Facing increased EGFR competition from a new drug combination by Johnson & Johnson, AstraZeneca has come up with its own solution to prolong the lives of patients who take the company’s decade-old medicine Tagrisso.
The method involves pairing Tagrisso with chemotherapy. The combo significantly reduced the risk of death by 23% compared with Tagrisso alone in patients with previously untreated EGFR-mutated advanced non-small cell lung cancer, an updated analysis of the phase 3 Flaura2 trial has found.
Patients who received Tagrisso and chemo lived a median 47.5 months, versus 37.6 months for the Tagrisso monotherapy group, according to data presented at the 2025 World Conference on Lung Cancer in Barcelona, Spain.
The latest data drop helps re-level the playing field for Tagrisso after J&J’s combination of Rybrevant and Lazcluze recently became the first regimen to demonstrate an overall survival benefit against Tagrisso in first-line EGFR-mutated NSCLC.
In the phase 3 Mariposa study, the Rybrevant-Lazcluze pair led to a statistically significant 25% reduction in the risk of death versus Tagrisso, extending patients’ projected median survival time by at least one year based on the investigators’ estimate.
The J&J regimen’s data appear to be better in terms of both magnitude of death risk reduction and median survival time improvement. However, the difference is narrow, especially considering the intrinsic flaws of cross-trial comparison.
J&J has argued that patients do not want to use toxic chemotherapy in a first-line setting and that using it in the first line can complicate subsequent treatment options. Pemetrexed and platinum-based chemo were Tagrisso’s combo partners for Flaura2.
“When patients express not wanting chemotherapy to be part of their treatment, what we understand that they’re really talking about is not wanting to go into an infusion center [...] and talking about not wanting to have a toxicity profile that they associate with chemotherapy,” AZ’s oncology business chief, David Fredrickson, said in an interview with Fierce Pharma.
In Flaura2, patients had a long chemo-free period, as the median exposure time to pemetrexed was just 8.3 months versus 30.5 months for Tagrisso. Importantly, the reason for half of pemetrexed discontinuations was side effects. Pemetrexed was supposed to be used together with Tagrisso in the maintenance phase.
By comparison, patients in the Tagrisso monotherapy arm stayed on the EGFR inhibitor for a median 21.2 months.
To Fredrickson, the combo’s ability to extend patients’ exposure to Tagrisso makes a compelling case to doctors.
“Those data will be particularly compelling for physicians to be now thinking about who can tolerate the addition of chemo, who has the ability to take a little bit less convenience because they’re able to come into the office,” Fredrickson said. “But if you’ve got patients that fit that criteria, I think that Flaura2 becomes a very attractive opportunity.”
Among patients who discontinued Tagrisso because of disease progression, 69% in Flaura2’s experimental arm received subsequent treatment. Within that subgroup, 44% patients were re-challenged with platinum-based chemo, whereas 30% received other types of chemo. In the Tagrisso monotherapy arm, the rates were 77%, 72% and 3%, respectively.
Again, the proportion of patients who were able to receive a subsequent treatment following disease progression was not materially different for J&J’s Rybrevant-Lazcluze combo, at 74% in Mariposa.
Whatever changes the use of chemo in the first line may introduce to subsequent treatment plans, investigators noted that the Flaura2 regimen’s overall survival benefit was clear against standard Tagrisso monotherapy followed by chemo.
Besides, although a chemo-free option, Rybrevant has its own tolerability issues. J&J is working on improving the drug’s profile by developing a subcutaneous version of the intravenous infusion and by introducing prophylactic regimens to reduce certain dermatological and cardiovascular adverse reactions. Even though the under-the-skin formulation significantly reduces the time of administration, patients still need to go to a healthcare facility to get the drug.
To further complicate physicians’ treatment decision-making process in the real world, Rybrevant plus chemo is approved as a second-line option for patients who have progressed on Tagrisso or other EGFR inhibitors.
So far, there are no direct data on whether using Rybrevant upfront is a better idea than saving it for the second line. Mariposa didn’t allow crossover in the control arm, and the majority—if not all—of the control arm patients in Flaura2 didn’t get Rybrevant as their second-line treatment.
Rybrevant and Lazcluze have been gaining traction since their first-line approval about a year ago. In the second quarter, the pair delivered $179 million in global sales for 26.5% sequential growth.
During an investor call in July before AZ announced Flaura2’s positive overall survival readout, J&J’s chair of innovative medicine, Jennifer Taubert, noted that Rybrevant-Lazcluze was the top regimen that doctors said they intend to prescribe for front-line patients.
But AZ is not seeing many signs of repeated use of the competitor regimen, according to Fredrickson. The AZ exec also suggested that academic centers tend to be more open to newer regimens with unfamiliar side effect profiles, whereas in the community setting, where the lion’s share of lung cancer patients are treated, doctors are more comfortable with the established profiles of Tagrisso and chemotherapy.
Even before the positive overall survival readout from Flaura2, the Tagrisso-chemo regimen has seen the fastest growth in the combo space, Fredrickson said. “I have every reason to believe that that momentum should only strengthen with the presentation of these data.”