Why keep a drug after resistance emerges?

A cancer grows again while the patient is still on treatment. Sometimes adding another drug is a better option than replacing the current regimen outright.

SAFFRON enrolled patients with advanced EGFR-mutated lung cancer that had progressed after treatment with Tagrisso (osimertinib) and showed high MET expression or gene amplification. The trial tested whether to keep Tagrisso in the regimen and add Orpathys (savolitinib), a MET inhibitor. Trial overview ↗

The reason for combining the drugs lies in how resistance develops.

Even when Tagrisso blocks growth signals from EGFR, a tumor can keep growing by using MET to activate a separate route. In that case, inhibiting MET alone and lifting the block on EGFR could let the original pathway work again. The idea is to suppress both at once.

A small earlier randomized study found greater antitumor activity with savolitinib plus osimertinib than with savolitinib alone. The trial stopped early after enrolling 30 patients, so it was too small to establish the regimen on its own. Phase 2 trial ↗

SAFFRON compared the combination with platinum and pemetrexed chemotherapy in 338 patients. Median progression-free survival was 7.6 versus 5.4 months, and median overall survival was 17.8 versus 12.9 months. The results showed a benefit for a regimen that retained the existing drug in a group selected for a particular resistance mechanism. NEJM trial report ↗

Taking two drugs by mouth does not necessarily make treatment easier. Grade 3 or higher adverse events occurred in 64% of the combination group and 63% of the chemotherapy group. The study compared this particular chemotherapy regimen, leaving comparisons with other subsequent treatments open. Results announcement ↗

From a business perspective, savolitinib could complement Tagrisso by expanding the group of patients who can continue to use it.

A new drug can have value by addressing a reason an existing drug stopped working and making the combination beneficial again. The SAFFRON results provide clinical evidence for that approach.

The addressable group depends on what kind of resistance emerges during treatment. It is a subset of all patients with EGFR-mutated lung cancer, which helps explain why the drug combination and testing the tumor after progression go together.