EU approves Rybrevant + Lazcluze for NSCLC

“For people living with advanced NSCLC harbouring EGFR mutations, new treatment options are urgently needed in the first-line setting,” said Enriqueta Felip, M.D., Ph.D, head of the thoracic cancer unit at Vall d’Hebron University Hospital, Barcelona, Spain. “The amivantamab and lazertinib combination has shown significant progression-free survival improvements in patients with previously untreated EGFR-mutated advanced NSCLC, including those with brain metastases, compared to osimertinib monotherapy. This approval by the European Commission offers the potential to broaden first-line treatment options and provide a new standard of care for eligible patients.”

Lung cancer is Europe’s biggest cancer killer, with NSCLC accounting for 85 percent of all lung cancer cases.  EGFR mutation-positive NSCLC refers to a subtype of lung cancer based on specific mutations in the EGFR gene.  While there are different types of EGFR mutations, EGFR ex19del and EGFR exon 21 L858R are the most common, accounting for approximately 85-90 percent of mutations. Patients are often treated with targeted therapies known as EGFR tyrosine kinase inhibitors (TKIs).  However, treatment resistance or disease reoccurrence remains a significant challenge and there is an urgent need for alternative, novel targeted therapies earlier in the treatment pathway to address resistance and improve survival outcomes.

The EC approval is supported by results from the Phase IIi MARIPOSA (NCT04487080) study, evaluating amivantamab in combination with lazertinib compared to osimertinib as first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or exon 21 L858R substitution mutations. The study, which was featured during a Presidential Symposium session at the 2023 European Society of Medical Oncology (ESMO) Congress, met its primary endpoint of progression-free survival (PFS), and at median follow-up of 22 months, amivantamab plus lazertinib reduced the risk of disease progression or death by 30 percent compared to osimertinib (median PFS: 23.7 months versus 16.6 months; hazard ratio [HR]=0.70; 95 percent confidence interval [CI], 0.58–0.85; P<0.001) as assessed by blinded independent central review (BICR). The median duration of response (DOR) was longer for patients receiving amivantamab plus lazertinib compared to osimertinib, with a nine-month improvement in median DOR (25.8 vs. 16.8 months).

The safety profile of the combination of amivantamab and lazertinib was consistent with previous reports from Phase 1-II studies, with mostly Grade 1 or 2 adverse events (AEs). Toxicity was largely manageable with dose interruptions and reductions, along with supportive care measures commonly used in the treatment of patients with NSCLC. The most common treatment emergent adverse events (TEAEs) of any grade were paronychia (68 percent), infusion-related reactions (63 percent), and rash (62 percent). Amivantamab plus lazertinib had higher rates of EGFR- and MET-related AEs and venous thromboembolism compared to osimertinib, except diarrhoea, for which rates were higher for osimertinib. The commonest grade 3 or higher TEAEs were rash (15 percent), paronychia (11 percent) and dermatitis acneiform (8 percent). The rate of discontinuation of all study treatments due to treatment-related AEs for the amivantamab combination was 10 percent. The rate of interstitial lung disease (including pneumonitis) was less than three percent in both arms.

An EC decision on a Marketing Authorisation (MA) for lazertinib for the corresponding combination regimen indication is pending, following a Committee for Medicinal Products for Human Use (CHMP) positive opinion last month.

In May 2024, an application for the extension of the amivantamab marketing authorisation was submitted seeking approval for the use of a subcutaneous (SC) formulation of amivantamab in combination with lazertinib for the first-line treatment of adult patients with advanced NSCLC with EGFR ex19del or L858R mutations, and for the use of SC amivantamab monotherapy in adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after failure of platinum-based therapy.