Dexamethasone reduces IRRs in patients with EGFR-mutated NSCLC treated with intravenous RYBREVANT

Johnson and Johnson announced results from the open-label Phase 2 SKIPPirr study, which evaluated additional prophylactic strategies to reduce the incidence of infusion-related reactions (IRRs) with intravenous (IV) RYBREVANT (amivantamab-vmjw) in patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or L858R substitution mutations.

The study, which included 40 patients, showed that prophylaxis with 8-mg dexamethasone taken for two days prior to the first infusion met the primary endpoint of incidence of IRRs at Cycle 1 Day 1 (C1D1), with an all-grades IRR rate for IV RYBREVANT of 22.5 percent.

This represents a three-fold reduction in the incidence of IRRs compared to standard management of IRRs with IV RYBREVANT, where historic data has observed an all-grades incidence rate of 67.4 percent.

Data were presented as a mini-oral presentation at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer (WCLC).

“These data offer important insights that may help improve the patient experience with intravenous amivantamab treatment.

This study shows us that an easily accessible approach of an increased dose regimen of dexamethasone as a pre-treatment prophylaxis can potentially help lower IRRs. It is encouraging to see a three-fold decrease in IRRs, when comparing the rates in SKIPPirr to historical data,” – said Gilberto Lopes, Associate Director of Global Oncology at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, and presenting author.

In the study, patients received an at-home regimen of oral dexamethasone, taking an 8-mg dose twice daily on the two prior days and one hour prior to receiving IV RYBREVANT. The RYBREVANT treatment was combined with LAZCLUZE (lazertinib). All IRRs were Grade 1 or 2 with no patients requiring hospitalization due to IRRs. There were no Grade 3 or higher IRR events reported.

The safety profile of RYBREVANT and LAZCLUZE with prophylactic dexamethasone at the initiation of treatment is consistent with previous studies, showing no significant increase in adverse events. The most common IRR-related symptoms observed in the study were nausea (8 percent), dyspnea (5 percent) and hypotension (5 percent).

“Reducing the risk of IRRs is a critical aspect of improving the overall treatment experience for patients receiving intravenous RYBREVANT and oral LAZCLUZE.

Incorporating oral dexamethasone into the treatment regimen suggests we can help mitigate this risk, with the goal of allowing patients to continue their therapy with fewer interruptions,” – said Mark Wildgust, Vice President of Oncology Global Medical Affairs, Johnson & Johnson Innovative Medicine.

Additional studies are ongoing to evaluate prophylactic strategies to reduce IRRs for patients receiving IV RYBREVANT.

About the SKIPPirr Study

SKIPPirr (NCT05663866) is a Phase 2 study evaluating RYBREVANT in combination with LAZCLUZE in patients with EGFR-mutated (Ex19del or L858R) advanced NSCLC after disease progression on osimertinib and platinum-based chemotherapy. All patients received oral LAZCLUZE and IV RYBREVANT. The study used a Simon’s 2-stage design to evaluate different preventive treatments across four groups.

The first group received dexamethasone (4 mg) orally, taken twice daily on the day before treatment, for a total of two doses.

The second group was given a higher dose of dexamethasone (8 mg), taken orally twice daily on the two days leading up to treatment and the morning of infusion (5 doses total).

The third group received montelukast (10 mg) orally, starting four days before treatment and continuing through the day of treatment, totaling five doses.

Lastly, the fourth group was treated with a single dose of methotrexate (25 mg), administered as a subcutaneous injection between days 7 and 3 before the treatment. The primary endpoint of the study is incidence of IRRs at C1D1.

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 other 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 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 lazertinib (LAZCLUZE) as a Category 1 recommendation for first-line therapy in patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.
• Amivantamab-vmjw (RYBREVANT) plus chemotherapy as a Category 1 recommendation 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 Category 1 recommendation for first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a 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 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 2 SKIPPirr study, RYBREVANT is being studied in multiple clinical trials in NSCLC, including:

• The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT in combination with LAZCLUZE versus osimertinib and versus LAZCLUZE alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations.
• 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.1
• 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 mutations.
• 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 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.

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