Tackling a caveat of the FLAURA trial and building solid evidence for frail patients in thoracic oncology

The discovery of EGFR mutations in non-small cell lung cancer (NSCLC) has profoundly changed the therapeutic management of these patients with the development of effective targeted therapies. First-generation tyrosine kinase inhibitor (TKI) were developed resulting in an improvement of progression-free survival (PFS) and overall survival (OS) (1).

Two phase III studies introduced third-generation TKIs osimertinib [FLAURA trial (2)] and lazertinib [LASER 301 trial (3)] as a new gold-standard treatment for metastatic EGFR-mutated (EGFRmut) NSCLC. Compared with first-generation TKI, osimertinib and lazertinib drastically improved PFS {18.9 vs. 10.2 months [hazard ratio (HR) for disease progression or death, 0.46; 95% confidence interval (CI): 0.37–0.57; P<0.001] for osimertinib and 20.6 vs. 9.7 months (HR, 0.45; 95% CI: 0.34–0.58; P<0.001) for lazertinib respectively}. These trials showed consistent improvement regarding objective response rate (ORR), median duration of response and OS. Furthermore, beyond the survival improvement, third-generation TKIs are significantly better tolerated than chemotherapy and first-generation TKIs.

First-line treatment for patients with EGFRmut NSCLC tends towards an intensification, associating third-generation TKIs and chemotherapy or biotherapy. Thus, in FLAURA 2 (4), patients were treated either with osimertinib alone or in combination with a platinum-based chemotherapy; the MARIPOSA trial (5) compared osimertinib alone, lazertinib alone or in combination with amivantamab. Also, future trials are exploring antibody-drug conjugates in association with osimertinib (6). However, those trials show an increase in toxicity and do not address the unmet need of aged and/or poor performance status (PS) patients who were not included and in whose adverse events (AEs) and safety are a major concern.

PS is a well-established prognostic factor reflecting physical condition of cancer patients and plays a significant role in therapeutic decision-making. A poor PS (score of 2 or higher) is associated with increased toxicity and reduced cancer treatment efficacy (7). Most trials set a low threshold of PS (0 or 1) to select patients. However, higher PS score might originate from various causes such as co-morbidities or cancer related symptoms. In addition, PS assessment is carried out by a physician, who has some degree of subjectivity. All these factors need to be acknowledged when analysing clinical evidence. The clinical course of poor PS patients is difficult to estimate because they are excluded from most prospective trials, arguably reflecting the differences that physicians see between results of trials and those observed in routine practice.

Currently, the standard of care for patients presenting a metastatic EGFRmut NSCLC and a poor PS is osimertinib [European Society for Medical Oncology (ESMO) guidelines] but it is based on scarce data.

Two studies evaluated first-generation TKI gefitinib in this population (8,9). They showed that gefitinib had an acceptable safety profile and provided clinical improvement. Regarding osimertinib, a retrospective study suggested a potential benefit for poor PS patients progressing after first-line first-generation TKI and EGFR T790M-mutated NSCLC (10), although lower than expected (11). Another retrospective study evaluated osimertinib as first-line treatment for patients who would have been excluded from the FLAURA trial; 120 patients with poor PS were assessed (12). Disease control and survival were significantly lower than in the FLAURA trial but toxicity was not increased. Still, a robust prospective evaluation was definitely needed.

In the May’s issue of the Journal of Thoracic Oncology, Fukui et al. reported the findings from OPEN/TORG2040, a multicenter prospective phase II trial evaluating the efficacy and safety of osimertinib as first-line treatment for patients with EGFRmut advanced NSCLC and poor PS (13).

