Combination Regimens Take Center Stage in Frontline NSCLC

During an OncLive® Scientific Interchange and Workshop held on December 4, 2025, an international group of thoracic oncology specialists convened to review updated data in frontline non–small cell lung cancer (NSCLC) management presented during the 2025 ESMO Asia Congress and other major conferences.¹ They aimed to elucidate the present role of anti–PD-(L)1 monotherapy and talked through data with CTLA-4 inhibitor/PD-(L)1–directed agent combinations.

What are the latest updates in frontline anti–PD-(L)1 monotherapy?

The faculty began their discussion by reviewing data from clinical trials of PD-(L)1–directed agents for the frontline treatment of patients with advanced NSCLC. The phase 3 EMPOWER-Lung 1 trial (NCT03088540) evaluated cemiplimab-rwlc (Libtayo) in treatment-naive patients with advanced NSCLC with a PD-L1 expression level of at least 50%.² Patients were randomly assigned 1:1 to receive cemiplimab monotherapy or investigator’s choice of platinum-based chemotherapy.

Findings from the 5-year analysis of EMPOWER-Lung 1 revealed that the median overall survival (OS) in the cemiplimab arm (n = 284) was 26.1 months (95% CI, 22.1-31.9) compared with 13.3 months (95% CI, 10.5-16.2) in the chemotherapy arm (n = 281; HR, 0.59; 95% CI, 0.48-0.72; P < .0001). The 5-year OS rates were 29.0% and 15.0%, respectively. The median progression-free survival (PFS) was 8.1 months (95% CI, 6.2-8.8) for cemiplimab vs 5.3 months (95% CI, 4.3-6.1) for chemotherapy (HR, 0.50; 95% CI, 0.41-0.61; P < .0001). The 36-month PFS rates were 20.8% and 3.1%, respectively.

“EMPOWER-1 was the newest kid on the block in a way; [the data were] fairly convincing and similar to some of the other earlier front runners,” Daniel SW Tan, PhD, MBBS, BSc, noted. “[In terms of] the adverse effect [AE] profile, I don't see anything that is particularly worrisome here, whether it [be] treatment-emergent or immune-related AEs. Patient-reported outcome [data] show that with the use of [immuno-oncology (IO)] monotherapy, you do maintain quality of life across all the different symptom points.”

Tan is a senior consultant medical oncologist in the Division of Medical Oncology at National Cancer Centre Singapore, a professor at Duke-NUS Medical School, and a senior clinician-scientist at Genome Institute in Singapore.

Furthermore, updated findings from the 8-year follow-up of the phase 3 KEYNOTE-024 trial (NCT02142738) presented during the 2025 ESMO Asia Congress revealed that pembrolizumab (Keytruda; n = 154) provided a significant OS benefit compared with chemotherapy (n = 151) among patients with NSCLC with a PD-L1 tumor proportion score of at least 50% (HR, 0.65; 95% CI, 0.50-0.83); the 8-year OS rates were 24.3% (95% CI, 17.6%-31.5%) and 12.8% (95% CI, 7.6%-19.3%), respectively.³ Pembrolizumab also produced a significant PFS benefit vs chemotherapy in these patients (HR, 0.58; 95% CI, 0.46-0.75); the 8-year PFS rates were 13.0% (95% CI, 8.2%-18.9%) and 3.6% (95% CI, 1.0%-8.9%), respectively.

“In KEYNOTE-024, the results are probably a little overestimated because all of the patients enrolled in this trial had to have a central review of the PD-L1 expression before being enrolled,” Jordi Remon, MD, PhD, coordinator of the Cancer Medicine Department at CIOCC Barcelona in Spain, commented. “[This] means that if you can, a patient can wait [approximately] 6 weeks to have the [testing results] because the metastatic disease [burden] is not high. For me, sex and tumor volume are factors for not deciding [to use] IO alone despite high PD-L1 expression, if there is no contraindication.”

How have CTLA-4 inhibitor/ PD-(L)1–directed combinations affected the frontline NSCLC treatment landscape?

The faculty transitioned their discussion to highlight data from clinical trials which examined combination regimens containing CTLA-4 inhibitors and PD-(L)1–directed agents. They began by reviewing the final 6-year data from the phase 3 CheckMate 9LA trial (NCT03215706), which examined nivolumab (Opdivo) plus ipilimumab (Yervoy) and chemotherapy for the treatment of patients with NSCLC.⁴

Findings from the final analysis of CheckMate 9LA demonstrated that patients who received the triplet (n = 361) achieved a median OS of 15.8 months (95% CI, 13.9-19.7) compared with 11.0 months (95% CI, 9.5-12.7) among those who received chemotherapy (n = 358; HR, 0.74; 95% CI, 0.63-0.87). The 6-year OS rates were 16% and 10%, respectively. The median PFS values were 6.7 months (95% CI, 5.6-8.0) and 5.3 months (95% CI, 4.4-5.6), respectively (HR, 0.70; 95% CI, 0.59-0.82).

In the phase 3 POSEIDON trial (NCT03164616), investigators evaluated another triplet regimen featuring durvalumab (Imfinzi) in combination with tremelimumab-actl (Imjudo) and chemotherapy for the first-line treatment of patients with NSCLC.⁵

Findings from the primary analysis of POSEIDON revealed that patients who received durvalumab plus tremelimumab and chemotherapy (n = 338) experienced a median OS of 14.0 months (95% CI, 11.7-16.1) vs 11.6 months (95% CI, 10.5-13.1) among patients who received chemotherapy alone (n = 337; HR, 0.76; 95% CI, 0.64-0.89). The median PFS values were 13.3 months (95% CI, 11.4-14.7) and 11.6 months (95% CI, 10.5-13.1), respectively.

References

1. Navigating management of advanced NSCLC: treatment strategies and practical considerations. An OncLive Scientific Interchange and Workshop. OncLive. December 4, 2025. Accessed January 6, 2026.
2. Kilickap S, Baramidze A, Sezer A, et al. Cemiplimab monotherapy for first-line treatment of patients with advanced NSCLC with PD-L1 expression of 50% or higher: five-year outcomes of EMPOWER-Lung 1. J Thorac Oncol. 2025;20(7):941-954. doi:10.1016/j.jtho.2025.03.033
3. Garon EB, Hui R, Leighl N, et al. 10-year outcomes from clinical trials of pembrolizumab (pembro) monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). Ann Oncol. 2025;36(suppl 2):S1179-S1180. doi:10.1016/j.annonc.2025.08.2714
4. Carbone DP, Ciuleanu TE, Cobo M, et al. Nivolumab plus ipilimumab with chemotherapy as first-line treatment of patients with metastatic non-small-cell lung cancer: final, 6-year outcomes from CheckMate 9LA. ESMO Open. 2025;10(6):105123. doi:10.1016/j.esmoop.2025.105123
5. Peters S, Cho BC, Luft AV, et al. Durvalumab with or without tremelimumab in combination with chemotherapy in first-line metastatic NSCLC: five-year overall survival outcomes from the phase 3 POSEIDON trial. J Thorac Oncol. 2025;20(1):76-93. doi:10.1016/j.jtho.2024.09.1381