Johnson & Johnson’s newly FDA-approved lung cancer combination of Rybrevant and Lazcluze is inching ever closer to a statistically significant survival showing, which could help it better challenge AstraZeneca’s Tagrisso.
The Rybrevant-Lazcluze combo lowered the risk of death by 23% compared with Tagrisso in an updated analysis of the phase 3 MARIPOSA trial in treatment-naïve, EGFR-mutated non-small cell lung cancer (NSCLC), according to results presented at the 2024 World Conference on Lung Cancer.
Patients who took Tagrisso lived a median 37.3 months in the trial, whereas the median overall survival period was not yet reached for the J&J combo.
The latest analysis was performed at the request of regulators after a median follow-up of 31.1 months. The assessment was not preplanned under the trial’s design, and its findings do not carry statistical significance. Nevertheless, with the upper bound of the confidence interval coming below 1 and a p-value of 0.019, the overall survival data were considered nominally significant, meaning the result would have met the statistical significance bar had it been part of the original statistical plan, Mark Wildgust, Ph.D., J&J’s vice president of oncology global medical affairs, explained in an interview with Fierce Pharma.
A statistically significant overall survival win against Tagrisso would be a huge deal for the Rybrevant-Lazcluze regimen, which just received an FDA go-ahead in first-line EGFR-mutated NSCLC a few days ago based on its superior ability to stall tumor progression or death versus Tagrisso in the MARIPOSA trial. Because Tagrisso is the well-established standard of care, many doctors are waiting for gold-standard overall survival data to decide whether to switch to the J&J combo, analysts have noted.
To hear Wildgust tell it, reaching statistical significance is only a matter of time, as Rybrevant and Lazcluze’s overall survival difference with Tagrisso has been widening. When results from MARIPOSA were first unveiled in fall 2023 at a median follow-up of 22 months, the combo’s death reduction improvement against Tagrisso was at 20%.
In the latest data set, 75% and 70% of patients on Rybrevant-Lazcluze and Tagrisso, respectively, were alive after two years. The corresponding numbers were 61% and 53% at three years.
Wildgust didn’t disclose the MARIPOSA trial’s statistical analysis plan, but he said the latest update was included in J&J’s application package to the FDA. With last month’s front-line nod, the two drugs’ U.S. labels show that the trial had accrued 55% of prespecified deaths for the final analysis.
J&J expects it’ll be able to report the final preplanned overall survival readout in the first half of 2025, Wildgust said.
For now, Wildgust argued that the widening of the overall survival trend and nominal significance provide the medical community “really good confidence” that the Rybrevant-Lazcluze combo is better than Tagrisso.
He also pointed to the cocktail’s ability to continuously control brain metastases. The updated MARIPOSA data showed that the three-year intracranial progression-free survival rate was 38% for the combo versus 18% for Tagrisso.
In addition, the percentage of patients with intracranial responses that lasted for three years was 51% for the combo versus none for Tagrisso.
Also at WCLC 2024, J&J shared data from the Lazcluze monotherapy arm of MARIPOSA. That arm was not meant for registrational purposes but was designed to establish Lazcluze's single-agent activity and hence its contribution to the combo.
Although the trial was not statistically powered to pit Lazcluze against Tagrisso, the two drugs, both third-generation EGFR tyrosine kinase inhibitors, showed very similar results. Median progression-free survival was 18.5 months for Lazcluze versus 16.1 months for Tagrisso. The risk of progression or death, the overall response rate and duration of response were all nearly identical between the two treatments, and so was the risk of death at interim analysis.
J&J in-licensed Lazcluze from South Korea’s Yuhan with the belief that it’s equally efficacious as Tagrisso with a tolerability profile that’s more suitable for combinations, Wildgust said. Tagrisso is known to cause QT prolongation, or an irregular heartbeat, a quality that's not present with Lazcluze. Besides, unlike Tagrisso, Lazcluze’s combination with other drugs doesn’t seem to increase the rate of interstitial lung disease, Wildgust noted.
Lazcluze’s unique safety profile could open a future in earlier-stage cancer, potentially mirroring Tagrisso’s additional FDA approval as a postsurgical adjuvant therapy. But Wildgust argued that there remains uncertainty about whether some early-stage patients may be overtreated.
“I think if we were to pursue something, I think we might think about something where we look at combinations,” the J&J exec said of a potential study in early-stage NSCLC. “Or, we might look at patient populations where we know there’s a significant unmet need.”