This study enrolled patients with previously untreated advanced EGFRmut NSCLC (including exon 19 del, exon 21 L858R, exon 18 G719X and exon 21 L861Q). Each patient’s overall condition was assessed using the ECOG PS and patients with a score of 2 or higher were eligible. Main exclusion criteria were a history of interstitial lung disease (ILD), clinically unstable brain metastases and an impaired PS due to complications other than lung cancer. Osimertinib was administrated at 80 mg daily until disease progression or observation of an unacceptable toxicity. Evaluation of the clinical response, PS assessment and a quality-of-life (QoL) questionary were performed every 6 weeks for the first 24 weeks and every 8 weeks thereafter. The primary endpoint was the ORR. Between February 2021 and February 2022, a total of 30 patients were enrolled. The median age was 75 years, and 90% of patients had stage IV disease. The EGFR mutations were exon 19 del in 12 (40%) and exon 21 L858R in 18 patients (60%).

The study met the primary endpoint with an ORR of 63,3% (n=19/30; 90% CI: 46.7–77.9%; one-sided exact P=0.033). The PS improvement rate was 63.3% (n=19/30; 95% CI: 43.9–80.1%; P<0.001; Wilcoxon signed-rank test) with a higher global QoL reported by the patients. Also, the median PFS and OS were 8.0 (95% CI: 5.6–20.4) and 25.4 (95% CI: 15.6–not available) months respectively. Regarding safety, AEs occurred in 28 of the 30 patients (93%), with 16 patients (53%) presenting grade 3 or higher. Nine patients (30%) experienced serious AEs. The treatment was discontinued because of AEs in eight cases (27%), of which 6 were ILD.

Although toxicity seems acceptable, the rate of AEs and of treatment discontinuation is higher than in FLAURA and maybe higher than was expected. Of note, 20% of discontinuation was due to ILD, a complication that is more prevalent in the Asian population and is unlikely to be extrapolated to non-Asian patients. However, a careful selection of patient remains necessary, and patients’ frailty due to comorbidities, especially pulmonary diseases, might not make them good candidates for osimertinib. Similarly, it is crucial to take those parameters into account when considering chemotherapy use in PS 3–4 patients, as it is associated with poorer QoL (14), disputable benefit (15) or even harm (16).

This prospective study suggests the efficacy of osimertinib for patients diagnosed with metastatic EGFRmut NSCLC and poor PS. As expected in this frail population, the ORR and the survival outcomes are lower than those achieved by osimertinib in the FLAURA trial (63% vs. 80% for ORR, 8.0 vs. 18.9 months for median PFS and 25.4 vs. 38.6 months for median OS). Thus, the population of the OPEN trial presents a high proportion of patients with adverse prognostic factors: L858R mutation (60% vs. 37%) and brain metastasis (60% vs. 23%). Of note, all patients of the OPEN trial were Japanese, which may limit the generalizability of the findings to non-Asian populations. While the FLAURA trial included both Asian and non-Asian patients, direct comparisons of efficacy across regions based on subgroup HRs are challenging and should be interpreted with caution, as they reflect differential benefit of osimertinib vs. first-generation EGFR-TKIs rather than the absolute effect of osimertinib in each population.

Despite the lower survival outcomes compared to FLAURA, ORR and PS improvement in around two-thirds of the patients reflects an important benefit in cancer-related symptoms and QoL. Thus, patients in which the poor PS might be consecutive to tumor burden are very likely to derive benefit from osimertinib.

It remains unclear what to do with patients with non-cancer-related impaired PS, namely other comorbidities, as they were excluded of the OPEN trial. They represent a distinct population that deserves a specific study and a different approach: we should expect less from osimertinib (and maybe use a lower dosage to limit the risk of AEs) and more from supportive care, including involvement of transversal medical specialties like geriatric oncology or the emerging cardio-oncology.

The small sample of this study limits its power to explore further prognostic factors such as TP53 comutations or liver metastasis. Notwithstanding, these results demonstrate that osimertinib is likely to improve cancer-related symptoms and quality of life, regardless of mutation, cerebral involvement or age, as long as the patient is carefully assessed for its race and medical history, and closely monitored for AEs.

This study provides new perspectives for treating patients with metastatic EGFRmut NSCLC and poor PS. It further supports osimertinib as an appropriate first-line treatment with a reasonable safety profile, and should be used as a standard arm in the necessary future trials to improve outcomes in this frail population.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-777/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-777/coif). L.D. receives support for attending meeting from MSD. J.R. receives consulting fees from AMCA. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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