When companies introduce an injectable version of an intravenously infused drug, better convenience with comparable efficacy is typically the goal. But to Johnson & Johnson’s surprise, a subcutaneous (SC) formulation of its lung cancer med Rybrevant proved to work better than the original infusion.
Rybrevant significantly reduced the risk of death by 38% compared with intravenous Rybrevant in their respective combinations with J&J’s Yuhan-partnered lazertinib in previously treated non-small cell lung cancer (NSCLC) patients with common EGFR ex19del or L858R mutations.
At 12 months, 65% of patients who received the SC version and lazertinib were alive, versus 51% who received the IV-lazertinib combo.
The results from the PALOMA-3 trial were shared May 31 at the American Society of Clinical Oncology annual meeting in Chicago. Although overall survival was only a prespecified exploratory endpoint, injectable Rybrevant’s showing is statistically significant with a nominal p-value at 0.017 and its confidence interval below 1.
Besides overall survival, SC Rybrevant’s duration of response and progression-free survival were also longer than its IV counterpart. The tumor response rates were similar at 30% and 33%, respectively, for SC and IV.
On the trial’s co-primary endpoints, SC Rybrevant showed noninferior pharmacokinetic efficacy, as measured by drug levels in the blood right before the next dose and on average during a 15-day period.
The SC version also showed a better tolerability profile. The rate of infusion-related reactions for patients who got SC Rybrevant was about fivefold lower (13% versus 66%) than those on the IV formulation. On some other common side effects such as paronychia, hypoalbuminemia and rash, SC Rybrevant showed slightly higher rates than the IV version. None of the adverse events were grade 4 or 5.
A win for SC Rybrevant could help J&J in its potential upcoming challenge against AstraZeneca’s EGFR king Tagrisso, which is an oral drug. While IV Rybrevant can take up to five hours to administer, the SC version only takes up to seven minutes, or five minutes at median.
J&J expects to file SC Rybrevant with the FDA this year, a company spokesperson told Fierce Pharma. J&J is currently waiting for an FDA decision on the combination of IV Rybrevant and lazertinib in front-line EGFR-mutated NSCLC, and the spokesperson said an SC submission is not contingent on that first-line approval.
A statistically significant survival benefit is rare in SC-versus-IV studies, which are often designed to measure pharmacokinetic noninferiority. Despite SC Rybrevant’s superior data, J&J said it will continue to sell the IV version.
Investigators have a hypothesis as to why SC Rybrevant performed better, according to the J&J spokesperson. They figured that SC absorption via the lymphatic system potentially enhances immune-mediated activity. Rybrevant, an EGFR-MET bispecific antibody, has shown immune-cell-directed activity by harnessing monocytes, macrophages and NK cells to induce immune-cell killing.