A new FDA approval has vaulted a Johnson & Johnson lung cancer drug combination into a key territory already dominated by AstraZeneca’s Tagrisso. But the real battle against the EGFR king has yet to start.
The J&J combination contains Rybrevant and a new drug called Lazcluze, or lazertinib. Tuesday, J&J said the FDA has approved the regimen for newly diagnosed non-small cell lung cancer patients with one of the two common EGFR mutations at exon 19 or exon 21.
J&J has high hopes for the lung cancer combination, having put its peak sales potential at above $5 billion. To get there, it needs to beat AZ’s Tagrisso, which has become the well-established standard of care in first-line EGFR-mutant NSCLC.
Rybrevant and Lazcluze already beat Tagrisso on at least one major efficacy endpoint in a head-to-head phase 3 trial. But industry watchers have argued that the J&J combo still needs two more triumphs to really be able to challenge Tagrisso, which generated $5.8 billion in sales worldwide in 2023 across several lung cancer settings.
In the phase 3 MARIPOSA trial, Rybrevant and Lazcluze reduced the risk of disease progression or death by 30% compared with Tagrisso as first-line treatments for EGFR-mutant NSCLC. Patients who took the combo lived a median 23.7 months without progression, versus 16.6 months for Tagrisso.
When the data were unveiled at the European Society for Medical Oncology 2023 congress in October, Leerink Partners analysts noted that doctors are really looking for evidence on whether Rybrevant and Lazcluze can extend patients’ lives to decide on whether to use the combo in the place of Tagrisso.
J&J has expressed confidence that its combo will eventually show an overall survival benefit, given that MARIPOSA showed a positive trend that was drawing very close to statistical significance at an interim analysis. If that survival mark were reached, J&J argued, it would be unreasonable for physicians to still prefer Tagrisso, especially for younger patients.
The other remaining challenge for the J&J regimen is that, compared with a single pill for Tagrisso, Rybrevant currently comes as a more cumbersome intravenous infusion.
What’s more, the combo has shown a high rate of venous thromboembolism (VTE), or the formation of blood clots in the veins. The overall rate of discontinuation due to treatment-related adverse events was higher at 10% for the Rybrevant-Lazcluze pairing, versus 3% for Tagrisso in the MARIPOSA trial.
Both the convenience and tolerability problems could be alleviated by a subcutaneous version of Rybrevant, which J&J developed with Halozyme.
In the phase 3 PALOMA-3 trial in previously treated EGFR-mutant NSCLC, subcutaneous Rybrevant showed comparable tumor shrinkage data to the original IV drug but significantly lower (13% versus 66%) infusion-related reactions. The Rybrevant administration time was also reduced from about two to five hours for IV to about five minutes for the subcutaneous version.
Among patients who took prophylactic anticoagulation, the rate of VTE for the under-the-skin version was 7%, which, as Leerink Partners analysts noted, is comparable to the 9% in the Tagrisso group without anticoagulation in MARIPOSA. For Rybrevant and Lazcluze’s first-line nod, the FDA recommends that patients take anticoagulation to prevent VTE for the first four months of treatment.
And in a pleasant surprise for J&J, subcutaneous Rybrevant demonstrated a statistically significant overall survival advantage over its IV counterpart in the PALOMA-3 second-line trial. This finding could give the new formulation an extra oomph in its battle against Tagrisso in the first-line arena.
The FDA has accepted J&J’s filing for subcutaneous Rybrevant earlier this month and has put it under priority review.
In May, two lung cancer experts told Leerink that J&J could make a stronger case in first-line NSCLC with the help of subcutaneous Rybrevant thanks to its fewer infusion reactions and potentially less toxicity.
Rybrevant is an EGFRxMET bispecific antibody. Before the latest FDA nod, Rybrevant was initially approved for the less common exon 20 EGFR mutation in NSCLC.
Lazcluze is a third-generation EGFR tyrosine kinase inhibitor, which was first approved in South Korea under the brand name Laclaza. The drug becomes the first novel anti-cancer drug out of Korea to be approved by the FDA.