Reviewing Key Trials Shaping IO Monotherapy in Advanced Lung Cancer

First-line treatment for advanced non-small cell lung cancer (NSCLC) has evolved significantly with immunotherapy (IO) becoming a cornerstone for patients with high PD-L1 expression. During a Community Case Forum event, moderator Bruna Pellini, MD​, assistant member in the Department of Thoracic Oncology​ at H. Lee Moffitt Cancer Center and Research Institute​ and assistant professor in the Department of Oncology Sciences at the University of South Florida, highlighted key insights into optimizing IO monotherapy with pivotal clinical trials.

Register today to join a Case-Based Roundtable near you.

CASE SUMMARY

• A 72-year-old White man was referred to a thoracic oncologist with chest discomfort, cough, and dyspnea.

Past Medical and Social History​

• Mild chronic obstructive pulmonary disease
• Former smoking: 10 pack-years​
• Quit tobacco smoking 25 years ago​

Physical Examination ​

• Pulmonary: notable for diminished breath sounds over the left lung base​
• Neurologic: alert and oriented times 3; appropriately follows commands; gross and fine motor skills intact ​
• ECOG performance status: 1

Diagnostics

• Laboratory profile: complete blood cell count, differential, and comprehensive metabolic panel within normal limits​
• CT scan of the chest and abdomen: ​9.0-cm spiculated mass in the left lower lobe;​ loculated pleural effusion in the left hemithorax;​ and suspicious for right adrenal metastasis​
• 18F-FDG (fluorodeoxyglucose) PET/CT: avid FDG uptake in the left lung mass, pleura, and right adrenal gland​
• Brain MRI: negative​
• Histopathology:​ Image-guided biopsy of the lung mass and histopathological examination confirms poorly differentiated adenocarcinoma​
• Staging: T4N0M1c (stage IV)

Findings on Immunohistochemistry and Genomic Assay

• Immunohistochemistry:
  • PD-L1 tumor proportion score: 90% (22C3 pharmDx assay)
  • HER2 immunohistochemistry 1+
• Molecular Testing:
  • Tissue next-generation sequencing: negative for driver alterations in EGFR, ROS1, BRAF, ALK, RET, MET, ERBB2, NTRK, KRAS, and HER2
  • Microsatellite stable

Targeted Oncology: What do the NCCN guidelines recommend for a patient with metastatic NSCLC such as this?

Bruna Pellini, MD: On a daily basis, we can always reference to NCCN or American Society of Clinical Oncology guidelines. In terms of preferred lines, pembrolizumab [Keytruda] alone is Category 1, atezolizumab [Tecentriq] alone is Category 1, and cemiplimab [Libtayo] alone is Category 1, but also chemotherapy/immunotherapy [IO] is Category 1, either with pembrolizumab or cemiplimab. You can use dual IO or [IO plus chemotherapy]; they are labeled as other recommended.¹

For this patient, the decision was to start immune checkpoint inhibitor monotherapy, so IO alone.

What are the main trials looking at the IO monotherapy regimens for patients with high PD-L1 expression?

For IO alone in patients with PD-L1 high expression, we should really focus on EMPOWER-Lung 1 [NCT03088540], KEYNOTE-024 [NCT02142738], and IMpower110 [NCT02409342]. KEYNOTE is for pembrolizumab, Impower110 is for atezolizumab, and EMPOWER-Lung 1 is for cemiplimab. In all of these studies, you could use the chemotherapy up to 6 cycles as the comparator arm.

All of these trials were for patients with PD-L1 expression of over 50%. IMpower110 did include some patients with PD-L1 intermediate expression, but I'll focus on the analysis of the PD-L1 high. So in terms of overall response rate [ORR], whenever you do IO alone for the PD-L1–high patient, you should expect a response rate in the mid-forties. That's usually what I quote for my patients, now around 45%. When it comes to median overall survival [OS], in both EMPOWER-Lung 1 and KEYNOTE-024, the median OS is around 26 months and the HR for both trials is around 0.6, so very similar results.^2,3 When it comes to median progression-free survival [PFS], EMPOWER-Lung 1 and KEYNOTE-024 also have similar median PFS, close to 8 months; 8.1 and 7.7 months, respectively.

IMpower110, when you look at the PD-L1 high, the median OS was around 20 months, so numerically, it is a little lower.⁴ There are always caveats to comparing data across trials, but the reality is, we have to make decisions, and we have a laundry list of regimens, so a lot of us, when we're discussing these regimens, we look at data next to each other.

Which trial evaluated a broader PD-L1 population and what were those results?

KEYNOTE-042 [NCT02220894] did include patients with PD-L1 low or intermediate, 1% or higher. The data are very different than the [ORR with the other trials], but either way, they're clumped together. In that population, the response rate was 27% and that's usually what we used to see back in the day, when we didn't have the IO in first line.⁵

In terms of median OS, if you're looking at everyone from [PD-L1 expression of] 1% to 100%, was around 16 months. The PD-L1 high goes close to the 20 months that we also see IMpower110.⁴

Register today to join a Case-Based Roundtable near you.

DISCLOSURES: Pellini previously reported honoraria from Foundation Medicine, Merck, and AstraZeneca; a consulting or advisory role with AstraZeneca, Regeneron, Illumina, Bristol Myers Squibb/Roche, Merus, Bayer, Gilead Sciences, Foundation Medicine, and oncohost; and travel, accommodations, or expenses from Bristol Myers Squibb/Roche and MSD.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Hepatocellular carcinoma; version 1.2025. Accessed July 22, 2025. https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf

2. 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(9):989-1001. doi:10.1016/S1470-2045(23)00329-7

3. 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(19):1823-1833. doi:10.1056/NEJMoa1606774

4. 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(11):1872-1882. doi:10.1016/j.jtho.2021.06.019

5. 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(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7