Dr Rotow on Osimertinib Plus Gefitinib for First-Line EGFR-Mutant NSCLC

I think this suggests what we've increasingly seen: that C797S, while a known mechanism of resistance, is still a minority mechanism, and that preempting it alone might not be enough to drive extended PFS. While this was an interesting strategy, it is probably not an upfront strategy, but it does add to our body of knowledge about the safety of the combination.

In the final segment of an interview with OncLive at the IASLC 2026 World Conference on Lung Cancer (WCLC) in Seoul, Julia K. Rotow, MD, clinical director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and assistant professor of medicine, Harvard Medical School, discussed mature results from an investigator-initiated study of first-line osimertinib (Tagrisso) plus gefitinib (Iressa) in EGFR-mutant non–small cell lung cancer (NSCLC).

At WCLC 2026, Rotow presented updated results from a Dana-Farber–led phase 1/2 study of concurrent osimertinib and gefitinib in previously untreated EGFR-mutant NSCLC. The premise was that dual inhibition, with osimertinib covering T790M and gefitinib covering C797S, could preempt sequential acquired EGFR resistance and avoid triple-mutant disease that resists all EGFR inhibitors.

The primary aims were safety and feasibility. Nearly half of enrolled patients had CNS metastases and nearly half had TP53 co-mutations.

The strategy was safe and feasible, Rotow said. Patients stayed on treatment for extended periods, a median of 13 cycles of gefitinib and 23 cycles of osimertinib, despite overlapping toxicity that increased cutaneous adverse effects relative to monotherapy.

It also worked as designed: no T790M or C797S emerged, and no known second-site EGFR resistance mutation appeared. A small amount of EGFR amplification was observed, always alongside other candidate drivers such as MET, BRAF, or KRAS, and one EGFR variant of unknown significance emerged that is not a known resistance mechanism.

Despite that, progression-free survival (PFS) was not extended relative to historical controls. Rotow cautioned that the comparison is to historical data rather than a randomized arm, and that the population was difficult, with historical PFS in patients with CNS disease running closer to 13-14 months. She characterized the study as proof-of-concept rather than a change in frontline practice.

Where the combination does fit, Rotow said, is acquired C797S after an osimertinib-based regimen, which remains a clinical challenge. In practice, she keeps osimertinib going and adds gefitinib. Although the safety dataset for that approach had been limited, this study gives clinicians better confidence in what to expect.

Other series have shown clinically meaningful, if not durable, activity in that setting. Next-generation EGFR inhibitors designed to cover C797S more cleanly, with less toxicity, may eventually offer a single-agent alternative, Rotow said, but for now the combination is useful in select patients with acquired resistance.