Janssen seeks European marketing approval for lazertinib in combo with Rybrevant to treat patients with EGFR-mutated NSCLC

The Janssen Pharmaceutical Companies of Johnson & Johnson announced the submission of a marketing authorisation application (MAA) to the European Medicines Agency (EMA) seeking approval of lazertinib, in combination with Rybrevant (amivantamab), for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutations including exon 19 deletions (ex19del) or exon 21 L858R (L858R) substitution mutations.

“Despite significant advances in the treatment of EGFR-mutated non-small cell lung cancer, the progression-free survival rate with the current first-line therapies remains low,” said Catherine Taylor, vice president, EMEA Medical Affairs, Therapy Area Strategy, Janssen-Cilag AG. “Novel targeted therapies are necessary to address resistance and disease progression, and provide new options for patients in this area of high unmet medical need.”

MARIPOSA (NCT04487080) is a randomised, phase 3 study evaluating amivantamab in combination with lazertinib compared to osimertinib in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations.

The MARIPOSA study met its primary endpoint, resulting in statistically significant and clinically meaningful improvement in progression-free survival (PFS) for amivantamab plus lazertinib versus osimertinib, as assessed by blinded independent central review (BICR). The safety profile of amivantamab plus lazertinib was consistent with prior reports of the combination, with mostly Grade 1 or 2 adverse events (AEs).

“Lung cancer remains the leading cause of cancer death worldwide and high unmet needs remain for patients with certain oncogenic driver mutations,” said Kiran Patel, M.D., vice president, clinical development, solid tumours, Janssen Research and Development, LLC. “We’re pleased to announce the submission of lazertinib, in combination with amivantamab as a chemotherapy-free regimen, in the first-line, common EGFR-mutated NSCLC setting, to the European Medicines Agency. Once again, this shows our commitment to advancing innovative therapies that have the potential to be a future standard of care.”

MARIPOSA (NCT04487080), which enrolled 1,074 patients, is a randomised, phase 3 study evaluating amivantamab in combination with lazertinib versus osimertinib and versus lazertinib 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 overall survival (OS), overall response rate (ORR), duration of response (DOR), second progression free survival (PFS2) and intracranial PFS.

The MARIPOSA study required all patients to have serial brain imaging with MRIs in order to detect or monitor brain metastases, a measure not implemented in most prior studies for CP-428352 December 2023 EGFR-mutated NSCLC.1 The primary endpoint of PFS in MARIPOSA included these central nervous system (CNS) events detected by serial brain MRIs.1 Extracranial PFS, which may more closely approximate what would be seen in other trials, was also explored in MARIPOSA.

Lazertinib 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 lazertinib from the phase 3 study LASER301 was published in The Journal of Clinical Oncology in 2023.

In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib.

Amivantamab is a fully-human EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating and resistance EGFR mutations and MET mutations and amplifications.

The European Commission granted conditional marketing authorisation of amivantamab in December 2021 for the treatment of adult patients with advanced NSCLC with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations, after failure of platinum-based therapy. Amivantamab is the first approved treatment in the European Union specifically targeting EGFR exon 20 insertion mutations for NSCLC. In October 2023, a type II extension of indication application was submitted to the EMA seeking approval of amivantamab in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with NSCLC with EGFR exon 20 insertion mutations. This was followed, in November 2023, with the submission of a second type II extension of indication application seeking approval of amivantamab in combination with chemotherapy (carboplatin and pemetrexed) for the treatment of adult patients with advanced NSCLC with EGFR ex19del or L858R substitution mutations, after failure of prior therapy including a third-generation EGFR TKI.

In Europe, over 477,500 patients were diagnosed with lung cancer in 2020. NSCLC accounts for 85 percent of all lung cancer cases. Lung cancer is Europe’s biggest cancer killer, with more deaths than breast cancer and prostate cancer combined.

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 per cent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 per cent 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 TKIs is less than 20 per cent. Patients with EGFR ex19del or L858R mutations have a real-world five-year OS of 19 per cent. In addition, it has been demonstrated that approximately 50 per cent of patients with NSCLC will develop brain metastases which are a substantial contributor to overall cancer mortality.

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