RYBREVANT plus LAZCLUZE versus osimertinib in EGFR-mutated advanced lung cancer

New longer-term data from the MARIPOSA study confirm superior outcomes of chemotherapy-free RYBREVANT plus LAZCLUZE regimen compared to osimertinib monotherapy as first-line therapy

Results from an interim analysis featured in late-breaker oral presentation at WCLC

Johnson and Johnson announced longer follow-up data from the landmark Phase 3 MARIPOSA study which showed first-line treatment with RYBREVANT (amivantamab-vmjw) combined with LAZCLUZE (lazertinib) provided consistent benefit across long-term outcomes compared to osimertinib monotherapy in adult patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or L858R substitution mutations.

The data show a strong and improving overall survival (OS) trend favoring RYBREVANT plus LAZCLUZE at approximately three years of follow-up. These results were presented in a late-breaking oral presentation at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer (WCLC) (Abstract #1146).

At three years (a median follow-up of 31.1 months), 61 percent of patients receiving RYBREVANT plus LACLUZE were alive compared to 53 percent of those treated with osimertinib based on an analysis performed at the request of a health authority.

• Median OS not estimable vs 37.3 months;
• hazard ratio [HR], 0.77;
• [95 percent confidence interval [CI], 0.61-0.96];
• nominal P=0.019.

Overall survival will continue to be assessed with longer term follow-up as a key secondary endpoint. The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR).

“By combining the multi-targeted mechanism of RYBREVANT with LAZCLUZE, a central nervous system-penetrant third-generation tyrosine kinase inhibitor, we are advancing a chemotherapy-free regimen for the first-line treatment of patients with EGFR-mutant NSCLC.

This approach blocks EGFR and MET pathways and leverages the immune system, offering patients an opportunity for prolonged benefits.

Even more encouraging is the marked improvement in the hazard ratio and the ongoing separation of survival curves, showing an eight percent improvement at three years for RYBREVANT plus LAZCLUZE compared to osimertinib.

This supports the long-term benefit of the combination as a first-line treatment option in this setting,” -said Shirish M. Gadgeel, Chief of Division of Hematology and Oncology, Associate Director at Henry Ford Cancer Institute and presenting author.

Results further showed RYBREVANT plus LAZCLUZE demonstrated a trend toward improved central nervous system disease control compared to osimertinib at three years.

• HR, 0.82;
• [95 percent CI, 0.62-1.09];
• nominal P=0.165.

At the three-year landmark, intracranial PFS was double for RYBREVANT plus LAZCLUZE versus osimertinib (38 percent vs 18 percent, respectively).

More patients remained on treatment at three years with the RYBREVANT combination compared to osimertinib (40 percent vs 29 percent, respectively).

• HR, 0.80;
• [95 percent CI, 0.68-0.96];
• nominal P=0.014.

Additionally, more patients receiving RYBREVANT and LAZCLUZE™ at the three-year follow-up had not started a subsequent therapy versus osimertinib (45 percent vs 32 percent, respectively; HR, 0.77; [95 percent CI, 0.65-0.93]; nominalP=0.005).

Progression-free survival after first subsequent therapy was 57 percent for the RYBREVANT combination compared to 49 percent for osimertinib.

• HR, 0.73;
• [95 percent CI, 0.59-0.91];
• nominal P=0.004.

“Promising results like these presented at WCLC reinforce our mission to improve the lives of patients diagnosed with lung cancer. We are encouraged by the favorable overall survival trend observed with RYBREVANT plus LAZCLUZE and are eager to see how these data evolve as we continue to follow patients over time,” – said Joshua Bauml, Vice President, Lung Cancer Disease Area Stronghold Leader, Johnson and Johnson Innovative Medicine.

As previously reported in the MARIPOSA study, the safety profile was consistent with the safety profiles of the individual treatments. The rate of discontinuation of all study treatments due to treatment-related adverse events for RYBREVANT plus LAZCLUZE was 10 percent. The rate of interstitial lung disease (including pneumonitis) was less than three percent in both arms.

In August 2024, RYBREVANT combined with LAZCLUZE was approved following a Priority Review by the U.S. Food and Drug Administration as a first-line therapy for patients with EGFR-mutated NSCLC based on the favorable efficacy and safety profile demonstrated in this study.

