Immune checkpoint inhibitors for advanced non-small cell lung cancer with poor performance status or older patients

We would like to comment on the randomized phase III GFPC 08–2015 ENERGY study (NCT03351361) by Léna et al., which was published in the Lancet Respiratory Medicine. The main objective of this study was to investigate whether the combination of nivolumab plus ipilimumab (NIVO-IPI) was superior to platinum-based doublet chemotherapy (PBC) in patients with treatment naïve advanced stage non-small cell lung cancer (NSCLC) who were older than 70 years and an Eastern Cooperative Oncology Group performance status 2 (ECOG PS 2) with a primary endpoint of overall survival (OS) (1). Unfortunately, at the pre-planned interim analysis, the data monitoring committee recommended that recruitment stop due to futility of NIVO-IPI for patients with PS 2.

This study evaluated 217 patients across 30 institutions in France, between February 2018 and December 2020. Almost 80% of enrolled patients were over 70 years old, and 37% of patients were PS 2. Though NIVO-IPI demonstrated numerically better median OS compared to PBC [14.7 vs. 9.9 months, hazard ratio (HR) 0.85, 95% confidence interval (CI): 0.62–1.16] in the overall study population, GFPC 08–2015 ENERGY did not meet its primary endpoint. OS curves crossed at 60% (6 months) assessed by Kaplan-Meier. At first, the survival curve of the PBC group was above NIVO-IPI; conversely, NIVO-IPI curve showed a higher benefit than PBC after 6 months. The authors broke down the survival curves by PS. Interestingly, in the PS 0–1 subset (median age 76 years), NIVO-IPI significantly prolonged OS compared to PBC (22.6 vs. 11.8 months, HR 0.64, 95% CI: 0.46–0.96). In contrast, the result was opposite in the PS 2 population, where the NIVO-IPI group had consistently worse OS (2.9 vs. 6.1 months, HR 1.32, 95% CI: 0.82–2.11). The authors concluded that NIVO-IPI demonstrated a doubling of survival benefit over PBC in older patients with PS 0–1. They speculated that rapid disease progression might influence the lack of clinical benefit of immunotherapy in patients with PS 2.

Currently, even in older patients, we treat good PS patients with standard therapy as established by pivotal phase III studies (2,3). In the present study, the survival benefit of NIVO-IPI was almost double that of PBC in PS 0–1 patients, which was consistent with the CheckMate 227 study (4). However, NIVO-IPI was less effective for patients with PS 2. The main concern of the present study was the two different subpopulations that were heterogeneously enrolled—older patients and poor PS patients. The investigators should clearly distinguish these two subpopulations to solve their clinical questions.

The unresolved clinical question that we oncologists are interested in is how to evaluate and care for poor PS patients. As the authors mentioned, some retrospective studies consistently revealed the futile impact of immune checkpoint inhibitors (ICIs) for poor PS (5). On the other hand, the IPSOS phase III study demonstrated that atezolizumab (anti-PD-L1 antibody) monotherapy significantly prolonged OS compared to single agent chemotherapy in over 80% of enrolled NSCLC patients with PS 2–3 who were ineligible for treatment with a platinum-containing regimen regardless of PD-L1 expression (6). Based on the results of the IPSOS study, the European Society of Medical Oncology (ESMO) guidelines recommend atezolizumab monotherapy for PS 2 patients (3). However, worsening PS may be due to a variety of factors, including comorbidities, age-related organ dysfunction, and nutritional status, in addition to cancer activity (7). It is unreasonable to consider treatment strategies only based on PS 2 with a heterogeneous patient population. Therefore, when we treat poor PS patients, we have to carefully evaluate the reasons and etiology of PS decline. For instance, in elderly patients with PS 2 due to chronic obstructive pulmonary disease (COPD), improvement of PS is often difficult to achieve even with a clinical response to ICIs. Conversely, in patients whose cancer-related pain results from thoracic wall invasion, a favorable response to ICIs could lead to symptom relief and subsequent improvement of PS. Based on the etiology of PS decline and individual patients’ conditions, including comprehensive geriatric assessment (CGA) (8) and advance care planning (ACP), we need to customize not only the choice of treatment regimens but also drug dose, treatment schedules, and comprehensive supportive care (Figure 1). The optimal prediction tool for the efficacy of ICIs considering heterogeneity in patients with PS 2 has not yet been established.

Figure 1 Treatment options of poor PS NSCLC based on the etiology PS decline and individual patients’ conditions. PS decline may result from cancer activity as well as comorbidities, age-related organ dysfunction, and nutritional status. Treatment options should be selected based on the etiology of PS decline and patient-specific factors, incorporating CGA, ACP, SDM, optimization of drug dose, treatment schedules, and supportive care. ACP, advance care planning; BSC, best supportive care; CGA, comprehensive geriatric assessment; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DTX, docetaxel; GEM, gemcitabine; ICI, immune checkpoint inhibitor; ILD, interstitial lung disease; NSCLC, non-small cell carcinoma; PS, performance status; SDM, shared decision making; VNR, vinorelbine.

How to establish the standard care for PS 2 patients is still a challenge for prospective clinical trials. Further studies, including high-quality real-world data analyzed by artificial intelligence (AI) and well-designed prospective studies, could give novel insights and appropriate patient selection for ICIs in poor PS or older patients.

Acknowledgments

The author wishes to thank Mr. Jason Tonge from St. Marianna University School of Medicine for reviewing the language of this article.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1472/coif). The author has no conflicts of interest to declare.

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References

1. Léna H, Greillier L, Cropet C, et al. Nivolumab plus ipilimumab versus carboplatin-based doublet as first-line treatment for patients with advanced non-small-cell lung cancer aged ≥70 years or with an ECOG performance status of 2 (GFPC 08-2015 ENERGY): a randomised, open-label, phase 3 study. Lancet Respir Med 2025;13:141-52. [Crossref] [PubMed]
2. Owen DH, Halmos B, Puri S, et al. Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1. J Clin Oncol 2025;43:e45-58. [Crossref] [PubMed]
3. ESMO Living Guideline. Non-Oncogene-Addicted Metastatic NSCLC. Available online: https://www.esmo.org/guidelines/living-guidelines/esmo-living-guideline-non-oncogene-addicted-metastatic-non-small-cell-lung-cancer/management-with-systemic-therapy/non-squamous-non-small-cell-carcinoma-without-contraindication-for-immunotherapy
4. Brahmer JR, Lee JS, Ciuleanu TE, et al. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol 2023;41:1200-12. [Crossref] [PubMed]
5. Furuya N, Nishino M, Wakuda K, et al. Real-world efficacy of atezolizumab in non-small cell lung cancer: A multicenter cohort study focused on performance status and retreatment after failure of anti-PD-1 antibody. Thorac Cancer 2021;12:613-8. [Crossref] [PubMed]
6. Lee SM, Schulz C, Prabhash K, et al. First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study. Lancet 2023;402:451-63. [Crossref] [PubMed]
7. Ikeda S, Naito T, Miura S, et al. Pharmacotherapy for Advanced Non-Small Cell Lung Cancer with Performance Status 2 without Druggable Gene Alterations: Could Immune Checkpoint Inhibitors Be a Game Changer? Cancers (Basel) 2022;14:4861. [Crossref] [PubMed]
8. Furuya N, Kanaji N, Yokoo K, et al. Geriatric assessment in older patients with non-small cell lung cancer: Insights from a cluster-randomized, phase III trial—ENSURE-GA study (NEJ041/CS-Lung001). J Clin Oncol 2024;42:1502.