1L osimertinib for EGFRm NSCLC: Who are the long-term responders?

A retrospective study by researchers from the Chinese University of Hong Kong has found that patients with EGFR mutation–positive (EGFRm) non-small-cell lung cancer (NSCLC) who had a good performance status (PS) and no brain, liver or bone metastases at diagnosis had lower odds of progression or death at 2 years with osimertinib monotherapy. Furthermore, patients with oligoprogressive disease (OPD) had better outcomes than those with systemic progressive disease (SPD), and local ablative therapy (LAT) was shown to effectively defer switching systemic therapy in patients with OPD.

Is monotherapy or combination better?

The global phase III FLAURA trial established osimertinib as the standard first-line (1L) treatment for patients with advanced EGFRm NSCLC. [N Engl J Med 2020;382:41-50] However, more recently, the FLAURA2 and MARIPOSA phase III studies reported improved progression-free survival (PFS) and overall survival (OS) in the 1L setting with osimertinib plus chemotherapy and osimertinib plus amivantamab plus lazertinib, respectively, vs osimertinib monotherapy. At the same time, these regimens are associated with increased toxicities and a need for regular clinic visits and intravenous infusions. [N Engl J Med 2023;1935-1948; N Engl J Med 2024;391:1486-1498]

It depends…

Current guidelines recommend that patients with OPD on tyrosine kinase inhibitor (TKI) treatment undergo LAT while continuing the same TKI, as LAT can eradicate localized drug-resistant clones, while the quiescent tumour sites may remain sensitive to TKI treatment. This strategy aims to preserve patients’ quality of life and reduce toxicities by maximizing the duration of targeted therapy and delaying the need for chemotherapy. [J Natl Compr Canc Netw 2024;22:249-274]

“In this retrospective study, we investigated the incidence and patterns of disease progression in patients with advanced EGFRm NSCLC treated with 1L osimertinib, and the impact of LAT on survival outcomes,” explained the researchers. [Lung Cancer 2025;doi:10.1016/j.lungcan.2025.108808]

They analyzed data from 282 patients (median age, 64 years; female, 64 percent) with advanced EGFRm NSCLC treated with 1L osimertinib monotherapy at Prince of Wales Hospital, Hong Kong, between 2017 and 2023. Of these, 19 percent were smokers, 79 percent had an Eastern Cooperative Oncology Group (ECOG) PS of 0–1, 47 percent had EGFR exon 19 deletion, 50 percent had exon 21 L858R mutation, 3 percent had uncommon mutations, and 21 percent had oligometastatic disease at baseline, which was defined by ≤5 metastases.

At a median follow-up of 30.2 months, the median real-world PFS, time to treatment failure (TTF) and OS were 18.3, 22.8 and 33.7 months, respectively. However, the outcomes were highly heterogeneous between individual patients.

LAT delays switching systemic therapy in OPD

At disease progression, 37 percent of patients presented with OPD, while 63 percent had SPD. Patients with OPD had longer TTF (26.0 vs 14.2 months; hazard ratio [HR], 0.44; 95 percent confidence interval [CI], 0.30–0.62; p<0.001) and OS (35.4 vs 24.8 months; HR, 0.57; 95 percent CI, 0.37–0.89; p=0.01) vs those with SPD. “This remained statistically significant after adjusting for gender, smoking status, ECOG PS, mutational status, baseline brain and liver metastases, and oligometastatic disease at baseline,” noted the researchers.

Of patients with OPD, 46 percent received LAT. They were younger, had better ECOG PS, more frequently harboured EGFR exon 19 deletion, and had fewer progressive lesions vs those who did not undergo LAT. Median PFS2 was significantly longer among those who received LAT vs those who did not (14.4 vs 6.0 months; HR, 0.32; 95 percent CI, 0.17–0.59; p<0.001), with the difference remaining statistically significant after adjustment for age, EGFR mutation, ECOG PS and metastatic sites.

There was also a trend for longer TTF and OS among patients who received LAT vs those who did not. “LAT effectively deferred switching systemic therapy among patients who developed OPD. At 2 years, 35 percent remained progression-free,” reported the researchers.

Long-term responders

“[Since] a significant proportion of patients achieve durable disease control on osimertinib monotherapy, it may be preferable for this population to avoid long-term toxicities associated with chemotherapy or amivantamab,” wrote the researchers. “[Therefore,] we analyzed the clinical characteristics of long-term responders to 1L osimertinib.”

At the 2-year data cutoff, 35 percent of patients were classified as long-term responders to 1L osimertinib monotherapy. Female gender, better ECOG PS (0–1), recurrent metastatic disease, oligometastatic disease at baseline, and absence of brain, bone, or liver metastases were associated with lower odds of progression after 2 years. After multivariate analysis, only ECOG 0–1 and absence of any brain, bone or liver metastases remained statistically significant. Median PFS for patients without vs with any brain, bone, or liver metastases was 30.6 vs 16.9 months (HR, 2.58; 95 percent CI, 1.6–4.1; p<0.001).

Take-home message

1L treatment with osimertinib monotherapy yielded variable outcomes in patients with EGFRm NSCLC. “Among those who progressed, one-third developed OPD, with LAT offering favourable disease control in this population. A good ECOG PS of 0–1 and absence of brain, liver or bone metastases were associated with lower odds of progression or death at 2 years with osimertinib monotherapy,” summarized the researchers.

“A personalized approach is essential in selecting the optimal treatment strategy for patients with advanced EGFRm NSCLC,” they stressed.