Empowering treatment: insights from 35 months follow-up highlight the benefits of cemiplimab monotherapy and continued immunotherapy plus chemotherapy beyond progression in advanced non-small cell lung cancer patients with high PD-L1 expression

Introduction

The development of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors has been a breakthrough for patients with advanced non-small cell lung cancer (aNSCLC) with non-targetable genomic alterations. Approximately 25–35% of aNSCLC patients are expected to have high PD-L1 expression [PD-L1 expression ≥50% of tumor cells (1-3)]. Two PD-1 inhibitors (pembrolizumab and cemiplimab) and one anti-PD-L1 inhibitor (atezolizumab) are currently approved as monotherapy in patients with high PD-L1 expression based on the overall survival (OS) benefit observed in the KEYNOTE-024 (1,4), IMPOWER-110 (2) and EMPOWER-Lung 1 trials (3,5).

In the EMPOWER-Lung 1 trial, cemiplimab monotherapy significantly improved OS and progression-free survival (PFS) in first-line treatment of PD-L1-positive aNSCLC. Updated results with extended follow-up have recently been published and the aim of this editorial is to comment on the results reported in this update (5).

EMPOWER-Lung 1: discussion of the results

EMPOWER-Lung 1 was a multicenter, open-label, randomized, controlled, phase 3 trial. A total of 710 smoker patients diagnosed with high PD-L1 expression aNSCLC (unresectable stage IIIB or IIIC patients ineligible for definitive chemoradiotherapy or stage IV) who were not previously treated were randomized (1:1) to receive either cemiplimab 350 mg every three weeks until disease progression (PD), unacceptable toxicity, or up to 2 years, or investigator-selected platinum-based doublet chemotherapy (CT). Primary endpoints were PFS and OS as assessed by blinded independent central review (BICR). This was the first study to allow the continuation of anti-PD-1 in the second line in combination with CT (up to 4 cycles of CT) in patients who progressed on cemiplimab. Cemiplimab provided a significant survival benefit compared to CT. Notably, the continuation of cemiplimab plus CT as second-line therapy also had an impact on survival.

The population included in the EMPOWER-Lung 1 trial has several notable characteristics: the underrepresentation of females (15%) and the exclusion of non-smokers are noteworthy. These factors may influence the survival outcomes, given that the female population tends to show a different genetic profile (6). Patients with EGFR, ALK and ROS-1 genetic alterations were also excluded. Nowadays, there is increasing evidence that other genetic alterations (i.e., KRAS, Her2 or BRAF mutations, MET point mutations in splicing and amplification or RET rearrangements) not studied in this trial could potentially modify the response to immunotherapy, so a comprehensive molecular profiling could help to better determine their impact (7,8). Both squamous histology (43%) and non-squamous histology were well represented, with similar outcomes in both. In addition, EMPOWER-Lung 1 was the first prospective phase III to include patients with locally advanced disease ineligible for chemoradiotherapy. Brain metastases were also present in 12% of patients at inclusion time, a frequency similar to that observed in the KEYNOTE-024 trial.

One of the strengths to be highlighted in the design of the EMPOWER-Lung 1 is the inclusion of stage III patients who are ineligible for local treatment. Another feature that can act as both a strength and a weakness is the exclusion of non-smoker patients.

An interim monitoring revision while the study was ongoing revealed discordances in the PD-L1 expression analysis. Therefore, a revision was performed after August 2018 an amendment was performed to analyze two different populations: intention to treat (ITT) population, including all randomized patients (N=712), and patients with centrally confirmed high PD-L1 expression (N=565). It is important to highlight that this reassignment did not appear to impact the efficacy results.

In the population with confirmed high PD-L1 expression, the median PFS [8.1 vs. 5.3 months; hazard ratio (HR) 0.51], the median OS (26.1 vs. 13.3 months; HR 0.57), overall response rate (ORR) (46% vs. 21%; P<0.001) and duration of response (DOR) (23.6 vs. 5.9 months) were significantly increased in the cemiplimab arm. In the ITT population, median survival outcomes and HRs were similar to the high PD-L1 expression. The population was divided into 3 tertiles: PD-L1 from 50% to 60%, PD-L1 greater than 60% and less than 90% and PD-L1 higher than 90%. Greater differences in favor of cemiplimab were observed in the higher PD-L1 expression tertile. In contrast, no differences were observed between these groups in the CT arm.

EMPOWER-Lung 1 provided the first prospective evidence of a significant survival benefit in aNSCLC patients with PD-L1 expression ≥90% compared to PD-L1 expression 50–89%. Previous retrospective analyses with other immune checkpoint inhibitors (ICI) also support these findings (9,10). Taken together, these data support the need for randomized trials evaluating the efficacy of PD-(L)1 inhibitors in combination with CT or as monotherapy in patients with PD-L1 expression 50–89%.

Of the 66% of patients who progressed in the CT arm, 56% received a subsequent treatment (almost all of them with cemiplimab, as cross-over was allowed). Despite this high crossover rate, OS was significantly better in the cemiplimab arm, supporting the benefit of ICI as first-line.

