Adding a MET inhibitor to an EGFR tablet beat chemotherapy in a resistant lung cancer

When a lung cancer driven by an EGFR mutation stops responding to a targeted tablet such as aumolertinib, doctors want to know why — because the reason can point to the next move. One common escape route is a second genetic change, amplification of a gene called MET. A phase 3 trial published in the Journal of Clinical Oncology on 26 October tested a treatment aimed at that specific escape route [s1].

The idea behind the combination

EGFR-targeted tablets work by shutting down the EGFR signal that tells the cancer to grow. Some tumours respond by switching to a parallel signal: they amplify MET, a different growth receptor, and grow through it even while EGFR stays blocked [s1]. The logic of the trial is to block both routes at once — keep the EGFR tablet going and add a drug that shuts down MET.

Dalmelitinib is an inhibitor of MET; aumolertinib is a third-generation EGFR tablet. Rather than abandoning the EGFR drug and switching to chemotherapy, this combination keeps EGFR suppressed while closing the MET escape route. The trial asked whether that two-pronged targeted approach beats the usual fallback of chemotherapy.

The strategy only makes sense for tumours that have actually taken the MET route, and identifying them takes a test. MET amplification is one of several ways an EGFR cancer can become resistant, so this is not a treatment for everyone whose tablet has stopped working — it is a treatment matched to a particular, testable reason it stopped. That matching is the whole premise: block the specific bypass the tumour has chosen rather than reaching for a drug that ignores the mechanism.

How the trial was built

This was a randomised, open-label, phase 3 trial registered as NCT06110663 [s1][s2]. It enrolled people with EGFR-mutated, MET-amplified advanced NSCLC whose disease had progressed after treatment with an EGFR tyrosine kinase inhibitor — a biologically defined group, selected because their tumours carried the MET amplification the combination is designed to target [s1].

In all, 314 patients were randomly assigned: 156 to dalmelitinib plus aumolertinib and 158 to platinum-based chemotherapy, the standard option in this setting [s1]. The primary endpoint was progression-free survival [s1].

What it found

The combination delayed progression longer than chemotherapy. Median progression-free survival was 6.2 months with dalmelitinib plus aumolertinib against 4.4 months with chemotherapy, a hazard ratio for progression or death of 0.60 (95% CI 0.45–0.81; p<0.001) [s1].

Tumours also shrank more often. The objective response rate — the share of patients whose tumours shrank by a defined amount — was 59.6% with the combination versus 38.6% with chemotherapy [s1]. So more than half of those on the combination saw their tumours shrink, against roughly four in ten on chemotherapy [s1]. Overall survival data were still immature at this analysis [s1].

On tolerability, the two arms were close in overall severe-event rates but differed in character. Grade 3 or higher treatment-emergent adverse events occurred in 50.0% of the combination group and 51.0% of the chemotherapy group [s1]. The combination produced more liver-enzyme abnormalities, while chemotherapy produced more blood-count toxicities — a difference in the kind of side effect rather than the overall burden [s1].

What is, and is not, established

What the trial supports is that, in the specific group whose EGFR-mutated lung cancer has progressed through a targeted tablet by amplifying MET, adding the MET inhibitor dalmelitinib to aumolertinib delayed progression longer and shrank more tumours than standard chemotherapy, with a comparable overall rate of severe side effects [s1]. For a resistance mechanism that previously meant switching to chemotherapy, that is a targeted alternative matched to the cause of resistance.

The qualifications matter. Overall survival — whether people lived longer — was immature and not yet reported, so the central question of survival benefit remains open [s1]. The absolute gain in median progression-free survival, 1.8 months, is real but modest, and must be weighed against the drugs' particular side effects, including the liver-enzyme abnormalities seen more often with the combination [s1]. The result applies only to patients whose tumours carry MET amplification as the resistance mechanism, a subset that has to be identified by testing [s1]. And the trial was open-label [s1].

Red flags: anyone on targeted lung cancer drugs who notices yellowing of the skin or eyes, dark urine, persistent nausea, or new breathlessness should contact their oncology team, as these can signal liver or lung trouble. This article describes research and is not medical advice. Choices after targeted therapy fails are for patients and their treating oncologists.