARIPOSA-2 study"-A. Passaro, Jie Wang, Y. Wang, J.M. Baum, R.G. Campelo, MD B.C. Cho . Open AccessPublished:October 23, 2023DOI:https://doi.org/10.1016/j.annonc.2023.10.117.