FDA Approves Janssen's Chemotherapy-Free Rybrevant (Amivantamab) Plus Lazcluze (Lazertinib) as First-Line Treatment for EGFR-Mutated NSCLC, Outperforming Osimertinib
Johnson & Johnson
Healthcare Product Manufacturers, Health Service Providers
Source: PharmaDJ
Writing: Huanmu Editing: Vitamin
Lung cancer is one of the most common cancers globally, with non-small cell lung cancer (NSCLC) accounting for 80% to 85% of all cases. One of the most common driver mutations in NSCLC is alterations in EGFR, a receptor tyrosine kinase that controls cell growth and division. EGFR mutations are present in 10%-15% of Western patients and 40%-50% of Asian patients with non-small cell lung cancer.EGFR ex19del, EGFR L858R mutation, and EGFR exon 20 insertion mutation are the most common EGFR mutations.The 5-year survival rate for all patients with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors is less than 20%.
The 5-year overall survival (OS) for patients with EGFR Ex19del or L858R mutations is 19%.
However, the 5-year overall survival (OS) rate for patients with EGFR exon 20 insertion mutations is only 8%.
Due to disease progression and the lack of treatment options, acquired resistance mechanisms after some drug treatments make subsequent therapies more challenging, and 25% to 39% of patients never receive second-line treatment.
On August 20, 2024, Johnson & Johnson announced that the FDA had approvedRybrevant（Amivantamab，AmivantamabUnitedLazcluze（Lazertinib，Lazertinib as a first-line chemotherapy-free treatment for patients with EGFR-mutated non-small cell lung cancer.Indications include patients with locally advanced or metastatic NSCLC who have been found to have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations through an FDA-approved test.This green light provides patients with a new first-line treatment option, and if drug resistance occurs later, chemotherapy can be further selected.
Amivantamab-vmjw（Rybrevant®) is a humanized EGFR/MET bispecific antibody. It has multiple mechanisms of anticancer action, not only blocking the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET)-mediated signaling pathways, but also guiding immune cells to target tumors carrying activating and drug-resistant EGFR/MET mutations and amplifications.RybrevantIn May 2021, it received accelerated approval from the U.S. FDA for the treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 20 insertion mutations as detected by an FDA-approved test and whose disease has progressed on or after platinum-based chemotherapy.
Lazertinib（LECLAZA®) is an orally administered third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is a brain-penetrant, irreversible EGFR-TKI that targets the T790M mutation (the T790M mutation refers to the substitution of threonine (T) with methionine (M) at the 790 amino acid position in exon 20 of EGFR), activates EGFR mutations Ex19del and L858R, while sparing wild-type EGFR. Co-developed by Yuhan and Janssen Biotech, Lazertinib was first approved in January 2021 for the treatment of patients with locally advanced or metastatic NSCLC who are positive for the EGFR T790M mutation and have previously received EGFR-TKI therapy.
According to Johnson & Johnson,The combination of the two drugs is the first and only multi-target, chemotherapy-free regimen that directly targets two common EGFR mutations.
FThe approval of DA was based on the positive results of the Phase 3 MARIPOSA (NCT04487080) study, a randomized Phase 3 trial that enrolled 1,074 patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or substitution mutations, whichRybrevant/Lazcluze combination head-to-head comparison with AstraZeneca's Tagrisso (osimertinib).The primary endpoint of the study is progression-free survival (PFS) assessed by blinded independent central review (BICR).Secondary endpoints include overall survival (OS), overall response rate (ORR), duration of response (DOR), second progression-free survival (PFS2), and intracranial PFS.
The study showed that, compared with Osimertinib,RybrevantUnitedLazcluzeReduced the risk of disease progression or death by 30%.Compared with Osimertinib,RybrevantUnitedLazcluzeThe median duration of response (DOR) was extended by 9 months (25.8 months VS 16.7 months).
For patients with a history of brain metastases, the PFS for the combination therapy group and the control drug group were 18.3 months and 13.0 months, respectively, with a 31% reduction in the risk of disease progression or death.
For patients with liver metastases at baseline, the PFS for the combination therapy and control drug groups were 18.2 months and 11.0 months, respectively, with a 42% reduction in the risk of disease progression or death.
In patients with TP53 co-mutations, the PFS for the combination therapy group and the control drug group were 18.2 months and 12.9 months, respectively, with a 35% reduction in the risk of disease progression or death.
For patients with detectable circulating tumor DNA (ctDNA) at baseline, the PFS for the combination therapy and control drug groups were 20.3 months and 14.8 months, respectively, with a 32% reduction in the risk of disease progression or death.
These findings suggest thatAndOsimertinibIn comparison, combination therapy has clinical significance.
For the MARIPOSA clinical trial, participants receivingRybrevantAndLazcluzeIn patients receiving combination therapy, the most common adverse reactions (≥20%) are rash, nail toxicity, and infusion-related reactions.Rybrevant®Related), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19 infection, bleeding, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity.RybrevantAndLazcluzeA serious safety signal for venous thromboembolic events (VTE) has been observed with combined use, and prophylactic anticoagulation therapy should be administered during the first 4 months of treatment.
To reduceRybrevantInfusion Reaction, In June 2024, Johnson & Johnson submitted to the U.S. FDARybrevant®Subcutaneous Formulation (Amivantamab with Recombinant Human Hyaluronidase for Subcutaneous Administration SC) Biologics License Application (BLA) for All Currently Approved or Submitted Intravenous (IV) UsesRybrevant®Indications. This application is based on the Phase 3 PALOMA-3 study,Preliminary results show that subcutaneous (SC) injection of amivantamab in five minutes can reduce infusion-related reactions (IRR) by 5 times.Subcutaneous injection (SC) of amivantamab also demonstrated longer OS, PFS, and DOR. On August 14, 2024, the FDA granted the application Priority Review designation.
For treatment-naïve patients with EGFR-mutant advanced NSCLC, the combination of Rybrevant and Lazcluze significantly delays symptom progression compared to osimertinib. This again demonstrates that this combination regimen provides better disease and symptom control and has the potential to become a new first-line treatment standard for EGFR-mutant non-small cell lung cancer.However,This approval may mean that AstraZeneca will face competition.
Both Rybrevant and Tagrisso target and inhibit specific mutations in the epidermal growth factor receptor (EGFR) gene, a common target in NSCLC.Tagrisso's sales last year were $5.8 billion.Currently, amivantamab is still undergoing various clinical trials for other indications, including a Phase 2 trial for the treatment of patients with advanced or metastatic solid tumors (including EGFR-mutated non-small cell lung cancer) and a Phase 1b/2 trial for subjects with advanced or metastatic colorectal cancer, among others. According to predictions from GlobalData's pharmaceutical intelligence center,Rybrevant will generate $3.9 billion in sales by 2030.
To this end, AstraZeneca has also advanced multiple combination regimens of osimertinib, with the combination chemotherapy regimen progressing the fastest. On June 25, 2024, the China National Medical Products Administration approved osimertinib in combination with chemotherapy as a first-line treatment for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Compared with osimertinib monotherapy, the combination of osimertinib and chemotherapy reduced the risk of disease progression or death by 38%, extending the median PFS by 8.8 months.
However, by comparison, Rybrevant + Lazcluze has set a new benchmark for first-line treatment in advanced stages. The chemotherapy-free combination of Rybrevant and Lazcluze is more acceptable to patients and is expected to become a new treatment option for first-line EGFR-mutated advanced NSCLC patients.
