ESMO: J&J's Rybrevant combo beats Tagrisso on lung cancer progression. Should AZ worry?

17 Oct 2023
www.fiercepharma.com
Clinical ResultPhase 3Drug Approval
ESMO: J&J's Rybrevant combo beats Tagrisso on lung cancer progression. Should AZ worry?
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Source: FiercePharma
Whether Johnson & Johnson's drug combo can steal meaningful market share from AstraZeneca's well-entrenched Tagrisso remains a big question.
Editor's note: This is an evolving story. Please check back on Oct. 23 when the full data of MARIPOSA are presented at ESMO 2023.
A drug combination from Johnson & Johnson outperformed AstraZeneca’s Tagrisso in slowing the worsening of newly diagnosed lung cancer. But it’ll take more than a tumor progression win to dethrone the EGFR king.
In a high-stakes head-to-head trial, J&J’s Rybrevant and the company’s Yuhan-partnered lazertinib reduced the risk of progression or death by 30% versus Tagrisso in patients with newly diagnosed, EGFR-mutant non-small cell lung cancer (NSCLC).
Compared with the Tagrisso group, the Rybrevant-lazertinib regimen improved the median time patients had lived without disease progression by 7.1 months to reach 23.7 months.
The data, from the closely watched MARIPOSA trial, were shared in a late-breaking abstract, and the full results will be presented during a presidential session at the European Society for Medical Oncology 2023 congress this coming Monday.
The trial establishes Rybrevant and lazertinib as a new first-line, standard of care for EGFR-mutated advanced NSCLC, the trial investigators wrote in the abstract. Being able to challenge Tagrisso is a big deal; last year, the well-entrenched EGFR inhibitorEGFR inhibitor reeled in $5.4 billion in sales.
But whether J&J can steal meaningful market share from AZ remains a big question. As Leerink Partners analyst Andrew Berens, M.D., noted during an interview with Fierce Pharma before the MARIPOSA data release, doctors and patients like Tagrisso not just because of its ability to stall cancer progression.
“I think the real question that doctors are going to ask when they decide to prescribe [Rybrevant and lazertinib] or not is, is it improving overall survival?” Berens said.
A better progression-free survival showing is expected from the combo given its mechanism of action, Berens explained. Lazertinib, like Tagrisso, is a small-molecule EGFR inhibitorEGFR inhibitor. Rybrevant is an EGFRxMET bispecific antibody, with MET known as an EGFR escape pathway.
For now, the J&J combo showed an encouraging trend toward further extending patients’ lives. The cocktail reduced the risk of death by 20% over Tagrisso, although the number hasn’t reached statistical significance.
But even on the PFS measurement, Rybrevant and lazertinib don’t really have the most resounding win. Before the MARIPOSA readout, another phase 3 trial called FLAURA2 showed that Tagrisso’s combination with chemotherapy could cut the risk of progression or death by 38% over Tagrisso monotherapy in first-line NSCLC. Adding chemo to Tagrisso prolonged the median PFS by about nine months.
In a Tuesday note to client, Berens argued that because MARIPOSA is proposing a chemo-free regimen, putting the PFS data from MARIPOSA and FLAURA2 side by side would be an apples-to-oranges comparison.
During his interview with Fierce Pharam, Berens said that in investors’ minds, the FLAURA2 readout raised the PFS efficacy bar for Rybrevant and lazertinib to around nine months, which the MARIPOSA regimen now apparently didn’t meet. But what doctors really care about is still overall survival, Berens added.
Berens said a statistically significant patient survival readout was not expected from MARIPOSA at this point. But he would be looking for how the two treatment arms’ survival curves are trending plus the survival rates at landmark time points.
For now, the J&J combo’s 20% death risk reduction looks better than FLAURA2’s 10% improvement over Tagrisso alone. In FLAURA2, the survival curve of the Tagrisso-chemo arm struggled to separate from that of the monotherapy.
Despite the chemo combo’s big showing in PFS, AZ said it still believes Tagrisso monotherapy will remain the standard of care for the majority of EGFR-mutant NSCLC patients. An overall survival win matters for J&J also because of Tagrisso’s favorable convenience and tolerability.
Tagrisso is an oral drug with a very benign side effect profile, Berens noted. By comparison, Rybrevant is an infusion currently approved by the FDA to treat a small subset of the NSCLC marked by EGFR exon 20 insertion mutations. Frequent infusions and toxicities have made Rybrevant a difficult drug to take for some patients, the Leerink analyst said.
It would be beneficial to have a few extra months before the tumor started growing again, Berens said. “But at the end of the day, if it doesn’t improve OS, I think patients are going to opt for the quality of life.”
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