J&J's Rybrevant okay challenges Tagrisso in first-line NSCLC

AstraZeneca's EGFR inhibitor Tagrisso has become the go-to therapy for EGFR-mutated non-small cell lung cancer (NSCLC), but now has competition from Johnson & Johnson's Rybrevant and Lazcluze combination.

The FDA has approved EGFRxMET bispecific antibody Rybrevant (amivantamab) with third-generation EGFR tyrosine kinase inhibitor Lazcluze (lazertinib) for first-line use in locally advanced and metastatic NSCLC with exon 19 deletions or exon 21 L858R substitutions, encroaching on territory currently dominated by AZ's drug.

J&J has big peak sales expectations for Rybrevant – $5 billion a year according to recent comments made by senior management. And this approval is a key stepping stone on that path, alongside a green light from the FDA earlier this year for Rybrevant plus chemotherapy as a frontline regimen for NSCLC patients with less frequent EGFR exon 20 mutations.

On J&J's second-quarter results call, head of innovative medicine Jennifer Taubert said that there is a pressing need for new therapy in first-line NSCLC, with about a quarter of patients never making it to second-line therapy, adding that the Rybrevant/Lazcluze combination is "going to have a significant place" in treatment.

She also noted that J&J has filed a subcutaneous version of Rybrevant with the FDA to make the drug more patient-friendly and easier to administer, which will offer a "winning combination" for previously untreated patients.

The big question is whether it can displace Tagrisso (osimertinib), like Lazcluze a third-generation EGFR TKI and AZ's top-selling drug, making $3.2 billion in the first half of the year. It has been approved as a first-line therapy for this type of cancer since 2018 and earlier this year was also cleared for use in combination with chemo.

Questions remain about how successful the two-drug regimen would be in taking market share away from Tagrisso, which is well-established and familiar to oncologists, not least because – for now – Rybrevant needs to be given as an infusion every two weeks after a lead-in period, while Tagrisso monotherapy is given orally. J&J's drug has also been linked to a higher rate of clotting side effects.

In J&J's favour is that the doublet therapy beat Tagrisso given as a monotherapy in the phase 3 MARIPOSA study on the main endpoint of progression-free survival, with patients living a median of 23.7 months without disease progression versus 16.6 months for Tagrisso monotherapy.

J&J is still waiting for data on overall survival (OS), which could tip the balance in favour of its regimen. Meanwhile, some analysts have suggested that the pivot point for Rybrevant will come if and when the subcutaneous version – which outperformed the IV version in the PALOMA-3 trial and has a reduced risk of clotting – reaches the market.

AZ, meanwhile, has the recent approval of the Tagrisso/chemo combination as a defense against its rival, although, this is expected to have a role to play mainly in a subset of patients who require more intensive treatment upfront; for example, as a result of a high tumour burden at diagnosis and/or tumours that have spread into the central nervous system.

There are around 200,000 people diagnosed with lung cancer in the US each year, with 80-85% of them having NSCLC. Of these, around 70% are diagnosed at an advanced stage and 15% have tumours with an EGFR mutation.