Johnson & Johnson has produced the most convincing data to date that its combination of Rybrevant and Lazcluze could replace AstraZeneca’s Tagrisso as the new standard of care in first-line EGFR-mutated non-small cell lung cancer—proof it could extend patients’ lives.
The Rybrevant-Lazcluze combo significantly reduced the risk of death by 25% versus Tagrisso in patients with newly diagnosed advanced EGFR-mutated NSCLC, according to data from the phase 3 Mariposa trial presented at the European Lung Cancer Congress (ELCC) 2025.
While the median overall survival time was not yet reached for the combo, investigators expect that the J&J regimen could offer at least an extra year of life versus Tagrisso, on which patients have logged a median 36.7 months of survival.
With the latest overall survival win in hand, J&J believes it holds the key to ending Tagrisso’s long reign in first-line EGFR lung cancer.
Previously, the FDA greenlighted Rybrevant and Lazcluze last year based on the regimen’s ability to delay tumor progression or death compared with Tagrisso. But, thanks to Tagrisso’s convenience as a pill and its well-established safety and efficacy profile, some physicians remained on the fence waiting for gold-standard overall survival data before deciding whether to switch patients.
“We now see very clearly that using first-line Rybrevant-Lazcluze helps patients live longer,” Mark Wildgust, vice president of oncology global medical affairs for J&J Innovative Medicine, said in an interview with Fierce Pharma. “It’s that simple—statistically significant, clinically meaningful improvement in survival.”
The readout “marks a moment, a change in how we think about treating patients with EGFR-mutated lung cancer,” Wildgust added.
J&J has a three-pronged biological explanation for the better efficacy. As a third-generation EGFR inhibitor, Yuhan-partnered Lazcluze is basically an alternative to Tagrisso. Rybrevant, an EGFRxMET bispecific antibody, provides extracellular targeting of EGFR—plus MET, an EGFR escape pathway, Wildgust explained. Besides, in a key component that J&J believes drives the survival benefit, the silent FC receptor on the antibody attracts immune cells such as macrophages and NK cells to kill the cancer cells.
Rybrevant and Lazcluze’s survival benefit started to show around 10 months after treatment, and its advantage over Tagrisso kept widening over time, according to a graphic visualizing patients who were surviving throughout the trial. At the three-year mark, about 60% of patients who got the combo were alive, versus 51% of those in the Tagrisso arm. By 42 months, the survival rates were 56% and 44%, respectively.
The cocktail showed a generally consistent survival benefit across predefined subgroups, including in smokers and non-smokers, those with or without brain metastases, and EGFR mutations in exon 19 and exon 21.
There was a short period at the beginning of the program during which more deaths emerged in the combo group versus Tagrisso. But Wildgust called those “noise,” because the small number of total deaths means that only a few events could make a difference on which survival curve came out on top.
The trial did record higher rates of early onset adverse events from Rybrevant and Lazcluze. But Wildgust stressed that those side effects did not cause excess death.
Overall, rates of several adverse events related to EGFR or MET inhibition were notably higher in the Rybrevant-Lazcluze arm. Grade 3 or above paronychia—an inflammation of the skin around the nail—and rash happened in 12% and 17% of patients in the combo arm, respectively. In the Tagrisso arm, both rates were below 1%.
Venous thromboembolism, a blood clot condition, occurred in 40% of patients who took the new therapy compared with 11% in the control group.
Thanks to the addition of Rybrevant, 65% of patients in the experimental arm experienced infusion-related side effects, including 6% at grade 3 or above. No Tagrisso takers experienced that.
These tolerability issues were one main reason doctors were initially not so persuaded by the combo’s better progression-free survival data alone. The latest overall survival showing could help dispel their doubts.
Compared with the Mariposa trial, J&J also believes it could further improve on the regimen’s safety profile in the real world. At ELCC, investigators will share an analysis of the phase 2 Cocoon trial, which is evaluating a prophylactic regimen to reduce the incidence of dermatologic adverse reactions with first-line use of Rybrevant and Lazcluze. It showed that the preventive regimen could roughly halve the rate of grade 2 or above dermatologic adverse events from 76.5% to 38.6%.
Another phase 2 trial called SKIPPirr recently showed that pretreating patients with the steroid dexamethasone led to a roughly threefold reduction in Rybrevant infusion-related reactions. There are also data suggesting that prophylactic anticoagulation treatment could substantially reduce the chance of patients developing deep vein blood clots.
By reducing these adverse effects, patients could stay on treatment at the primal dose longer, so they can really benefit from the combo’s survival benefit, Wildgust argued.
“With all of these implemented, I quite honestly am very confident that these results are going to be better in the real world,” Biljana Naumovic, J&J’s president of the U.S. solid tumor franchise, said about the Mariposa data in an interview with Fierce Pharma.
J&J is also trying to improve patients’ treatment experience—and better challenge Tagrisso—by introducing a subcutaneous version of infused Rybrevant. Results from the Paloma-3 trial in previously treated EGFR-mutated NSCLC has shown that the under-the-skin formulation may come with better efficacy on top of an ability to reduce Rybrevant administration time from five hours to a median of five minutes.
But J&J’s plan recently hit a setback as the FDA in December rejected subcutaneous Rybrevant because of manufacturing problems identified during a preapproval inspection of a J&J plant.
The company is currently awaiting FDA feedback and is confident that it can address all questions that the agency has, Naumovic said. J&J aims to bring the subcutaneous formulation to the market this year, she said.
Single-agent Tagrisso isn’t the only competition standing in J&J’s way. AZ a year ago bagged an FDA approval for Tagrisso’s combination with chemotherapy in first-line EGFR lung cancer based on a progression-free survival improvement over Tagrisso alone.
At last year’s ELCC, investigators provided a second interim analysis of overall survival from the phase 3 Flaura2 trial. It showed several interesting similarities to the current Mariposa readout but some important differences as well.
After about 30 months’ follow-up of Flaura2, Tagrisso-chemo offered the same 25% death risk reduction as Rybrevant-Lazcluze did after a median 37.8 months of follow-up in Mariposa. However, unlike the J&J regimen, the benefit conferred by Tagrisso-chemo didn’t reach the prespecified statistical significance bar.
At that time, the median overall survival time in Flaura2 was also not reached for Tagrisso-chemo, while Tagrisso monotherapy registered 36.7 months—again, the same as what the AZ med showed in Mariposa.
Like Rybrevant-Lazcluze, Tagrisso-chemo didn’t immediately show a survival benefit against Tagrisso right out of the gate, either. But it took the chemo-containing regimen more than 15 months to finally show a favorable trend in survival. What’s more, while Rybrevant-Lazcluze’s survival benefit continued to expand over time, the difference between Tagrisso-chemo and Tagrisso appeared to be narrowing after three years.
The Flaura2 analysis was conducted as 41% of patients had passed away, and the final overall survival analysis is planned at about 60% data maturity.
After the Flaura2 readout, AZ itself has acknowledged that Tagrisso will remain the main first-line therapy and estimated that only a small number of patients with large tumor burdens would need to add chemotherapy to quickly control that tumor growth at the cost of additional side effects.But J&J figures that Rybrevant-Lazcluze should take Tagrisso’s place and become the standard front-line treatment for most EGFR-mutated NSCLC patients.
“When you have the only regimen that has the overall survival benefit over the standard of care, it should be a realistic assumption that this becomes the standard of care,” Naumovic said, adding that only a minority of patients would benefit from not intensifying therapy.
The J&J exec declined to comment on what market share the company thinks it can achieve but said, “my desire is really for us to reach every single person who needs best therapy in the front-line setting.”
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