The SAFFRON trial found that continuing osimertinib and adding a MET-blocking pill called savolitinib (Orpathys) controlled these cancers longer than chemotherapy, reducing the risk of the cancer progressing or death by 45%.  Patients also lived longer. The combination lowered the risk of death by 32%.

The real-world message is that when osimertinib stops working, ask whether the cancer should be tested again. The answer may point to another treatment target.

“I think this continues to highlight the importance of repeat molecular analysis testing at progression,” said Dr. Angel Qin, a lung cancer specialist and clinical associate professor of internal medicine at the University of Michigan.

Why Can Tagrisso Stop Working?

EGFR is a protein that helps some lung cancer cells grow. When a tumor carries an EGFR mutation, the protein can remain switched on and send constant growth signals.

Osimertinib blocks that signal. It can control the cancer for a long time, but cancer cells may eventually find a different route around the drug. This is called treatment resistance.

One possible escape route involves MET, another protein that can send growth signals.

MET overexpression means cancer cells produce unusually high amounts of the MET protein. MET amplification means the cancer has extra copies of the MET gene. Either change may allow the cancer to grow even while osimertinib continues blocking EGFR.

Savolitinib is designed to block MET. The idea behind the SAFFRON combination is to continue blocking EGFR with osimertinib while also shutting down the new MET pathway.

What Did SAFFRON Find?

The phase 3 trial included 338 people with advanced EGFR-mutated non-small cell lung cancer. Their cancers had progressed during osimertinib and tested positive for high MET overexpression, MET amplification, or both.

Patients received either:

• Osimertinib plus savolitinib, both taken as pills
• Platinum chemotherapy plus pemetrexed, given through a vein

Median progression-free survival was 7.6 months with the targeted combination and 5.4 months with chemotherapy.

Progression-free survival, or PFS, is the time patients live without the cancer growing or spreading. “Median” means that half the patients had a longer result and half had a shorter one.

At one year, 36% of patients taking the two targeted drugs were alive without cancer progression, compared with 10% receiving chemotherapy.

Median overall survival was 17.8 months with osimertinib and savolitinib, compared with 12.9 months with chemotherapy. Overall survival, or OS, measures how long patients lived after entering the study, regardless of whether the cancer later grew.

At one year, 70% of patients receiving the targeted combination were alive, compared with 53% receiving chemotherapy.

Tumors shrank in 51% of patients taking the combination and 27% receiving chemotherapy.

What Does This Mean for Patients?

This is not a treatment for every patient whose cancer progresses on osimertinib. The tumor must have the specific MET changes used to select patients for the study.

That is why repeat testing matters. A tumor can change during treatment, so the original biopsy results may no longer tell the full story.

Testing may require a new tissue biopsy. Doctors can use that sample to look for excess MET protein and extra copies of the MET gene.

Dr. Qin said the combination offers “a potential new treatment option” for patients with EGFR-mutated lung cancer that progresses on osimertinib and develops MET overexpression or amplification.

Dr. Syed Jafri, a professor of oncology at UTHealth Houston, agreed that the findings provide another option for this group. The combination is especially appealing because both drugs are pills and are directed at the biologic reason the cancer became resistant, he said.

Savolitinib plus osimertinib is not yet approved for this use in the United States. An application has been submitted to the FDA.

What About Side Effects?

Serious side effects remain possible. Grade 3 or higher side effects occurred in 64% of patients taking the targeted combination and 63% receiving chemotherapy.

The most common problems with osimertinib and savolitinib were:

• Swelling, usually in the legs or ankles
• Anemia, meaning a low red blood cell count
• Diarrhea

Nearly half of patients developed swelling. Patients should tell their care team if they notice new leg swelling, rapid weight gain, shortness of breath or difficulty walking.

An all-pill treatment does not necessarily mean an easy treatment. Blood tests, heart monitoring, and regular visits may still be needed.

An Important Unanswered Question

Many patients today receive osimertinib together with chemotherapy as their first treatment. Others receive amivantamab and lazertinib.

SAFFRON does not clearly establish whether the same benefit will apply after those newer first-line combinations.

Dr. Qin said it remains uncertain whether patients previously treated with combination therapy would receive the same degree of benefit. Dr. Jafri raised the same concern about patients who already received chemotherapy with osimertinib.

Even with that limitation, the study offers grounded hope. Cancer progression may uncover a new weakness that can be treated. The key is looking for it.

Questions to Ask Your Doctor

• Should my cancer be tested again now that osimertinib has stopped working?
• Do I need a new tissue biopsy or can we reevaluate prior biopsies?
• Does my tumor have MET overexpression, MET amplification, or both?
• Would the SAFFRON combination apply to my previous treatment history?
• Is savolitinib available through FDA approval, a clinical trial, or another access program?
• How would the side effects compare with chemotherapy?

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