Two-pill combination helped lung cancer patients outlive chemo

Adding a second tablet, savolitinib, to the lung cancer drug osimertinib helped people live longer than switching to chemotherapy, in the phase 3 SAFFRON trial. Everyone in the study had EGFR-mutated non-small cell lung cancer that had started growing again on osimertinib (sold as Tagrisso), and their tumours showed high levels of a protein called MET. Median overall survival was 17.8 months with the two pills, against 12.9 months with platinum and pemetrexed chemotherapy.

Shun Lu of Shanghai Chest Hospital presented the results on 25 October 2026 in the Presidential Symposium at the ESMO Congress in Madrid. The paper appeared the same day in the New England Journal of Medicine. AstraZeneca, which sells both drugs and funded the trial, has already asked the US Food and Drug Administration to approve the combination.

The trial ran in the same session as Roche's divarasib study in KRAS G12C lung cancer. Both point the same way. When lung cancer is driven by a known genetic change, a matched tablet can now beat chemotherapy even after the first targeted drug has failed.

Why does osimertinib stop working?

Osimertinib blocks EGFR, a growth signal that is stuck in the "on" position in some lung cancers. It is the usual first treatment for these tumours and it often works for years. Cancers adapt, though. One common escape route is to boost a second signalling protein, MET, so the cell can keep growing even with EGFR switched off.

HUTCHMED, which discovered savolitinib and develops it with AstraZeneca, says about one in three tumours develop high levels of MET overexpression or amplification after a third-generation EGFR drug such as osimertinib. That figure comes from the company's statement and the phase 2 SAVANNAH study. Savolitinib is a MET blocker. The idea behind SAFFRON was simple: keep osimertinib going to hold EGFR down, and add savolitinib to shut the MET escape route.

Until now, people in this position have usually moved on to chemotherapy, sometimes with an added antibody. That means infusions in hospital and, for many, the side effects that come with platinum drugs.

Who took part in SAFFRON?

SAFFRON was an open-label trial, so patients and doctors knew which treatment each person was getting. Our guide to open-label and blinded trials explains what that means for reading the results. The main outcome was checked by radiologists who did not know the treatment, which reduces the risk of bias in judging when a tumour grew.

According to the NEJM abstract, 1,746 people were screened and 338 were randomly assigned. Of those, 171 got osimertinib 80 mg once a day plus savolitinib 300 mg twice a day, and 167 got four cycles of pemetrexed with carboplatin or cisplatin, followed by pemetrexed maintenance. AstraZeneca says the trial ran at 230 centres in 29 countries across North America, Europe, South America and Asia.

To get in, a person needed a fresh biopsy taken after their cancer progressed on osimertinib, with the MET result confirmed by a central laboratory. The bar was high on purpose. MET overexpression meant strong (3+) staining in at least 90% of tumour cells. MET amplification meant at least 10 copies of the MET gene on a FISH test.

OncLive's report of the presentation gives the make-up of the group. The median age was 64. Around two thirds were women, about two thirds were Asian, and 68% had never smoked. About 31% had cancer that had spread to the brain when they joined.

What did the trial find?

The two-pill combination did better on every efficacy measure reported. These figures come from the NEJM paper, AstraZeneca's statement and the ESMO presentation as reported by OncLive, at a data cut-off of 6 July 2026.

The hazard ratio for progression or death was 0.55 (95% CI 0.42 to 0.72), which AstraZeneca describes as a 45% lower risk. For death, the hazard ratio was 0.68 (95% CI 0.50 to 0.91; p=0.010), a 32% lower risk. The NEJM abstract labels the survival result a final analysis, though OncLive reports that only 53% of the expected deaths had occurred, so longer follow-up could shift the numbers a little.

The benefit held in the subgroups. People whose tumours overexpressed MET had a median of 8.5 months without progression on the combination against 5.6 on chemotherapy (hazard ratio 0.51). In people with brain metastases the hazard ratio was 0.50. The MET-amplified group also did better, at 7.6 against 4.2 months, but that group was not formally tested for statistical significance.

What do those numbers mean in plain terms?

Medians and hazard ratios are hard to picture, so here is our own arithmetic using the 12-month figures. Our guide to absolute and relative risk goes through the method.

Imagine 100 people starting each treatment. After a year, about 70 of those on the two pills would still be alive, against about 53 on chemotherapy. That is 17 more people alive per 100, or roughly one extra survivor at one year for every six people treated (100 divided by 17 is 5.9).

The gap is wider for keeping the cancer in check. At 12 months, 36 in 100 on the combination had no sign of growth, against 10 in 100 on chemotherapy. That is 26 more per 100, or about one for every four people treated.

