Although osimertinib has transformed outcomes for EGFR-mutated lung cancer, most tumours eventually develop resistance. One of the most common escape mechanisms is activation of the MET pathway, allowing cancer cells to bypass EGFR inhibition and continue growing.
The PHARAOH-A trial will evaluate whether combining savolitinib, a MET inhibitor, with osimertinib can overcome MET-driven resistance in patients whose cancer has progressed after modern first-line treatment. Recruitment is expected to commence in Australia and Taiwan in the second quarter of 2027.
Why does MET Become Important?
EGFR-targeted therapies have transformed the treatment of advanced EGFR-mutated NSCLC. However, under the selective pressure of treatment, cancer cells can acquire new mechanisms that allow them to continue growing.
One of the best recognised is MET amplification or MET protein overexpression. Rather than relying solely on the EGFR pathway, tumour cells activate MET signalling as an alternative growth pathway, allowing them to bypass EGFR inhibition and continue proliferating despite treatment.
This has led researchers to investigate whether blocking both EGFR and MET simultaneously can restore treatment sensitivity.
What are Savolitinib and Osimertinib?
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor and remains a cornerstone of treatment for EGFR-mutated NSCLC.
Savolitinib is a selective MET tyrosine kinase inhibitor designed to block MET signalling.
Together, the drugs target both sides of the resistance pathway:
- Osimertinib continues blocking the original EGFR mutation
- Savolitinib blocks the MET pathway that has emerged as the tumour’s escape route
By shutting down both pathways simultaneously, researchers hope to restore tumour control.
Clinical evidence supporting dual EGFR and MET inhibition
Several clinical studies have already demonstrated encouraging activity with combined EGFR and MET inhibition in patients with MET-positive disease following osimertinib.
These studies demonstrated that MET-driven resistance is clinically actionable and established dual EGFR-MET inhibition as a promising treatment strategy.
Why is PHARAOH-A Needed?
The challenge is that the treatment landscape has changed. Most previous studies enrolled patients treated during the era when osimertinib alone was the standard first-line therapy.
Today, many patients receive more intensive first-line treatment, including:
- osimertinib plus platinum-pemetrexed chemotherapy (FLAURA2)
- amivantamab plus lazertinib (MARIPOSA).
In addition, the COMPEL study showed that continuing osimertinib with chemotherapy after disease progression improved both progression-free and overall survival compared with chemotherapy alone. These advances mean that patients entering later lines of treatment are different from those enrolled in earlier MET inhibitor studies.
Importantly, although MET appears to remain one of the major resistance pathways after these newer treatment approaches, it is not yet known whether dual EGFR-MET inhibition provides the same benefit in this contemporary setting. That is the clinical question PHARAOH-A has been designed to answer.
How PHARAOH-A builds on the SAFFRON Trial
Topline results from the global phase III SAFFRON trial showed that savolitinib plus osimertinib significantly improved progression-free and overall survival compared with platinum-doublet chemotherapy in patients with EGFR-mutated NSCLC with high MET overexpression or amplification following progression on osimertinib. Full efficacy, subgroup and safety results have not yet been reported.
SAFFRON provides phase III validation of combined EGFR and MET inhibition before chemotherapy. PHARAOH-A addresses a different and increasingly important population: patients whose cancer has progressed after both EGFR-directed therapy and systemic chemotherapy (ie the regimen from the practice-changing FLAURA2 clinical trial). It will examine whether this targeted combination remains effective after these additional treatments and associated resistance pressures.
Further reading
- de Marinis F, Kim TM, Bonanno L, Cheng S, Kim SW, Tiseo M, et al. (2025) Savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer with MET overexpression and/or amplification following disease progression on osimertinib: primary results from the phase II SAVANNAH study. Annal Oncol. 36:920-933. doi: 10.1016/j.jtho.2025.05.017.
- Oxnard GR, Yang JCH, Yu H, Kim SW, Saka H, Horn L, et al. (2020) TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann Oncol. 31:507-516. doi: 10.1016/j.annonc.2020.01.013.
- Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389:1935–1948. doi: 10.1056/NEJMoa2306434
- Wu YL, Guarneri V, Voon PJ, Lim BK, Yang JJ, Wislez M, et al. (2024) Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial. Lancet Oncol. 25:989-1002. doi: 10.1016/S1470-2045(24)00270-5.
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