Immune Checkpoint Inhibitors Have Transformed Treatment Landscape for Resectable NSCLC

The incorporation of adjuvant immune checkpoint inhibitors (ICIs) and the development of new targeted therapies have helped transform the treatment landscape for resectable non–small cell lung cancer (NSCLC), according to presenter Gregory J. Riely, MD, PhD, in a session at the 2023 Community Oncology Alliance meeting.

NSCLC is still largely defined by histology, biomarkers, and stages, Riely said, with adenocarcinoma accounting for approximately 80% of all lung cancers. There are also 2 primary categories of biomarkers: programmed death-ligand 1 (PD-L1) status and mutations or gene fusions.

First, Riely discussed the early-stage setting. Among patients with lung cancer, approximately 20% have the earliest stage of disease but are still dying of metastatic lung cancer within about 5 years, Riely said. Before the 2000s, resected or resectable disease was primarily treated with surgery alone, but the development of cisplatin double chemotherapy and other regimens showed that those with stage 2 or 3 disease could strongly benefit from further treatments.

Adjuvant atezolizumab is a key option in this context. The Impower010 trial was the first to examine atezolizumab in patients with stage 2 and 3 lung cancer who were completely resected and who received platinum-based chemotherapy before being randomized to either atezolizumab or observation. Investigators in this trial saw improved disease-free survival (DFS) with atezolizumab, although this benefit was not evenly distributed. Notably, those with high PD-L1 expression had a greater benefit.

Additionally, there was no overall survival (OS) benefit in the all-randomized stage 2A and 3A populations. The OS interim analysis in the subgroup with PD-L1 tumor cells of 1 or greater saw some improvement, but it was not statistically significant. When removing the group with high PD-L1 expression, Riely said there was a much clearer OS benefit.

Similarly, studies with adjuvant pembrolizumab have seen DFS benefits. However, early data on the benefit of pembrolizumab with PD-L1 analyses are more confusing, with no clear message on PD-L1 status. At this point, Riely said it appears that all patients get some benefit from this treatment regardless of PD-L1 status and no single group stands out.

Treatment timelines are also currently being investigated with the use of ICIs. The typical treatment timeline is surgery, followed by chemotherapy for 3 months, then immunotherapy for 12 months; however, combining chemotherapy and immunotherapy could accelerate this timeline, Riely said.

Clinical trial data released in 2022 show that neoadjuvant nivolumab plus chemotherapy had a superior OS, and future trials will explore optimal timelines for surgery followed by chemotherapy and targeted therapy.

In patients with late-stage NSCLC, first-line treatment approaches are largely determined by biomarkers. Chemotherapy plus an ICI is advised for those with PD-L1 <50%; targeted therapy is advised for those with EGFR, ALK, ROS1, BRAF, RET, or METex14 mutations; and patients with high PD-L1 expression have more options with single-agent checkpoint inhibitors or an ICI in addition to chemotherapy.

Some agents have been specifically investigated for various mutations. For example, trastuzumab deruxtecan has shown a 50% response rate as a second-line therapy for lung cancer with HER2 mutations, and sotorasib was the first to receive accelerated approval in KRAS G12C molecular subtypes.

In addition to these developments, Riely said there are quite a few novel immune-targeting agents in early phase 1 or 2 trials, including a multi-peptide cancer vaccine, a ROR1-targeted chimeric antigen receptor T-cell therapy, and a CTLA-4 antibody.

“There’s really been a transformation in the treatment of people with surgically resectable or resected NSCLC,” Riely concluded. “Incorporating immune checkpoint inhibitors has improved overall survival, and chemotherapy plus nivolumab is a great option prior to the operation. There are new targeted therapies…and I think these are new options for our patients in the second line.”

REFERENCE

Riely G. Current Advances: Lung Cancer. Presented at: 2023 Community Oncology Alliance meeting. March 23, 2023.