About the MARIPOSA Study

MARIPOSA (NCT04487080), which enrolled 1,074 patients, is a randomized, Phase 3 study evaluating RYBREVANT in combination with LAZCLUZE versus osimertinib and versus LAZCLUZE alone in first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations. The primary endpoint of the study is PFS (using RECIST v1.1 guidelines) as assessed by BICR. Secondary endpoints include OS, overall response rate (ORR), duration of response (DOR), second progression-free survival (PFS2) and intracranial PFS.

About RYBREVANT

RYBREVANT (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, is approved in the U.S., Europe, and in other markets around the world as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

RYBREVANT is approved in the U.S., Europe and in markets around the world in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test.

RYBREVANT is approved in the U.S. in combination with LAZCLUZE (lazertinib) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, as detected by an FDA-approved test. A marketing authorization application (MAA) and type II extension of indication application were submitted to the European Medicines Agency (EMA) seeking approval of LAZCLUZE™ in combination with RYBREVANT based on the MARIPOSA study.

In November 2023, Johnson & Johnson submitted a supplemental Biologics License Application (sBLA) to the U.S. FDA for RYBREVANT in combination with chemotherapy for the treatment of patients with EGFR-mutated NSCLC who progressed on or after osimertinib based on the MARIPOSA-2 study. This indication was approved in Europe in August 2024.

In June 2024, Johnson & Johnson submitted a BLA to the U.S. FDA for the subcutaneous formulation of RYBREVANT in combination with LAZCLUZE for all currently approved or submitted indications of intravenous (IV) RYBREVANT in certain patients with NSCLC. A submission for the extension of the RYBREVANT marketing authorization (line extension) was also submitted to the EMA seeking approval for this indication.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC prefer next-generation sequencing–based strategies over polymerase chain reaction–based approaches for the detection of EGFR exon 20 insertion variants. The NCCN Guidelines include:

• Amivantamab-vmjw (RYBREVANT) plus chemotherapy as a preferred (Category 1 preferred recommendation) subsequent therapy for patients with locally advanced or metastatic NCSLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with Osimertinib.
• Amivantamab-vmjw (RYBREVANT) plus carboplatin and pemetrexed as a preferred (Category 1 preferred recommendation) first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.
• Amivantamab-vmjw (RYBREVANT) as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.

In addition to the Phase 3 MARIPOSA study, RYBREVANT is being studied in multiple clinical trials in NSCLC, including:

• The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT (with or without LAZCLUZE™) and carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib
• The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.
• The Phase 3 PALOMA-3 (NCT05388669) study assessing LAZCLUZE with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.
• The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.
• The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab subcutaneous delivery.
• The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT in patients with advanced NSCLC.
• The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT in combination with LAZCLUZE and LAZCLUZE as a monotherapy in patients with advanced NSCLC with EGFR.
• The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT and capmatinib combination therapy in locally advanced or metastatic NSCLC.
• The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT and cetrelimab combination therapy in locally advanced or metastatic NSCLC.
• The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT in combination with LAZCLUZE in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.
• The Phase 1/2 swalloWTail (NCT06532032) study assessing RYBREVANT and docetaxel combination therapy in patients with metastatic NSCLC.
• The Phase 1b/2 OrigAMI-1 (NCT05379595) study assessing RYBREVANT monotherapy and in addition to standard-of-care chemotherapy in patients with advanced or metastatic colorectal cancer.
• The Phase 1b/2 OrigAMI-4 (NCT06385080) study assessing RYBREVANT monotherapy and in addition to standard-of-care therapeutic agents in patients with recurrent/metastatic head and neck squamous cell carcinoma.

About LAZCLUZE

In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of LAZCLUZE (marketed as LACLAZA in Korea). LAZCLUZE is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild-type EGFR. An analysis of the efficacy and safety of LAZCLUZE from the Phase 3 LASER301 study was published in The Journal of Clinical Oncology in 2023.

About Non-Small Cell Lung Cancer

Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division. EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.

EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations. The five- year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent. EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation. Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival (OS) of eight percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent.

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