At data cut-off, 60% (N=214) of patients with confirmed high PD-L1 expression had progressed in the cemiplimab arm. In 60 patients (28%) cemiplimab was maintained beyond progression and platinum doublet CT was added. The median PFS from the start of CT was 6.6 months and the median OS was 15.1 months. These results may suggest a synergistic effect of combination therapy and the benefit of maintaining anti-PD-1 beyond progression in second-line setting. However, these results cannot be directly compared with those obtained in the first-line setting because they represent two different scenarios, and some biases could affect their results (i.e., previous response to cemiplimab). Prognostic factors that would allow the identification of patients who would benefit from this strategy have not yet been defined. Safety results were consistent with previous reports of chemoimmunotherapy combinations (1,2) and no new safety signals were described with longer follow-up.

Potential impact of EMPOWER-Lung 1 results on current clinical practice

Updated results from the EMPOWER-Lung 1 trial reinforce the benefit of first-line cemiplimab in monotherapy in patients with high PD-L1 expression aNSCLC. These results add yet another asset in the treatment of this patients, with atezolizumab and pembrolizumab also approved in this scenario. It should be noted that although a direct comparison has not been performed, the efficacy results and safety profile of cemiplimab were similar to those previously observed with atezolizumab or pembrolizumab.

In addition, the potential benefit of PD-(L)1 inhibitors in combination with CT in the high PD-L1 population has been shown in several trials: EMPOWER-Lung 3 (11), KEYNOTE 189 (12), KEYNOTE 407 (13), IMPOWER 130 (14) and CHECKMATE 9LA (15), the latter exploring the combination of nivolumab and ipilimumab with platinum doublet CT (although the greatest benefit falls is in the low and negative PD-L1 expression population). It should be noted that the cut-off point for PD-L1 in those trials was different from that in EMPOWER-Lung1, so interpretation of the results should be performed with caution. Table 1 shows the results of the major trials investigating immunotherapy as monotherapy or in combination with CT in patients with high PD-L1 expression. Cemiplimab should be considered as a first-line treatment option in smoker aNSCLC patients with high PD-L1 expression (PD-L1 ≥50%).

Selecting the right patient for each treatment remains a daily challenge and requires multidisciplinary decision-making and physician expertise. The choice between PD-(L)1 inhibitor in monotherapy or in combination with CT remains unclear. Regarding this issue, EMPOWER-Lung 1 is the first prospective study to provide results according to different PD-L1 expression populations, demonstrating higher responses and longer survival with PD-L1 levels. This may favor the use of monotherapy in higher PD-L1 expression levels, while the combination with CT could may be preferable in PD-L1 expression near 50%. The other trials mentioned above may not have been adequately powered to analyze these subgroups.

Cross-trial comparisons and subgroup analyses must be interpreted with extreme caution, as studies are often underpowered to detect differences between subgroups. However, EMPOWER-Lung 1 showed a similar OS benefit in the cemiplimab arm for squamous histology with a HR: 0.506 [95% confidence interval (CI): 0.370–0.693] and a HR: 0.642 (95% CI: 0.476–0.866) for the non-squamous histology at 3-year follow-up. KEYNOTE 024 (18) showed no significant results in squamous histology with a HR of 0.73 (95% CI: 0.38–1.39), as did IMPOWER 110 (16), with a HR of 0.91 (95% CI: 0.45–1.83).

Importantly, EMPOWER-Lung 1 also included stage III patients ineligible for radical treatment (N=45) and showed a benefit for cemiplimab similar to that seen in the general population, with a HR of 0.667 (0.382–0.693). These patients were not included in KEYNOTE 024 or the IMPOWER110. This population was also studied in KEYNOTE 042 (19) with significantly higher median OS in PD-L1 ≥50% patients [HR 0.69 (95% CI: 0.56–0.85)], in favor of the pembrolizumab arm (n=27).

In addition, 12% of the EMPOWER-Lung 1 patients had treated and clinically stable brain metastases. Subgroup analysis also supports the benefit of cemiplimab in this population. A previously published meta-analysis including various phase II and phase III trials of immunotherapy with or without CT in aNSCLC showed that patients with brain metastases were more likely to have an OS benefit from combinations (20). On the other hand, never smoker patients were excluded in EMPOWER-Lung 1, so these patients should not be treated with cemiplimab. It is worth to note that since these patients have shown less benefit from ICI as monotherapy in other studies (1,2,4,16), it is reasonable to treat with a combination of anti-PD-1 and CT if no oncogenic drivers with approved first-line therapies are available.

In terms of treatment at progression, this is the first trial to consider maintenance of PD-(L)1 inhibitor while initiating second-line platinum-doublet CT. The efficacy results are promising compared to patients treated with first-line CT in the trial, and safety does not appear to be a concern. However, post-progression data in KEYNOTE 024 showed a promising PFS2 of 24 months without pembrolizumab maintenance at progression (1). Comparative studies at the time of progression (with attention to prior first line response as well as the timing and pattern of progression) comparing platinum doublets with or without maintenance immunotherapy may help to determine its pertinence.

