J&J's Lung Cancer Combo Outperforms AstraZeneca's Tagrisso, Signaling Potential Shift in EGFR-Mutated NSCLC Treatment

Johnson & Johnson's combination therapy of Rybrevant (amivantamab) and Lazcluze (lazertinib) has demonstrated superior efficacy over AstraZeneca's Tagrisso (osimertinib) in patients with EGFR-mutated non-small cell lung cancer (NSCLC), potentially heralding a new standard of care in first-line treatment.

Significant Survival Benefit

In the Phase III MARIPOSA trial, the Rybrevant-Lazcluze combination significantly reduced the risk of death by 25% compared to Tagrisso in patients with newly diagnosed advanced EGFR-mutated NSCLC. At a median follow-up of 37.8 months, median overall survival (OS) had not yet been reached for patients treated with the J&J combo, while median OS for Tagrisso-treated patients was 36.7 months.

J&J's survival projections suggest that the Rybrevant-Lazcluze regimen could extend median OS by at least 12 months over Tagrisso. Mark Wildgust, vice president of oncology global medical affairs for J&J Innovative Medicine, stated, "We now see very clearly that using first-line Rybrevant-Lazcluze helps patients live longer. It's that simple—statistically significant, clinically meaningful improvement in survival."

Mechanism of Action and Secondary Endpoints

The J&J combination's efficacy is attributed to a three-pronged biological approach. Lazcluze, a third-generation EGFR inhibitor, acts similarly to Tagrisso. Rybrevant, an EGFRxMET bispecific antibody, provides extracellular targeting of EGFR and MET, an EGFR escape pathway. Additionally, Rybrevant's enhanced FC function attracts immune cells to kill cancer cells, which is believed to drive the survival benefit.

The MARIPOSA trial also met multiple secondary endpoints, demonstrating superiority over Tagrisso in intracranial progression-free survival, intracranial duration of response, and intracranial overall response rate. The J&J regimen also significantly delayed symptom progression.

Safety Profile and Future Developments

While the Rybrevant-Lazcluze combination showed improved efficacy, it also demonstrated higher rates of certain adverse events compared to Tagrisso. These included higher rates of paronychia, rash, and venous thromboembolism. Infusion-related side effects were also observed in 65% of patients receiving the J&J combo.

To address these tolerability issues, J&J is exploring ways to improve the regimen's safety profile. The phase 2 Cocoon trial is evaluating a prophylactic regimen to reduce dermatologic adverse reactions, while the SKIPPirr trial showed that pretreatment with dexamethasone could significantly reduce infusion-related reactions.

J&J is also developing a subcutaneous version of Rybrevant to improve patient experience and better challenge Tagrisso's convenience as an oral medication. However, the FDA recently rejected the subcutaneous formulation due to manufacturing issues. J&J aims to address these concerns and bring the subcutaneous version to market this year.

As the pharmaceutical landscape evolves, J&J's Rybrevant-Lazcluze combination appears poised to potentially replace Tagrisso as the new standard of care in first-line EGFR-mutated NSCLC treatment, pending further real-world data and regulatory decisions.