A Potential Challenger For AstraZeneca's Blockbuster Lung Cancer Drug?

In the high-stakes world of oncology, AstraZeneca's Tagrisso has long been the gold standard for treating advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC). But a new contender is emerging, and it's shaking up the market. Johnson & Johnson's combination therapy of Rybrevant and Leclaza has shown promising results in head-to-head trials, raising the question: could this duo dethrone Tagrisso?

The MARIPOSA study, a phase 3 trial, has provided some intriguing data. The combination of Rybrevant (amivantamab) and Leclaza (lazertinib) reduced the risk of progression or death by 30% compared to Tagrisso. This translated to an improvement in the median time patients lived without disease progression by 7.1 months, reaching 23.7 months. While these results are impressive, they come with a caveat: Rybrevant needs to be given as an infusion every two weeks after a lead-in period, while Tagrisso is administered orally. This difference in dosing regimen could be a significant barrier to adoption.

But the story doesn't end there. There was also a trend towards improved overall survival with the J&J combo, reducing the risk of death by 20% over Tagrisso. Although this number hasn’t reached statistical significance, J&J’s Wildgust said that based on the current trend, J&J would anticipate “the potential to see a significant difference” in overall survival in the future. A graphic presented at ESMO showed that the Rybrevant-lazertinib combo began to lead AZ's drug on patient survival starting at about 12 months. The two survival curves continued to stay separated after that time point.

However, the implications for market share are not straightforward. While the PFS data is compelling, Tagrisso is well-established and familiar to oncologists, which could make it difficult for the J&J combo to gain significant market share. Additionally, the potential for increased side effects with the combination therapy could be a concern for both oncologists and patients. While the safety profile of the two-drug therapy has not raised concerns so far, the possibility of additional side effects could make Tagrisso, which is well-established and familiar to oncologists, a more attractive option.

Moreover, AZ recently reported data from the FLAURA2 study showing a benefit when chemotherapy was added to Tagrisso in the first-line setting, giving AZ an opportunity to push back if Rybrevant/Leclaza moves into the first-line setting. There’s also the ever-present debate about the order in which EGFR-targeting drugs should be administered, given that resistance to them invariably develops and they stop working. That was a debate when Tagrisso moved into earlier lines of therapy, and may well recur with Rybrevant/Leclaza, with some likely arguing the most effective regimen should be used first, while others will say it should be reserved for patients who stop responding to first-line therapy.

In conclusion, while J&J's combination therapy of Rybrevant and Leclaza shows promise, it faces significant challenges in gaining market acceptance. The dosing regimen, potential side effects, and the established position of Tagrisso are all factors that could influence its adoption. However, if the trend towards improved overall survival translates into a significant difference, it could tip the scales in favor of the dual regimen, despite the additional dosing burden and potentially increased side effects. Only time will tell if this new contender can dethrone the reigning champion.