There are some challenges that we may face in the real world: It is likely that there will be patients with worse ECOG PS than those included in the study, as well as patients with untreated brain metastases or requiring corticosteroids. In addition, it is uncertain whether the subgroup of patients with a light smoking history is similar to the population included in the trial. Additionally, in the absence of randomized clinical trials, it may be difficult to justify the reimbursement for maintenance of cemiplimab with CT after progression.

Conclusions

The results reported in EMPOWER-Lung 1 place cemiplimab as a treatment option in patients with high PD-L1 expression aNSCLC and explore the potential benefit of maintaining ICI plus platinum-doublet at progression. Given these results, first-line cemiplimab would be one of the first choices in a smoking patient without targetable mutations and high PD-L1 expression aNSCLC. The indication for second-line ICI maintenance should be further evaluated in prospective studies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-107/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-107/coif). M.A.S. reports grants from Hospital de la Santa Creu i Sant Pau. S.M. reports speaker fees from Sanofi, BMS, support for attending meetings and/or travel from Sanofi, Roche, BMS, MSD. A.B.J. reports grants from Hospital de la Santa Creu i Sant Pau, speaker bureaus from BMS, Sanofi, Takeda, Pfizer, AstraZeneca, Piere-Fabre, Johnson & Johson, payment for expert testimony from AstraZeneca, BMS, Support for attending meetings and/or travel from MSD, Pfizer, BMS, Piere-Fabre, Roche, and serves on the advisory boards of Roche, Sanofi. M.P.G. reports grants from Hospital de la Santa Creu i Sant Pau. M.M.T. reports grants from AstraZeneca, BMS, Roche, consulting fees from Amgen, AstraZeneca, BMS, Casen Recordati, Janssen, Pzifer, Roche, Sanofi, Takeda, speaker fees from Amgen, AstraZeneca, Casen Recordati, Helsinn, Pzifer, Roche and Takeda. The authors have no other 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/.

References

1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
2. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 2020;383:1328-39. [Crossref] [PubMed]
3. Özgüroğlu M, Kilickap S, Sezer A, et al. First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2023;24:989-1001. Erratum in: Lancet Oncol 2023;24:e405. [Crossref] [PubMed]
4. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol 2021;39:2339-49. [Crossref] [PubMed]
5. Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 2021;397:592-604. [Crossref] [PubMed]
6. Florez N, Kiel L, Riano I, et al. Lung Cancer in Women: The Past, Present, and Future. Clin Lung Cancer 2024;25:1-8. [Crossref] [PubMed]
7. Peng L, Guo J, Kong L, et al. Efficacy of immunotherapy in KRAS-mutant advanced NSCLC: A real-world study in a Chinese population. Front Oncol 2022;12:1070761. [Crossref] [PubMed]
8. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30:1321-8. [Crossref] [PubMed]
9. Edahiro R, Kanazu M, Kurebe H, et al. Clinical outcomes in non-small cell lung cancer patients with an ultra-high expression of programmed death ligand-1 treated using pembrolizumab as a first-line therapy: A retrospective multicenter cohort study in Japan. PLoS One 2019;14:e0220570. [Crossref] [PubMed]
10. Shah M, Hubbard RA, Mamtani R, et al. Very high PD-L1 expression as a prognostic indicator of overall survival among patients with advanced non-small cell lung cancer receiving anti-PD-(L)1 monotherapies in routine practice. Pharmacoepidemiol Drug Saf 2022;31:1121-6. [Crossref] [PubMed]
11. Makharadze T, Gogishvili M, Melkadze T, et al. Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial. J Thorac Oncol 2023;18:755-68. Erratum in: J Thorac Oncol 2025;20:119-21. [Crossref] [PubMed]
12. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol 2023;41:1992-8. [Crossref] [PubMed]
13. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol 2023;41:1999-2006. [Crossref] [PubMed]
14. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019;20:924-37. [Crossref] [PubMed]
15. Carbone DP, Ciuleanu TE, Schenker M, et al. Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial. J Immunother Cancer 2024;12:e008189. [Crossref] [PubMed]
16. Jassem J, de Marinis F, Giaccone G, et al. Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol 2021;16:1872-82. [Crossref] [PubMed]
17. de Castro G Jr, Kudaba I, Wu YL, et al. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study. J Clin Oncol 2023;41:1986-91. [Crossref] [PubMed]
18. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol 2019;37:537-46. [Crossref] [PubMed]
19. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-30. [Crossref] [PubMed]
20. Li S, Zhang H, Liu T, et al. The Effect of Asymptomatic and/or Treated Brain Metastases on Efficacy of Immune Checkpoint Inhibitors in Metastatic Non-Small Cell Lung Cancer: A Meta-Analysis. Front Oncol 2021;11:702924. [Crossref] [PubMed]