The screening numbers tell a different story. Only 338 of 1,746 people screened, about 19%, made it into the trial. Not every screening failure was about MET, and the papers we read do not break the reasons down. Still, the result applies to a fairly narrow group, and finding that group takes a new biopsy and two specialist lab tests.

What were the side effects?

Side effects were common in both groups, which is usual for advanced lung cancer treatment. Grade 3 or worse adverse events of any cause hit 64% of people on the combination and 63% on chemotherapy. When OncLive counted only events doctors judged to be caused by treatment, the figures were 40% against 52%, in the combination's favour.

Other measures went the other way. Serious adverse events were reported in 41% of people on the two pills and 28% on chemotherapy, and 14% against 8% stopped at least one drug because of side effects. Some of this gap may reflect time on treatment: the median exposure was 8.5 months on the combination and 3.5 months on chemotherapy, so there was more time for problems to show up.

Twelve people (7%) on the combination died from an adverse event, against none on chemotherapy. OncLive reports that 9 of those 12 had documented cancer progression before death or had progression listed as a cause. One death, from pneumonitis (lung inflammation), was judged to be caused by treatment. Pneumonitis is a known risk with osimertinib, and the US label for Tagrisso carries a warning about it.

The most frequent side effects on the combination were:

• swelling in the legs and ankles (peripheral oedema) in 49%, severe in 8%
• anaemia in 26%
• diarrhoea in 26%
• nausea in 25%

On chemotherapy, anaemia (54%) and nausea (37%) led the list. The safety analysis included 170 people on the combination and 145 on chemotherapy, out of 167 assigned to chemotherapy. The reports we read do not explain that gap.

How does this fit with other treatments after osimertinib?

There are already approved options in the US for people whose EGFR lung cancer grows on osimertinib, but none picks out MET. In September 2024 the FDA approved amivantamab with carboplatin and pemetrexed for this group, based on the MARIPOSA-2 trial, where median time without progression was 6.3 months against 4.2 on chemotherapy alone. In June 2025 the FDA gave accelerated approval to datopotamab deruxtecan (Datroway) for people who had already had EGFR-targeted treatment and platinum chemotherapy. Amivantamab, in a different form, was also approved this month for head and neck cancer.

Two more trials at the same ESMO congress tested antibody-drug conjugates in EGFR lung cancer after targeted therapy. In HERON-Lung01, run at 62 sites in China, ruzaltatug rezetecan gave a median of 8.3 months without progression against 5.4 on chemotherapy, reported by The ASCO Post. In PANKU-Lung01, izalontamab brengitecan gave 11.1 against 5.7 months, with severe treatment-related side effects in 79% of patients, per The ASCO Post. Neither trial selected patients by MET status. Comparing medians across different trials is unreliable, because the patients and the chemotherapy arms differ.

What SAFFRON offers is an all-oral option chosen by a biomarker. Institut Curie in Paris, whose lung cancer specialist Nicolas Girard is the paper's second author, said in a statement that the trial shows the value of blocking EGFR and MET together to get around resistance without going straight to chemotherapy.

When could it be available?

AstraZeneca submitted a new drug application to the FDA in September 2026, based on SAFFRON. HUTCHMED says filings in Europe and Japan are "progressing as planned". The combination is already approved in China for MET-amplified cancer after an EGFR drug, based on a separate trial called SACHI, and Switzerland has granted a temporary authorisation based on the phase 2 SAVANNAH results.

We found no announcement of a UK application to the MHRA as of 11 November 2026, and NICE has not appraised savolitinib. Our explainer on how new medicines get approved by the FDA, MHRA and NICE covers the steps and typical timelines.

Lu told the congress the combination establishes "a new global standard of care" for this group, according to OncLive. In AstraZeneca's statement he added that the results reinforce "the critical need for MET testing to guide patient care." That second point is the practical one for patients today.

Questions to ask if your cancer grows on osimertinib

If you have EGFR-mutated lung cancer that has progressed on osimertinib, these are reasonable things to raise with your oncologist:

1. Will I have a new biopsy, and will it be tested for MET overexpression and MET amplification?
2. Does my tumour meet the SAFFRON thresholds (3+ staining in at least 90% of cells, or at least 10 gene copies)?
3. Is savolitinib available here through a trial or an access scheme?
4. How do amivantamab with chemotherapy, Datroway and standard chemotherapy compare for someone like me?
5. If I have brain metastases, how does that change the choice?

SAFFRON is listed on ClinicalTrials.gov as NCT05261399. Other trials testing MET and EGFR combinations may be recruiting, and our guide to finding and joining a clinical trial shows how to search for them.

This article reports trial results for general information. It is not medical advice, and treatment decisions should be made with your own cancer team.