Challenges for first-line therapy in elderly patients with metastatic non-small cell lung cancer

The therapeutic landscape of advanced non-small-cell lung cancer (NSCLC) has been profoundly reshaped by immune checkpoint inhibitors, with chemo-immunotherapy combinations now widely adopted as first-line standards in fit, trial-eligible patients. However, pivotal registration trials largely enrolled younger individuals with preserved physiological reserve, limiting the generalisability of these standards to older adults, in whom competing risks, comorbidities, and treatment tolerance strongly influence outcomes. In this context, three dedicated randomised trials—IFCT-1805 ELDERLY, ENERGY, and IPSOS—offer a timely and coherent body of evidence to reframe first-line decision-making in older or frail patients (1-3).

The IFCT-1805 ELDERLY trial (1) directly tested the transposability of chemo-immunotherapy to fit older patients. In 510 patients aged 70–89 years [performance status (PS) 0–1], first-line carboplatin-paclitaxel plus atezolizumab did not significantly improve overall survival (OS) vs. platin based chemotherapy: median OS 18.6 vs. 15.0 months; hazard ratio (HR) 0.87 [95% confidence interval (CI): 0.70–1.08], P=0.20 (1). Although disease control was improved, this came at the cost of greater toxicity, with grade 3 treatment-related adverse events (TRAEs) 71.4% vs. 61.9% (P=0.03) and serious grade ≥3 TRAEs 16.3% vs. 7.7% (P=0.008) in the combination arm (1). This dissociation between improved progression-free survival (PFS) and unchanged OS is clinically meaningful in geriatric oncology, where treatment burden and competing mortality risks may offset gains in tumour control.

The phase III ENERGY trial explored a chemotherapy-free strategy by comparing nivolumab plus ipilimumab with platinum-doublet chemotherapy in a population enriched for older age (≥70 years) and/or impaired PS. In the overall population, the primary endpoint was not met: median OS 14.7 vs. 9.9 months; HR 0.85 (95% CI: 0.62–1.16), and the trial was stopped early for futility (2). However, results were strikingly heterogeneous by fitness. Among older fit patients [≥70 years; Eastern Cooperative Oncology Group (ECOG) 0–1], dual checkpoint blockade showed a clinically relevant signal: median OS 22.6 vs. 11.8 months; HR 0.64 (0.46–0.96) (2). In contrast, in ECOG PS2 patients, outcomes were numerically worse with nivolumab-ipilimumab combination: median OS 2.9 vs. 6.1 months; HR 1.32 (0.82–2.11) (2). These data reinforce a key principle: in older adults, the benefit-risk balance of intensified immunotherapy is primarily fitness-driven rather than age-driven, and dual immunotherapy may be inappropriate—potentially harmful—in unfit patients.

Complementing these findings, the IPSOS trial established single-agent immunotherapy as a pragmatic standard in patients deemed ineligible for platinum-based chemotherapy, a population that closely mirrors “real-world” older NSCLC. In this phase III global study, atezolizumab monotherapy significantly improved OS versus single-agent chemotherapy (vinorelbine or gemcitabine): median OS 10.3 vs. 9.2 months; HR 0.78 (95% CI: 0.63–0.97), P=0.028 (3). The benefit was accompanied by better long-term outcomes (2-year survival 24% vs. 12%) and a more favourable safety profile (grade 3–4 TRAEs 16% vs. 33%) with maintained or improved patient-reported quality of life compared with chemotherapy (3). Importantly, IPSOS enrolled a notably vulnerable cohort (median age 75 years; a large majority ECOG PS2–3), supporting the external validity of chemo-free immunotherapy for frail patients.

Viewed together, these trials outline a coherent clinical framework for older patients with advanced NSCLC. First, IFCT-1805 ELDERLY suggests that routine adoption of chemo-immunotherapy in fit older adults is not evidence-based in terms of OS, despite improved PFS and response (1). Second, ENERGY indicates that dual checkpoint blockade may represent a viable chemotherapy-free option in carefully selected fit older patients, while cautioning against its use in ECOG PS2 populations (2). Third, IPSOS provides level I evidence supporting programmed death-ligand 1 (PD-L1) monotherapy as a preferred first-line option for patients ineligible for platinum chemotherapy, with survival, safety, and quality-of-life advantages over single-agent chemotherapy (3).

In this heterogeneous population, the incorporation of biomarkers such as PD-L1 expression could refine treatment selection beyond clinical criteria alone. These observations also resonate with signals from PD-L1-selected strategies across broader first-line immunotherapy programmes, where high PD-L1 expression has consistently identified populations deriving substantial benefit from single-agent programmed cell death 1 (PD-1)/PD-L1 blockade (4,5). In older adults, this raises a clinically practical question: for PD-L1-high tumours, does chemotherapy meaningfully add benefit, or does it primarily add toxicity? Regulatory subgroup work has contributed to this discussion, suggesting that the incremental value of adding chemotherapy in PD-L1-high disease may be modest in selected contexts (5).

The practical implications are straightforward. Chronological age should not be the primary determinant of treatment selection. Instead, geriatric assessment, comorbidity burden, and functional status should drive whether a patient should be considered for dual immunotherapy, monotherapy, or chemotherapy-based approaches (6).

In this context, comprehensive geriatric assessment (CGA) may guide immunotherapy decision-making according to patients’ fitness levels, helping to tailor treatment intensity to individual functional status. Few studies have prospectively investigated the impact of CGA in cancer treatment decision making for elderly patients. A phase III, randomized study (7) comparing a standard strategy of chemotherapy allocation on the basis of PS and age with an experimental strategy on the basis of CGA found no difference between the 2 arms in terms of PFS and OS but patients in the CGA arm, experienced significantly less all grade toxicity (85.6% vs. 93.4%, respectively P=0.015) and fewer treatment failures as a result of toxicity (4.8% vs. 11.8%, respectively; P=0.007). A secondary analysis of this study (8) showed that mobility, instrumental activities of daily living (IADL) dependence, and weight loss were predictive of 3-month mortality while comorbidities were independently associated with severe chemotherapy toxicity. Beyond the initial assessment, the implementation of corrective actions for the identified vulnerabilities seems essential to improve the outcomes of these patients (9).

In conclusion, several therapeutic options are possible in the first-line treatment for elderly people with metastatic NSCLC, but CGA remains necessary to best assess the benefit-risk balance of each of these options.

Acknowledgments

None.

Footnote

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0222/coif). The authors have no conflicts of interest to declare.

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